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Zhang N, Zhang Q, Shao H, Shan Z, Xu J, Tong W, Wong RMY, Qin L. Magnesium as an emerging bioactive material for orthopedic applications: bedside needs lead the way from innovation to clinical translation. Regen Biomater 2025; 12:rbaf032. [PMID: 40405870 PMCID: PMC12094927 DOI: 10.1093/rb/rbaf032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Revised: 03/21/2025] [Accepted: 04/21/2025] [Indexed: 05/26/2025] Open
Abstract
With the rapid increase in population aging, the number of surgical operations in orthopedics is expected to increase. The gap between the materials applied in clinical orthopedics and materials in discovery and research is obvious due to regulatory requirements for biosafety and treatment efficacy. For the bedside needs, it is important to overcome hurdles by achieving impactful innovation and clinical translation of orthopedic materials. Magnesium (Mg), as an emerging bioactive material, is one of the vital components of the human body and mainly stored in the musculoskeletal system as either a matrix component or an intracellular element for the homeostasis of various physiological functions. However, the degradation and biomechanical performance limit the applications of Mg. This review aims to explore the current challenges and future directions of Mg for clinical translation and provide an update on biomaterials used in orthopedics, factors driving orthopedic innovation, physiology of magnesium ions (Mg2+) and its potential clinical applications. To achieve orthopedic application, modification of the performance of Mg as implantable metals and function of the degradation products of Mg in vivo are described. For the clinical needs of treating the steroid-associated osteonecrosis (SAON), Mg screws and Mg-based composite porous scaffolds (Mg/PLGA/TCP: magnesium/poly(lactic-co-glycolic acid) (PLGA)/tricalcium phosphate (TCP)) have been developed, but the challenges of Mg-based implants in load-bearing skeletal sites still exist. To utilize the beneficial biological effects of Mg degradation and overcome the weakness in mechanical stability for fracture fixation, the concept of developing Mg/titanium (Ti) hybrid orthopedic implants is reported, where the Ti component provides effective mechanical support while the inclusion of Mg component potentially optimizes the biomechanical properties of Ti component and facilitate bone healing. This review provides a reference frame for the translation of novel materials and promotes the development of innovative orthopedic biomaterials for clinical applications.
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Affiliation(s)
- Ningze Zhang
- Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Hong Kong SAR 999077, China
- Innovative Orthopaedic Biomaterial and Drug Translational Research Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR 999077, China
| | - Qida Zhang
- Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Hong Kong SAR 999077, China
- Innovative Orthopaedic Biomaterial and Drug Translational Research Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR 999077, China
| | - Hongwei Shao
- Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Hong Kong SAR 999077, China
- Innovative Orthopaedic Biomaterial and Drug Translational Research Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR 999077, China
| | - Zhengming Shan
- Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Hong Kong SAR 999077, China
- Innovative Orthopaedic Biomaterial and Drug Translational Research Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR 999077, China
| | - Jiankun Xu
- Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Hong Kong SAR 999077, China
- Innovative Orthopaedic Biomaterial and Drug Translational Research Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR 999077, China
- Joint Laboratory of Chinese Academic of Science and Hong Kong for Biomaterials, The Chinese University of Hong Kong, Hong Kong SAR 999077, China
| | - Wenxue Tong
- Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Hong Kong SAR 999077, China
- Innovative Orthopaedic Biomaterial and Drug Translational Research Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR 999077, China
- Joint Laboratory of Chinese Academic of Science and Hong Kong for Biomaterials, The Chinese University of Hong Kong, Hong Kong SAR 999077, China
| | - Ronald Man Yeung Wong
- Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Hong Kong SAR 999077, China
| | - Ling Qin
- Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Hong Kong SAR 999077, China
- Innovative Orthopaedic Biomaterial and Drug Translational Research Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR 999077, China
- Joint Laboratory of Chinese Academic of Science and Hong Kong for Biomaterials, The Chinese University of Hong Kong, Hong Kong SAR 999077, China
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Wang H, Li Y, Li H, Yan X, Jiang Z, Feng L, Hu W, Fan Y, Lin S, Li G. T cell related osteoimmunology in fracture healing: Potential targets for augmenting bone regeneration. J Orthop Translat 2025; 51:82-93. [PMID: 39991456 PMCID: PMC11847249 DOI: 10.1016/j.jot.2024.12.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 11/15/2024] [Accepted: 12/01/2024] [Indexed: 02/25/2025] Open
Abstract
UNLABELLED Last decade has witnessed increasing evidence which highlights the roles of immune cells in bone regeneration. Numerous immune cell types, including macrophages, T cells, and neutrophils are involved in fracture healing by orchestrating a series of events that modulate bone formation and remodeling. In this review, the role of T cell immunity in fracture healing has been summarized, and the modulatory effects of T cell immunity in inflammation, bone formation and remodeling have been highlighted. The review also summarizes the specific roles of different T cell subsets, including CD4+ T cells, CD8+ T cells, regulatory T cells, T helper 17 cells, and γδ T cells in modulating fracture healing. The current therapeutics targeting T cell immunity to enhance fracture healing have also been reviewed, aiming to provide insights from a translational standpoint. Overall, this work discusses recent advances and challenges in the interdisciplinary research field of T cell related osteoimmunology and its implications in fracture healing. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE Delayed unions or non-unions of bone fractures remain a challenge in clinical practice. Developing a deep understanding of the roles of immune cells, including T cells, in fracture healing will facilitate the advancement of novel therapeutics of fracture nonunion. This review summarizes the current understanding of different T cell subsets involved in various phases of fracture healing, providing insights for targeting T cells as an alternative strategy to enhance bone regeneration.
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Affiliation(s)
- Haixing Wang
- Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong Province, China
- Department of Orthopaedics & Traumatology, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Yashi Li
- Department of Biomedical Engineering, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Haoxin Li
- Department of Biomedical Engineering, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Xu Yan
- Department of Orthopaedics & Traumatology, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Zhaowei Jiang
- Department of Orthopaedics & Traumatology, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Lu Feng
- Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong, China
| | - Wenhui Hu
- Orthopaedic Center, Affiliated Hospital of Guangdong Medical University, Guangdong Medical University, Zhanjiang, Guangdong Province, China
| | - Yinuo Fan
- The Third Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, China
| | - Sien Lin
- Department of Orthopaedics & Traumatology, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Gang Li
- Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong Province, China
- Department of Orthopaedics & Traumatology, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
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Wei J, Liu Q, Yuen HY, Lam ACH, Jiang Y, Yang Y, Liu Y, Zhao X, Xiao L. Gut-bone axis perturbation: Mechanisms and interventions via gut microbiota as a primary driver of osteoporosis. J Orthop Translat 2025; 50:373-387. [PMID: 40171106 PMCID: PMC11960541 DOI: 10.1016/j.jot.2024.11.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 09/27/2024] [Accepted: 11/12/2024] [Indexed: 04/03/2025] Open
Abstract
A growing number of studies have highlighted the significance of human gut microbiota (GM) as a potential target for osteoporosis. In this review, we discuss the effect of GM to bone metabolism focusing on two aspects: the local alterations of the human gut permeability that modify how the GM interact with the gut-bone axis (e.g., intestinal leakage, nutrient absorption), and the alterations of the GM itself (e.g., changes in microbiota metabolites, immune secretion, hormones) that modify the events of the gut-bone axis. We then classify these changes as possible therapeutic targets of bone metabolism and highlight some associated promising microbiome-based therapies. We also extend our discussions into combinatorial treatments that incorporate conservative treatments, such as exercise. We anticipate our review can provide an overview of the current pathophysiological and therapeutic paradigms of the gut-bone axis, as well as the prospects of ongoing clinical trials for readers to gain further insights into better microbiome-based treatments to osteoporosis and other bone-degenerative diseases. The translational potential of this article: This paper reviewed the potential links between gut microbiota and osteoporosis, as well as the prospective therapeutic avenues targeting gut microbiota for osteoporosis management, presenting a thorough and comprehensive literature review.
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Affiliation(s)
- Jingyuan Wei
- Translational Medical Innovation Center, Zhangjiagang Traditional Chinese Medicine Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, Jiangsu, 215600, China
- Department of Acupuncture and Moxibustion, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Qi Liu
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Hong Kong, China
| | - Ho-Yin Yuen
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Hong Kong, China
| | - Avery Chik-Him Lam
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Hong Kong, China
| | - Yuanyuan Jiang
- Translational Medical Innovation Center, Zhangjiagang Traditional Chinese Medicine Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, Jiangsu, 215600, China
| | - Yuhe Yang
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Hong Kong, China
| | - Yaxiong Liu
- Jihua Laboratory, Foshan, Guangdong, 528000, China
| | - Xin Zhao
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Hong Kong, China
| | - Long Xiao
- Translational Medical Innovation Center, Zhangjiagang Traditional Chinese Medicine Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, Jiangsu, 215600, China
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Arafat Hossain M. A comprehensive review of immune checkpoint inhibitors for cancer treatment. Int Immunopharmacol 2024; 143:113365. [PMID: 39447408 DOI: 10.1016/j.intimp.2024.113365] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2024] [Revised: 09/28/2024] [Accepted: 10/05/2024] [Indexed: 10/26/2024]
Abstract
Immunology-based therapies are emerging as an effective cancer treatment, using the body's immune system to target tumors. Immune checkpoints, which regulate immune responses to prevent tissue damage and autoimmunity, are often exploited by cancer cells to avoid destruction. The discovery of checkpoint proteins like PD-1/PD-L1 and CTLA-4 was pivotal in developing cancer immunotherapy. Immune checkpoint inhibitors (ICIs) have shown great success, with FDA-approved drugs like PD-1 inhibitors (Nivolumab, Pembrolizumab, Cemiplimab), PD-L1 inhibitors (Atezolizumab, Durvalumab, Avelumab), and CTLA-4 inhibitors (Ipilimumab, Tremelimumab), alongside LAG-3 inhibitor Relatlimab. Research continues on new checkpoints like TIM-3, VISTA, B7-H3, BTLA, and TIGIT. Biomarkers like PDL-1 expression, tumor mutation burden, interferon-γ presence, microbiome composition, and extracellular matrix characteristics play a crucial role in predicting responses to immunotherapy with checkpoint inhibitors. Despite their effectiveness, not all patients experience the same level of benefit, and organ-specific immune-related adverse events (irAEs) such as rash or itching, colitis, diarrhea, hyperthyroidism, and hypothyroidism may occur. Given the rapid advancements in this field and the variability in patient outcomes, there is an urgent need for a comprehensive review that consolidates the latest findings on immune checkpoint inhibitors, covering their clinical status, biomarkers, resistance mechanisms, strategies to overcome resistance, and associated adverse effects. This review aims to fill this gap by providing an analysis of the current clinical status of ICIs, emerging biomarkers, mechanisms of resistance, strategies to enhance therapeutic efficacy, and assessment of adverse effects. This review is crucial to furthering our understanding of ICIs and optimizing their application in cancer therapy.
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Affiliation(s)
- Md Arafat Hossain
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj 8100, Bangladesh.
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Prina MM, Alberti A, Tovazzi V, Ravanelli M, Schivardi G, Baggi A, Ammoni L, Guarneri L, Salvotti F, Zamparini M, Farina D, Parolise M, Grisanti S, Berruti A. Progression of vertebral fractures in metastatic melanoma and non-small cell lung cancer patients given immune checkpoint inhibitors. J Bone Oncol 2024; 49:100642. [PMID: 40134558 PMCID: PMC11934284 DOI: 10.1016/j.jbo.2024.100642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 10/03/2024] [Accepted: 10/04/2024] [Indexed: 03/27/2025] Open
Abstract
Introduction The immune system mediates important effects on bone metabolism, but little has been done to understand immunotherapy's role in this interaction. This study aims to describe and identify risk factors for the occurrence and/or exacerbation of vertebral fractures (vertebral fracture progression) during immune checkpoint inhibitors (ICIs). Methods We conducted an observational, retrospective, monocentric study. We collected data on melanoma and NSCLC patients, treated with first-line ICIs at the Medical Oncology Department ASST Spedali Civili of Brescia, between January 2015 and November 2021, and with a median follow-up of 20.1 (6-36) months. We collected data on patients, diseases, immune-related adverse events, and cortico-steroid therapy initiated on concomitant ICIs. Results We identified 135 patients, 65 (48.2 %) with locally advanced/metastatic melanoma and 70 (51.8 %) with locally advanced/metastatic non-small cell lung cancer (NSCLC). Twenty-one (15.6 %) patients already had an asymptomatic vertebral fracture at baseline before starting ICIs in monotherapy. A total of ten patients, or 7.4 %, had a vertebra fracture progression defined as a new vertebral fracture or a worsening of a previous fracture. There was a strong relation between the steroid therapy and irAEs with vertebra fracture progression [OR (95 % CI) 8.1 (3.7-17.8) p-value < 0.001] in univariable analysis. However, only steroid therapy resulted to be an independent risk factor [8.260 (95 % CI 0.909-75.095); p-value 0.061] at the multivariable analysis. Conclusion Concurrent steroid therapy in patients receiving immunotherapy exposes them to a high risk of fractures due to skeletal fragility. The use of bone resorption inhibitors should be considered in these patients to prevent these adverse events.
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Affiliation(s)
- Marco Meazza Prina
- Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, Medical Oncology, University of Brescia, ASST Spedali Civili, Brescia, Italy
| | - Andrea Alberti
- Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, Medical Oncology, University of Brescia, ASST Spedali Civili, Brescia, Italy
| | - Valeria Tovazzi
- Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, Medical Oncology, University of Brescia, ASST Spedali Civili, Brescia, Italy
| | - Marco Ravanelli
- Radiology Unit, ASST Spedali Civili, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy
| | - Greta Schivardi
- Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, Medical Oncology, University of Brescia, ASST Spedali Civili, Brescia, Italy
| | - Alice Baggi
- Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, Medical Oncology, University of Brescia, ASST Spedali Civili, Brescia, Italy
| | - Luca Ammoni
- Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, Medical Oncology, University of Brescia, ASST Spedali Civili, Brescia, Italy
| | - Lucilla Guarneri
- Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, Medical Oncology, University of Brescia, ASST Spedali Civili, Brescia, Italy
| | - Francesca Salvotti
- Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, Medical Oncology, University of Brescia, ASST Spedali Civili, Brescia, Italy
| | - Manuel Zamparini
- Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, Medical Oncology, University of Brescia, ASST Spedali Civili, Brescia, Italy
| | - Davide Farina
- Radiology Unit, ASST Spedali Civili, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy
| | - Margherita Parolise
- Radiology Unit, ASST Spedali Civili, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy
| | - Salvatore Grisanti
- Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, Medical Oncology, University of Brescia, ASST Spedali Civili, Brescia, Italy
| | - Alfredo Berruti
- Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, Medical Oncology, University of Brescia, ASST Spedali Civili, Brescia, Italy
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Hamza FN, Mohammad KS. Immunotherapy in the Battle Against Bone Metastases: Mechanisms and Emerging Treatments. Pharmaceuticals (Basel) 2024; 17:1591. [PMID: 39770433 PMCID: PMC11679356 DOI: 10.3390/ph17121591] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Revised: 11/20/2024] [Accepted: 11/23/2024] [Indexed: 01/11/2025] Open
Abstract
Bone metastases are a prevalent complication in advanced cancers, particularly in breast, prostate, and lung cancers, and are associated with severe skeletal-related events (SREs), including fractures, spinal cord compression, and debilitating pain. Conventional bone-targeted treatments like bisphosphonates and RANKL inhibitors (denosumab) reduce osteoclast-mediated bone resorption but do not directly impact tumor progression within the bone. This review focuses on examining the growing potential of immunotherapy in targeting the unique challenges posed by bone metastases. Even though immune checkpoint inhibitors (ICIs) have significantly changed cancer treatment, their impact on bone metastases appears limited because of the bone microenvironment's immunosuppressive traits, which include high levels of transforming growth factor-beta (TGFβ) and the immune-suppressing cells, such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). This review underscores the investigation of combined therapeutic approaches that might ease these difficulties, such as the synergy of immune checkpoint inhibitors with agents aimed at bones (denosumab, bisphosphonates), chemotherapy, and radiotherapy, as well as the combination of immune checkpoint inhibitors with different immunotherapeutic methods, including CAR T-cell therapy. This review provides a comprehensive analysis of preclinical studies and clinical trials that show the synergistic potential of these combination approaches, which aim to both enhance immune responses and mitigate bone destruction. By offering an in-depth exploration of how these strategies can be tailored to the bone microenvironment, this review underscores the need for personalized treatment approaches. The findings emphasize the urgent need for further research into overcoming immune evasion in bone metastases, with the goal of improving patient survival and quality of life.
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Affiliation(s)
- Fatheia N. Hamza
- Department of Biochemistry, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia;
| | - Khalid Said Mohammad
- Department of Anatomy and Genetics, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
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Saotome M, Kuraji R, Numabe Y. Hyperglycemia Exacerbates Periodontal Destruction via Systemic Suppression of Regulatory T Cell Number and Function. J Periodontal Res 2024. [PMID: 39578679 DOI: 10.1111/jre.13366] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 10/28/2024] [Accepted: 11/07/2024] [Indexed: 11/24/2024]
Abstract
AIM Diabetes is a significant risk factor that exacerbates the pathological progression of periodontal disease. In recent years, attention has focused on the effect of regulatory T cells (Tregs), which play a central role in immune tolerance, on inflammatory processes in periodontal tissue, suggesting a link with diabetes-associated periodontitis. In this study, we examined the dynamics of Tregs in periodontal tissue of mice with streptozotocin (STZ)-induced hyperglycemia. METHODS Eleven-week-old male C57BL/6J mice were divided into four treatment groups: Untreated (C group), ligature placed around the maxillary second molars with silk sutures (PD group), intraperitoneal administration of STZ (HG group), and ligature placed after STZ administration (PHG group). Establishment of hyperglycemia was assessed 14 days after STZ administration, and ligation was performed 7 days later. After another 7 days of ligation, the mice were euthanized. The right side of the maxilla was observed histopathologically, whereas the palatal gingiva on the left side of the maxilla was analyzed genetically, and the microstructure of the alveolar bone was also assessed. In addition, lymphocytes from peripheral blood, spleen, and periodontal tissue were analyzed using flow cytometry. RESULTS In bone structure analyses, alveolar bone height, bone volume/tissue volume (BV/TV), and bone mineral density (BMD) were lower in the PHG group than the PD group. In the gingival tissue, expression of the Foxp3 gene was up-regulated in the PHG group compared with the C group, and IL-17a was up-regulated in the PHG group compared with the PD group. Flow cytometry analyses showed that the number of Tregs (CD4+CD25+Foxp3+ cells) in the blood and gingival tissue was significantly higher in the PD and PHG groups than the C group. The number of CD4+CD25-Foxp3+ cells, which are reportedly functionally attenuated as Tregs, was increased in blood of the PHG group. Immunofluorescence staining of periodontal tissue showed that the number of CD25+Foxp3+ cells was significantly increased only in the PD group, whereas a trend toward an increased number of CD25-Foxp3+ cells was observed in the PHG group. CONCLUSION The present study showed that STZ-induced hyperglycemia numerically and functionally attenuates Tregs in a mouse model of experimental periodontitis. Furthermore, impaired immune tolerance capacity appears to be involved in exacerbating inflammation and bone destruction in periodontal tissue.
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Affiliation(s)
- Masami Saotome
- Department of Periodontology, The Nippon Dental University School of Life Dentistry at Tokyo, Tokyo, Japan
| | - Ryutaro Kuraji
- Department of Periodontology, The Nippon Dental University School of Life Dentistry at Tokyo, Tokyo, Japan
| | - Yukihiro Numabe
- Department of Periodontology, The Nippon Dental University School of Life Dentistry at Tokyo, Tokyo, Japan
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Iwamoto N, Chiba K, Sato S, Tashiro S, Shiraishi K, Watanabe K, Ohki N, Okada A, Koga T, Kawashiri SY, Tamai M, Osaki M, Kawakami A. Preferable effect of CTLA4-Ig on both bone erosion and bone microarchitecture in rheumatoid arthritis revealed by HR-pQCT. Sci Rep 2024; 14:27673. [PMID: 39532911 PMCID: PMC11557861 DOI: 10.1038/s41598-024-77392-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Accepted: 10/22/2024] [Indexed: 11/16/2024] Open
Abstract
This exploratory study aimed to examine the impact of abatacept treatment on bone structure in patients with rheumatoid arthritis (RA) using high-resolution peripheral quantitative computed tomography (HR-pQCT). RA patients initiating either abatacept or newly introduced csDMARDs were enrolled in this prospective, non-randomized, two-group study. Bone structure in the 2nd and 3rd metacarpal heads was assessed using HR-pQCT at 0, 6, and 12 months after enrollment. Synovitis was evaluated using musculoskeletal ultrasound and MRI. The adjusted mean between-group differences (abatacept-csDMARDs group) were estimated using a mixed-effect model. Thirty-five patients (abatacept group: n = 15; csDMARDs group: n = 20) were analyzed. Changes in erosion volume, depth and width were numerically smaller in the abatacept group compared to the csDMARDs group (adjusted mean between-group differences: - 1.86 mm3, - 0.02 mm, and - 0.09 mm, respectively). Over a 12-month period, 5 erosions emerged in the csDMARDs group, while only 1 erosion appeared in the abatacept group. Compared to csDMARDs, abatacept better preserved bone microarchitecture; several components of bone microarchitecture were significantly worsened at 6 months in the csDMARDs group, but were not deteriorated at 6 months in the abatacept group. Changes in synovitis scores were similar between the two treatment groups. Our results indicate that abatacept prevented the progression of bone erosion including new occurrence, and also prevented worsening of bone strength independently with synovitis compared to csDMARDs including MTX. Thus, abatacept treatment may provide benefits not only in inhibiting the progress of bone erosion but also in preventing bone microarchitectural deterioration.
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Affiliation(s)
- Naoki Iwamoto
- Division of Advanced Preventive Medical Sciences, Department of Immunology and Rheumatology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan.
| | - Ko Chiba
- Department of Orthopedic Surgery, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Shuntaro Sato
- Clinical Research Center, Nagasaki University Hospital, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Shigeki Tashiro
- Clinical Research Center, Nagasaki University Hospital, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Kazuteru Shiraishi
- Department of Orthopedic Surgery, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Kounosuke Watanabe
- Department of Orthopedic Surgery, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Nozomi Ohki
- Department of Radiological Sciences, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Akitomo Okada
- Department of Rheumatology, National Hospital Organization Nagasaki Medical Center, Kubara 2-1001-1, Omura, Nagasaki, 856-8562, Japan
| | - Tomohiro Koga
- Division of Advanced Preventive Medical Sciences, Department of Immunology and Rheumatology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Shin-Ya Kawashiri
- Division of Advanced Preventive Medical Sciences, Department of Immunology and Rheumatology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
- Center for Collaborative Medical Education and Development, Nagasaki University Institute of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Mami Tamai
- Division of Advanced Preventive Medical Sciences, Department of Immunology and Rheumatology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Makoto Osaki
- Department of Orthopedic Surgery, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Atsushi Kawakami
- Division of Advanced Preventive Medical Sciences, Department of Immunology and Rheumatology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
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Breinbauer R, Mäling M, Ehnert S, Blumenstock G, Schwarz T, Jazewitsch J, Erne F, Reumann MK, Rollmann MF, Braun BJ, Histing T, Nüssler AK. B7-1 and PlGF-1 are two possible new biomarkers to identify fracture-associated trauma patients at higher risk of developing complications: a cohort study. BMC Musculoskelet Disord 2024; 25:677. [PMID: 39210389 PMCID: PMC11360573 DOI: 10.1186/s12891-024-07789-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Accepted: 08/16/2024] [Indexed: 09/04/2024] Open
Abstract
BACKGROUND Around 10% of fractures lead to complications. With increasing fracture incidences in recent years, this poses a serious burden on the healthcare system, with increasing costs for treatment. In the present study, we aimed to identify potential 'new' blood markers to predict the development of post-surgical complications in trauma patients following a fracture. METHODS A total of 292 trauma patients with a complete three-month follow-up were included in this cohort study. Blood samples were obtained from 244 of these patients. Two complication groups were distinguished based on the Clavien-Dindo (CD) classification: CD grade I and CD grade III groups were compared to the controls (CD 0). The Mann-Whitney U test was used to compare the complication groups to the control group. RESULTS Analysis of the patients' data revealed that risk factors are dependent on sex. Both, males and females who developed a CD III complication showed elevated blood levels of B7-1 (p = 0.015 and p = 0.018, respectively) and PlGF-1 (p = 0.009 and p = 0.031, respectively), with B7-1 demonstrating greater sensitivity (B7-1: 0.706 (male) and 0.692 (female), PlGF-1: 0.647 (male) and 0.615 (female)). Further analysis of the questionnaires and medical data revealed the importance of additional risk factors. For males (CD 0: 133; CD I: 12; CD III: 18 patients) alcohol consumption was significantly increased for CD I and CD III compared to control with p = 0.009 and p = 0.007, respectively. For females (CD 0: 107; CD I: 10; CD III: 12 patients) a significantly increased average BMI [kg/m2] from 25.5 to 29.7 with CD III was observed, as well as an elevation from one to three comorbidities (p = 0.003). CONCLUSIONS These two potential new blood markers hold promise for predicting complication development in trauma patients. Nevertheless, further studies are necessary to evaluate the diagnostic utility of B7-1 and PlGF-1 in predicting complications in trauma patients and consider sex differences before their possible use as routine clinical screening tools.
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Affiliation(s)
- Regina Breinbauer
- Siegfried-Weller-Institute, BG Unfallklinik Tuebingen, Eberhard Karls University Tuebingen, 72076, Tuebingen, Germany
| | - Michelle Mäling
- Siegfried-Weller-Institute, BG Unfallklinik Tuebingen, Eberhard Karls University Tuebingen, 72076, Tuebingen, Germany
| | - Sabrina Ehnert
- Siegfried-Weller-Institute, BG Unfallklinik Tuebingen, Eberhard Karls University Tuebingen, 72076, Tuebingen, Germany
| | - Gunnar Blumenstock
- Department of Clinical Epidemiology and Applied Biometry, Eberhard Karls University Tuebingen, Silcherstrasse 5, 72076, Tuebingen, Germany
| | - Tobias Schwarz
- Siegfried-Weller-Institute, BG Unfallklinik Tuebingen, Eberhard Karls University Tuebingen, 72076, Tuebingen, Germany
| | - Johann Jazewitsch
- Siegfried-Weller-Institute, BG Unfallklinik Tuebingen, Eberhard Karls University Tuebingen, 72076, Tuebingen, Germany
| | - Felix Erne
- Siegfried-Weller-Institute, BG Unfallklinik Tuebingen, Eberhard Karls University Tuebingen, 72076, Tuebingen, Germany
- Department of Traumatology and Reconstructive Surgery, BG Unfallklinik Tuebingen, Eberhard Karls University Tuebingen, Schnarrenbergstr. 95, 72076, Tuebingen, Germany
| | - Marie K Reumann
- Siegfried-Weller-Institute, BG Unfallklinik Tuebingen, Eberhard Karls University Tuebingen, 72076, Tuebingen, Germany
- Department of Traumatology and Reconstructive Surgery, BG Unfallklinik Tuebingen, Eberhard Karls University Tuebingen, Schnarrenbergstr. 95, 72076, Tuebingen, Germany
| | - Mika F Rollmann
- Department of Traumatology and Reconstructive Surgery, BG Unfallklinik Tuebingen, Eberhard Karls University Tuebingen, Schnarrenbergstr. 95, 72076, Tuebingen, Germany
| | - Benedikt J Braun
- Department of Traumatology and Reconstructive Surgery, BG Unfallklinik Tuebingen, Eberhard Karls University Tuebingen, Schnarrenbergstr. 95, 72076, Tuebingen, Germany
| | - Tina Histing
- Department of Traumatology and Reconstructive Surgery, BG Unfallklinik Tuebingen, Eberhard Karls University Tuebingen, Schnarrenbergstr. 95, 72076, Tuebingen, Germany
| | - Andreas K Nüssler
- Siegfried-Weller-Institute, BG Unfallklinik Tuebingen, Eberhard Karls University Tuebingen, 72076, Tuebingen, Germany.
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10
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Zhao X, Lin S, Ren H, Sun S, Zheng L, Chen LF, Wang Z. The histone methyltransferase ASH1L protects against bone loss by inhibiting osteoclastogenesis. Cell Death Differ 2024; 31:605-617. [PMID: 38431690 PMCID: PMC11094046 DOI: 10.1038/s41418-024-01274-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 02/16/2024] [Accepted: 02/20/2024] [Indexed: 03/05/2024] Open
Abstract
Absent, small, or homeotic1-like (ASH1L) is a histone lysine methyltransferase that generally functions as a transcriptional activator in controlling cell fate. So far, its physiological relevance in bone homeostasis and osteoclast differentiation remains elusive. Here, by conditional deleting Ash1l in osteoclast progenitors of mice, we found ASH1L deficiency resulted in osteoporosis and potentiation of osteoclastogenesis in vivo and in vitro. Mechanistically, ASH1L binds the promoter of the Src homology 3 and cysteine-rich domain 2 (Stac2) and increases the gene's transcription via histone 3 lysine 4 (H3K4) trimethylation modification, thus augmenting the STAC2's protection against receptor activator of nuclear factor kB ligand (RANKL)-initiated inflammation during osteoclast formation. Collectively, we demonstrate the first piece of evidence to prove ASH1L as a critical checkpoint during osteoclastogenesis. The work sheds new light on our understanding about the biological function of ASH1L in bone homeostasis, therefore providing a valuable therapeutic target for the treatment of osteoporosis or inflammatory bone diseases.
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Affiliation(s)
- Xiaoli Zhao
- Department of Biochemistry, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shuai Lin
- Department of Biochemistry, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Orthodontics, School and Hospital of Stomatology, Peking University, Beijing, China
| | - Hangjiang Ren
- Department of Biochemistry, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shenghui Sun
- Department of Biochemistry, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Liyun Zheng
- Department of Biochemistry, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lin-Feng Chen
- Department of Biochemistry, School of Molecular and Cellular Biology, University of Illinois at Urbana-Champaign, Urbana, USA
| | - Zhen Wang
- Department of Biochemistry, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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11
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Engin AB, Engin A. Tryptophan Metabolism in Obesity: The Indoleamine 2,3-Dioxygenase-1 Activity and Therapeutic Options. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1460:629-655. [PMID: 39287867 DOI: 10.1007/978-3-031-63657-8_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
Obesity activates both innate and adaptive immune responses in adipose tissue. Adipose tissue macrophages are functional antigen-presenting cells that promote the proliferation of interferon-gamma (IFN-γ)-producing cluster of differentiation (CD)4+ T cells in adipose tissue of obese subjects. The increased formation of neopterin and degradation of tryptophan may result in decreased T-cell responsiveness and lead to immunodeficiency. The activity of inducible indoleamine 2,3-dioxygenase-1 (IDO1) plays a major role in pro-inflammatory, IFN-γ-dominated settings. The expression of several kynurenine pathway enzyme genes is significantly increased in obesity. IDO1 in obesity shifts tryptophan metabolism from serotonin and melatonin synthesis to the formation of kynurenines and increases the ratio of kynurenine to tryptophan as well as with neopterin production. Reduction in serotonin (5-hydroxytryptamine; 5-HT) production provokes satiety dysregulation that leads to increased caloric uptake and obesity. According to the monoamine-deficiency hypothesis, a deficiency of cerebral serotonin is involved in neuropsychiatric symptomatology of depression, mania, and psychosis. Indeed, bipolar disorder (BD) and related cognitive deficits are accompanied by a higher prevalence of overweight and obesity. Furthermore, the accumulation of amyloid-β in Alzheimer's disease brains has several toxic effects as well as IDO induction. Hence, abdominal obesity is associated with vascular endothelial dysfunction. kynurenines and their ratios are prognostic parameters in coronary artery disease. Increased kynurenine/tryptophan ratio correlates with increased intima-media thickness and represents advanced atherosclerosis. However, after bariatric surgery, weight reduction does not lead to the normalization of IDO1 activity and atherosclerosis. IDO1 is involved in the mechanisms of immune tolerance and in the concept of tumor immuno-editing process in cancer development. Serum IDO1 activity is still used as a parameter in cancer development and growth. IDO-producing tumors show a high total IDO immunostaining score, and thus, using IDO inhibitors, such as Epacadostat, Navoximod, and L isomer of 1-methyl-tryptophan, seems an important modality for cancer treatment. There is an inverse correlation between serum folate concentration and body mass index, thus folate deficiency leads to hyperhomocysteinemia-induced oxidative stress. Immune checkpoint blockade targeting cytotoxic T-lymphocyte-associated protein-4 synergizes with imatinib, which is an inhibitor of mitochondrial folate-mediated one-carbon (1C) metabolism. Antitumor effects of imatinib are enhanced by increasing T-cell effector function in the presence of IDO inhibition. Combining IDO targeting with chemotherapy, radiotherapy and/or immunotherapy, may be an effective tool against a wide range of malignancies. However, there are some controversial results regarding the efficacy of IDO1 inhibitors in cancer treatment.
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Affiliation(s)
- Ayse Basak Engin
- Faculty of Pharmacy, Department of Toxicology, Gazi University, Hipodrom, Ankara, Turkey.
| | - Atilla Engin
- Faculty of Medicine, Department of General Surgery, Gazi University, Besevler, Ankara, Turkey
- Mustafa Kemal Mah. 2137. Sok. 8/14, 06520, Cankaya, Ankara, Turkey
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Padovano C, Bianco SD, Sansico F, De Santis E, Tamiro F, Colucci M, Totti B, Di Iasio S, Bruno G, Panelli P, Miscio G, Mazza T, Giambra V. The Notch1 signaling pathway directly modulates the human RANKL-induced osteoclastogenesis. Sci Rep 2023; 13:21199. [PMID: 38040752 PMCID: PMC10692129 DOI: 10.1038/s41598-023-48615-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Accepted: 11/28/2023] [Indexed: 12/03/2023] Open
Abstract
Notch signaling is an evolutionary conserved pathway with a key role in tissue homeostasis, differentiation and proliferation. It was reported that Notch1 receptor negatively regulates mouse osteoclast development and formation by inhibiting the expression of macrophage colony-stimulating factor in mesenchymal cells. Nonetheless, the involvement of Notch1 pathway in the generation of human osteoclasts is still controversial. Here, we report that the constitutive activation of Notch1 signaling induced a differentiation block in human mononuclear CD14+ cells directly isolated from peripheral blood mononuclear cells (PBMCs) upon in vitro stimulation to osteoclasts. Additionally, using a combined approach of single-cell RNA sequencing (scRNA-Seq) simultaneously with a panel of 31 oligo-conjugated antibodies against cell surface markers (AbSeq assay) as well as unsupervised learning methods, we detected four different cell stages of human RANKL-induced osteoclastogenesis after 5 days in which Notch1 signaling enforces the cell expansion of specific subsets. These cell populations were characterized by distinct gene expression and immunophenotypic profiles and active Notch1, JAK/STAT and WNT signaling pathways. Furthermore, cell-cell communication analyses revealed extrinsic modulators of osteoclast progenitors including the IL7/IL7R and WNT5a/RYK axes. Interestingly, we also report that Interleukin-7 receptor (IL7R) was a downstream effector of Notch1 pathway and that Notch1 and IL7R interplay promoted cell expansion of human RANKL-induced osteoclast progenitors. Taken together, these findings underline a novel cell pattern of human osteoclastogenesis, outlining the key role of Notch1 and IL-7R signaling pathways.
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Affiliation(s)
- Costanzo Padovano
- Hematopathology Laboratory, Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies (ISBReMIT), Fondazione IRCCS "Casa Sollievo della Sofferenza", 71013, San Giovanni Rotondo (FG), Italy
| | - Salvatore Daniele Bianco
- Bioinformatics Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013, San Giovanni Rotondo, Italy
| | - Francesca Sansico
- Hematopathology Laboratory, Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies (ISBReMIT), Fondazione IRCCS "Casa Sollievo della Sofferenza", 71013, San Giovanni Rotondo (FG), Italy
| | - Elisabetta De Santis
- Hematopathology Laboratory, Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies (ISBReMIT), Fondazione IRCCS "Casa Sollievo della Sofferenza", 71013, San Giovanni Rotondo (FG), Italy
| | - Francesco Tamiro
- Hematopathology Laboratory, Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies (ISBReMIT), Fondazione IRCCS "Casa Sollievo della Sofferenza", 71013, San Giovanni Rotondo (FG), Italy
| | - Mattia Colucci
- Hematopathology Laboratory, Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies (ISBReMIT), Fondazione IRCCS "Casa Sollievo della Sofferenza", 71013, San Giovanni Rotondo (FG), Italy
| | - Beatrice Totti
- Hematopathology Laboratory, Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies (ISBReMIT), Fondazione IRCCS "Casa Sollievo della Sofferenza", 71013, San Giovanni Rotondo (FG), Italy
| | - Serena Di Iasio
- Hematopathology Laboratory, Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies (ISBReMIT), Fondazione IRCCS "Casa Sollievo della Sofferenza", 71013, San Giovanni Rotondo (FG), Italy
| | - Gaja Bruno
- Hematopathology Laboratory, Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies (ISBReMIT), Fondazione IRCCS "Casa Sollievo della Sofferenza", 71013, San Giovanni Rotondo (FG), Italy
| | - Patrizio Panelli
- Hematopathology Laboratory, Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies (ISBReMIT), Fondazione IRCCS "Casa Sollievo della Sofferenza", 71013, San Giovanni Rotondo (FG), Italy
| | - Giuseppe Miscio
- Clinical Laboratory Analysis and Transfusional Medicine, Fondazione IRCCS "Casa Sollievo della Sofferenza", 71013, San Giovanni Rotondo (FG), Italy
| | - Tommaso Mazza
- Bioinformatics Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013, San Giovanni Rotondo, Italy
| | - Vincenzo Giambra
- Hematopathology Laboratory, Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies (ISBReMIT), Fondazione IRCCS "Casa Sollievo della Sofferenza", 71013, San Giovanni Rotondo (FG), Italy.
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13
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Joseph GJ, Johnson DB, Johnson RW. Immune checkpoint inhibitors in bone metastasis: Clinical challenges, toxicities, and mechanisms. J Bone Oncol 2023; 43:100505. [PMID: 37842554 PMCID: PMC10568292 DOI: 10.1016/j.jbo.2023.100505] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 09/19/2023] [Accepted: 09/19/2023] [Indexed: 10/17/2023] Open
Abstract
Immune checkpoint inhibitors (ICIs) have revolutionized the field of anti-cancer therapy over the last decade; they provide durable clinical responses against tumors by inhibiting immune checkpoint proteins that canonically regulate the T cell-mediated immune response. Despite their success in many primary tumors and soft tissue metastases, ICIs function poorly in patients with bone metastases, and these patients do not have the same survival benefit as patients with the same primary tumor type (e.g., non-small cell lung cancer [NSCLC], urothelial, renal cell carcinoma [RCC], etc.) that has not metastasized to the bone. Additionally, immune-related adverse events including rheumatologic and musculoskeletal toxicities, bone loss, and increased fracture risk develop after treatment with ICIs. There are few preclinical studies that investigate the interplay of the immune system in bone metastases; however, the current literature suggests a role for CD8+ T cells and myeloid cell subsets in bone homeostasis. As such, this review focuses on findings from the clinical and pre-clinical studies that have investigated immune checkpoint blockade in the bone metastatic setting and highlights the need for more comprehensive investigations into the relationship between immune cell subsets, ICIs, and the bone-tumor microenvironment.
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Affiliation(s)
- Gwenyth J. Joseph
- Program in Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA
- Vanderbilt Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Douglas B. Johnson
- Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Rachelle W. Johnson
- Program in Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA
- Vanderbilt Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
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14
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Adami G, Orsolini G, Rossini M, Pedrollo E, Fratucello A, Fassio A, Viapiana O, Milleri S, Fracassi E, Bixio R, Gatti D. Changes in bone turnover markers and bone modulators during abatacept treatment. Sci Rep 2023; 13:17183. [PMID: 37821541 PMCID: PMC10567677 DOI: 10.1038/s41598-023-44374-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2023] [Accepted: 10/07/2023] [Indexed: 10/13/2023] Open
Abstract
Rheumatoid arthritis (RA) causes bone loss, only partly related to inflammation. The impact of RA treatments on bone metabolism and their ability to mitigate bone loss remains uncertain. The primary goal of our study was to examine the influence of abatacept on serum levels of markers and regulators involved in bone turnover. Secondary objectives included evaluating changes in bone mineral density (BMD), bone health parameters, erosions, and exploring potential correlations among these parameters. We conducted a prospective observational study on patients with active seropositive RA failure to biological disease modifying anti-rheumatic drugs initiating treatment with abatacept. We measured at baseline and after 1, 2, 3, 6, 9 and 12 months: serum bone turnover markers (CTX, P1nP, B-ALP), bone modulators (Dkk-1, sclerostin, vitamin D, PTH, OPG and RANKL), BMD and radiographic parameters (modified Sharp van der Heijde score [mSvdH], bone health index [BHI] and metacarpal index [MCI]). Disease activity and glucocorticoid intake was monitored. 33 patients were enrolled in the study. We found a significant increase in markers of bone formation (B-ALP and P1nP) from baseline to M6 and M12. PTH increased significantly at M6 but not at M12. All other bone markers and modulators did not change. We found a significant decrease in BHI and MCI from baseline to M12 (median difference - 0.17 95% CI - 0.42 to - 0.10, p 0.001 and - 0.09 95% CI - 0.23 to - 0.07, respectively). BMD at femoral neck transitorily decreased at M6 (mean difference - 0.019 g/cm2 95% CI - 0.036 to - 0.001 p 0.04). BMD at total hip, lumbar spine and mSvdH score did not change significantly. P1nP delta at M12 correlated with delta mSvdH. Treatment with abatacept was associated with a significant increase in bone formation markers. The secondary and transient increase in PTH serum levels may be responsible of the transitory bone loss.
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Affiliation(s)
- Giovanni Adami
- Rheumatology Unit, Azienda Ospedaliera Universitaria Integrata di Verona, University of Verona, Pz Scuro 10, 37134, Verona, Italy.
| | - Giovanni Orsolini
- Rheumatology Unit, Azienda Ospedaliera Universitaria Integrata di Verona, University of Verona, Pz Scuro 10, 37134, Verona, Italy
| | - Maurizio Rossini
- Rheumatology Unit, Azienda Ospedaliera Universitaria Integrata di Verona, University of Verona, Pz Scuro 10, 37134, Verona, Italy
| | - Elisa Pedrollo
- Rheumatology Unit, Azienda Ospedaliera Universitaria Integrata di Verona, University of Verona, Pz Scuro 10, 37134, Verona, Italy
| | - Anna Fratucello
- Research Unit, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy
| | - Angelo Fassio
- Rheumatology Unit, Azienda Ospedaliera Universitaria Integrata di Verona, University of Verona, Pz Scuro 10, 37134, Verona, Italy
| | - Ombretta Viapiana
- Rheumatology Unit, Azienda Ospedaliera Universitaria Integrata di Verona, University of Verona, Pz Scuro 10, 37134, Verona, Italy
| | - Stefano Milleri
- Centro Ricerche Cliniche (CRC), Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy
| | - Elena Fracassi
- Rheumatology Unit, Azienda Ospedaliera Universitaria Integrata di Verona, University of Verona, Pz Scuro 10, 37134, Verona, Italy
| | - Riccardo Bixio
- Rheumatology Unit, Azienda Ospedaliera Universitaria Integrata di Verona, University of Verona, Pz Scuro 10, 37134, Verona, Italy
| | - Davide Gatti
- Rheumatology Unit, Azienda Ospedaliera Universitaria Integrata di Verona, University of Verona, Pz Scuro 10, 37134, Verona, Italy
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15
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Sun Q, Hong Z, Zhang C, Wang L, Han Z, Ma D. Immune checkpoint therapy for solid tumours: clinical dilemmas and future trends. Signal Transduct Target Ther 2023; 8:320. [PMID: 37635168 PMCID: PMC10460796 DOI: 10.1038/s41392-023-01522-4] [Citation(s) in RCA: 216] [Impact Index Per Article: 108.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 05/11/2023] [Accepted: 05/28/2023] [Indexed: 08/29/2023] Open
Abstract
Immune-checkpoint inhibitors (ICBs), in addition to targeting CTLA-4, PD-1, and PD-L1, novel targeting LAG-3 drugs have also been approved in clinical application. With the widespread use of the drug, we must deeply analyze the dilemma of the agents and seek a breakthrough in the treatment prospect. Over the past decades, these agents have demonstrated dramatic efficacy, especially in patients with melanoma and non-small cell lung cancer (NSCLC). Nonetheless, in the field of a broad concept of solid tumours, non-specific indications, inseparable immune response and side effects, unconfirmed progressive disease, and complex regulatory networks of immune resistance are four barriers that limit its widespread application. Fortunately, the successful clinical trials of novel ICB agents and combination therapies, the advent of the era of oncolytic virus gene editing, and the breakthrough of the technical barriers of mRNA vaccines and nano-delivery systems have made remarkable breakthroughs currently. In this review, we enumerate the mechanisms of each immune checkpoint targets, associations between ICB with tumour mutation burden, key immune regulatory or resistance signalling pathways, the specific clinical evidence of the efficacy of classical targets and new targets among different tumour types and put forward dialectical thoughts on drug safety. Finally, we discuss the importance of accurate triage of ICB based on recent advances in predictive biomarkers and diagnostic testing techniques.
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Affiliation(s)
- Qian Sun
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
- Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Zhenya Hong
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Cong Zhang
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
- Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Liangliang Wang
- Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Zhiqiang Han
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
- Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
| | - Ding Ma
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
- Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
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16
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Hascoët E, Blanchard F, Blin-Wakkach C, Guicheux J, Lesclous P, Cloitre A. New insights into inflammatory osteoclast precursors as therapeutic targets for rheumatoid arthritis and periodontitis. Bone Res 2023; 11:26. [PMID: 37217496 DOI: 10.1038/s41413-023-00257-w] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 03/02/2023] [Accepted: 03/09/2023] [Indexed: 05/24/2023] Open
Abstract
Rheumatoid arthritis (RA) and periodontitis are chronic inflammatory diseases leading to increased bone resorption. Preventing this inflammatory bone resorption is a major health challenge. Both diseases share immunopathogenic similarities and a common inflammatory environment. The autoimmune response or periodontal infection stimulates certain immune actors, leading in both cases to chronic inflammation that perpetuates bone resorption. Moreover, RA and periodontitis have a strong epidemiological association that could be explained by periodontal microbial dysbiosis. This dysbiosis is believed to be involved in the initiation of RA via three mechanisms. (i) The dissemination of periodontal pathogens triggers systemic inflammation. (ii) Periodontal pathogens can induce the generation of citrullinated neoepitopes, leading to the generation of anti-citrullinated peptide autoantibodies. (iii) Intracellular danger-associated molecular patterns accelerate local and systemic inflammation. Therefore, periodontal dysbiosis could promote or sustain bone resorption in distant inflamed joints. Interestingly, in inflammatory conditions, the existence of osteoclasts distinct from "classical osteoclasts" has recently been reported. They have proinflammatory origins and functions. Several populations of osteoclast precursors have been described in RA, such as classical monocytes, a dendritic cell subtype, and arthritis-associated osteoclastogenic macrophages. The aim of this review is to synthesize knowledge on osteoclasts and their precursors in inflammatory conditions, especially in RA and periodontitis. Special attention will be given to recent data related to RA that could be of potential value in periodontitis due to the immunopathogenic similarities between the two diseases. Improving our understanding of these pathogenic mechanisms should lead to the identification of new therapeutic targets involved in the pathological inflammatory bone resorption associated with these diseases.
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Affiliation(s)
- Emilie Hascoët
- Nantes Université, Oniris, Univ Angers, CHU Nantes, INSERM, Regenerative Medicine and Skeleton, RMeS, UMR 1229, F-44000, Nantes, France
| | - Frédéric Blanchard
- Nantes Université, Oniris, Univ Angers, CHU Nantes, INSERM, Regenerative Medicine and Skeleton, RMeS, UMR 1229, F-44000, Nantes, France
| | | | - Jérôme Guicheux
- Nantes Université, Oniris, Univ Angers, CHU Nantes, INSERM, Regenerative Medicine and Skeleton, RMeS, UMR 1229, F-44000, Nantes, France.
| | - Philippe Lesclous
- Nantes Université, Oniris, Univ Angers, CHU Nantes, INSERM, Regenerative Medicine and Skeleton, RMeS, UMR 1229, F-44000, Nantes, France
| | - Alexandra Cloitre
- Nantes Université, Oniris, Univ Angers, CHU Nantes, INSERM, Regenerative Medicine and Skeleton, RMeS, UMR 1229, F-44000, Nantes, France
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17
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Chen Y, Chen S, Chuang Y, Chiang B. Attenuation of the severity and changes in the microbiota in an animal model of primary biliary cholangitis by FOXP3 − regulatory T cells. CLINICAL AND TRANSLATIONAL DISCOVERY 2023; 3. [DOI: 10.1002/ctd2.187] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 03/16/2023] [Indexed: 01/04/2025]
Abstract
AbstractBackgroundPrimary biliary cholangitis (PBC), an autoimmune liver disease, presents with progressive damage to the intrahepatic bile ducts with infiltrating mononuclear cells and the appearance of anti‐mitochondrial antibodies (AMAs). The initiation of autoimmune liver disease is permissively mediated by dysfunctional regulatory T cells (Treg cells). Naïve CD4+ T cells cultured with splenic B220+ cells without additional cytokines or chemicals can differentiate into specific types of Treg cells (Treg/B cells) without expressing forkhead box P3. In this study, we explored the effects of Treg/B cells on disease severity and changes in intestinal microbiota in a murine model of PBC.MethodsTreg/B cells were administered to 2‐octenoic acid‐induced PBC mice. Enzyme‐linked immunosorbent assay, flow cytometry and histopathological techniques were used to evaluate the severity of PBC and to assess its therapeutic effect. Diversity of the intestinal microbiota was determined using 16S rRNA sequencing. The suppressive mechanisms of Treg/B cells were investigated using the bone marrow‐derived dendritic cells (BMDCs).ResultsTreg/B‐cell treatment significantly decreased the levels of serum AMAs against pyruvate dehydrogenase complex E2, lowered the levels of serum bile acids, attenuated inflammatory cell infiltration, reduced dendritic cell activation, altered the population of T cells in the liver and alleviated liver collagen synthesis in PBC mice. In addition, the Treg/B‐cell treatment changed the faecal microbial diversity in PBC mice. Furthermore, Treg/B‐cell treatment decreased the levels of proinflammatory cytokines and expression of costimulatory molecules in BMDCs. This inhibitory effect was partially mediated by the cytotoxic T‐lymphocyte‐associated antigen 4 pathway.ConclusionTreatment with Treg/B cells in a murine model of PBC attenuated liver inflammation and altered the gut microbiota. Immune regulation of Treg/B cells may be a potential therapeutic strategy for treating autoimmune liver disease.
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Affiliation(s)
- Yi‐Lien Chen
- Graduate Institute of Clinical Medicine College of Medicine National Taiwan University Taipei Taiwan
| | - Szu‐Ying Chen
- Graduate Institute of Clinical Medicine College of Medicine National Taiwan University Taipei Taiwan
| | - Ya‐Hui Chuang
- Department of Clinical Laboratory Sciences and Medical Biotechnology College of Medicine National Taiwan University Taipei Taiwan
| | - Bor‐Luen Chiang
- Graduate Institute of Clinical Medicine College of Medicine National Taiwan University Taipei Taiwan
- Department of Medical Research National Taiwan University Hospital Taipei Taiwan
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18
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Matsuda K, Shiba N, Hiraoka K. New Insights into the Role of Synovial Fibroblasts Leading to Joint Destruction in Rheumatoid Arthritis. Int J Mol Sci 2023; 24:ijms24065173. [PMID: 36982247 PMCID: PMC10049180 DOI: 10.3390/ijms24065173] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 03/06/2023] [Accepted: 03/07/2023] [Indexed: 03/30/2023] Open
Abstract
Rheumatoid arthritis (RA), one of the most common autoimmune diseases, is characterized by multiple-joint synovitis with subsequent destruction of bone and cartilage. The excessive autoimmune responses cause an imbalance in bone metabolism, promoting bone resorption and inhibiting bone formation. Preliminary studies have revealed that receptor activator of NF-κB ligand (RANKL)-mediated osteoclast induction is an important component of bone destruction in RA. Synovial fibroblasts are the crucial producers of RANKL in the RA synovium; novel analytical techniques, primarily, single-cell RNA sequencing, have confirmed that synovial fibroblasts include heterogeneous subsets of both pro-inflammatory and tissue-destructive cell types. The heterogeneity of immune cells in the RA synovium and the interaction of synovial fibroblasts with immune cells have recently received considerable attention. The current review focused on the latest findings regarding the crosstalk between synovial fibroblasts and immune cells, and the pivotal role played by synovial fibroblasts in joint destruction in RA.
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Affiliation(s)
- Kotaro Matsuda
- Department of Orthopedic Surgery, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Fukuoka, Japan
| | - Naoto Shiba
- Department of Orthopedic Surgery, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Fukuoka, Japan
| | - Koji Hiraoka
- Department of Orthopedic Surgery, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Fukuoka, Japan
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19
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Azadeh H. Association between disease-modifying antirheumatic drugs and bone turnover biomarkers. Int J Rheum Dis 2023; 26:437-445. [PMID: 36573666 DOI: 10.1111/1756-185x.14550] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 11/24/2022] [Accepted: 12/15/2022] [Indexed: 12/28/2022]
Abstract
Rheumatoid arthritis (RA) has been linked to an increased risk of osteoporosis as well as fractures. Patients diagnosed with RA had a 25% increased risk of osteoporotic fracture, according to a recent population-based cohort study that compared them to people without RA. Several studies have found a correlation between osteoporosis and the presence of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1, and 6. These cytokines play a crucial part in the process of bone resorption by boosting osteoclast activation and encouraging osteoclast differentiation. Based on the correlation between RA, osteoporosis, and inflammation, it is possible that systemic immunosuppression with disease-modifying antirheumatic drugs (DMARDs) can help individuals with RA have a lower chance of developing osteoporosis and osteoporotic fractures. There is little information on how different DMARDs, biologic or non-biologic, affect RA patients' bone metabolism. In this study, we present an overview of the influence that targeted therapies, such as biologics, non-biologics, and small molecule inhibitors, have on bone homeostasis in RA patients.
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Affiliation(s)
- Hossein Azadeh
- Department of Internal Medicine, Rheumatology Division, Orthopedic Research Center, Mazandaran University of Medical Sciences, Sari, Iran
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20
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Abstract
Bone and immune systems mutually influence each other by sharing a variety of regulatory molecules and the tissue microenvironment. The interdisciplinary research field "osteoimmunology" has illuminated the complex and dynamic interactions between the two systems in the maintenance of tissue homeostasis as well as in the development of immune and skeletal disorders. T cells play a central role in the immune response by secreting various immune factors and stimulating other immune cells and structural cells such as fibroblasts and epithelial cells, thereby contributing to pathogen elimination and pathogenesis of immune diseases. The finding on regulation of osteoclastic bone resorption by activated CD4+ T cells in rheumatoid arthritis was one of the driving forces for the development of osteoimmunology. With advances in research on helper T cell subsets and rare lymphoid cells such as γδ T cells in the immunology field, it is becoming clear that various types of T cells exert multiple effects on bone metabolism depending on immune context. Understanding the diverse effects of T cells on bone is essential for deciphering the osteoimmune regulatory network in various biological settings.
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Affiliation(s)
- Kazuo Okamoto
- Department of Osteoimmunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
| | - Hiroshi Takayanagi
- Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan
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21
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Kim Y, Kim GT. Positive Effects of Biologics on Osteoporosis in Rheumatoid Arthritis. JOURNAL OF RHEUMATIC DISEASES 2023; 30:3-17. [PMID: 37476528 PMCID: PMC10351356 DOI: 10.4078/jrd.22.0046] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 12/10/2022] [Accepted: 12/10/2022] [Indexed: 07/22/2023]
Abstract
Osteoporosis is a systemic skeletal disorder that causes vulnerability of bones to fracture owing to reduction in bone density and deterioration of the bone tissue microstructure. The prevalence of osteoporosis is higher in patients with autoimmune inflammatory rheumatic diseases, including rheumatoid arthritis (RA), than in those of the general population. In this autoimmune inflammatory rheumatic disease, in addition to known risk factors for osteoporosis, various factors such as chronic inflammation, autoantibodies, metabolic disorders, drugs, and decreased physical activity contribute to additional risk. In RA, disease-related inflammation plays an important role in local or systemic bone loss, and active treatment for inflammation can help prevent osteoporosis. In addition to conventional synthetic disease-modifying anti-rheumatic drugs that have been traditionally used for treatment of RA, biologic DMARDs and targeted synthetic DMARDs have been widely used. These agents can be employed more selectively and precisely based on disease pathogenesis. It has been reported that these drugs can inhibit bone loss by not only reducing inflammation in RA, but also by inhibiting bone resorption and promoting bone formation. In this review, the pathogenesis and research results of the increase in osteoporosis in RA are reviewed, and the effects of biological agents on osteoporosis are discussed.
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Affiliation(s)
- Yunkyung Kim
- Division of Rheumatology, Department of Internal Medicine, Kosin University Gospel Hospital, Kosin University College of Medicine, Busan, Korea
| | - Geun-Tae Kim
- Division of Rheumatology, Department of Internal Medicine, Kosin University Gospel Hospital, Kosin University College of Medicine, Busan, Korea
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22
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Wu C, Hu Y, Schafer P, Connolly SE, Wong R, Nielsen SH, Bay-Jensen AC, Emery P, Tanaka Y, Bykerk VP, Bingham CO, Huizinga TW, Fleischmann R, Liu J. Baseline serum levels of cross-linked carboxy-terminal telopeptide of type I collagen predict abatacept treatment response in methotrexate-naive, anticitrullinated protein antibody-positive patients with early rheumatoid arthritis. RMD Open 2022; 8:e002683. [PMID: 36585217 PMCID: PMC9809248 DOI: 10.1136/rmdopen-2022-002683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 12/07/2022] [Indexed: 12/31/2022] Open
Abstract
OBJECTIVE To investigate correlations between biomarkers of bone remodelling and extracellular matrix turnover with baseline disease activity and treatment response in patients with early rheumatoid arthritis (RA). METHODS Assessing Very Early Rheumatoid arthritis Treatment-2 (AVERT-2; NCT02504268) included disease-modifying antirheumatic drug-naive, anti-citrullinated protein antibody (ACPA)-positive patients randomised to weekly subcutaneous abatacept+methotrexate (MTX) or abatacept placebo+MTX for 56 weeks. This post hoc exploratory subanalysis assessed the association between baseline disease activity and eight biomarkers (Spearman's correlation coefficient), and whether baseline biomarkers (continuous or categorical variables) could predict treatment response at weeks 24 and 52 (logistic regression). RESULTS Patient characteristics were similar between overall (n=752) and biomarker subgroup (n=535) populations and across treatments. At baseline, neoepitopes of matrix metalloproteinase-mediated degradation products of types III and IV collagen and of C reactive protein (CRP) showed the greatest correlations with disease activity; cross-linked carboxy-terminal telopeptide of type I collagen (CTX-I) showed weak correlation. Only CTX-I predicted treatment response; baseline CTX-I levels were significantly associated with achieving Simplified Disease Activity Index remission and Disease Activity Score in 28 joints (DAS28 (CRP)) <2.6 (weeks 24 and 52), and American College of Rheumatology 70 response (week 52), in patients treated with abatacept+MTX but not abatacept placebo+MTX. CTX-I predicted significant differential response between arms for DAS28 (CRP) <2.6 (week 24). Treatment differences were greater for abatacept+MTX in patients with medium/high versus low baseline CTX-I. CONCLUSION In MTX-naive, ACPA-positive patients with early RA, baseline CTX-I predicted treatment response to abatacept+MTX but not abatacept placebo+MTX.
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Affiliation(s)
- Chun Wu
- Bristol Myers Squibb, Princeton, New Jersey, USA
| | - Yanhua Hu
- Bristol Myers Squibb, Princeton, New Jersey, USA
| | | | | | - Robert Wong
- Bristol Myers Squibb, Princeton, New Jersey, USA
| | | | | | - Paul Emery
- University of Leeds and Leeds NIHR Biomedical Research Centre, Leeds, UK
| | - Yoshiya Tanaka
- University of Occupational and Environmental Health, Kitakyushu, Japan
| | | | | | | | - Roy Fleischmann
- University of Texas Southwestern Medical Center, Metroplex Clinical Research Center, Dallas, Texas, USA
| | - Jinqi Liu
- Bristol Myers Squibb, Princeton, New Jersey, USA
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23
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Zhou P, Zheng T, Zhao B. Cytokine-mediated immunomodulation of osteoclastogenesis. Bone 2022; 164:116540. [PMID: 36031187 PMCID: PMC10657632 DOI: 10.1016/j.bone.2022.116540] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 08/18/2022] [Accepted: 08/23/2022] [Indexed: 11/23/2022]
Abstract
Cytokines are an important set of proteins regulating bone homeostasis. In inflammation induced bone resorption, cytokines, such as RANKL, TNF-α, M-CSF, are indispensable for the differentiation and activation of resorption-driving osteoclasts, the process we know as osteoclastogenesis. On the other hand, immune system produces a number of regulatory cytokines, including IL-4, IL-10 and IFNs, and limits excessive activation of osteoclastogenesis and bone loss during inflammation. These unique properties make cytokines powerful targets as rheostat to maintain bone homeostasis and for potential immunotherapies of inflammatory bone diseases. In this review, we summarize recent advances in cytokine-mediated regulation of osteoclastogenesis and provide insights of potential translational impact of bench-side research into clinical treatment of bone disease.
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Affiliation(s)
- Pengcheng Zhou
- Department of Laboratory Medicine, Affiliated Hospital of Jiangnan University, Wuxi, China; Department of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, Australia.
| | - Ting Zheng
- Arthritis and Tissue Degeneration Program and David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY, USA
| | - Baohong Zhao
- Arthritis and Tissue Degeneration Program and David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY, USA; Department of Medicine, Weill Cornell Medical College, New York, NY, USA; Graduate Program in Biochemistry, Cell and Molecular Biology, Weill Cornell Graduate School of Medical Sciences, New York, NY, USA
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24
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Iwamoto N, Kawakami A. The monocyte-to-osteoclast transition in rheumatoid arthritis: Recent findings. Front Immunol 2022; 13:998554. [PMID: 36172385 PMCID: PMC9510592 DOI: 10.3389/fimmu.2022.998554] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Accepted: 08/24/2022] [Indexed: 11/13/2022] Open
Abstract
Rheumatoid arthritis (RA) is an autoimmune disease characterized by joint inflammation leading to joint destruction and deformity. The crucial role of osteoclasts in the bone erosion in RA has been demonstrated. Deregulated osteoclastogenesis which is affected by environmental factors including the inflammatory state, as well as genetic and epigenetic factors, is one of hallmarks of RA pathogenesis. An enhanced-monocyte-to-osteoclast transition plays an important role in osteoclast upregulation in RA because under specific stimuli, circulating monocytes might migrate to a specific location in the bones and fuse with each other to become mature multinucleated osteoclasts. To understand the mechanism of bone damage in RA and to develop novel treatments targeting osteoclast upregulation, it is important to clarify our understanding of the monocyte-to-osteoclast transition in RA. Several potential targets which inhibit both inflammation and osteoclastogenesis, as well as regulators that affect the monocyte-to-osteoclast transition have been revealed by recent studies. Here, we review the factors affecting osteoclastogenesis in RA, summarize the anti-osteoclastogenic effects of current RA treatments, and identify promising therapeutic targets relating to both inflammation and osteoclastogenesis.
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25
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Andreev D, Kachler K, Schett G, Bozec A. Rheumatoid arthritis and osteoimmunology: The adverse impact of a deregulated immune system on bone metabolism. Bone 2022; 162:116468. [PMID: 35688359 DOI: 10.1016/j.bone.2022.116468] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 05/30/2022] [Accepted: 06/06/2022] [Indexed: 11/20/2022]
Abstract
The term osteoimmunology describes an interdisciplinary research field that links the investigation of osteology (bone cells) with immunology. The crosstalk between innate and adaptive immune cells and cells involved in bone remodeling, mainly bone-resorbing osteoclasts and bone-forming osteoblasts, becomes particularly obvious in the inflammatory autoimmune disease rheumatoid arthritis (RA). Besides striking inflammation of the joints, RA causes bone loss, leading to joint damage and disabilities as well as generalized osteoporosis. Mechanistically, RA-associated immune cells (macrophages, T cells, B cells etc.) produce high levels of pro-inflammatory cytokines, receptor activator of nuclear factor κB ligand (RANKL) and autoantibodies that promote bone degradation and at the same time counteract new bone formation. Today, antirheumatic therapy effectively ceases joint inflammation and arrests bone erosion. However, the repair of established bone lesions still presents a challenging task and requires improved treatment options. In this review, we outline the knowledge gained over the past years about the immunopathogenesis of RA and the impact of a dysregulated immune system on bone metabolism.
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Affiliation(s)
- Darja Andreev
- Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany; Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
| | - Katerina Kachler
- Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany; Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany.
| | - Georg Schett
- Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany; Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
| | - Aline Bozec
- Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany; Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany.
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26
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Fukue R, Okazaki Y, Gono T, Kuwana M. Abatacept downregulates Fcγ receptor I on circulating monocytes: a potential therapeutic mechanism in patients with rheumatoid arthritis. Arthritis Res Ther 2022; 24:194. [PMID: 35964055 PMCID: PMC9375333 DOI: 10.1186/s13075-022-02886-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Accepted: 08/03/2022] [Indexed: 11/22/2022] Open
Abstract
Background Abatacept is a recombinant fusion protein composed of the extracellular domain of cytotoxic T-lymphocyte antigen 4 and the Fc portion of immunoglobulin (Ig) G. The mechanism of action of abatacept in rheumatoid arthritis (RA) is believed to be competitive inhibition of T cell costimulation mediated by the binding of CD28 to CD80/CD86 on antigen-presenting cells, and recent studies have shown that abatacept induces reverse signaling in macrophages and osteoclast precursors in a T cell-independent manner. This study aimed to investigate the therapeutic effects of abatacept on circulating monocytes that contribute to RA pathogenesis. Methods Purified circulating monocytes derived from RA patients and controls were cultured in the absence or presence of abatacept or CD28-Ig for 24 h. The recovered cells were subjected to flow cytometry to evaluate the expression levels of cell surface molecules, and cytokines and chemokines in the culture supernatant were measured by multiplex bead arrays. The expression of candidate molecules was further examined by immunoblotting using total cellular extracts of the cultured monocytes. Finally, the effects of abatacept on cytokine production in monocytes stimulated with the immune complex of anti-citrullinated peptide antibodies (ACPAs) were examined. Results CD64/FcγRI was identified as a monocyte-derived molecule that was downregulated by abatacept but not CD28-Ig. This effect was observed in both RA patients and controls. The abatacept-induced downregulation of CD64/FcγRI was abolished by treatment with anti-CD86 antibodies but not anti-CD80 antibodies. Abatacept suppressed the production of interleukin (IL)-1β, IL-6, C-C motif chemokine ligand 2, and tumor necrosis factor-α in cultured monocytes stimulated with the ACPA immune complex. Conclusions The therapeutic effects of abatacept on RA are mediated, in part, by the downregulation of CD64/FcγRI on circulating monocytes via direct binding to CD86 and the suppression of immune complex-mediated inflammatory cytokine production. Supplementary Information The online version contains supplementary material available at 10.1186/s13075-022-02886-8.
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Affiliation(s)
- Ryosuke Fukue
- Department of Allergy and Rheumatology, Nippon Medical School Graduate School of Medicine, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan
| | - Yuka Okazaki
- Department of Allergy and Rheumatology, Nippon Medical School Graduate School of Medicine, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan
| | - Takahisa Gono
- Department of Allergy and Rheumatology, Nippon Medical School Graduate School of Medicine, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan
| | - Masataka Kuwana
- Department of Allergy and Rheumatology, Nippon Medical School Graduate School of Medicine, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan.
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Komatsu N, Takayanagi H. Mechanisms of joint destruction in rheumatoid arthritis - immune cell-fibroblast-bone interactions. Nat Rev Rheumatol 2022; 18:415-429. [PMID: 35705856 DOI: 10.1038/s41584-022-00793-5] [Citation(s) in RCA: 247] [Impact Index Per Article: 82.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/10/2022] [Indexed: 12/29/2022]
Abstract
Rheumatoid arthritis (RA) is characterized by inflammation and destruction of bone and cartilage in affected joints. Autoimmune responses lead to increased osteoclastic bone resorption and impaired osteoblastic bone formation, the imbalance of which underlies bone loss in RA, which includes bone erosion, periarticular bone loss and systemic osteoporosis. The crucial role of osteoclasts in bone erosion has been demonstrated in basic studies as well as by the clinical efficacy of antibodies targeting RANKL, an important mediator of osteoclastogenesis. Synovial fibroblasts contribute to joint damage by stimulating both pro-inflammatory and tissue-destructive pathways. New technologies, such as single-cell RNA sequencing, have revealed the heterogeneity of synovial fibroblasts and of immune cells including T cells and macrophages. To understand the mechanisms of bone damage in RA, it is important to clarify how the immune system promotes the tissue-destructive properties of synovial fibroblasts and influences bone cells. The interaction between immune cells and fibroblasts underlies the imbalance between regulatory T cells and T helper 17 cells, which in turn exacerbates not only inflammation but also bone destruction, mainly by promoting RANKL expression on synovial fibroblasts. An improved understanding of the immune mechanisms underlying joint damage and the interplay between the immune system, synovial fibroblasts and bone will contribute to the identification of novel therapeutic targets in RA.
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Affiliation(s)
- Noriko Komatsu
- Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hiroshi Takayanagi
- Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
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28
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Duscha A, Hegelmaier T, Dürholz K, Desel C, Gold R, Zaiss MM, Haghikia A. Propionic acid beneficially modifies osteoporosis biomarkers in patients with multiple sclerosis. Ther Adv Neurol Disord 2022; 15:17562864221103935. [PMID: 35755968 PMCID: PMC9218497 DOI: 10.1177/17562864221103935] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 05/12/2022] [Indexed: 01/05/2023] Open
Abstract
Background The impact of the gut and its microbiota are increasingly appreciated in health and disease. Short-chain fatty acids (SCFAs) are among the main metabolites synthesized from bacterial fermentation. Recently, we showed the anti-inflammatory and potentially neuroprotective effect of propionic acid (PA) in multiple sclerosis (MS). Osteoporosis is one of the most common co-morbidities for MS patients with limited therapeutic options available. Osteoporosis is closely linked to an imbalance of cells of the immune system and an immune-mediated impact on bone structure via the gut has been shown. Interestingly, intake of SCFA leads to bone mass increase and concomitant reduction of inflammation-induced bone loss in mice. Objective To determine the impact of PA supplementation on markers of bone metabolism in MS patients. Methods We investigated the influence of 14 days supplementation with PA on bone metabolism in 20 MS patients. To this end, β-CrossLaps and osteocalcin, established markers of bone metabolism, were measured in serum before and after PA intake and correlated with phenotypic and functional immunodata. Results Supplementation with PA induced a significant increase in serum levels of osteocalcin, a surrogate marker for bone formation. Levels of β-CrossLaps, a marker for bone resorption, were significantly decreased after therapy. Regulatory T-cell (Treg) numbers and suppressive capacity positively correlated with serum levels of osteocalcin while Th17 cell numbers showed an inverse correlation. Our findings are in line with animal studies showing that SCFA induced increased bone formation and reduced bone resorption. Conclusion In addition to its immune regulatory, disease-modifying effect on MS disease course, supplementation with PA beneficially influences serum levels of β-CrossLaps and osteocalcin and may thus also protect against osteoporosis, a common co-morbidity in MS.
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Affiliation(s)
- Alexander Duscha
- Department of Neurology, Universitätsklinikum Magdeburg A.ö.R., Otto von Guericke University Magdeburg, Magdeburg, Germany
| | - Tobias Hegelmaier
- Department of Neurology, Universitätsklinikum Magdeburg A.ö.R., Otto von Guericke University Magdeburg, Magdeburg, Germany
| | - Kerstin Dürholz
- Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinik Erlangen, Erlangen, Germany
| | - Christiane Desel
- Department of Neurology, Universitätsklinikum Magdeburg A.ö.R., Otto von Guericke University Magdeburg, Magdeburg, Germany
| | - Ralf Gold
- Department of Neurology, St. Josef-Hospital Bochum, Ruhr-University Bochum, Bochum, Germany
| | - Mario M. Zaiss
- Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinik Erlangen, Erlangen, Germany
| | - Aiden Haghikia
- Chair and Head of Department, Department of Neurology, Universitätsklinikum Magdeburg A.ö.R., Otto von Guericke University Magdeburg, Leipziger Straße 44, 39120 Magdeburg, Germany
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Cheng T, Zhang SX, Wang J, Qiao J, Chang MJ, Niu HQ, Liu GY, Li XF. Abnormalities of Peripheral Lymphocyte Subsets in Rheumatoid Arthritis Patients Complicated with Osteoporosis. Rheumatol Ther 2022; 9:1049-1059. [PMID: 35499817 PMCID: PMC9314529 DOI: 10.1007/s40744-022-00452-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Accepted: 04/11/2022] [Indexed: 12/13/2022] Open
Abstract
Introduction Osteoporosis (OP) is one of the major comorbidities of rheumatoid arthritis (RA). Recent studies have shown that immune cells modulate bone health and regulate bone remodeling. However, the alterations of lymphocyte subsets in RA patients with OP are unclear. Here, we assessed the absolute numbers and proportions of the subsets in RA sufferers with OP and investigated the clinical significance. Methods A total of 777 RA patients and 117 gender- and age-matched healthy controls (HCs) were enrolled in this study. Patients were divided into RA-non-OP and RA-OP group according to their bone mineral density (BMD) and the history of fragility fracture. Peripheral lymphocyte subsets of participants were assessed by flow cytometry. Results Among 220 (28.31%) RA-OP patients, there were higher levels of erythrocyte sedimentation rate (ESR) (P = 0.011), C-reactive protein (CRP) (P = 0.028), rheumatoid factor (RF) (P = 0.013) and anti-cyclic citrullinated peptide antibody (ACPA) (P = 0.010), while red blood cells (RBC) (P = 0.039) were lower than those in RA-non-OP group. Compared with those of HCs and RA-non-OP group, the level of circulating Th17 cells in RA-OP patients was significantly increased (P < 0.05), while those of Tregs decreased (P < 0.01), leading to a higher ratio of Th17/Treg (P < 0.01). Notably, the level of B cells in both RA-non-OP and RA-OP group was reduced, this alteration was more obvious in patients with OP (P < 0.05). Conclusions Immune disorders characterized by peripheral Th17/Treg imbalance and reduced B cells may contribute directly or indirectly to OP in RA, and this deserves more clinical attention. Supplementary Information The online version contains supplementary material available at 10.1007/s40744-022-00452-x.
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Affiliation(s)
- Ting Cheng
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
- Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Taiyuan, China
| | - Sheng-Xiao Zhang
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
- Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Taiyuan, China
| | - Jia Wang
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
- Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Taiyuan, China
| | - Jun Qiao
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
- Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Taiyuan, China
| | - Min-Jing Chang
- School of Management, Shanxi Medical University, Taiyuan, China
| | - Hong-Qing Niu
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
- Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Taiyuan, China
| | - Guang-Ying Liu
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Xiao-Feng Li
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China.
- Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Taiyuan, China.
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Dohnke S, Moehser S, Surnov A, Kurth T, Jessberger R, Kretschmer K, Garbe AI. Role of Dynamic Actin Cytoskeleton Remodeling in Foxp3+ Regulatory T Cell Development and Function: Implications for Osteoclastogenesis. Front Immunol 2022; 13:836646. [PMID: 35359955 PMCID: PMC8963504 DOI: 10.3389/fimmu.2022.836646] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 02/17/2022] [Indexed: 01/20/2023] Open
Abstract
In T cells, processes such as migration and immunological synapse formation are accompanied by the dynamic reorganization of the actin cytoskeleton, which has been suggested to be mediated by regulators of RhoGTPases and by F-actin bundlers. SWAP-70 controls F-actin dynamics in various immune cells, but its role in T cell development and function has remained incompletely understood. CD4+ regulatory T (Treg) cells expressing the transcription factor Foxp3 employ diverse mechanisms to suppress innate and adaptive immunity, which is critical for maintaining immune homeostasis and self-tolerance. Here, we propose Swap-70 as a novel member of the Foxp3-dependent canonical Treg cell signature. We show that Swap-70-/- mice have increased numbers of Foxp3+ Treg cells with an effector/memory-like phenotype that exhibit impaired suppressor function in vitro, but maintain overall immune homeostasis in vivo. Upon formation of an immunological synapse with antigen presenting cells in vitro, cytosolic SWAP-70 protein is selectively recruited to the interface in Treg cells. In this context, Swap-70-/- Treg cells fail to downregulate CD80/CD86 on osteoclast precursor cells by trans-endocytosis and to efficiently suppress osteoclastogenesis and osteoclast function. These data provide first evidence for a crucial role of SWAP-70 in Treg cell biology and further highlight the important non-immune function of Foxp3+ Treg cells in bone homeostasis mediated through direct SWAP-70-dependent mechanisms.
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Affiliation(s)
- Sebastian Dohnke
- Osteoimmunology, Center for Regenerative Therapies Dresden (CRTD), Center for Molecular and Cellular Bioengineering (CMCB), Technische Universität Dresden, Dresden, Germany
- Molecular and Cellular Immunology/Immune Regulation, Center for Regenerative Therapies Dresden (CRTD), Center for Molecular and Cellular Bioengineering (CMCB), Technische Universität Dresden, Dresden, Germany
| | - Stephanie Moehser
- Osteoimmunology, Center for Regenerative Therapies Dresden (CRTD), Center for Molecular and Cellular Bioengineering (CMCB), Technische Universität Dresden, Dresden, Germany
- Molecular and Cellular Immunology/Immune Regulation, Center for Regenerative Therapies Dresden (CRTD), Center for Molecular and Cellular Bioengineering (CMCB), Technische Universität Dresden, Dresden, Germany
| | - Alexey Surnov
- Institute of Physiological Chemistry, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Thomas Kurth
- Center for Molecular and Cellular Bioengineering, Technology Platform, Electron Microscopy and Histology Facility, Technische Universität Dresden, Dresden, Germany
| | - Rolf Jessberger
- Institute of Physiological Chemistry, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Karsten Kretschmer
- Molecular and Cellular Immunology/Immune Regulation, Center for Regenerative Therapies Dresden (CRTD), Center for Molecular and Cellular Bioengineering (CMCB), Technische Universität Dresden, Dresden, Germany
| | - Annette I. Garbe
- Osteoimmunology, Center for Regenerative Therapies Dresden (CRTD), Center for Molecular and Cellular Bioengineering (CMCB), Technische Universität Dresden, Dresden, Germany
- *Correspondence: Annette I. Garbe,
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Maeda K, Yoshida K, Nishizawa T, Otani K, Yamashita Y, Okabe H, Hadano Y, Kayama T, Kurosaka D, Saito M. Inflammation and Bone Metabolism in Rheumatoid Arthritis: Molecular Mechanisms of Joint Destruction and Pharmacological Treatments. Int J Mol Sci 2022; 23:2871. [PMID: 35270012 PMCID: PMC8911191 DOI: 10.3390/ijms23052871] [Citation(s) in RCA: 66] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 02/28/2022] [Accepted: 03/02/2022] [Indexed: 12/31/2022] Open
Abstract
Rheumatoid arthritis (RA) is an inflammatory disease characterized by a variety of symptoms and pathologies often presenting with polyarthritis. The primary symptom in the initial stage is joint swelling due to synovitis. With disease progression, cartilage and bone are affected to cause joint deformities. Advanced osteoarticular destruction and deformation can cause irreversible physical disabilities. Physical disabilities not only deteriorate patients' quality of life but also have substantial medical economic effects on society. Therefore, prevention of the progression of osteoarticular destruction and deformation is an important task. Recent studies have progressively improved our understanding of the molecular mechanism by which synovitis caused by immune disorders results in activation of osteoclasts; activated osteoclasts in turn cause bone destruction and para-articular osteoporosis. In this paper, we review the mechanisms of bone metabolism under physiological and RA conditions, and we describe the effects of therapeutic intervention against RA on bone.
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Affiliation(s)
- Kazuhiro Maeda
- Department of Orthopaedic Surgery, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan; (T.N.); (Y.Y.); (H.O.); (Y.H.); (T.K.); (M.S.)
| | - Ken Yoshida
- Division of Rheumatology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan; (K.Y.); (K.O.); (D.K.)
| | - Tetsuro Nishizawa
- Department of Orthopaedic Surgery, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan; (T.N.); (Y.Y.); (H.O.); (Y.H.); (T.K.); (M.S.)
| | - Kazuhiro Otani
- Division of Rheumatology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan; (K.Y.); (K.O.); (D.K.)
| | - Yu Yamashita
- Department of Orthopaedic Surgery, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan; (T.N.); (Y.Y.); (H.O.); (Y.H.); (T.K.); (M.S.)
| | - Hinako Okabe
- Department of Orthopaedic Surgery, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan; (T.N.); (Y.Y.); (H.O.); (Y.H.); (T.K.); (M.S.)
| | - Yuka Hadano
- Department of Orthopaedic Surgery, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan; (T.N.); (Y.Y.); (H.O.); (Y.H.); (T.K.); (M.S.)
| | - Tomohiro Kayama
- Department of Orthopaedic Surgery, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan; (T.N.); (Y.Y.); (H.O.); (Y.H.); (T.K.); (M.S.)
| | - Daitaro Kurosaka
- Division of Rheumatology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan; (K.Y.); (K.O.); (D.K.)
| | - Mitsuru Saito
- Department of Orthopaedic Surgery, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan; (T.N.); (Y.Y.); (H.O.); (Y.H.); (T.K.); (M.S.)
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González-Osuna L, Sierra-Cristancho A, Cafferata EA, Melgar-Rodríguez S, Rojas C, Carvajal P, Cortez C, Vernal R. Senescent CD4 +CD28 - T Lymphocytes as a Potential Driver of Th17/Treg Imbalance and Alveolar Bone Resorption during Periodontitis. Int J Mol Sci 2022; 23:ijms23052543. [PMID: 35269683 PMCID: PMC8910032 DOI: 10.3390/ijms23052543] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 02/19/2022] [Accepted: 02/22/2022] [Indexed: 01/10/2023] Open
Abstract
Senescent cells express a senescence-associated secretory phenotype (SASP) with a pro-inflammatory bias, which contributes to the chronicity of inflammation. During chronic inflammatory diseases, infiltrating CD4+ T lymphocytes can undergo cellular senescence and arrest the surface expression of CD28, have a response biased towards T-helper type-17 (Th17) of immunity, and show a remarkable ability to induce osteoclastogenesis. As a cellular counterpart, T regulatory lymphocytes (Tregs) can also undergo cellular senescence, and CD28− Tregs are able to express an SASP secretome, thus severely altering their immunosuppressive capacities. During periodontitis, the persistent microbial challenge and chronic inflammation favor the induction of cellular senescence. Therefore, senescence of Th17 and Treg lymphocytes could contribute to Th17/Treg imbalance and favor the tooth-supporting alveolar bone loss characteristic of the disease. In the present review, we describe the concept of cellular senescence; particularly, the one produced during chronic inflammation and persistent microbial antigen challenge. In addition, we detail the different markers used to identify senescent cells, proposing those specific to senescent T lymphocytes that can be used for periodontal research purposes. Finally, we discuss the existing literature that allows us to suggest the potential pathogenic role of senescent CD4+CD28− T lymphocytes in periodontitis.
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Affiliation(s)
- Luis González-Osuna
- Periodontal Biology Laboratory, Faculty of Dentistry, Universidad de Chile, Santiago 8380492, Chile; (A.S.-C.); (E.A.C.); (S.M.-R.); (C.R.)
- Correspondence: (L.G.-O.); (R.V.)
| | - Alfredo Sierra-Cristancho
- Periodontal Biology Laboratory, Faculty of Dentistry, Universidad de Chile, Santiago 8380492, Chile; (A.S.-C.); (E.A.C.); (S.M.-R.); (C.R.)
- Faculty of Dentistry, Universidad Andres Bello, Santiago 8370035, Chile
| | - Emilio A. Cafferata
- Periodontal Biology Laboratory, Faculty of Dentistry, Universidad de Chile, Santiago 8380492, Chile; (A.S.-C.); (E.A.C.); (S.M.-R.); (C.R.)
- Department of Periodontology, School of Dentistry, Universidad Científica del Sur, Lima 15067, Peru
| | - Samanta Melgar-Rodríguez
- Periodontal Biology Laboratory, Faculty of Dentistry, Universidad de Chile, Santiago 8380492, Chile; (A.S.-C.); (E.A.C.); (S.M.-R.); (C.R.)
- Department of Conservative Dentistry, Faculty of Dentistry, Universidad de Chile, Santiago 8380492, Chile;
| | - Carolina Rojas
- Periodontal Biology Laboratory, Faculty of Dentistry, Universidad de Chile, Santiago 8380492, Chile; (A.S.-C.); (E.A.C.); (S.M.-R.); (C.R.)
| | - Paola Carvajal
- Department of Conservative Dentistry, Faculty of Dentistry, Universidad de Chile, Santiago 8380492, Chile;
| | - Cristian Cortez
- Center for Genomics and Bioinformatics, Faculty of Sciences, Universidad Mayor, Santiago 8580745, Chile;
| | - Rolando Vernal
- Periodontal Biology Laboratory, Faculty of Dentistry, Universidad de Chile, Santiago 8380492, Chile; (A.S.-C.); (E.A.C.); (S.M.-R.); (C.R.)
- Department of Conservative Dentistry, Faculty of Dentistry, Universidad de Chile, Santiago 8380492, Chile;
- Correspondence: (L.G.-O.); (R.V.)
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Xie Y, Jiang X, Wang P, Zheng X, Song J, Bai M, Tang Y, Fang X, Jia Y, Li Z, Hu F. SR-A neutralizing antibody: potential drug candidate for ameliorating osteoclastogenesis in rheumatoid arthritis. Clin Exp Immunol 2022; 207:297-306. [PMID: 35553634 PMCID: PMC9113148 DOI: 10.1093/cei/uxac010] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 01/17/2022] [Accepted: 02/02/2022] [Indexed: 02/04/2023] Open
Abstract
Rheumatoid arthritis (RA) is an autoimmune disease characterized by proliferative synovitis with deterioration of cartilage and bone. Osteoclasts (OCs) are the active participants in the bone destruction of RA. Although with great advances, most current therapeutic strategies for RA have limited effects on bone destruction. Macrophage scavenger receptor A (SR-A) is a class of pattern recognition receptors (PRRs) involved in bone metabolism and OC differentiation. More recently, our study revealed the critical role of SR-A in RA diagnosis and pathogenesis. Here, we further demonstrated that serum SR-A levels were positively correlated with bone destruction in patients with RA. Anti-SR-A neutralizing antibodies significantly inhibited OC differentiation and bone absorption in vitro in patients with RA, but not in healthy individuals, dampening the expression of OC-specific genes such as tartrate-resistant acid phosphatase (TRAP), cathepsin K (CTSK), and matrix metalloproteinase-9 (MMP-9). Similar results were also seen in collagen-induced arthritis (CIA) mice in vitro. Moreover, the anti-SR-A neutralizing antibody could further ameliorate osteoclastogenesis in vivo and ex vivo in CIA mice, accompanied by decreased serum levels of C-terminal telopeptide and IL-6, exhibiting potential protective effects. These results suggest that blockade of SR-A using anti-SR-A neutralizing antibodies might provide a promising therapeutic strategy for bone destruction in the RA.
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Affiliation(s)
- Yang Xie
- Department of Rheumatology and Immunology, Peking University People’s Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Xiang Jiang
- Department of Rheumatology and Immunology, Peking University People’s Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China,Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
| | - Ping Wang
- Department of Rheumatology and Immunology, Peking University People’s Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Xi Zheng
- Department of Rheumatology and Immunology, Peking University People’s Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China,Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
| | - Jing Song
- Department of Rheumatology and Immunology, Peking University People’s Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China,Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
| | - Mingxin Bai
- Department of Rheumatology and Immunology, Peking University People’s Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Yundi Tang
- Department of Rheumatology and Immunology, Peking University People’s Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Xiangyu Fang
- Department of Rheumatology and Immunology, Peking University People’s Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Yuan Jia
- Department of Rheumatology and Immunology, Peking University People’s Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Zhanguo Li
- Department of Rheumatology and Immunology, Peking University People’s Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China,Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China,State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
| | - Fanlei Hu
- Correspondence: Fanlei Hu, Department of Rheumatology and Immunology, Peking University People’s Hospital, 11 Xizhimen South Street, Beijing 100044, China.
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Peckert-Maier K, Royzman D, Langguth P, Marosan A, Strack A, Sadeghi Shermeh A, Steinkasserer A, Zinser E, Wild AB. Tilting the Balance: Therapeutic Prospects of CD83 as a Checkpoint Molecule Controlling Resolution of Inflammation. Int J Mol Sci 2022; 23:732. [PMID: 35054916 PMCID: PMC8775349 DOI: 10.3390/ijms23020732] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 01/05/2022] [Accepted: 01/08/2022] [Indexed: 12/15/2022] Open
Abstract
Chronic inflammatory diseases and transplant rejection represent major challenges for modern health care. Thus, identification of immune checkpoints that contribute to resolution of inflammation is key to developing novel therapeutic agents for those conditions. In recent years, the CD83 (cluster of differentiation 83) protein has emerged as an interesting potential candidate for such a "pro-resolution" therapy. This molecule occurs in a membrane-bound and a soluble isoform (mCD83 and sCD83, respectively), both of which are involved in resolution of inflammation. Originally described as a maturation marker on dendritic cells (DCs), mCD83 is also expressed by activated B and T cells as well as regulatory T cells (Tregs) and controls turnover of MHC II molecules in the thymus, and thereby positive selection of CD4+ T cells. Additionally, it serves to confine overshooting (auto-)immune responses. Consequently, animals with a conditional deletion of CD83 in DCs or regulatory T cells suffer from impaired resolution of inflammation. Pro-resolving effects of sCD83 became evident in pre-clinical autoimmune and transplantation models, where application of sCD83 reduced disease symptoms and enhanced allograft survival, respectively. Here, we summarize recent advances regarding CD83-mediated resolution of inflammatory responses, its binding partners as well as induced signaling pathways, and emphasize its therapeutic potential for future clinical trials.
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Affiliation(s)
- Katrin Peckert-Maier
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich-Alexander Universität—Erlangen-Nürnberg, 91052 Erlangen, Germany; (D.R.); (P.L.); (A.M.); (A.S.); (A.S.S.); (A.S.); (E.Z.)
| | | | | | | | | | | | | | | | - Andreas B. Wild
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich-Alexander Universität—Erlangen-Nürnberg, 91052 Erlangen, Germany; (D.R.); (P.L.); (A.M.); (A.S.); (A.S.S.); (A.S.); (E.Z.)
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Wang Z, Huang J, Xie D, He D, Lu A, Liang C. Toward Overcoming Treatment Failure in Rheumatoid Arthritis. Front Immunol 2021; 12:755844. [PMID: 35003068 PMCID: PMC8732378 DOI: 10.3389/fimmu.2021.755844] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Accepted: 12/06/2021] [Indexed: 12/29/2022] Open
Abstract
Rheumatoid arthritis (RA) is an autoimmune disorder characterized by inflammation and bone erosion. The exact mechanism of RA is still unknown, but various immune cytokines, signaling pathways and effector cells are involved. Disease-modifying antirheumatic drugs (DMARDs) are commonly used in RA treatment and classified into different categories. Nevertheless, RA treatment is based on a "trial-and-error" approach, and a substantial proportion of patients show failed therapy for each DMARD. Over the past decades, great efforts have been made to overcome treatment failure, including identification of biomarkers, exploration of the reasons for loss of efficacy, development of sequential or combinational DMARDs strategies and approval of new DMARDs. Here, we summarize these efforts, which would provide valuable insights for accurate RA clinical medication. While gratifying, researchers realize that these efforts are still far from enough to recommend specific DMARDs for individual patients. Precision medicine is an emerging medical model that proposes a highly individualized and tailored approach for disease management. In this review, we also discuss the potential of precision medicine for overcoming RA treatment failure, with the introduction of various cutting-edge technologies and big data.
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Affiliation(s)
- Zhuqian Wang
- Department of Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, China
- Institute of Integrated Bioinfomedicine and Translational Science (IBTS), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, Hong Kong SAR, China
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, Hong Kong SAR, China
| | - Jie Huang
- Department of Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, China
| | - Duoli Xie
- Institute of Integrated Bioinfomedicine and Translational Science (IBTS), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, Hong Kong SAR, China
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, Hong Kong SAR, China
| | - Dongyi He
- Institute of Arthritis Research in Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
- Department of Rheumatology, Shanghai Guanghua Hospital of Integrative Medicine, Shanghai, China
| | - Aiping Lu
- Institute of Integrated Bioinfomedicine and Translational Science (IBTS), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, Hong Kong SAR, China
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, Hong Kong SAR, China
- Institute of Arthritis Research in Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
- Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou, China
| | - Chao Liang
- Department of Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, China
- Institute of Integrated Bioinfomedicine and Translational Science (IBTS), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, Hong Kong SAR, China
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, Hong Kong SAR, China
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Vescini F, Chiodini I, Falchetti A, Palermo A, Salcuni AS, Bonadonna S, De Geronimo V, Cesareo R, Giovanelli L, Brigo M, Bertoldo F, Scillitani A, Gennari L. Management of Osteoporosis in Men: A Narrative Review. Int J Mol Sci 2021; 22:ijms222413640. [PMID: 34948434 PMCID: PMC8705761 DOI: 10.3390/ijms222413640] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Revised: 12/13/2021] [Accepted: 12/15/2021] [Indexed: 12/12/2022] Open
Abstract
Male osteoporosis is a still largely underdiagnosed pathological condition. As a consequence, bone fragility in men remains undertreated mainly due to the low screening frequency and to controversies in the bone mineral density (BMD) testing standards. Up to the 40% of overall osteoporotic fractures affect men, in spite of the fact that women have a significant higher prevalence of osteoporosis. In addition, in males, hip fractures are associated with increased morbidity and mortality as compared to women. Importantly, male fractures occur about 10 years later in life than women, and, therefore, due to the advanced age, men may have more comorbidities and, consequently, their mortality is about twice the rate in women. Gender differences, which begin during puberty, lead to wider bones in males as compared with females. In men, follicle-stimulating hormones, testosterone, estrogens, and sex hormone-binding levels, together with genetic factors, interact in determining the peak of bone mass, BMD maintenance, and lifetime decrease. As compared with women, men are more frequently affected by secondary osteoporosis. Therefore, in all osteoporotic men, a complete clinical history should be collected and a careful physical examination should be done, in order to find clues of a possible underlying diseases and, ultimately, to guide laboratory testing. Currently, the pharmacological therapy of male osteoporosis includes aminobisphosphonates, denosumab, and teriparatide. Hypogonadal patients may be treated with testosterone replacement therapy. Given that the fractures related to mortality are higher in men than in women, treating male subjects with osteoporosis is of the utmost importance in clinical practice, as it may impact on mortality even more than in women.
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Affiliation(s)
- Fabio Vescini
- Endocrinology and Metabolism Unit, University-Hospital S. Maria della Misericordia, 33100 Udine, Italy; (F.V.); (A.S.S.)
| | - Iacopo Chiodini
- Istituto Auxologico Italiano, IRCCS, 20149 Milan, Italy; (A.F.); (S.B.)
- Department of Medical Biotechnology and Translational Medicine, University of Milan, 20122 Milan, Italy;
- Correspondence:
| | - Alberto Falchetti
- Istituto Auxologico Italiano, IRCCS, 20149 Milan, Italy; (A.F.); (S.B.)
| | - Andrea Palermo
- Unit of Endocrinology and Diabetes, Campus Bio-Medico University, 00128 Rome, Italy;
| | - Antonio Stefano Salcuni
- Endocrinology and Metabolism Unit, University-Hospital S. Maria della Misericordia, 33100 Udine, Italy; (F.V.); (A.S.S.)
| | - Stefania Bonadonna
- Istituto Auxologico Italiano, IRCCS, 20149 Milan, Italy; (A.F.); (S.B.)
- Department of Medical Biotechnology and Translational Medicine, University of Milan, 20122 Milan, Italy;
| | | | - Roberto Cesareo
- Center of Metabolic Disease, S.M. Goretti Hospital, 04100 Latina, Italy;
| | - Luca Giovanelli
- Department of Medical Biotechnology and Translational Medicine, University of Milan, 20122 Milan, Italy;
| | - Martina Brigo
- Department of Medicine, University of Verona, 37129 Verona, Italy; (M.B.); (F.B.)
| | - Francesco Bertoldo
- Department of Medicine, University of Verona, 37129 Verona, Italy; (M.B.); (F.B.)
| | - Alfredo Scillitani
- Unit of Endocrinology, Ospedale “Casa Sollievo della Sofferenza”, IRCCS, San Giovanni Rotondo, 71013 Foggia, Italy;
| | - Luigi Gennari
- Department of Medicine, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy;
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Lightman SM, Peresie JL, Carlson LM, Holling GA, Honikel MM, Chavel CA, Nemeth MJ, Olejniczak SH, Lee KP. Indoleamine 2,3-dioxygenase 1 is essential for sustaining durable antibody responses. Immunity 2021; 54:2772-2783.e5. [PMID: 34788602 PMCID: PMC9323746 DOI: 10.1016/j.immuni.2021.10.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 07/09/2021] [Accepted: 10/06/2021] [Indexed: 01/28/2023]
Abstract
Humoral immunity is essential for protection against pathogens, emphasized by the prevention of 2-3 million deaths worldwide annually by childhood immunizations. Long-term protective immunity is dependent on the continual production of neutralizing antibodies by the subset of long-lived plasma cells (LLPCs). LLPCs are not intrinsically long-lived, but require interaction with LLPC niche stromal cells for survival. However, it remains unclear which and how these interactions sustain LLPC survival and long-term humoral immunity. We now have found that the immunosuppressive enzyme indoleamine 2,3- dioxygenase 1 (IDO1) is required to sustain antibody responses and LLPC survival. Activation of IDO1 occurs upon the engagement of CD80/CD86 on the niche dendritic cells by CD28 on LLPC. Kynurenine, the product of IDO1 catabolism, activates the aryl hydrocarbon receptor in LLPC, reinforcing CD28 expression and survival signaling. These findings expand the immune function of IDO1 and uncover a novel pathway for sustaining LLPC survival and humoral immunity.
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Affiliation(s)
- Shivana M. Lightman
- Department of Immunology, Roswell Park Cancer Institute; Buffalo, NY 14203, USA
| | - Jennifer L. Peresie
- Department of Immunology, Roswell Park Cancer Institute; Buffalo, NY 14203, USA
| | - Louise M. Carlson
- Department of Immunology, Roswell Park Cancer Institute; Buffalo, NY 14203, USA
| | - G. Aaron Holling
- Department of Immunology, Roswell Park Cancer Institute; Buffalo, NY 14203, USA
| | | | - Colin A. Chavel
- Department of Immunology, Roswell Park Cancer Institute; Buffalo, NY 14203, USA
| | - Michael J Nemeth
- Department of Immunology, Roswell Park Cancer Institute; Buffalo, NY 14203, USA
| | - Scott H. Olejniczak
- Department of Immunology, Roswell Park Cancer Institute; Buffalo, NY 14203, USA
| | - Kelvin P. Lee
- Department of Immunology, Roswell Park Cancer Institute; Buffalo, NY 14203, USA
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Wee HN, Liu JJ, Ching J, Kovalik JP, Lim SC. The Kynurenine Pathway in Acute Kidney Injury and Chronic Kidney Disease. Am J Nephrol 2021; 52:771-787. [PMID: 34753140 PMCID: PMC8743908 DOI: 10.1159/000519811] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 09/15/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND The kynurenine pathway (KP) is the major catabolic pathway for tryptophan degradation. The KP plays an important role as the sole de novo nicotinamide adenine dinucleotide (NAD+) biosynthetic pathway in normal human physiology and functions as a counter-regulatory mechanism to mitigate immune responses during inflammation. Although the KP has been implicated in a variety of disorders including Huntington's disease, seizures, cardiovascular disease, and osteoporosis, its role in renal diseases is seldom discussed. SUMMARY This review summarizes the roles of the KP and its metabolites in acute kidney injury (AKI) and chronic kidney disease (CKD) based on current literature evidence. Metabolomics studies demonstrated that the KP metabolites were significantly altered in patients and animal models with AKI or CKD. The diagnostic and prognostic values of the KP metabolites in AKI and CKD were highlighted in cross-sectional and longitudinal human observational studies. The biological impact of the KP on the pathophysiology of AKI and CKD has been studied in experimental models of different etiologies. In particular, the activation of the KP was found to confer protection in animal models of glomerulonephritis, and its immunomodulatory mechanism may involve the regulation of T cell subsets such as Th17 and regulatory T cells. Manipulation of the KP to increase NAD+ production or diversion toward specific KP metabolites was also found to be beneficial in animal models of AKI. Key Messages: KP metabolites are reported to be dysregulated in human observational and animal experimental studies of AKI and CKD. In AKI, the magnitude and direction of changes in the KP depend on the etiology of the damage. In CKD, KP metabolites are altered with the onset and progression of CKD all the way to advanced stages of the disease, including uremia and its related vascular complications. The activation of the KP and diversion to specific sub-branches are currently being explored as therapeutic strategies in these diseases, especially with regards to the immunomodulatory effects of certain KP metabolites. Further elucidation of the KP may hold promise for the development of biomarkers and targeted therapies for these kidney diseases.
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Affiliation(s)
| | - Jian-Jun Liu
- Clinical Research Unit, Khoo Teck Puat Hospital, Singapore, Singapore
| | - Jianhong Ching
- Duke-NUS Medical School, Singapore, Singapore
- KK Research Centre, KK Women's and Children's Hospital, Singapore, Singapore
| | | | - Su Chi Lim
- Clinical Research Unit, Khoo Teck Puat Hospital, Singapore, Singapore
- Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore
- Diabetes Centre, Admiralty Medical Centre, Singapore, Singapore
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39
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Oh Y, Park R, Kim SY, Park SH, Jo S, Kim TH, Ji JD. B7-H3 regulates osteoclast differentiation via type I interferon-dependent IDO induction. Cell Death Dis 2021; 12:971. [PMID: 34671026 PMCID: PMC8528854 DOI: 10.1038/s41419-021-04275-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 09/13/2021] [Accepted: 10/06/2021] [Indexed: 12/29/2022]
Abstract
While their function, as immune checkpoint molecules, is well known, B7-family proteins also function as regulatory molecules in bone remodeling. B7-H3 is a receptor ligand of the B7 family that functions primarily as a negative immune checkpoint. While the regulatory function of B7-H3 in osteoblast differentiation has been established, its role in osteoclast differentiation remains unclear. Here we show that B7-H3 is highly expressed in mature osteoclasts and that B7-H3 deficiency leads to the inhibition of osteoclastogenesis in human osteoclast precursors (OCPs). High-throughput transcriptomic analyses reveal that B7-H3 inhibition upregulates IFN signaling as well as IFN-inducible genes, including IDO. Pharmacological inhibition of type-I IFN and IDO knockdown leads to reversal of B7-H3-deficiency-mediated osteoclastogenesis suppression. Although synovial-fluid macrophages from rheumatoid-arthritis patients express B7-H3, inhibition of B7-H3 does not affect their osteoclastogenesis. Thus, our findings highlight B7-H3 as a physiologic positive regulator of osteoclast differentiation and implicate type-I IFN-IDO signaling as its downstream mechanism.
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MESH Headings
- Animals
- Antibodies, Neutralizing/pharmacology
- Arthritis, Rheumatoid/pathology
- B7 Antigens/deficiency
- B7 Antigens/genetics
- B7 Antigens/metabolism
- Cell Differentiation
- Enzyme Induction/drug effects
- Humans
- Indoleamine-Pyrrole 2,3,-Dioxygenase/biosynthesis
- Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism
- Interferon Type I/metabolism
- Interferon-beta/metabolism
- Macrophage Colony-Stimulating Factor/pharmacology
- Macrophages/drug effects
- Macrophages/metabolism
- Macrophages/pathology
- Male
- Mice, Inbred C57BL
- Mice, Knockout
- Monocytes/drug effects
- Monocytes/metabolism
- Nitric Oxide Synthase Type II/metabolism
- Osteoclasts/metabolism
- Osteoclasts/pathology
- Osteogenesis/drug effects
- Proto-Oncogene Proteins c-fos/metabolism
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Signal Transduction/drug effects
- Stem Cells/drug effects
- Stem Cells/metabolism
- Suppressor of Cytokine Signaling 1 Protein/metabolism
- Synovial Fluid/metabolism
- Tryptophan/metabolism
- Mice
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Affiliation(s)
- Younseo Oh
- Hanyang University Institute for Rheumatology Research, Seoul, Republic of Korea
- Rheumatology, College of Medicine, Korea University, Seoul, South Korea
| | - Robin Park
- MetroWest Medical Center/Tufts University School of Medicine, Framingham, MA, 01702, USA
| | - So Yeon Kim
- Hanyang University Institute for Rheumatology Research, Seoul, Republic of Korea
- Department of Translational Medicine, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea
| | - Sung-Ho Park
- School of Life Sciences, Ulsan National Institute of Science & Technology (UNIST), Ulsan, 44919, Korea
| | - Sungsin Jo
- Hanyang University Institute for Rheumatology Research, Seoul, Republic of Korea
| | - Tae-Hwan Kim
- Hanyang University Institute for Rheumatology Research, Seoul, Republic of Korea.
- Department of Translational Medicine, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea.
- Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Republic of Korea.
| | - Jong Dae Ji
- Rheumatology, College of Medicine, Korea University, Seoul, South Korea.
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Kondo N, Kuroda T, Kobayashi D. Cytokine Networks in the Pathogenesis of Rheumatoid Arthritis. Int J Mol Sci 2021; 22:ijms222010922. [PMID: 34681582 PMCID: PMC8539723 DOI: 10.3390/ijms222010922] [Citation(s) in RCA: 261] [Impact Index Per Article: 65.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 10/06/2021] [Accepted: 10/08/2021] [Indexed: 12/13/2022] Open
Abstract
Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic systemic inflammation causing progressive joint damage that can lead to lifelong disability. The pathogenesis of RA involves a complex network of various cytokines and cells that trigger synovial cell proliferation and cause damage to both cartilage and bone. Involvement of the cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-6 is central to the pathogenesis of RA, but recent research has revealed that other cytokines such as IL-7, IL-17, IL-21, IL-23, granulocyte macrophage colony-stimulating factor (GM-CSF), IL-1β, IL-18, IL-33, and IL-2 also play a role. Clarification of RA pathology has led to the development of therapeutic agents such as biological disease-modifying anti-rheumatic drugs (DMARDs) and Janus kinase (JAK) inhibitors, and further details of the immunological background to RA are emerging. This review covers existing knowledge regarding the roles of cytokines, related immune cells and the immune system in RA, manipulation of which may offer the potential for even safer and more effective treatments in the future.
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Affiliation(s)
- Naoki Kondo
- Division of Orthopedic Surgery, Department of Regenerative and Transplant Medicine, Graduate School of Medical and Dental Sciences, Niigata University, 1-757 Asahimachi-Dori, Chuo-ku, Niigata City 951-8510, Japan;
| | - Takeshi Kuroda
- Health Administration Center, Niigata University, 2-8050 Ikarashi, Nishi-ku, Niigata City 950-2181, Japan
- Correspondence: ; Tel.: +81-25-262-6244; Fax: +81-25-262-7517
| | - Daisuke Kobayashi
- Division of Clinical Nephrology and Rheumatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757 Asahimachi-Dori, Chuo-ku, Niigata City 951-8510, Japan;
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Shi Y, Yu Y, Zhou Y, Zhao J, Zhang W, Zou D, Song W, Wang S. A single-cell interactome of human tooth germ from growing third molar elucidates signaling networks regulating dental development. Cell Biosci 2021; 11:178. [PMID: 34600587 PMCID: PMC8487529 DOI: 10.1186/s13578-021-00691-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Accepted: 09/16/2021] [Indexed: 01/17/2023] Open
Abstract
Background Development of dental tissue is regulated by extensive cell crosstalk based on various signaling molecules, such as bone morphogenetic protein (BMP) and fibroblast growth factor (FGF) pathways. However, an intact network of the intercellular regulation is still lacking. Result To gain an unbiased and comprehensive view of this dental cell interactome, we applied single-cell RNA-seq on immature human tooth germ of the growing third molar, discovered refined cell subtypes, and applied multiple network analysis to identify the central signaling pathways. We found that immune cells made up over 80% of all tooth germ cells, which exhibited profound regulation on dental cells via Transforming growth factor-β, Tumor necrosis factor (TNF) and Interleukin-1. During osteoblast differentiation, expression of genes related to extracellular matrix and mineralization was continuously elevated by signals from BMP and FGF family. As for the self-renewal of apical papilla stem cell, BMP-FGFR1-MSX1 pathway directly regulated the G0-to-S cell cycle transition. We also confirmed that Colony Stimulating Factor 1 secreted from pericyte and TNF Superfamily Member 11 secreted from osteoblast regulated a large proportion of genes related to osteoclast transformation from macrophage and monocyte. Conclusions We constructed the intercellular signaling networks that regulated the essential developmental process of human tooth, which served as a foundation for future dental regeneration engineering and the understanding of oral pathology. Supplementary Information The online version contains supplementary material available at 10.1186/s13578-021-00691-5.
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Affiliation(s)
- Yueqi Shi
- Department of Oral Surgery, Shanghai Key Laboratory of Stomatology, National Center for Stomatology, National Clinical Research Center for Oral Diseases, College of Stomatology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Department of Stomatology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200336, China
| | - Yejia Yu
- Department of Oral Surgery, Shanghai Key Laboratory of Stomatology, National Center for Stomatology, National Clinical Research Center for Oral Diseases, College of Stomatology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yuqiong Zhou
- Department of Oral Surgery, Shanghai Key Laboratory of Stomatology, National Center for Stomatology, National Clinical Research Center for Oral Diseases, College of Stomatology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jun Zhao
- Department of Orthodontics, Shanghai Key Laboratory of Stomatology, National Center for Stomatology, National Clinical Research Center for Oral Diseases, College of Stomatology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Wenjie Zhang
- Department of Prosthodontics, Shanghai Key Laboratory of Stomatology, National Center for Stomatology, National Clinical Research Center for Oral Diseases, College of Stomatology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Duohong Zou
- Department of Oral Surgery, Shanghai Key Laboratory of Stomatology, National Center for Stomatology, National Clinical Research Center for Oral Diseases, College of Stomatology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Weichen Song
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Shaoyi Wang
- Department of Oral Surgery, Shanghai Key Laboratory of Stomatology, National Center for Stomatology, National Clinical Research Center for Oral Diseases, College of Stomatology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
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Luo B, Zhou X, Tang Q, Yin Y, Feng G, Li S, Chen L. Circadian rhythms affect bone reconstruction by regulating bone energy metabolism. J Transl Med 2021; 19:410. [PMID: 34579752 PMCID: PMC8477514 DOI: 10.1186/s12967-021-03068-x] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Accepted: 09/02/2021] [Indexed: 01/02/2023] Open
Abstract
Metabolism is one of the most complex cellular biochemical reactions, providing energy and substances for basic activities such as cell growth and proliferation. Early studies have shown that glucose is an important nutrient in osteoblasts. In addition, amino acid metabolism and fat metabolism also play important roles in bone reconstruction. Mammalian circadian clocks regulate the circadian cycles of various physiological functions. In vertebrates, circadian rhythms are mediated by a set of central clock genes: muscle and brain ARNT like-1 (Bmal1), muscle and brain ARNT like-2 (Bmal2), circadian rhythmic motion output cycle stagnates (Clock), cryptochrome 1 (Cry1), cryptochrome2 (Cry2), period 1 (Per1), period 2 (Per2), period 3 (Per3) and neuronal PAS domain protein 2 (Npas2). Negative feedback loops, controlled at both the transcriptional and posttranslational levels, adjust these clock genes in a diurnal manner. According to the results of studies on circadian transcriptomic studies in several tissues, most rhythmic genes are expressed in a tissue-specific manner and are affected by tissue-specific circadian rhythms. The circadian rhythm regulates several activities, including energy metabolism, feeding time, sleeping, and endocrine and immune functions. It has been reported that the circadian rhythms of mammals are closely related to bone metabolism. In this review, we discuss the regulation of the circadian rhythm/circadian clock gene in osteoblasts/osteoclasts and the energy metabolism of bone, and the relationship between circadian rhythm, bone remodeling, and energy metabolism. We also discuss the therapeutic potential of regulating circadian rhythms or changing energy metabolism on bone development/bone regeneration.
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Affiliation(s)
- Beibei Luo
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.,School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.,Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
| | - Xin Zhou
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.,School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.,Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
| | - Qingming Tang
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.,School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.,Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
| | - Ying Yin
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.,School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.,Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
| | - Guangxia Feng
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.,School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.,Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
| | - Shue Li
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. .,School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. .,Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China.
| | - Lili Chen
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. .,School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. .,Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China.
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Li X, Xu H, Huang J, Luo D, Lv S, Lu X, Xiao C. Dysfunctions, Molecular Mechanisms, and Therapeutic Strategies of Regulatory T Cells in Rheumatoid Arthritis. Front Pharmacol 2021; 12:716081. [PMID: 34512345 PMCID: PMC8428974 DOI: 10.3389/fphar.2021.716081] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 07/19/2021] [Indexed: 12/20/2022] Open
Abstract
Regulatory T cells (Tregs) represent a distinct subpopulation of CD4+ T lymphocytes that promote immune tolerance and maintain immune system homeostasis. The dysfunction of Tregs is tightly associated with rheumatoid arthritis (RA). Although the complex pathogenic processes of RA remain unclear, studies on Tregs in RA have achieved substantial progress not only in fundamental research but also in clinical application. This review discusses the current knowledge of the characterizations, functions, and molecular mechanisms of Tregs in the pathogenesis of RA, and potential therapies for these disorders are also involved.
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Affiliation(s)
- Xiaoya Li
- The Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing, China.,Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Huihui Xu
- Beijing Key Laboratory of Research of Chinese Medicine on Prevention and Treatment for Major Diseases, Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing, China
| | - Jing Huang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Dan Luo
- Department of Ophthalmology, Traditional Chinese Medicine Hospital of Changping District, Beijing, China
| | - Shuang Lv
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Xiangchen Lu
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China.,School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Cheng Xiao
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China.,Department of Emergency, China-Japan Friendship Hospital, Beijing, China
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44
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Rossi M, Rana I, Buonuomo PS, Battafarano G, De Martino V, D'Agostini M, Porzio O, Cipriani C, Minisola S, De Vito R, Vecchio D, Gonfiantini MV, Jenkner A, Bartuli A, Del Fattore A. Stimulation of Treg Cells to Inhibit Osteoclastogenesis in Gorham-Stout Disease. Front Cell Dev Biol 2021; 9:706596. [PMID: 34513837 PMCID: PMC8430039 DOI: 10.3389/fcell.2021.706596] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Accepted: 08/10/2021] [Indexed: 11/18/2022] Open
Abstract
Gorham-Stout disease (GSD) is a very rare syndrome displaying excessive bone erosion and vascular lesion. Due to the rarity of the disease and to the limited studies, its etiopathogenesis is not entirely known. The involvement of immune system in the progressive osteolysis was recently suggested. Indeed, extensive reciprocal interactions between the immune and skeletal systems have been demonstrated. This study aimed to evaluate alterations of immune cells in GSD. An increase of CD8+ cells and reduction of CD4+ and CD4+CD25+CD127low cells was revealed in patients. Interestingly, patients’ regulatory T cells maintain the ability to respond to extracellular stimuli and to regulate osteoclastogenesis; GSD cells proliferate under aCD3/CD28 signal reaching similar levels to those observed in control culture and exert their immunomodulatory activity on effector T cells. GSD Treg cells preserved their inhibitory effects on the osteoclastogenesis. These results suggest that stimulation of Treg cells could open the way for the identification and testing of new therapeutic approaches for patients affected by GSD.
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Affiliation(s)
- Michela Rossi
- Bone Physiopathology Research Unit, Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Ippolita Rana
- Rare Diseases and Medical Genetic Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Paola Sabrina Buonuomo
- Rare Diseases and Medical Genetic Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Giulia Battafarano
- Bone Physiopathology Research Unit, Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Viviana De Martino
- Department of Clinical, Internal, Anaesthesiological and Cardiovascular Sciences, Sapienza University, Rome, Italy
| | - Matteo D'Agostini
- Clinical Laboratory, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Ottavia Porzio
- Clinical Laboratory, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.,Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Cristiana Cipriani
- Department of Clinical, Internal, Anaesthesiological and Cardiovascular Sciences, Sapienza University, Rome, Italy
| | - Salvatore Minisola
- Department of Clinical, Internal, Anaesthesiological and Cardiovascular Sciences, Sapienza University, Rome, Italy
| | - Rita De Vito
- Department of Histopathology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Davide Vecchio
- Rare Diseases and Medical Genetic Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | | | - Alessandro Jenkner
- Division of Immunology and Infectious Diseases, Department of Pediatrics, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Andrea Bartuli
- Rare Diseases and Medical Genetic Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Andrea Del Fattore
- Bone Physiopathology Research Unit, Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
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Roszkowski L, Ciechomska M. Tuning Monocytes and Macrophages for Personalized Therapy and Diagnostic Challenge in Rheumatoid Arthritis. Cells 2021; 10:cells10081860. [PMID: 34440629 PMCID: PMC8392289 DOI: 10.3390/cells10081860] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 07/19/2021] [Accepted: 07/20/2021] [Indexed: 12/21/2022] Open
Abstract
Monocytes/macrophages play a central role in chronic inflammatory disorders, including rheumatoid arthritis (RA). Activation of these cells results in the production of various mediators responsible for inflammation and RA pathogenesis. On the other hand, the depletion of macrophages using specific antibodies or chemical agents can prevent their synovial tissue infiltration and subsequently attenuates inflammation. Their plasticity is a major feature that helps the switch from a pro-inflammatory phenotype (M1) to an anti-inflammatory state (M2). Therefore, understanding the precise strategy targeting pro-inflammatory monocytes/macrophages should be a powerful way of inhibiting chronic inflammation and bone erosion. In this review, we demonstrate potential consequences of different epigenetic regulations on inflammatory cytokines production by monocytes. In addition, we present unique profiles of monocytes/macrophages contributing to identification of new biomarkers of disease activity or predicting treatment response in RA. We also outline novel approaches of tuning monocytes/macrophages by biologic drugs, small molecules or by other therapeutic modalities to reduce arthritis. Finally, the importance of cellular heterogeneity of monocytes/macrophages is highlighted by single-cell technologies, which leads to the design of cell-specific therapeutic protocols for personalized medicine in RA in the future.
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Kawashiri SY, Endo Y, Nishino A, Okamoto M, Tsuji S, Takatani A, Shimizu T, Sumiyoshi R, Koga T, Iwamoto N, Ichinose K, Tamai M, Nakamura H, Origuchi T, Aramaki T, Ueki Y, Yoshitama T, Eiraku N, Matsuoka N, Okada A, Fujikawa K, Hamada H, Nagano S, Tada Y, Kawakami A. Effect of abatacept treatment on serum osteoclast-related biomarkers in patients with rheumatoid arthritis (RA): A multicenter RA ultrasound prospective cohort in Japan. Medicine (Baltimore) 2021; 100:e26592. [PMID: 34260539 PMCID: PMC8284735 DOI: 10.1097/md.0000000000026592] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Accepted: 06/17/2021] [Indexed: 11/25/2022] Open
Abstract
We evaluated the effect of abatacept treatment on osteoclast-related biomarkers and explored whether the biomarkers are associated with the therapeutic response in rheumatoid arthritis (RA) patients treated with abatacept.We enrolled 44 RA patients treated with abatacept from a multicenter prospective ultrasound cohort study of patients who received biologic or targeted synthetic disease-modifying antirheumatic drug therapy. We evaluated the disease activity score (DAS) 28-CRP (C-reactive protein), musculoskeletal ultrasound scores including the total grayscale score (GS)/power Doppler (PD) score and the serum concentrations of isoform 5b of tartrate-resistant acid phosphate (TRACP-5b) and soluble receptor activator of nuclear factor-κB ligand (sRANKL) at baseline and at 3 and 6 months of treatment. "PD responder" was defined as a patient whose Δtotal PD score over 6 months was greater than the median change of that.Abatacept significantly improved DAS28-CRP as well as the total GS/PD score over 6 months. Serum TRACP-5b was significantly elevated and serum sRANKL was significantly decreased at 6 months (P < .0001 and P < .01, respectively). At 6 months, serum sRANKL was significantly decreased in the patients who achieved DAS28-CRP remission and the PD responders but not in those who did not. However, serum TRACP-5b rose regardless of the therapeutic response.Among RA patients treated with abatacept, serum sRANKL decreased in the patients with a good therapeutic response, but serum TRACP-5b elevated paradoxically regardless of the therapeutic response.
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Affiliation(s)
- Shin-Ya Kawashiri
- Departments of Community Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
- Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Yushiro Endo
- Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Ayako Nishino
- Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Momoko Okamoto
- Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Sosuke Tsuji
- Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Ayuko Takatani
- Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Toshimasa Shimizu
- Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Remi Sumiyoshi
- Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Tomohiro Koga
- Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Naoki Iwamoto
- Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Kunihiro Ichinose
- Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Mami Tamai
- Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Hideki Nakamura
- Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Tomoki Origuchi
- Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Toshiyuki Aramaki
- Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Yukitaka Ueki
- Kyushu Multicenter Rheumatoid Arthritis Ultrasound Prospective Observational Cohort Study (KUDOS) Group, Japan
| | - Tamami Yoshitama
- Kyushu Multicenter Rheumatoid Arthritis Ultrasound Prospective Observational Cohort Study (KUDOS) Group, Japan
| | - Nobutaka Eiraku
- Kyushu Multicenter Rheumatoid Arthritis Ultrasound Prospective Observational Cohort Study (KUDOS) Group, Japan
| | - Naoki Matsuoka
- Kyushu Multicenter Rheumatoid Arthritis Ultrasound Prospective Observational Cohort Study (KUDOS) Group, Japan
| | - Akitomo Okada
- Kyushu Multicenter Rheumatoid Arthritis Ultrasound Prospective Observational Cohort Study (KUDOS) Group, Japan
| | - Keita Fujikawa
- Kyushu Multicenter Rheumatoid Arthritis Ultrasound Prospective Observational Cohort Study (KUDOS) Group, Japan
| | - Hiroaki Hamada
- Kyushu Multicenter Rheumatoid Arthritis Ultrasound Prospective Observational Cohort Study (KUDOS) Group, Japan
| | - Shuji Nagano
- Kyushu Multicenter Rheumatoid Arthritis Ultrasound Prospective Observational Cohort Study (KUDOS) Group, Japan
| | - Yoshifumi Tada
- Kyushu Multicenter Rheumatoid Arthritis Ultrasound Prospective Observational Cohort Study (KUDOS) Group, Japan
| | - Atsushi Kawakami
- Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
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Lu L, Chen X, Liu Y, Yu X. Gut microbiota and bone metabolism. FASEB J 2021; 35:e21740. [PMID: 34143911 DOI: 10.1096/fj.202100451r] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 06/03/2021] [Accepted: 06/04/2021] [Indexed: 02/05/2023]
Abstract
Osteoporosis is the most common metabolic skeletal disease. It is characterized by the deterioration of the skeletal microarchitecture and bone loss, leading to ostealgia, and even bone fractures. Accumulating evidence has indicated that there is an inextricable relationship between the gut microbiota (GM) and bone homeostasis involving host-microbiota crosstalk. Any perturbation of the GM can play an initiating and reinforcing role in disrupting the bone remodeling balance during the development of osteoporosis. Although the GM is known to influence bone metabolism, the mechanisms associated with these effects remain unclear. Herein, we review the current knowledge of how the GM affects bone metabolism in health and disease, summarize the correlation between pathogen-associated molecular patterns of GM structural components and bone metabolism, and discuss the potential mechanisms underlying how GM metabolites regulate bone turnover. Deciphering the complicated relationship between the GM and bone health will provide new insights into the prevention and treatment of osteoporosis.
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Affiliation(s)
- Lingyun Lu
- Department of Endocrinology and Metabolism, Laboratory of Endocrinology and Metabolism, Rare Disease Center, West China Hospital, Sichuan University, Chengdu, China.,Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaoxuan Chen
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yi Liu
- Department of Rheumatology and Immunology, Rare Disease Center, West China Hospital, Sichuan University, Chengdu, China
| | - Xijie Yu
- Department of Endocrinology and Metabolism, Laboratory of Endocrinology and Metabolism, Rare Disease Center, West China Hospital, Sichuan University, Chengdu, China
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Jia L, Tu Y, Jia X, Du Q, Zheng X, Yuan Q, Zheng L, Zhou X, Xu X. Probiotics ameliorate alveolar bone loss by regulating gut microbiota. Cell Prolif 2021; 54:e13075. [PMID: 34101283 PMCID: PMC8249787 DOI: 10.1111/cpr.13075] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 04/16/2021] [Accepted: 05/15/2021] [Indexed: 02/05/2023] Open
Abstract
OBJECTIVES Oestrogen deficiency is an aetiological factor of postmenopausal osteoporosis (PMO), which not only decreases bone density in vertebrae and long bone but also aggravates inflammatory alveolar bone loss. Recent evidence has suggested the critical role of gut microbiota in osteoimmunology and its influence on bone metabolisms. The present study aimed to evaluate the therapeutic effects of probiotics on alveolar bone loss under oestrogen-deficient condition. MATERIALS AND METHODS Inflammatory alveolar bone loss was established in ovariectomized (OVX) rats, and rats were daily intragastrically administered with probiotics until sacrifice. Gut microbiota composition, intestinal permeability, systemic immune status and alveolar bone loss were assessed to reveal the underlying correlation between gut microbiota and bone metabolisms. RESULTS We found administration of probiotics significantly prevented inflammatory alveolar bone resorption in OVX rats. By enriching butyrate-producing genera and enhancing gut butyrate production, probiotics improved intestinal barrier and decreased gut permeability in the OVX rats. Furthermore, the oestrogen deprivation-induced inflammatory responses were suppressed in probiotics-treated OVX rats, as reflected by reduced serum levels of inflammatory cytokines and a balanced distribution of CD4+ IL-17A+ Th17 cells and CD4+ CD25+ Foxp3+ Treg cells in the bone marrow. CONCLUSIONS This study demonstrated that probiotics can effectively attenuate alveolar bone loss by modulating gut microbiota and further regulating osteoimmune response and thus represent a promising adjuvant in the treatment of alveolar bone loss under oestrogen deficiency.
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Affiliation(s)
- Leming Jia
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral DiseasesWest China Hospital of StomatologySichuan UniversityChengduChina
- Department of Cariology and EndodonticsWest China Hospital of StomatologySichuan UniversityChengduChina
| | - Ye Tu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral DiseasesWest China Hospital of StomatologySichuan UniversityChengduChina
- Department of Cariology and EndodonticsWest China Hospital of StomatologySichuan UniversityChengduChina
| | - Xiaoyue Jia
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral DiseasesWest China Hospital of StomatologySichuan UniversityChengduChina
- Department of Pediatric DentistryWest China Hospital of StomatologySichuan UniversityChengduChina
| | - Qian Du
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral DiseasesWest China Hospital of StomatologySichuan UniversityChengduChina
- Department of Cariology and EndodonticsWest China Hospital of StomatologySichuan UniversityChengduChina
| | - Xin Zheng
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral DiseasesWest China Hospital of StomatologySichuan UniversityChengduChina
- Department of Cariology and EndodonticsWest China Hospital of StomatologySichuan UniversityChengduChina
| | - Quan Yuan
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral DiseasesWest China Hospital of StomatologySichuan UniversityChengduChina
- Department of Dental ImplantologyWest China Hospital of StomatologySichuan UniversityChengduChina
| | - Liwei Zheng
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral DiseasesWest China Hospital of StomatologySichuan UniversityChengduChina
- Department of Pediatric DentistryWest China Hospital of StomatologySichuan UniversityChengduChina
| | - Xuedong Zhou
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral DiseasesWest China Hospital of StomatologySichuan UniversityChengduChina
- Department of Cariology and EndodonticsWest China Hospital of StomatologySichuan UniversityChengduChina
| | - Xin Xu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral DiseasesWest China Hospital of StomatologySichuan UniversityChengduChina
- Department of Cariology and EndodonticsWest China Hospital of StomatologySichuan UniversityChengduChina
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Nakane S, Imamura K, Hisanaga R, Ishihara K, Saito A. Systemic administration of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4)-Ig abrogates alveolar bone resorption in induced periodontitis through inhibition of osteoclast differentiation and activation: An experimental investigation. J Periodontal Res 2021; 56:972-981. [PMID: 34129238 DOI: 10.1111/jre.12909] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 05/06/2021] [Accepted: 05/27/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND/OBJECTIVES Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is a critical immunoregulatory molecule expressed on T cells. CTLA-4 also binds to the surfaces of monocytes and macrophages, precursors of osteoclasts. Research on rheumatoid arthritis demonstrated that CTLA-4 suppresses inflammation and bone resorption. However, its effects on alveolar bone have yet to be understood. The purpose of this study was to investigate the role and potential mechanism of CTLA-4 in bone resorption in periodontitis. MATERIALS AND METHODS In vivo, the effects of systemic administration of CTLA-4 immunoglobulin fusion protein (CTLA-4-Ig) on alveolar bone resorption were investigated using a periodontitis mouse model. A total of 20 C57BL/6J mice were randomly assigned to two groups according to the administration modes. Periodontitis was induced by placing a ligature around the left maxillary second molar. The contralateral tooth was left un-ligated. In the CTLA-4-Ig (+) group, CTLA-4-Ig was administered by intraperitoneal injection at 1 and 3 days after ligature placement. Animals in the CTLA-4-Ig (-) group were given only phosphate-buffered saline each time. At 5 days after ligature placement, bone resorption was assessed by micro-computed tomography and histological examination, and the prevalence of osteoclast-like cells was assessed by tartrate-resistant acid phosphatase (TRAP) staining. In vitro, the effects of CTLA-4-Ig on osteoclasts were evaluated. Viability of RAW 264.7 cells treated with receptor activator of nuclear factor-κB ligand (RANKL) and CTLA-4-Ig was tested by WST-1 assay. Osteoclast-like cells were enumerated by TRAP staining, and osteoclast activity was evaluated by resorption pit assay. Gene expression levels of osteoclast differentiation markers (macrophage-colony stimulating factor receptor, carbonic anhydrase II, cathepsin K, and Trap) and protein phosphatase 2A (PP2A), a major serine-threonine phosphatase, were assessed by quantitative real-time polymerase chain reaction. The effect of CTLA-4-Ig on the nuclear factor-κB (NF-κB) activation was assessed by enzyme-linked immunosorbent assay. RESULTS In vivo, ligature-induced bone resorption and the numbers of osteoclast-like cells were significantly decreased by the administration of CTLA-4-Ig. In vitro, treatment with RANKL and CTLA-4-Ig had no significant effect on cell viability. CTLA-4-Ig significantly reduced the prevalence and activation of osteoclast-like cells and decreased the expressions of osteoclast differentiation markers, compared with the RANKL-treated control. CTLA-4-Ig significantly suppressed RANKL-induced phosphorylation of NF-κB p65 but increased PP2A expression. CONCLUSION These results suggest that CTLA-4-Ig abrogates bone resorption in induced periodontitis, possibly via inhibition of osteoclast differentiation and activation. The regulation of the NF-κB pathway and PP2A expression may be one mechanism by which CTLA-4-Ig suppresses osteoclast behavior.
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Affiliation(s)
- Saki Nakane
- Department of Periodontology, Tokyo Dental College, Tokyo, Japan.,Oral Health Science Center, Tokyo Dental College, Tokyo, Japan
| | - Kentaro Imamura
- Department of Periodontology, Tokyo Dental College, Tokyo, Japan.,Oral Health Science Center, Tokyo Dental College, Tokyo, Japan
| | - Rio Hisanaga
- Department of Periodontology, Tokyo Dental College, Tokyo, Japan.,Oral Health Science Center, Tokyo Dental College, Tokyo, Japan
| | - Kazuyuki Ishihara
- Oral Health Science Center, Tokyo Dental College, Tokyo, Japan.,Department of Microbiology, Tokyo Dental College, Tokyo, Japan
| | - Atsushi Saito
- Department of Periodontology, Tokyo Dental College, Tokyo, Japan.,Oral Health Science Center, Tokyo Dental College, Tokyo, Japan
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50
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Kawashiri SY, Endo Y, Nishino A, Okamoto M, Tsuji S, Takatani A, Shimizu T, Sumiyoshi R, Koga T, Iwamoto N, Ichinose K, Tamai M, Nakamura H, Origuchi T, Aramaki T, Ueki Y, Yoshitama T, Eiraku N, Matsuoka N, Okada A, Fujikawa K, Hamada H, Nagano S, Tada Y, Kawakami A. Association between serum bone biomarker levels and therapeutic response to abatacept in patients with rheumatoid arthritis (RA): a multicenter, prospective, and observational RA ultrasound cohort study in Japan. BMC Musculoskelet Disord 2021; 22:506. [PMID: 34074293 PMCID: PMC8171043 DOI: 10.1186/s12891-021-04392-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 05/24/2021] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND To evaluate the effect of treatment on serum bone biomarkers and explore whether serum bone biomarkers are associated with therapeutic response in rheumatoid arthritis (RA) patients treated with abatacept. METHODS We enrolled 59 RA patients treated with abatacept from a multicenter, exploratory, short-term, prospective and observational ultrasound cohort study of patients who received biologic or targeted synthetic disease-modifying antirheumatic drug (DMARD) therapy. We evaluated the patients' clinical disease activity and musculoskeletal ultrasound (MSUS) scores. The serum concentrations of five bone biomarkers were evaluated (dickkopf-1 [Dkk-1], sclerostin [SOST], osteocalcin [OC], osteopontin [OPN], and osteoprotegerin [OPG]) by multiplex bead assays at baseline, 3, and 6 months: the change over 6 months was defined as the Δ value. 'Power Doppler (PD) responder' was defined as a patient whose Δtotal PD score over 6 months was greater than the median change. RESULTS Abatacept significantly improved the clinical disease activity and MSUS score over 6 months. Serum OPG was significantly elevated at 6 months after the abatacept introduction (p = 0.016). The ΔSOST and ΔOPG were significantly greater in the PD responders versus the non-PD responders (p = 0.0041 and 0.0073, respectively). The serum Dkk-1 at baseline was significantly lower in the PD responders (n = 30) vs. the non-PD responders (n = 29) (p = 0.026). A multivariate logistic regression analysis showed that the serum Dkk-1 at baseline (odds ratio 0.50, 95% confidence interval [CI] 0.23-0.91, p = 0.043) was an independent predictor of PD responder status. CONCLUSION Serum levels of bone biomarkers may be useful for predicting RA patients' therapeutic responses to abatacept. TRIAL REGISTRATION Name of the registry: Assessment of therapeutic responsiveness by imaging of the joints in patients with rheumatoid arthritis; A observational cohort study Trial registration number: UMIN000012524 Date of registration: 12/9/2013 URL of trial registry record: https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000014657.
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Affiliation(s)
- Shin-Ya Kawashiri
- Departments of Community Medicine, Nagasaki University Graduate School of Medical Sciences, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan. .,Departments of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Medical Sciences, Nagasaki, Japan. .,Kyushu Multicenter Rheumatoid Arthritis Ultrasound Prospective Observational Cohort Study (KUDOS) Group, Kyushu, Japan.
| | - Yushiro Endo
- Departments of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Medical Sciences, Nagasaki, Japan.,Kyushu Multicenter Rheumatoid Arthritis Ultrasound Prospective Observational Cohort Study (KUDOS) Group, Kyushu, Japan
| | - Ayako Nishino
- Departments of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Medical Sciences, Nagasaki, Japan.,Kyushu Multicenter Rheumatoid Arthritis Ultrasound Prospective Observational Cohort Study (KUDOS) Group, Kyushu, Japan
| | - Momoko Okamoto
- Departments of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Medical Sciences, Nagasaki, Japan
| | - Sosuke Tsuji
- Departments of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Medical Sciences, Nagasaki, Japan
| | - Ayuko Takatani
- Departments of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Medical Sciences, Nagasaki, Japan
| | - Toshimasa Shimizu
- Departments of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Medical Sciences, Nagasaki, Japan
| | - Remi Sumiyoshi
- Departments of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Medical Sciences, Nagasaki, Japan
| | - Tomohiro Koga
- Departments of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Medical Sciences, Nagasaki, Japan
| | - Naoki Iwamoto
- Departments of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Medical Sciences, Nagasaki, Japan
| | - Kunihiro Ichinose
- Departments of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Medical Sciences, Nagasaki, Japan
| | - Mami Tamai
- Departments of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Medical Sciences, Nagasaki, Japan
| | - Hideki Nakamura
- Departments of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Medical Sciences, Nagasaki, Japan
| | - Tomoki Origuchi
- Departments of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Medical Sciences, Nagasaki, Japan
| | - Toshiyuki Aramaki
- Kyushu Multicenter Rheumatoid Arthritis Ultrasound Prospective Observational Cohort Study (KUDOS) Group, Kyushu, Japan
| | - Yukitaka Ueki
- Kyushu Multicenter Rheumatoid Arthritis Ultrasound Prospective Observational Cohort Study (KUDOS) Group, Kyushu, Japan
| | - Tamami Yoshitama
- Kyushu Multicenter Rheumatoid Arthritis Ultrasound Prospective Observational Cohort Study (KUDOS) Group, Kyushu, Japan
| | - Nobutaka Eiraku
- Kyushu Multicenter Rheumatoid Arthritis Ultrasound Prospective Observational Cohort Study (KUDOS) Group, Kyushu, Japan
| | - Naoki Matsuoka
- Kyushu Multicenter Rheumatoid Arthritis Ultrasound Prospective Observational Cohort Study (KUDOS) Group, Kyushu, Japan
| | - Akitomo Okada
- Kyushu Multicenter Rheumatoid Arthritis Ultrasound Prospective Observational Cohort Study (KUDOS) Group, Kyushu, Japan
| | - Keita Fujikawa
- Kyushu Multicenter Rheumatoid Arthritis Ultrasound Prospective Observational Cohort Study (KUDOS) Group, Kyushu, Japan
| | - Hiroaki Hamada
- Kyushu Multicenter Rheumatoid Arthritis Ultrasound Prospective Observational Cohort Study (KUDOS) Group, Kyushu, Japan
| | - Shuji Nagano
- Kyushu Multicenter Rheumatoid Arthritis Ultrasound Prospective Observational Cohort Study (KUDOS) Group, Kyushu, Japan
| | - Yoshifumi Tada
- Kyushu Multicenter Rheumatoid Arthritis Ultrasound Prospective Observational Cohort Study (KUDOS) Group, Kyushu, Japan
| | - Atsushi Kawakami
- Departments of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Medical Sciences, Nagasaki, Japan.,Kyushu Multicenter Rheumatoid Arthritis Ultrasound Prospective Observational Cohort Study (KUDOS) Group, Kyushu, Japan
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