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Gems D. How aging causes osteoarthritis: An evolutionary physiology perspective. Osteoarthritis Cartilage 2025:S1063-4584(25)01024-6. [PMID: 40381687 DOI: 10.1016/j.joca.2025.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Revised: 04/29/2025] [Accepted: 05/05/2025] [Indexed: 05/20/2025]
Abstract
Late-life diseases result from the poorly understood process of senescence (aging), that is largely genetically determined. According to a recently proposed evolutionary physiology-based account, the multifactorial model, senescence is largely caused by evolved but non-adaptive programmatic mechanisms specified by the wild-type (i.e. normal) genome. These act together with disruptions to wild-type function (due e.g. to infectious pathogens, mechanical injury and malnutrition) in a variety of combinations to generate diverse late-life diseases. Here I explore the utility of this model by testing its capacity to provide an account of one complex, late-life disease, osteoarthritis (OA), and suggest a framework for understanding OA etiology. In this cartilage-focused framework, a core OA disease mechanism is a futile (non-adaptive) developmental program of endochondral ossification, in which hypertrophic articular cartilage chondrocytes alter joint architecture. Programmatic changes prime chondrocytes for futile program activation, which can be triggered by secondary causes of OA (e.g. joint mechanical injury). I suggest that an evolutionary cause of this priming, involving antagonistic pleiotropy, is selection to maximize early life tissue repair benefits at the expense of late-life programmatic costs.
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Affiliation(s)
- David Gems
- Institute of Healthy Ageing, and Department of Genetics, Evolution and Environment, University College London, Gower Street, London, UK.
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2
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Lynskey SJ, Ling Z, Ziemann M, Gill SD, McGee SL, Page RS. Loosening the Lid on Shoulder Osteoarthritis: How the Transcriptome and Metabolic Syndrome Correlate with End-Stage Disease. Int J Mol Sci 2025; 26:3145. [PMID: 40243895 PMCID: PMC11988960 DOI: 10.3390/ijms26073145] [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: 01/31/2025] [Revised: 03/22/2025] [Accepted: 03/23/2025] [Indexed: 04/18/2025] Open
Abstract
Metabolic syndrome (MetS) associated with Osteoarthritis (OA) is an increasingly recognised entity. Whilst the degenerative pattern in cuff-tear arthropathy (CTA) has been well documented, the biological processes behind primary shoulder OA and CTA remain less understood. This study investigates transcriptomic differences in these conditions, alongside the impact of MetS in patients undergoing total shoulder replacement. In a multi-centre study, 20 OA patients undergoing total shoulder replacement were included based on specific treatment indications for OA and cuff-tear arthropathy as well as 25 patients undergoing rotator cuff repair (RCR) as a comparator group. Tissues from subchondral bone, capsule (OA and RCR), and synovium were biopsied, and RNA sequencing was performed using Illumina platforms. Differential gene expression was conducted using DESeq2, adjusting for demographic factors, followed by pathway enrichment using the mitch package. Gene expressions in CTA and primary OA was differentially affected. CTA showed mitochondrial dysfunction, GATD3A downregulation, and increased cartilage degradation, while primary OA was marked by upregulated inflammatory and catabolic pathways. The effect of MetS on these pathologies was further shown. MetS further disrupted WNT/β-catenin signalling in CTA, and in OA. Genes such as ACAN, PANX3, CLU, and VAT1L were upregulated, highlighting potential biomarkers for early OA detection. This transcriptomic analysis reveals key differences between end-stage CTA and primary glenohumeral OA. CTA shows heightened metabolic/protein synthesis activity with less immune-driven inflammation. Under MetS, mitochondrial dysfunction (including GATD3A downregulation) and altered Wnt/β-catenin signalling intensify cartilage and bone damage. In contrast, primary OA features strong complement activation, inflammatory gene expression, and collagen remodelling. MetS worsens both conditions via oxidative stress, advanced glycation end products, and ECM disruption-particularly, increased CS/DS degradation. These distinctions support targeted treatments, from antioxidants and Wnt modulators to aggrecanase inhibitors or clusterin augmentation. Addressing specific molecular disruptions, especially those amplified by MetS, may preserve shoulder function, delay surgical intervention, and improve long-term patient outcomes.
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Affiliation(s)
- Samuel J. Lynskey
- Department of Orthopaedic Surgery, Geelong University Hospital, Geelong, VIC 3220, Australia
- School of Medicine, Faculty of Health, Deakin University, Waurn Ponds, Geelong, VIC 3220, Australia
| | - Zihui Ling
- Peninsula Health, 2 Hastings Rd, Frankston, VIC 3199, Australia
| | - Mark Ziemann
- Burnet Institute, Melbourne, VIC 3004, Australia
- School of Life and Environmental Sciences, Deakin University, Waurn Ponds, Geelong, VIC 3216, Australia
| | - Stephen D. Gill
- Department of Orthopaedic Surgery, Geelong University Hospital, Geelong, VIC 3220, Australia
- Barwon Centre for Orthopaedic Research and Education (BCORE), St. John of God Hospital, Geelong, VIC 3220, Australia
- IMPACT—The Institute for Mental and Physical Health and Clinical Translation, Barwon Health, Deakin University, Geelong, VIC 3220, Australia
| | - Sean L. McGee
- School of Medicine, Faculty of Health, Deakin University, Waurn Ponds, Geelong, VIC 3220, Australia
| | - Richard S. Page
- Department of Orthopaedic Surgery, Geelong University Hospital, Geelong, VIC 3220, Australia
- Barwon Centre for Orthopaedic Research and Education (BCORE), St. John of God Hospital, Geelong, VIC 3220, Australia
- IMPACT—The Institute for Mental and Physical Health and Clinical Translation, Barwon Health, Deakin University, Geelong, VIC 3220, Australia
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Famili-Youth EHH, Famili-Youth A, Yang D, Siddique A, Wu EY, Liu W, Resnick MB, Chen Q, Brodsky AS. Aberrant expression of collagen type X in solid tumor stroma is associated with EMT, immunosuppressive and pro-metastatic pathways, bone marrow stromal cell signatures, and poor survival prognosis. BMC Cancer 2025; 25:247. [PMID: 39939916 PMCID: PMC11823173 DOI: 10.1186/s12885-025-13641-y] [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: 05/17/2024] [Accepted: 02/04/2025] [Indexed: 02/14/2025] Open
Abstract
BACKGROUND Collagen type X (ColXα1, encoded by COL10A1) is expressed specifically in the cartilage-to-bone transition, in bone marrow cells, and in osteoarthritic (OA) cartilage. We have previously shown that ColXα1 is expressed in breast tumor stroma, correlates with tumor-infiltrating lymphocytes, and predicts poor adjuvant therapy outcomes in ER+/HER2+ breast cancer. However, the underlying molecular mechanisms for these effects are unknown. In this study, we performed bioinformatic analysis of COL10A1-associated gene modules in breast and pancreatic cancer as well as in cells from bone marrow and OA cartilage. These findings provide important insights into the mechanisms of transcriptional and extracellular matrix changes which impact the local stromal microenvironment and tumor progression. METHODS Immunohistochemistry was performed to examine collagen type X expression in solid tumors. WGCNA was used to generate COL10A1-associated gene networks in breast and pancreatic tumor cohorts using RNA-Seq data from The Cancer Genome Atlas. Computational analysis was employed to assess the impact of these gene networks on development and progression of cancer and OA. Data processing and statistical analysis was performed using R and various publicly-available computational tools. RESULTS Expression of COL10A1 and its associated gene networks highlights inflammatory and immunosuppressive microenvironments, which identify aggressive breast and pancreatic tumors and contribute to metastatic potential in a sex-dependent manner. Both cancer types are enriched in stroma, and COL10A1 implicates bone marrow-derived fibroblasts as contributors to the epithelial-to-mesenchymal transition (EMT) in these tumors. Heightened expression of COL10A1 and its associated gene networks is correlated with poorer patient outcomes in both breast and pancreatic cancer. Common transcriptional changes and chondrogenic activity are shared between cancer and OA cartilage, suggesting that similar microenvironmental alterations may underlie both diseases. CONCLUSIONS COL10A1-associated gene networks may hold substantial value as regulators and biomarkers of aggressive tumor phenotypes with implications for therapy development and clinical outcomes. Identification of tumors which exhibit high expression of COL10A1 and its associated genes may reveal the presence of bone marrow-derived stromal microenvironments with heightened EMT capacity and metastatic potential. Our analysis may enable more effective risk assessment and more precise treatment of patients with breast and pancreatic cancer.
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Affiliation(s)
- Elliot H H Famili-Youth
- Medical Scientist Training Program, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
- Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Warren Alpert Medical School of Brown University, Providence, RI, USA.
| | - Aryana Famili-Youth
- Medical Scientist Training Program, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
- Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Warren Alpert Medical School of Brown University, Providence, RI, USA.
| | - Dongfang Yang
- Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Ayesha Siddique
- Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Elizabeth Y Wu
- Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Wenguang Liu
- Department of Orthopedics, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, RI, USA
- Present address: School of Food Science and Engineering, Shaanxi University of Science and Technology, Xi'an, 710021, Shaanxi, China
| | - Murray B Resnick
- Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Qian Chen
- Department of Orthopedics, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, RI, USA.
| | - Alexander S Brodsky
- Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Warren Alpert Medical School of Brown University, Providence, RI, USA
- Center for Computational Molecular Biology, Brown University, Providence, RI, USA
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Jin Y, Hu C, Xia J, Xie D, Ye L, Ye X, Jiang L, Song H, Zhu Y, Jiang S, Li W, Qi W, Yang Y, Hu Z. Bimetallic clusterzymes-loaded dendritic mesoporous silica particle regulate arthritis microenvironment via ROS scavenging and YAP1 stabilization. Bioact Mater 2024; 42:613-627. [PMID: 39314862 PMCID: PMC11417149 DOI: 10.1016/j.bioactmat.2024.09.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 08/28/2024] [Accepted: 09/02/2024] [Indexed: 09/25/2024] Open
Abstract
Clusterzymes are synthetic enzymes exhibiting substantial catalytic activity and selectivity, which are uniquely driven by single-atom constructs. A dramatic increase in antioxidant capacity, 158 times more than natural trolox, is noted when single-atom copper is incorporated into gold-based clusterzymes to form Au24Cu1. Considering the inflammatory and mildly acidic microenvironment characteristic of osteoarthritis (OA), pH-dependent dendritic mesoporous silica nanoparticles (DMSNs) coupled with PEG have been employed as a delivery system for the spatial-temporal release of clusterzymes within active articular regions, thereby enhancing the duration of effectiveness. Nonetheless, achieving high therapeutic efficacy remains a significant challenge. Herein, we describe the construction of a Clusterzymes-DMSNs-PEG complex (CDP) which remarkably diminishes reactive oxygen species (ROS) and stabilizes the chondroprotective protein YAP by inhibiting the Hippo pathway. In the rabbit ACLT (anterior cruciate ligament transection) model, the CDP complex demonstrated inhibition of matrix metalloproteinase activity, preservation of type II collagen and aggregation protein secretion, thus prolonging the clusterzymes' protective influence on joint cartilage structure. Our research underscores the efficacy of the CDP complex in ROS-scavenging, enabled by the release of clusterzymes in response to an inflammatory and slightly acidic environment, leading to the obstruction of the Hippo pathway and downstream NF-κB signaling pathway. This study illuminates the design, composition, and use of DMSNs and clusterzymes in biomedicine, thus charting a promising course for the development of novel therapeutic strategies in alleviating OA.
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Affiliation(s)
- Yang Jin
- Department of Orthopaedic Surgery, Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Sir Run Run Shaw Hospital, Medical College of Zhejiang University, Hangzhou, 310016, China
| | - Chuan Hu
- Department of Orthopaedic Surgery, Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Sir Run Run Shaw Hospital, Medical College of Zhejiang University, Hangzhou, 310016, China
| | - Jiechao Xia
- Department of Orthopaedic Surgery, Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Sir Run Run Shaw Hospital, Medical College of Zhejiang University, Hangzhou, 310016, China
| | - Dingqi Xie
- Department of Orthopaedic Surgery, Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Sir Run Run Shaw Hospital, Medical College of Zhejiang University, Hangzhou, 310016, China
| | - Lin Ye
- Department of Orthopaedic Surgery, Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Sir Run Run Shaw Hospital, Medical College of Zhejiang University, Hangzhou, 310016, China
| | - Xinyi Ye
- Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China
| | - Li Jiang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou, China
| | - Honghai Song
- Department of Orthopaedic Surgery, Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Sir Run Run Shaw Hospital, Medical College of Zhejiang University, Hangzhou, 310016, China
| | - Yutao Zhu
- Department of Orthopaedic Surgery, Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Sir Run Run Shaw Hospital, Medical College of Zhejiang University, Hangzhou, 310016, China
| | - Sicheng Jiang
- Department of Orthopaedic Surgery, Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Sir Run Run Shaw Hospital, Medical College of Zhejiang University, Hangzhou, 310016, China
| | - Weiqing Li
- Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China
| | - Weiming Qi
- Zhejiang Center for Medical Device Evaluation, Zhejiang Medical Products Administration Hangzhou 310009, Zhejiang, China
| | - Yannan Yang
- Institute of Optoelectronics, Fudan University, Shanghai, 200433, China
- South Australian ImmunoGENomics Cancer Institute, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, South Australia, 5005, Australia
| | - Zhijun Hu
- Department of Orthopaedic Surgery, Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Sir Run Run Shaw Hospital, Medical College of Zhejiang University, Hangzhou, 310016, China
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Famili-Youth EHH, Famili-Youth A, Yang D, Siddique A, Wu EY, Liu W, Resnick MB, Chen Q, Brodsky AS. Aberrant expression of collagen type X in solid tumor stroma is associated with EMT, immunosuppressive and pro-metastatic pathways, bone marrow stromal cell signatures, and poor survival prognosis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.11.13.621984. [PMID: 39605631 PMCID: PMC11601388 DOI: 10.1101/2024.11.13.621984] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/29/2024]
Abstract
Background Collagen type X (ColXα1, encoded by COL10A1) is expressed specifically in the cartilage-to-bone transition, in bone marrow cells, and in osteoarthritic (OA) cartilage. We have previously shown that ColXα1 is expressed in breast tumor stroma, correlates with tumor-infiltrating lymphocytes, and predicts poor adjuvant therapy outcomes in ER+/HER2+ breast cancer. However, the underlying molecular mechanisms for these effects are unknown. In this study, we performed bioinformatic analysis of COL10A1-associated gene modules in breast and pancreatic cancer as well as in cells from bone marrow and OA cartilage. These findings provide important insights into the mechanisms of transcriptional and extracellular matrix changes which impact the local stromal microenvironment and tumor progression. Methods Immunohistochemistry was performed to examine collagen type X expression in solid tumors. WGCNA was used to generate COL10A1-associated gene networks in breast and pancreatic tumor cohorts using RNA-Seq data from The Cancer Genome Atlas. Computational analysis was employed to assess the impact of these gene networks on development and progression of cancer and OA. Data processing and statistical analysis was performed using R and various publicly-available computational tools. Results Expression of COL10A1 and its associated gene networks highlights inflammatory and immunosuppressive microenvironments, which identify aggressive breast and pancreatic tumors and contribute to metastatic potential in a sex-dependent manner. Both cancer types are enriched in stroma, and COL10A1 implicates bone marrow-derived fibroblasts as drivers of the epithelial-to-mesenchymal transition (EMT) in these tumors. Heightened expression of COL10A1 and its associated gene networks is correlated with poorer patient outcomes in both breast and pancreatic cancer. Common transcriptional changes and chondrogenic activity are shared between cancer and OA cartilage, suggesting that similar microenvironmental alterations may underlie both diseases. Conclusions COL10A1-associated gene networks may hold substantial value as regulators and biomarkers of aggressive tumor phenotypes with implications for therapy development and clinical outcomes. Identification of tumors which exhibit high expression of COL10A1 and its associated genes may reveal the presence of bone marrow-derived stromal microenvironments with heightened EMT capacity and metastatic potential. Our analysis may enable more effective risk assessment and more precise treatment of patients with breast and pancreatic cancer.
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Affiliation(s)
- Elliot H H Famili-Youth
- Medical Scientist Training Program, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
- Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Aryana Famili-Youth
- Medical Scientist Training Program, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
- Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Dongfang Yang
- Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Ayesha Siddique
- Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Elizabeth Y Wu
- Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Wenguang Liu
- Department of Orthopedics, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Murray B Resnick
- Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Qian Chen
- Department of Orthopedics, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Alexander S Brodsky
- Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Warren Alpert Medical School of Brown University, Providence, RI, USA
- Center for Computational Molecular Biology, Brown University, Providence, RI, USA
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Pemmari A, Moilanen E. Macrophage and chondrocyte phenotypes in inflammation. Basic Clin Pharmacol Toxicol 2024; 135:537-549. [PMID: 39319534 DOI: 10.1111/bcpt.14085] [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: 05/12/2024] [Revised: 09/05/2024] [Accepted: 09/12/2024] [Indexed: 09/26/2024]
Abstract
Inflammation is a complex biological process protecting the body from diverse external threats. Effectively performing this task requires an intricate, well-regulated interplay of different cells and tissues. Furthermore, several cells participating in inflammation can assume diverse phenotypes. A classic and relatively well-studied example of phenotypic diversity in inflammation is macrophage polarization. Based on the TH1/TH2 phenotypes of T helper cells, this scheme has proinflammatory "classical/M1" activation contrasted with the anti-inflammatory and healing-promoting "alternative/M2" phenotype. Some authors have extended the concept into an M17 phenotype induced by the classic TH17 cytokine IL-17. Phenotypic changes in chondrocytes have also been studied especially in the context of osteoarthritis (OA), and there are indications that these cells can also assume polarized phenotypes at least partly analogous to those of TH cells and macrophages. The therapeutic success of biological agents targeting TH1/TH2/TH17 inductor and/or effector cytokines displays the utility of the concept of polarization. The aim of this focused review is to survey the internal and external factors affecting macrophage and chondrocyte phenotypes (such as inflammatory cytokines, widely used medications and natural products) and to explore the possibility of ameliorating pathological states by modulating these phenotypes.
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Affiliation(s)
- Antti Pemmari
- The Immunopharmacology Research Group, Faculty of Medicine and Health Technology, Tampere University and Tampere University Hospital, Tampere, Finland
| | - Eeva Moilanen
- The Immunopharmacology Research Group, Faculty of Medicine and Health Technology, Tampere University and Tampere University Hospital, Tampere, Finland
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Liu Z, Xie W, Li H, Liu X, Lu Y, Lu B, Deng Z, Li Y. Novel perspectives on leptin in osteoarthritis: Focus on aging. Genes Dis 2024; 11:101159. [PMID: 39229323 PMCID: PMC11369483 DOI: 10.1016/j.gendis.2023.101159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Revised: 09/10/2023] [Accepted: 09/16/2023] [Indexed: 09/05/2024] Open
Abstract
Osteoarthritis (OA) is a common chronic joint disease characterized by articular cartilage degeneration, subchondral sclerosis, synovitis, and osteophyte formation. OA is associated with disability and impaired quality of life, particularly among the elderly. Leptin, a 16-kD non-glycosylated protein encoded by the obese gene, is produced on a systemic and local basis in adipose tissue and the infrapatellar fat pad located in the knee. The metabolic mechanisms employed by leptin in OA development have been widely studied, with attention being paid to aging as a corroborative risk factor for OA. Hence, in this review, we have attempted to establish a potential link between leptin and OA, by focusing on aging-associated mechanisms and proposing leptin as a potential diagnostic and therapeutic target in aging-related mechanisms of OA that may provide fruitful guidance and emphasis for future research.
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Affiliation(s)
- Zimo Liu
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
- Xiangya School of Medicine, Central South University, Changsha, Hunan 410083, China
| | - Wenqing Xie
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Hengzhen Li
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Xu Liu
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Yao Lu
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
- Xiangya School of Medicine, Central South University, Changsha, Hunan 410083, China
| | - Bangbao Lu
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Zhenhan Deng
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Yusheng Li
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
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Zhang Y, Zhao X, Shan L, Liu M, Zhang Z, Wang Z, Zhang X, Meng H, Song Y, Zhang W, Sang Z. Chronic Iodine Intake Excess Damages the Structure of Articular Cartilage and Epiphyseal Growth Plate. Biol Trace Elem Res 2024; 202:4078-4086. [PMID: 38060174 DOI: 10.1007/s12011-023-03985-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Accepted: 11/27/2023] [Indexed: 12/08/2023]
Abstract
This study aimed to explore the influence of excess iodine on the articular cartilage and epiphyseal growth plate in rats. Wistar rats (n = 200) were randomly divided into five groups with 40 rats in each: normal iodine (NI), 5-fold high iodine group (5HI), 10-fold high iodine group (10HI), 50-fold high iodine group (50HI), and 100-fold high iodine group (100HI). The rats were executed in 6 and 12 months. 24-h urinary iodine concentration (UIC) was monitored by arsenic-cerium catalytic spectrophotometry. The chemiluminescence method was used to determine the thyroid function. The pathological changes in the epiphyseal plate, articular cartilage, and thickness of the epiphyseal plate were observed. The mRNA expression of collagen II (ColII), collagen X, matrix metalloproteinase-13 (MMP-13), and fibroblast growth factor receptor 1 in articular chondrocytes was detected by RT-PCR. 24-h UIC increased as iodine intake increased. In the 12th month, there was a significant increase in serum sTSH and a decrease in serum FT4 in HI groups, compared to the NI group. There was a decrease in the number of proliferating cells in the epiphyseal plate and an increase in the number of mast cell layers. The chondrocytes appeared disorganized, and the tidal lines were disturbed or even broken. Growth plate thickness decreased with increasing iodine intake. Compared with the NI group, ColII and MMP-13 mRNA expression in chondrocytes in all HI groups significantly increased. Chronic iodine overdose increases the risk of hypothyroidism. Chronic iodine overdose leads to abnormal morphology of epiphyseal growth plates and articular cartilage, increasing the risk of osteoarthritis.
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Affiliation(s)
- Ying Zhang
- Department of Nutrition and Food Hygiene, School of Public Health, Tianjin Key Laboratory of Environmental Nutrition and Population Health, Key Laboratory of Prevention and Control of Major Diseases in the Population, Ministry of Education, Tianjin Medical University, No. 22 Qixiangtai Road, Heping District, Tianjin, 300070, China
| | - Xin Zhao
- Department of Hand Microsurgery, Tianjin Hospital, Tianjin, China
| | - Le Shan
- Department of Nutrition and Food Hygiene, School of Public Health, Tianjin Key Laboratory of Environmental Nutrition and Population Health, Key Laboratory of Prevention and Control of Major Diseases in the Population, Ministry of Education, Tianjin Medical University, No. 22 Qixiangtai Road, Heping District, Tianjin, 300070, China
| | - Miao Liu
- Department of Comprehensive Office, Tianjin Medical University Chu Hsien-I Memorial Hospital, Tianjin, China
| | - Zixuan Zhang
- Department of Preventive Medicine, School of Public Health, Jilin University, Changchun City, China
| | - Zeji Wang
- Department of Medical Technology, Clinical Medical College of Tianjin Medical University, Tianjin, China
| | - Xinbao Zhang
- Department of Nutrition and Food Hygiene, School of Public Health, Tianjin Key Laboratory of Environmental Nutrition and Population Health, Key Laboratory of Prevention and Control of Major Diseases in the Population, Ministry of Education, Tianjin Medical University, No. 22 Qixiangtai Road, Heping District, Tianjin, 300070, China
| | - Haohao Meng
- Department of Nutrition and Food Hygiene, School of Public Health, Tianjin Key Laboratory of Environmental Nutrition and Population Health, Key Laboratory of Prevention and Control of Major Diseases in the Population, Ministry of Education, Tianjin Medical University, No. 22 Qixiangtai Road, Heping District, Tianjin, 300070, China
| | - Yan Song
- Department of Nutrition and Food Hygiene, School of Public Health, Tianjin Key Laboratory of Environmental Nutrition and Population Health, Key Laboratory of Prevention and Control of Major Diseases in the Population, Ministry of Education, Tianjin Medical University, No. 22 Qixiangtai Road, Heping District, Tianjin, 300070, China
| | - Wanqi Zhang
- Department of Nutrition and Food Hygiene, School of Public Health, Tianjin Key Laboratory of Environmental Nutrition and Population Health, Key Laboratory of Prevention and Control of Major Diseases in the Population, Ministry of Education, Tianjin Medical University, No. 22 Qixiangtai Road, Heping District, Tianjin, 300070, China
| | - Zhongna Sang
- Department of Nutrition and Food Hygiene, School of Public Health, Tianjin Key Laboratory of Environmental Nutrition and Population Health, Key Laboratory of Prevention and Control of Major Diseases in the Population, Ministry of Education, Tianjin Medical University, No. 22 Qixiangtai Road, Heping District, Tianjin, 300070, China.
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Huang J, Ren Q, Jiao L, Niu S, Liu C, Zhou J, Wu L, Yang Y. TMF suppresses chondrocyte hypertrophy in osteoarthritic cartilage by mediating the FOXO3a/BMPER pathway. Exp Ther Med 2024; 28:283. [PMID: 38800044 PMCID: PMC11117099 DOI: 10.3892/etm.2024.12571] [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: 11/21/2023] [Accepted: 04/26/2024] [Indexed: 05/29/2024] Open
Abstract
Osteoarthritis (OA) is a disease of the joints, characterized by chronic inflammation, cartilage destruction and extracellular matrix (ECM) remodeling. Aberrant chondrocyte hypertrophy promotes cartilage destruction and OA development. Collagen X, the biomarker of chondrocyte hypertrophy, is upregulated by runt-related transcription factor 2 (Runx2), which is mediated by the bone morphogenetic protein 4 (BMP4)/Smad1 signaling pathway. BMP binding endothelial regulator (BMPER), a secreted glycoprotein, acts as an agonist of BMP4. 5,7,3',4'-tetramethoxyflavone (TMF) is a natural flavonoid derived from Murraya exotica L. Results of our previous study demonstrated that TMF exhibits chondroprotective effects against OA development through the activation of Forkhead box protein O3a (FOXO3a) expression. However, whether TMF suppresses chondrocyte hypertrophy through activation of FOXO3a expression and inhibition of BMPER/BMP4/Smad1 signaling remains unknown. Results of the present study revealed that TMF inhibited collagen X and Runx2 expression, inhibited BMPER/BMP4/Smad1 signaling, and activated FOXO3a expression; thus, protecting against chondrocyte hypertrophy and OA development. However, BMPER overexpression and FOXO3a knockdown impacted the protective effects of TMF. Thus, TMF inhibited chondrocyte hypertrophy in OA cartilage through mediating the FOXO3a/BMPER signaling pathway.
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Affiliation(s)
- Jishang Huang
- Department of Orthopedics, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China
| | - Qun Ren
- College of Pharmacy, Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China
| | - Linhui Jiao
- College of Pharmacy, Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China
| | - Shuo Niu
- Department of Orthopedics, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China
| | - Chenghong Liu
- Department of Orthopedics, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China
| | - Juan Zhou
- School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China
| | - Longhuo Wu
- College of Pharmacy, Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China
| | - Yadong Yang
- Department of Orthopedics, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China
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10
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Kennedy O, Kitson A, Okpara C, Chow LW, Gonzalez-Fernandez T. Immunomodulatory Strategies for Cartilage Regeneration in Osteoarthritis. Tissue Eng Part A 2024; 30:259-271. [PMID: 38126327 DOI: 10.1089/ten.tea.2023.0255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2023] Open
Abstract
Osteoarthritis (OA) is the most prevalent musculoskeletal disorder and a leading cause of disability globally. Although many efforts have been made to treat this condition, current tissue engineering (TE) and regenerative medicine strategies fail to address the inflammatory tissue environment that leads to the rapid progression of the disease and prevents cartilage tissue formation. First, this review addresses in detail the current anti-inflammatory therapies for OA with a special emphasis on pharmacological approaches, gene therapy, and mesenchymal stromal cell (MSC) intra-articular administration, and discusses the reasons behind the limited clinical success of these approaches at enabling cartilage regeneration. Then, we analyze the state-of-the-art TE strategies and how they can be improved by incorporating immunomodulatory capabilities such as the optimization of biomaterial composition, porosity and geometry, and the loading of anti-inflammatory molecules within an engineered structure. Finally, the review discusses the future directions for the new generation of TE strategies for OA treatment, specifically focusing on the spatiotemporal modulation of anti-inflammatory agent presentation to allow for tailored patient-specific therapies. Impact statement Osteoarthritis (OA) is a prevalent and debilitating musculoskeletal disorder affecting millions worldwide. Despite significant advancements in regenerative medicine and tissue engineering (TE), mitigating inflammation while simultaneously promoting cartilage tissue regeneration in OA remains elusive. In this review article, we discuss current anti-inflammatory therapies and explore their potential synergy with cutting-edge cartilage TE strategies, with a special focus on novel spatiotemporal and patient-specific anti-inflammatory strategies.
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Affiliation(s)
- Orlaith Kennedy
- Department of Bioengineering, Lehigh University, Bethlehem, Pennsylvania, USA
- Department of Biomedical Engineering, College of Science and Engineering, University of Galway, Galway, Ireland
| | - Andrew Kitson
- Department of Materials Science and Engineering, Lehigh University, Bethlehem, Pennsylvania, USA
| | - Chiebuka Okpara
- Department of Bioengineering, Lehigh University, Bethlehem, Pennsylvania, USA
| | - Lesley W Chow
- Department of Bioengineering, Lehigh University, Bethlehem, Pennsylvania, USA
- Department of Materials Science and Engineering, Lehigh University, Bethlehem, Pennsylvania, USA
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11
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Yang S, Xie J, Pan Z, Guan H, Tu Y, Ye Y, Huang S, Fu S, Li K, Huang Z, Li X, Shi Z, Li L, Zhang Y. Advanced glycation end products promote meniscal calcification by activating the mTOR-ATF4 positive feedback loop. Exp Mol Med 2024; 56:630-645. [PMID: 38424194 PMCID: PMC10985079 DOI: 10.1038/s12276-024-01190-6] [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: 06/02/2023] [Revised: 10/25/2023] [Accepted: 12/19/2023] [Indexed: 03/02/2024] Open
Abstract
The meniscus is vital for maintaining knee homeostasis and function. Meniscal calcification is one of the earliest radiological indicators of knee osteoarthritis (KOA), and meniscal calcification is associated with alterations in biomechanical properties. Meniscal calcification originates from a biochemical process similar to vascular calcification. Advanced glycation end products (AGEs) and their receptors (RAGEs) reportedly play critical roles in vascular calcification. Herein, we investigated whether targeting AGE-RAGE is a potential treatment for meniscal calcification. In our study, we demonstrated that AGE-RAGE promotes the osteogenesis of meniscal cells and exacerbates meniscal calcification. Mechanistically, AGE-RAGE activates mTOR and simultaneously promotes ATF4 accumulation, thereby facilitating the ATF4-mTOR positive feedback loop that enhances the osteogenic capacity of meniscal cells. In this regard, mTOR inhibits ATF4 degradation by reducing its ubiquitination, while ATF4 activates mTOR by increasing arginine uptake. Our findings substantiate the unique role of AGE-RAGE in the meniscus and reveal the role of the ATF4-mTOR positive feedback loop during the osteogenesis of meniscal cells; these results provide potential therapeutic targets for KOA.
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Affiliation(s)
- Sheng Yang
- Division of Orthopaedic Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Department of Orthopedics, 920 Hospital of the Joint Logistic Support Force, Kunming, Yunnan, China
| | - JiaJun Xie
- Division of Orthopaedic Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - ZhiJie Pan
- Division of Orthopaedic Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Department of Orthopaedics, The First People's Hospital of Zhaoqing, Zhaoqing, Guangdong, China
| | - HongMei Guan
- Department of Obstetrics and Gynecology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - YueSheng Tu
- Division of Orthopaedic Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - YuanJian Ye
- Department of Orthopaedics, Huizhou First Hospital, Guangdong Medical University, Huizhou, Guangdong, China
| | - ShouBin Huang
- Department of Orthopaedics, Huizhou First Hospital, Guangdong Medical University, Huizhou, Guangdong, China
| | - ShiQiang Fu
- Huizhou First Maternal and Child Health Care Hospital, Huizhou, Guangdong, China
| | - KangXian Li
- Division of Orthopaedic Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - ZhiWei Huang
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - XiaoQi Li
- School of Public Health, Southern Medical University, Guangzhou, Guangdong, China
| | - ZhanJun Shi
- Division of Orthopaedic Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Le Li
- Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
| | - Yang Zhang
- Division of Orthopaedic Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
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12
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Kurz B, Lange T, Voelker M, Hart ML, Rolauffs B. Articular Cartilage-From Basic Science Structural Imaging to Non-Invasive Clinical Quantitative Molecular Functional Information for AI Classification and Prediction. Int J Mol Sci 2023; 24:14974. [PMID: 37834422 PMCID: PMC10573252 DOI: 10.3390/ijms241914974] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 09/25/2023] [Accepted: 09/27/2023] [Indexed: 10/15/2023] Open
Abstract
This review presents the changes that the imaging of articular cartilage has undergone throughout the last decades. It highlights that the expectation is no longer to image the structure and associated functions of articular cartilage but, instead, to devise methods for generating non-invasive, function-depicting images with quantitative information that is useful for detecting the early, pre-clinical stage of diseases such as primary or post-traumatic osteoarthritis (OA/PTOA). In this context, this review summarizes (a) the structure and function of articular cartilage as a molecular imaging target, (b) quantitative MRI for non-invasive assessment of articular cartilage composition, microstructure, and function with the current state of medical diagnostic imaging, (c), non-destructive imaging methods, (c) non-destructive quantitative articular cartilage live-imaging methods, (d) artificial intelligence (AI) classification of degeneration and prediction of OA progression, and (e) our contribution to this field, which is an AI-supported, non-destructive quantitative optical biopsy for early disease detection that operates on a digital tissue architectural fingerprint. Collectively, this review shows that articular cartilage imaging has undergone profound changes in the purpose and expectations for which cartilage imaging is used; the image is becoming an AI-usable biomarker with non-invasive quantitative functional information. This may aid in the development of translational diagnostic applications and preventive or early therapeutic interventions that are yet beyond our reach.
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Affiliation(s)
- Bodo Kurz
- Department of Anatomy, Christian-Albrechts-University, Otto-Hahn-Platz 8, 24118 Kiel, Germany
| | - Thomas Lange
- Medical Physics Department of Radiology, Faculty of Medicine, Medical Center—Albert-Ludwigs-University of Freiburg, 79085 Freiburg im Breisgau, Germany;
| | - Marita Voelker
- G.E.R.N. Research Center for Tissue Replacement, Regeneration & Neogenesis, Department of Orthopedics and Trauma Surgery, Faculty of Medicine, Medical Center—Albert-Ludwigs-University of Freiburg, 79085 Freiburg im Breisgau, Germany; (M.V.); (M.L.H.)
| | - Melanie L. Hart
- G.E.R.N. Research Center for Tissue Replacement, Regeneration & Neogenesis, Department of Orthopedics and Trauma Surgery, Faculty of Medicine, Medical Center—Albert-Ludwigs-University of Freiburg, 79085 Freiburg im Breisgau, Germany; (M.V.); (M.L.H.)
| | - Bernd Rolauffs
- G.E.R.N. Research Center for Tissue Replacement, Regeneration & Neogenesis, Department of Orthopedics and Trauma Surgery, Faculty of Medicine, Medical Center—Albert-Ludwigs-University of Freiburg, 79085 Freiburg im Breisgau, Germany; (M.V.); (M.L.H.)
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13
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Poudel SB, Ruff RR, Yildirim G, Dixit M, Michot B, Gibbs JL, Ortiz SD, Kopchick JJ, Kirsch T, Yakar S. Excess Growth Hormone Triggers Inflammation-Associated Arthropathy, Subchondral Bone Loss, and Arthralgia. THE AMERICAN JOURNAL OF PATHOLOGY 2023; 193:829-842. [PMID: 36870529 PMCID: PMC10284029 DOI: 10.1016/j.ajpath.2023.02.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 01/29/2023] [Accepted: 02/10/2023] [Indexed: 03/06/2023]
Abstract
Growth hormone (GH) is a key mediator of skeletal growth. In humans, excess GH secretion due to pituitary adenoma, seen in patients with acromegaly, results in severe arthropathies. This study investigated the effects of long-term excess GH on the knee joint tissues. One year-old wild-type (WT) and bovine GH (bGH) transgenic mice were used as a model for excess GH. bGH mice showed increased sensitivity to mechanical and thermal stimuli, compared with WT mice. Micro-computed tomography analyses of the distal femur subchondral bone revealed significant reductions in trabecular thickness and significantly reduced bone mineral density of the tibial subchondral bone-plate associated with increased osteoclast activity in both male and female bGH compared with WT mice. bGH mice showed severe loss of matrix from the articular cartilage, osteophytosis, synovitis, and ectopic chondrogenesis. Articular cartilage loss in the bGH mice was associated with elevated markers of inflammation and chondrocyte hypertrophy. Finally, hyperplasia of synovial cells was associated with increased expression of Ki-67 and diminished p53 levels in the synovium of bGH mice. Unlike the low-grade inflammation seen in primary osteoarthritis, arthropathy caused by excess GH affects all joint tissues and triggers severe inflammatory response. Data from this study suggest that treatment of acromegalic arthropathy should involve inhibition of ectopic chondrogenesis and chondrocyte hypertrophy.
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Affiliation(s)
- Sher B Poudel
- Department of Molecular Pathobiology, David B. Kriser Dental Center, New York University College of Dentistry, New York, New York
| | - Ryan R Ruff
- Department of Epidemiology and Health Promotion, David B. Kriser Dental Center, New York University College of Dentistry, New York, New York
| | - Gozde Yildirim
- Department of Molecular Pathobiology, David B. Kriser Dental Center, New York University College of Dentistry, New York, New York
| | - Manisha Dixit
- Department of Molecular Pathobiology, David B. Kriser Dental Center, New York University College of Dentistry, New York, New York
| | - Benoit Michot
- Department of Restorative Dentistry and Biomaterials Sciences, Harvard School of Dental Medicine, Boston, Massachusetts
| | - Jennifer L Gibbs
- Department of Restorative Dentistry and Biomaterials Sciences, Harvard School of Dental Medicine, Boston, Massachusetts
| | - Silvana D Ortiz
- Department of Biomedical Sciences, Edison Biotechnology Institute, Ohio University, Athens, Ohio
| | - John J Kopchick
- Department of Biomedical Sciences, Edison Biotechnology Institute, Ohio University, Athens, Ohio
| | - Thorsten Kirsch
- Department of Orthopaedic Surgery, New York University Grossman School of Medicine, New York, New York; Department of Biomedical Engineering, New York University Tandon School of Engineering, New York, New York
| | - Shoshana Yakar
- Department of Molecular Pathobiology, David B. Kriser Dental Center, New York University College of Dentistry, New York, New York.
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14
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Posa F, Zerlotin R, Ariano A, Cosola MD, Colaianni G, Fazio AD, Colucci S, Grano M, Mori G. Irisin Role in Chondrocyte 3D Culture Differentiation and Its Possible Applications. Pharmaceutics 2023; 15:pharmaceutics15020585. [PMID: 36839906 PMCID: PMC9961836 DOI: 10.3390/pharmaceutics15020585] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 02/02/2023] [Accepted: 02/06/2023] [Indexed: 02/12/2023] Open
Abstract
Irisin is a recently discovered cytokine, better known as an exercise-induced myokine, produced primarily in skeletal muscle tissue as a response to exercise. Although the skeleton was initially identified as the main target of Irisin, its action is also proving effective in many other tissues. Physical activity determines a series of beneficial effects on health, including the possibility of counteracting the damage that is caused by arthritis to the cartilage of people suffering from osteoarthritis. Nevertheless, up to now, the studies that have taken into consideration the possible involvement of Irisin on the well-being of cartilage tissue are particularly limited. In this study, we postulated that the protective effect of physical activity on cartilage tissue may depend on the paracrine action of Irisin secreted during exercise; therefore, we analyzed the effects of Irisin, in vitro, on chondrogenic differentiation. To achieve this goal, three-dimensional cultures of commercially available human articular chondrocytes (HACs) were treated with the molecule under study. Our results revealed new crosstalk mechanisms between muscle and cartilage tissue. Furthermore, the confirmation of Irisin ability to induce chondrogenic differentiation could favor the development of exercise-mimetic drugs, with application relevance for patients who cannot perform physical activity.
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Affiliation(s)
- Francesca Posa
- Department of Clinical and Experimental Medicine, University of Foggia, Viale Pinto 1, 71122 Foggia, Italy
| | - Roberta Zerlotin
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari Aldo Moro, Piazza Giulio Cesare 11, 70124 Bari, Italy
| | - Anastasia Ariano
- Department of Clinical and Experimental Medicine, University of Foggia, Viale Pinto 1, 71122 Foggia, Italy
| | - Michele Di Cosola
- Department of Clinical and Experimental Medicine, University of Foggia, Viale Pinto 1, 71122 Foggia, Italy
| | - Graziana Colaianni
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari Aldo Moro, Piazza Giulio Cesare 11, 70124 Bari, Italy
| | - Aldo Di Fazio
- Regional Complex Intercompany Institute of Legal Medicine, San Carlo Hospital, 85100 Potenza, Italy
| | - Silvia Colucci
- Department of Translational Biomedicine and Neuroscience (DiBraiN), University of Bari Aldo Moro, Piazza Giulio Cesare 11, 70124 Bari, Italy
| | - Maria Grano
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari Aldo Moro, Piazza Giulio Cesare 11, 70124 Bari, Italy
| | - Giorgio Mori
- Department of Clinical and Experimental Medicine, University of Foggia, Viale Pinto 1, 71122 Foggia, Italy
- Correspondence:
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15
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Darwiche SE, Tegelkamp M, Nuss K, von Rechenberg B. Histological Preparation and Evaluation of Cartilage Specimens. Methods Mol Biol 2023; 2598:227-263. [PMID: 36355296 DOI: 10.1007/978-1-0716-2839-3_17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
In this chapter, an introduction is given into histological techniques to research related to hyaline cartilage and subchondral bone. Emphasis is placed on the importance to investigate cartilage and bone as a unit, which includes the transition zone of the calcified cartilage and tidemark. Reasons for the appropriate selection of histological methods are presented such as when to use (decalcified) specimens for routine paraffin embedding including immunohistology, cryosections of cartilage alone, or non-decalcified specimens for embedding in polymethylmethacrylate with or without additional biomaterials. Appropriate staining methods are also outlined. Apart from detailed laboratory protocols for different embedding and staining methods including open communication about difficulties related to the various techniques, also practical instructions for state-of-the-art evaluation methods and their strengths and weaknesses are given. Sample figures for scoring methods are included.
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Affiliation(s)
- Salim E Darwiche
- Musculoskeletal Research Unit (MSRU), Vetsuisse Faculty, University of Zürich, Zürich, Switzerland
- Center for Applied Biotechnology and Molecular Medicine (CABMM), Vetsuisse Faculty, University of Zürich, Zürich, Switzerland
| | - Milena Tegelkamp
- Musculoskeletal Research Unit (MSRU), Vetsuisse Faculty, University of Zürich, Zürich, Switzerland
| | - Katja Nuss
- Musculoskeletal Research Unit (MSRU), Vetsuisse Faculty, University of Zürich, Zürich, Switzerland
- Center for Applied Biotechnology and Molecular Medicine (CABMM), Vetsuisse Faculty, University of Zürich, Zürich, Switzerland
| | - Brigitte von Rechenberg
- Musculoskeletal Research Unit (MSRU), Vetsuisse Faculty, University of Zürich, Zürich, Switzerland.
- Center for Applied Biotechnology and Molecular Medicine (CABMM), Vetsuisse Faculty, University of Zürich, Zürich, Switzerland.
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16
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Chondrocyte Hypertrophy in Osteoarthritis: Mechanistic Studies and Models for the Identification of New Therapeutic Strategies. Cells 2022; 11:cells11244034. [PMID: 36552796 PMCID: PMC9777397 DOI: 10.3390/cells11244034] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Accepted: 12/08/2022] [Indexed: 12/16/2022] Open
Abstract
Articular cartilage shows limited self-healing ability owing to its low cellularity and avascularity. Untreated cartilage defects display an increased propensity to degenerate, leading to osteoarthritis (OA). During OA progression, articular chondrocytes are subjected to significant alterations in gene expression and phenotype, including a shift towards a hypertrophic-like state (with the expression of collagen type X, matrix metalloproteinases-13, and alkaline phosphatase) analogous to what eventuates during endochondral ossification. Present OA management strategies focus, however, exclusively on cartilage inflammation and degradation. A better understanding of the hypertrophic chondrocyte phenotype in OA might give new insights into its pathogenesis, suggesting potential disease-modifying therapeutic approaches. Recent developments in the field of cellular/molecular biology and tissue engineering proceeded in the direction of contrasting the onset of this hypertrophic phenotype, but knowledge gaps in the cause-effect of these processes are still present. In this review we will highlight the possible advantages and drawbacks of using this approach as a therapeutic strategy while focusing on the experimental models necessary for a better understanding of the phenomenon. Specifically, we will discuss in brief the cellular signaling pathways associated with the onset of a hypertrophic phenotype in chondrocytes during the progression of OA and will analyze in depth the advantages and disadvantages of various models that have been used to mimic it. Afterwards, we will present the strategies developed and proposed to impede chondrocyte hypertrophy and cartilage matrix mineralization/calcification. Finally, we will examine the future perspectives of OA therapeutic strategies.
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17
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Lesage R, Ferrao Blanco MN, Narcisi R, Welting T, van Osch GJVM, Geris L. An integrated in silico-in vitro approach for identifying therapeutic targets against osteoarthritis. BMC Biol 2022; 20:253. [PMID: 36352408 PMCID: PMC9648005 DOI: 10.1186/s12915-022-01451-8] [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: 01/28/2022] [Accepted: 10/27/2022] [Indexed: 11/11/2022] Open
Abstract
BACKGROUND Without the availability of disease-modifying drugs, there is an unmet therapeutic need for osteoarthritic patients. During osteoarthritis, the homeostasis of articular chondrocytes is dysregulated and a phenotypical transition called hypertrophy occurs, leading to cartilage degeneration. Targeting this phenotypic transition has emerged as a potential therapeutic strategy. Chondrocyte phenotype maintenance and switch are controlled by an intricate network of intracellular factors, each influenced by a myriad of feedback mechanisms, making it challenging to intuitively predict treatment outcomes, while in silico modeling can help unravel that complexity. In this study, we aim to develop a virtual articular chondrocyte to guide experiments in order to rationalize the identification of potential drug targets via screening of combination therapies through computational modeling and simulations. RESULTS We developed a signal transduction network model using knowledge-based and data-driven (machine learning) modeling technologies. The in silico high-throughput screening of (pairwise) perturbations operated with that network model highlighted conditions potentially affecting the hypertrophic switch. A selection of promising combinations was further tested in a murine cell line and primary human chondrocytes, which notably highlighted a previously unreported synergistic effect between the protein kinase A and the fibroblast growth factor receptor 1. CONCLUSIONS Here, we provide a virtual articular chondrocyte in the form of a signal transduction interactive knowledge base and of an executable computational model. Our in silico-in vitro strategy opens new routes for developing osteoarthritis targeting therapies by refining the early stages of drug target discovery.
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Affiliation(s)
- Raphaëlle Lesage
- Prometheus, Division of Skeletal Tissue Engineering, KU Leuven, Leuven, Belgium
- Biomechanics Section, KU Leuven, Leuven, Belgium
| | - Mauricio N Ferrao Blanco
- Department of Orthopaedics and Sports Medicine, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
| | - Roberto Narcisi
- Department of Orthopaedics and Sports Medicine, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
| | - Tim Welting
- Orthopedic Surgery Department, UMC+, Maastricht, the Netherlands
| | - Gerjo J V M van Osch
- Department of Orthopaedics and Sports Medicine, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
- Department of Otorhinolaryngology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
- Department of Biomechanical Engineering, Delft University of Technology, Delft, the Netherlands
| | - Liesbet Geris
- Prometheus, Division of Skeletal Tissue Engineering, KU Leuven, Leuven, Belgium.
- Biomechanics Section, KU Leuven, Leuven, Belgium.
- GIGA In silico Medicine, University of Liège, Liège, Belgium.
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18
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Long Z, Nakagawa K, Wang Z, Amadio PC, Zhao C, Gingery A. Age-related cellular and microstructural changes in the rotator cuff enthesis. J Orthop Res 2022; 40:1883-1895. [PMID: 34783060 PMCID: PMC9107523 DOI: 10.1002/jor.25211] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 10/21/2021] [Accepted: 10/30/2021] [Indexed: 02/04/2023]
Abstract
Rotator cuff injuries increase with age. The enthesis is the most frequent site of rotator cuff injury and degeneration. Understanding age-related changes of the enthesis are essential to determine the mechanism of rotator cuff injuries, degeneration, and to guide mechanistically driven therapies. In this study, we explored age-related cellular changes of the rotator cuff enthesis in young, mature, and aged rats. Here we found that the aged enthesis is typified by an increased mineralized zone and decreased nonmineralized zone. Proliferation, migration, and colony-forming potential of rotator cuff derived cells (RCECs) was attenuated with aging. The tenogenic and chondrogenic potential were significantly reduced, while the osteogenic potential increased in aged RCECs. The adipogenic potential increased in RCECs with age. This study explores the cellular differences found between young, mature, and aged rotator cuff enthesis cells and highlights the importance of using age-appropriate models, as well as provides a basis for further delineation of mechanisms and potential therapeutics for rotator cuff injuries.
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Affiliation(s)
- Zeling Long
- Tendon and Soft Tissue Biomechanics Laboratory, Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN,Department of Orthopedics, The Second People’s Hospital of Shenzhen, Shenzhen, Guangdong, China
| | - Koichi Nakagawa
- Tendon and Soft Tissue Biomechanics Laboratory, Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN
| | - Zhanwen Wang
- Tendon and Soft Tissue Biomechanics Laboratory, Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN,Department of Orthopedics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Peter C. Amadio
- Tendon and Soft Tissue Biomechanics Laboratory, Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN
| | - Chunfeng Zhao
- Tendon and Soft Tissue Biomechanics Laboratory, Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN
| | - Anne Gingery
- Tendon and Soft Tissue Biomechanics Laboratory, Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN,Department of Orthopaedic Surgery, Indiana University Medical School, Indianapolis, IN
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19
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Autologous chondrocyte implantation provides good long-term clinical results in the treatment of knee osteoarthritis: a systematic review. Knee Surg Sports Traumatol Arthrosc 2022; 31:2338-2348. [PMID: 35716187 DOI: 10.1007/s00167-022-07030-2] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 05/24/2022] [Indexed: 10/18/2022]
Abstract
PURPOSE To evaluate the mid- and long-term efficacy of autologous chondrocyte implantation (ACI) and matrix-assisted chondrocyte implantation (MACI) to treat patients with knee cartilage defects in the presence of osteoarthritis (OA). METHODS PubMed and Cochrane databases were systematically searched for studies describing the treatment of knee OA with ACI or MACI (Kellgren-Lawrence (KL) ≥ 1, minimum follow-up 36 months). Results were reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines and included Lysholm, Western Ontario McMaster University and International Knee Documentation Committee scores. RESULTS Of the 127 full-text articles assessed for eligibility, only five studies were selected based on inclusion/exclusion criteria (2 on ACI and 3 on MACI). In both groups, the defects were mainly located at femoral level, size 2.2-15.1 cm2 in the ACI and 2.0-7.6 cm2 in the MACI group. ACI was mostly used for patients affected by KL I, whereas MACI for patients with KL II-IV. The data obtained from 235 patients (161 ACI, 74 MACI) showed that ACI and MACI sustained stable clinical improvements up to 11 and 15 years, respectively, with a failure rate of about 10% up to 11 years. Scarce biological details regarding chondrocyte implantation were reported. CONCLUSIONS ACI and MACI procedures for the treatment of knee cartilage lesions associated to OA showed long-term success and allowed delaying arthroplasty. Additional trials reporting homogenous data and precise patient characterization are needed to conduct an effective literature meta-analysis and identify the clinical relevance of these procedures. LEVEL OF EVIDENCE IV.
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20
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Quincey A, Mohan S, Edderkaoui B. Monocyte Chemotactic Proteins Mediate the Effects of Hyperglycemia in Chondrocytes: In Vitro Studies. Life (Basel) 2022; 12:life12060836. [PMID: 35743867 PMCID: PMC9224901 DOI: 10.3390/life12060836] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 05/30/2022] [Accepted: 06/02/2022] [Indexed: 11/16/2022] Open
Abstract
Chemokines are secreted by a large variety of cells. They are involved in controlling cell trafficking, maturation, and differentiation. However, the specific responses and effects of chemokines on specific skeletal cell types under high glucose conditions have not been investigated. Chondrocytes play an important role in osteoarthritis and fracture healing. Delayed fracture healing is one of the major health complications caused by diabetes, so the goal of this study was to evaluate the response of several chemokines to high glucose conditions in chondrocyte cells and analyze their role in the catabolic effect of hyperglycemia. ATDC5 chondrocytes were cultured in normal and high glucose media, and mRNA expression levels of several chemokines and chondrocyte differentiation markers were quantified. Bindarit, a specific inhibitor of monocyte chemotactic proteins (MCPs), was used to determine the role of MCPs in mediating the effects of high glucose conditions in chondrocyte cells. High glucose treatment upregulated the expression of three Mcps, as well as the expression of matrix metalloproteinase 13 (Mmp13) and Osteocalcin (Oc). Furthermore, bindarit treatment downregulated Mmp13 and Oc but upregulated Collagen 2 (Col2) mRNA levels in chondrocytes treated with high glucose. Moreover, treatment of chondrocytes with ascorbic acid reduced the effect of high glucose conditions on the expression of chemokines and Mmps. These data together suggest that MCPs mediate the catabolic effect of high glucose in chondrocytes.
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Affiliation(s)
- Adam Quincey
- Musculoskeletal Disease Center, Research Service, VA Loma Linda Healthcare Systems, Loma Linda, CA 92357, USA; (A.Q.); (S.M.)
| | - Subburaman Mohan
- Musculoskeletal Disease Center, Research Service, VA Loma Linda Healthcare Systems, Loma Linda, CA 92357, USA; (A.Q.); (S.M.)
- Department of Medicine, Loma Linda University, Loma Linda, CA 92354, USA
- Department of Biochemistry, Loma Linda University, Loma Linda, CA 92354, USA
- Department of Orthopedic Surgery, Loma Linda University, Loma Linda, CA 92354, USA
| | - Bouchra Edderkaoui
- Musculoskeletal Disease Center, Research Service, VA Loma Linda Healthcare Systems, Loma Linda, CA 92357, USA; (A.Q.); (S.M.)
- Department of Medicine, Loma Linda University, Loma Linda, CA 92354, USA
- Correspondence:
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21
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Takemura S, Ohta Y, Sugama R, Minoda Y, Ohyama Y, Nakamura H. Eldecalcitol regulates the gene expressions of articular cartilage markers and differentiation markers in chondrocytes. Biochem Biophys Res Commun 2022; 597:58-63. [PMID: 35124460 DOI: 10.1016/j.bbrc.2022.01.119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 01/27/2022] [Accepted: 01/29/2022] [Indexed: 11/21/2022]
Abstract
Vitamin D has been shown to reduce symptoms in patients with osteoarthritis (OA). In a previous study, local administration of eldecalcitol, an active vitamin D3 analog, reduced degenerative changes in articular cartilage in the early phase of experimental OA. However, the target of vitamin D in OA remains unknown. Here, we investigated the effect of eldecalcitol treatment on chondrocytes, which were divided into superficial zone chondrocytes (SZC), deep zone chondrocytes (DZC), and differentiated chondrocytes. SZC and DZC were cultured in monolayer and 3D pellet cultures treated with eldecalcitol. The gene expressions of articular cartilage and chondrocyte differentiation markers were evaluated. Histological analysis of SZC and DZC 3D pellet cultures was performed. The results showed that the articular cartilage markers ETS-related gene (Erg) and lubricin/proteoglycan 4 (PRG4) were significantly increased in SZC, but not in DZC, in the monolayer culture treated with eldecalcitol. The chondrocyte differentiation markers type X collagen and alkaline phosphatase (ALP) were significantly decreased in the DZC pellet culture treated with eldecalcitol. Immunochemical analysis also showed that Erg and lubricin/PRG4 expressions were elevated in the SZC pellet culture treated with eldecalcitol, while type X collagen and ALP expressions were decreased in the DZC pellet culture treated with eldecalcitol. In conclusion, this study showed that eldecalcitol upregulated articular cartilage markers in SZC and suppressed differentiation markers in DZC. Such regulation of chondrocytes by eldecalcitol could be potentially effective against OA progression.
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Affiliation(s)
- Susumu Takemura
- Department of Orthopaedic Surgery, Osaka City University Graduate School of Medicine, 1-4-3, Asahimachi, Abeno-ku, Osaka, 545-8585, Japan
| | - Yoichi Ohta
- Department of Orthopaedic Surgery, Osaka City University Graduate School of Medicine, 1-4-3, Asahimachi, Abeno-ku, Osaka, 545-8585, Japan.
| | - Ryo Sugama
- Department of Orthopaedic Surgery, Osaka City University Graduate School of Medicine, 1-4-3, Asahimachi, Abeno-ku, Osaka, 545-8585, Japan
| | - Yukihide Minoda
- Department of Orthopaedic Surgery, Osaka City University Graduate School of Medicine, 1-4-3, Asahimachi, Abeno-ku, Osaka, 545-8585, Japan
| | - Yohei Ohyama
- Department of Orthopaedic Surgery, Osaka City University Graduate School of Medicine, 1-4-3, Asahimachi, Abeno-ku, Osaka, 545-8585, Japan
| | - Hiroaki Nakamura
- Department of Orthopaedic Surgery, Osaka City University Graduate School of Medicine, 1-4-3, Asahimachi, Abeno-ku, Osaka, 545-8585, Japan
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22
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Stromal-vascular fraction and adipose-derived stem cell therapies improve cartilage regeneration in osteoarthritis-induced rats. Sci Rep 2022; 12:2828. [PMID: 35181731 PMCID: PMC8857326 DOI: 10.1038/s41598-022-06892-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Accepted: 02/01/2022] [Indexed: 11/26/2022] Open
Abstract
This study aimed to evaluate the effects of the stromal vascular fraction (SVF) and adipose-derived stem cells (ADSCs) on cartilage injury in an osteoarthritis (OA) rat model. Sodium iodoacetate (3 mg/50 μL) was used to induce OA in the left knee joint of rats. On day 14 after OA induction, 50 μL of SVF (5 × 106cells), ADSCs (1 × 106 cells), or 0.9% normal saline (NS) was injected into the left knee-joint cavity of each group. The macroscopic view and histological sections revealed that the articular cartilage in the NS group was damaged, inflamed, uneven and thin, and had hyperchromatic cell infiltration. Notably, the cartilage surface had recovered to nearly normal and appeared smooth and bright on day 14 in the SVF and ADSC groups. Additionally, the white blood cell counts in the SVF and ADSC groups were higher than those in the NS group on day 14. Plasma IL-1β levels on days 7 and 14 were reduced in the SVF and ADSC groups. These results indicated that both SVF and ADSC treatments may assist in articular cartilage regeneration after cartilage injury. Cell therapy may benefit patients with OA. However, clinical trials with humans are required before the application of SVF and ADSC treatments in patients with OA.
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Zhao X, Ma L, Guo H, Wang J, Zhang S, Yang X, Yang L, Jin Q. Osteoclasts secrete leukemia inhibitory factor to promote abnormal bone remodeling of subchondral bone in osteoarthritis. BMC Musculoskelet Disord 2022; 23:87. [PMID: 35078447 PMCID: PMC8790929 DOI: 10.1186/s12891-021-04886-2] [Citation(s) in RCA: 12] [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: 08/08/2021] [Accepted: 11/17/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Osteoarthritis (OA) is a common chronic degenerative joint disease. At present, there is no effective treatment to check the progression of osteoarthritis. Osteochondral units are considered to be one of the most important structures affecting the occurrence and development of osteoarthritis. Osteoclasts mediate an increase in abnormal bone remodeling in subchondral bone in the early stage of osteoarthritis. Here, alendronate (ALN) that inhibit osteoclasts was used to study the regulatory effect of osteoclast-derived leukemia inhibitory factor (LIF) on early abnormal bone remodeling. METHODS This study involved 10-week-old wild-type female C57BL/6 mice and female SOST knockout (KO) mice that were divided into the sham, vehicle, ALN, and SOST KO groups. RESULTS The expression of LIF was found to decrease by inhibiting osteoclasts, and the histological OA score suggested that the degeneration of articular cartilage was attenuated. Additionally, micro-CT showed that osteoclasts inhibited in the early stage of OA could maintain the microstructure of the subchondral bone. The parameters of bone volume fraction (BV/TV), subchondral bone plate thickness (SBP.Th), and trabecular separation (Tb.Sp) of the treated group were better than those of the vehicle group. CONCLUSIONS These results suggested that downregulating the expression of sclerostin in osteocytes by secreting LIF from osteoclasts, activate the Wnt/β-catenin signaling pathway, and promote abnormal bone remodeling in OA. Therefore, clastokine LIF might be a potential molecular target to promote abnormal bone remodeling in early OA.
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Affiliation(s)
- Xin Zhao
- Department of Orthopedics, General Hospital of Ningxia Medical University, 804 Shengli Street, Yinchuan, Ningxia, China.,School of Clinical Medicine, Ningxia Medical University, Yinchuan, Ningxia, China
| | - Long Ma
- Department of Orthopedics, General Hospital of Ningxia Medical University, 804 Shengli Street, Yinchuan, Ningxia, China
| | - Haohui Guo
- Department of Orthopedics, General Hospital of Ningxia Medical University, 804 Shengli Street, Yinchuan, Ningxia, China
| | - Jian Wang
- School of Clinical Medicine, Ningxia Medical University, Yinchuan, Ningxia, China
| | - Shuai Zhang
- Department of Orthopedics, General Hospital of Ningxia Medical University, 804 Shengli Street, Yinchuan, Ningxia, China
| | - Xiaochun Yang
- Department of Orthopedics, General Hospital of Ningxia Medical University, 804 Shengli Street, Yinchuan, Ningxia, China
| | - Lvlin Yang
- School of Clinical Medicine, Ningxia Medical University, Yinchuan, Ningxia, China
| | - Qunhua Jin
- Department of Orthopedics, General Hospital of Ningxia Medical University, 804 Shengli Street, Yinchuan, Ningxia, China.
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Rellmann Y, Eidhof E, Hansen U, Fleischhauer L, Vogel J, Clausen-Schaumann H, Aszodi A, Dreier R. ER Stress in ERp57 Knockout Knee Joint Chondrocytes Induces Osteoarthritic Cartilage Degradation and Osteophyte Formation. Int J Mol Sci 2021; 23:ijms23010182. [PMID: 35008608 PMCID: PMC8745280 DOI: 10.3390/ijms23010182] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 12/14/2021] [Accepted: 12/22/2021] [Indexed: 12/14/2022] Open
Abstract
Ageing or obesity are risk factors for protein aggregation in the endoplasmic reticulum (ER) of chondrocytes. This condition is called ER stress and leads to induction of the unfolded protein response (UPR), which, depending on the stress level, restores normal cell function or initiates apoptotic cell death. Here the role of ER stress in knee osteoarthritis (OA) was evaluated. It was first tested in vitro and in vivo whether a knockout (KO) of the protein disulfide isomerase ERp57 in chondrocytes induces sufficient ER stress for such analyses. ER stress in ERp57 KO chondrocytes was confirmed by immunofluorescence, immunohistochemistry, and transmission electron microscopy. Knee joints of wildtype (WT) and cartilage-specific ERp57 KO mice (ERp57 cKO) were analyzed by indentation-type atomic force microscopy (IT-AFM), toluidine blue, and immunofluorescence/-histochemical staining. Apoptotic cell death was investigated by a TUNEL assay. Additionally, OA was induced via forced exercise on a treadmill. ER stress in chondrocytes resulted in a reduced compressive stiffness of knee cartilage. With ER stress, 18-month-old mice developed osteoarthritic cartilage degeneration with osteophyte formation in knee joints. These degenerative changes were preceded by apoptotic death in articular chondrocytes. Young mice were not susceptible to OA, even when subjected to forced exercise. This study demonstrates that ER stress induces the development of age-related knee osteoarthritis owing to a decreased protective function of the UPR in chondrocytes with increasing age, while apoptosis increases. Therefore, inhibition of ER stress appears to be an attractive therapeutic target for OA.
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Affiliation(s)
- Yvonne Rellmann
- Institute of Physiological Chemistry and Pathobiochemistry, Waldeyerstraße 15, 48149 Muenster, Germany; (Y.R.); (E.E.)
| | - Elco Eidhof
- Institute of Physiological Chemistry and Pathobiochemistry, Waldeyerstraße 15, 48149 Muenster, Germany; (Y.R.); (E.E.)
| | - Uwe Hansen
- Institute of Musculoskeletal Medicine, University Hospital Münster, Albert-Schweitzer-Campus 1, Building D3, 48149 Muenster, Germany;
| | - Lutz Fleischhauer
- Center for Applied Tissue Engineering and Regenerative Medicine-CANTER, Munich University of Applied Sciences, 80335 Munich, Germany; (L.F.); (J.V.); (H.C.-S.)
- Center for Nanoscience-CeNS, 80335 Munich, Germany
- Department for Orthopaedics and Trauma Surgery, Musculoskeletal University Center Munich (MUM), University Hospital, LMU Munich, 80335 Munich, Germany;
| | - Jonas Vogel
- Center for Applied Tissue Engineering and Regenerative Medicine-CANTER, Munich University of Applied Sciences, 80335 Munich, Germany; (L.F.); (J.V.); (H.C.-S.)
- Center for Nanoscience-CeNS, 80335 Munich, Germany
| | - Hauke Clausen-Schaumann
- Center for Applied Tissue Engineering and Regenerative Medicine-CANTER, Munich University of Applied Sciences, 80335 Munich, Germany; (L.F.); (J.V.); (H.C.-S.)
- Center for Nanoscience-CeNS, 80335 Munich, Germany
| | - Attila Aszodi
- Department for Orthopaedics and Trauma Surgery, Musculoskeletal University Center Munich (MUM), University Hospital, LMU Munich, 80335 Munich, Germany;
| | - Rita Dreier
- Institute of Physiological Chemistry and Pathobiochemistry, Waldeyerstraße 15, 48149 Muenster, Germany; (Y.R.); (E.E.)
- Correspondence: ; Tel.: +49-251-8355573
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25
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Ferrao Blanco MN, Bastiaansen-Jenniskens YM, Chambers MG, Pitsillides AA, Narcisi R, van Osch GJ. Effect of Inflammatory Signaling on Human Articular Chondrocyte Hypertrophy: Potential Involvement of Tissue Repair Macrophages. Cartilage 2021; 13:168S-174S. [PMID: 34165367 PMCID: PMC8739598 DOI: 10.1177/19476035211021907] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
OBJECTIVE In osteoarthritis, chondrocytes tend to acquire a hypertrophic phenotype, which contributes to the modification of the extracellular matrix, resulting in permanent cartilage changes. In mouse chondrocytes, pro-inflammatory macrophages and pro-inflammatory cytokines have been shown to stimulate hypertrophy via the activation of the nuclear factor kappa B (NF-κB) pathway. Whether or not this also occurs in human chondrocytes remains unclear. We therefore aimed to investigate whether hypertrophy-like responses in human cartilage are driven mainly by intrinsic inflammatory signaling or shaped by specific macrophage populations. DESIGN Human articular chondrocytes were cultured with pro-inflammatory cytokines or medium conditioned by defined macrophage subsets. Furthermore, the effect of inhibition of NF-κB-dependent gene expression was evaluated using the NF-κB inhibitor SC-514. Hypertrophy was assessed by measuring the transcription level of alkaline phosphatase (ALPL), type X collagen (COL10A1), Indian hedgehog (IHH), and runt-related transcription factor 2 (RUNX2). RESULTS The expression of hypertrophic genes was not promoted in human chondrocytes by pro-inflammatory cytokines neither pro-inflammatory M(IFNγ + TNFα) macrophages. Inhibition of the NF-κB-dependent gene expression did not affect human articular chondrocyte hypertrophy. However, tissue repair M(IL4) macrophages induced hypertrophy by promoting the expression of COL10A1, RUNX2, and IHH. CONCLUSION Intrinsic inflammatory signaling activation is not involved in the hypertrophic shift observed in human articular chondrocytes cultured in vitro. However, tissue repair macrophages may contribute to the onset of this detrimental phenotype in human osteoarthritic cartilage, given the effect observed in our experimental models.
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Affiliation(s)
- Mauricio N. Ferrao Blanco
- Department of Orthopaedics and
Sports Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam,
The Netherlands
| | | | - Mark G. Chambers
- Lilly Research Laboratories, Eli
Lilly Pharmaceuticals, Indianapolis, IN, USA
| | | | - Roberto Narcisi
- Department of Orthopaedics and
Sports Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam,
The Netherlands
| | - Gerjo J.V.M. van Osch
- Department of Orthopaedics and
Sports Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam,
The Netherlands,Department of
Otorhinolaryngology, Erasmus MC, University Medical Center Rotterdam,
Rotterdam, The Netherlands,Department of Biomechanical
Engineering, TU Delft, Delft, The Netherlands,Gerjo J.V.M. van Osch, Erasmus MC,
University Medical Center Rotterdam, Wytemaweg 80, Room Ee 16.51b,
Rotterdam, 3015 CN, The Netherlands.
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26
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Wu Z, Korntner SH, Mullen AM, Zeugolis DI. Collagen type II: From biosynthesis to advanced biomaterials for cartilage engineering. BIOMATERIALS AND BIOSYSTEMS 2021; 4:100030. [PMID: 36824570 PMCID: PMC9934443 DOI: 10.1016/j.bbiosy.2021.100030] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 11/02/2021] [Accepted: 11/19/2021] [Indexed: 12/11/2022] Open
Abstract
Collagen type II is the major constituent of cartilage tissue. Yet, cartilage engineering approaches are primarily based on collagen type I devices that are associated with suboptimal functional therapeutic outcomes. Herein, we briefly describe cartilage's development and cellular and extracellular composition and organisation. We also provide an overview of collagen type II biosynthesis and purification protocols from tissues of terrestrial and marine species and recombinant systems. We then advocate the use of collagen type II as a building block in cartilage engineering approaches, based on safety, efficiency and efficacy data that have been derived over the years from numerous in vitro and in vivo studies.
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Affiliation(s)
- Z Wu
- Regenerative, Modular & Developmental Engineering Laboratory (REMODEL) and Science Foundation Ireland (SFI) Centre for Research in Medical Devices (CÚRAM), National University of Ireland Galway (NUI Galway), Galway, Ireland
| | - SH Korntner
- Regenerative, Modular & Developmental Engineering Laboratory (REMODEL) and Science Foundation Ireland (SFI) Centre for Research in Medical Devices (CÚRAM), National University of Ireland Galway (NUI Galway), Galway, Ireland
| | - AM Mullen
- Teagasc Research Centre, Ashtown, Ireland
| | - DI Zeugolis
- Regenerative, Modular & Developmental Engineering Laboratory (REMODEL) and Science Foundation Ireland (SFI) Centre for Research in Medical Devices (CÚRAM), National University of Ireland Galway (NUI Galway), Galway, Ireland
- Regenerative, Modular & Developmental Engineering Laboratory (REMODEL), Charles Institute of Dermatology, Conway Institute of Biomolecular & Biomedical Research and School of Mechanical & Materials Engineering, University College Dublin (UCD), Dublin, Ireland
- Correspondence author at: REMODEL, NUI Galway & UCD.
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SPRY4 acts as an indicator of osteoarthritis severity and regulates chondrocyte hypertrophy and ECM protease expression. NPJ Regen Med 2021; 6:56. [PMID: 34535669 PMCID: PMC8448831 DOI: 10.1038/s41536-021-00165-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 08/11/2021] [Indexed: 11/09/2022] Open
Abstract
Osteoarthritis (OA) causes serious changes in the metabolic and signaling pathways of chondrocytes, including the mitogen-activated protein kinase (MAPK) pathway. However, the role of sprouty RTK signaling antagonist 4 (SPRY4), an inhibitor of MAPK, in the human cartilage tissues and chondrocytes remains to be understood. Here, using SPRY4 gene delivery into healthy and degenerated chondrocytes, we elucidated the role of SPRY4 in preventing chondrocyte hypertrophy. In addition to using the human cartilage tissues with the destabilization of the medial meniscus (DMM) model in Sprague-Dawley (SD) rats, the role of SPRY4 in cartilage tissues and chondrocytes was explored through their molecular and histological analyses. In order to determine the effects of SPRY4 on healthy human chondrocyte hypertrophy, small interfering RNA (siRNA) was used to knock down SPRY4. Lentiviral transduction of SPRY4 into degenerated human chondrocytes allowed us to investigate its ability to prevent hypertrophy. SPRY4 expression levels were higher in healthy human cartilage tissue and chondrocytes than in degenerated human cartilage tissues and hypertrophy-induced chondrocytes. The knockdown of SPRY4 in healthy chondrocytes caused an increase in hypertrophy, senescence, reactive oxygen species (ROS) production, and extracellular matrix (ECM) protease expression. However, all these factors decreased upon overexpression of SPRY4 in degenerated chondrocytes via regulation of the MAPK signaling pathway. We conclude that SPRY4 is a crucial indicator of osteoarthritis (OA) severity and could play an important role in preventing OA in the cartilage by inhibiting chondrocyte hypertrophy.
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Deng C, Yang J, He H, Ma Z, Wang W, Zhang Y, Li T, He C, Wang J. 3D bio-printed biphasic scaffolds with dual modification of silk fibroin for the integrated repair of osteochondral defects. Biomater Sci 2021; 9:4891-4903. [PMID: 34047307 DOI: 10.1039/d1bm00535a] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Repair of osteochondral defects is still a challenge, especially the regeneration of hyaline cartilage. Parathyroid hormone (PTH) can inhibit the hypertrophy of chondrocytes to maintain the phenotype of hyaline cartilage. Here, we aimed to construct a bio-printed biphasic scaffold with a mechanical gradient based on dual modification of silk fibroin (SF) for the integrated repair of osteochondral defects. Briefly, SF was grafted with PTH (SF-PTH) and covalently immobilized with methacrylic anhydride (SF-MA), respectively. Next, gelatin methacryloyl (GM) mixed with SF-PTH or SF-MA was used as a bio-ink for articular cartilage and subchondral bone regeneration. Finally, the GM + SF-PTH/GM + SF-MA osteochondral biphasic scaffold was constructed using 3D bioprinting technology, and implanted in a rabbit osteochondral defect model. In this study, the SF-PTH bio-ink was synthesized for the first time. In vitro results indicated that the GM + SF-MA bio-ink had good mechanical properties, while the GM + SF-PTH bio-ink inhibited the hypertrophy of chondrocytes and was beneficial for the production of hyaline cartilage extracellular matrix. Importantly, an integrated GM + SF-PTH/GM + SF-MA biphasic scaffold with a mechanical gradient was successfully constructed. The results in vivo demonstrated that the GM + SF-PTH/GM + SF-MA scaffold could promote the regeneration of osteochondral defects and maintain the phenotype of hyaline cartilage to a large extent. Collectively, our results indicate that the integrated GM + SF-PTH/GM + SF-MA biphasic scaffold constructed by 3D bioprinting is expected to become a new strategy for the treatment of osteochondral defects.
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Affiliation(s)
- Changxu Deng
- Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No. 639 Zhizaoju Road, Shanghai, 200011, China.
| | - Jin Yang
- Key Laboratory of Science and Technology of Eco-Textiles, Ministry of Education, College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, No. 2999, People North Road, Shanghai 201620, China.
| | - Hongtao He
- The Third Ward of Department of Orthopedics, The Second Affiliated Hospital of Dalian Medical University, No. 467, Zhongshan Road, Shahekou District, Dalian 116000, Liaoning Province, China
| | - Zhenjiang Ma
- Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No. 639 Zhizaoju Road, Shanghai, 200011, China.
| | - Wenhao Wang
- Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No. 639 Zhizaoju Road, Shanghai, 200011, China.
| | - Yuxin Zhang
- Department of Rehabilitation Medicine, Shanghai Ninth People's Hospital Affiliated to Shanghai JiaoTong University School of Medicine, No. 639 Zhizaoju Road, Shanghai, 200011, China
| | - Tao Li
- Department of Orthopaedics, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, No.1665 Kongjiang Road, Shanghai, 200092, China
| | - Chuanglong He
- Key Laboratory of Science and Technology of Eco-Textiles, Ministry of Education, College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, No. 2999, People North Road, Shanghai 201620, China.
| | - Jinwu Wang
- Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No. 639 Zhizaoju Road, Shanghai, 200011, China. and Med-X Research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, No. 1956 Huashan Road, Shanghai, 200030, China
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29
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Jia Y, Xie L, Tang Z, Wang D, Hu Y, Zhang G, Chen Y, Gao Q. Parathyroid hormone promotes cartilage healing after free reduction of mandibular condylar fractures by upregulating Sox9. Exp Biol Med (Maywood) 2021; 246:2249-2258. [PMID: 34233524 DOI: 10.1177/15353702211027114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
After high fractures of the mandibular condyle, the insufficient blood supply to the condyle often leads to poor bone and cartilage repair ability and poor clinical outcome. Parathyroid hormone (PTH) can promote the bone formation and mineralization of mandibular fracture, but its effects on cartilage healing after the free reduction and internal fixation of high fractures of the mandibular condyle are unknown. In this study, a rabbit model of free reduction and internal fixation of high fractures of the mandibular condyle was established, and the effects and mechanisms of PTH on condylar cartilage healing were explored. Forty-eight specific-pathogen-free (SPF) grade rabbits were randomly divided into two groups. In the experimental group, PTH was injected subcutaneously at 20 µg/kg (PTH (1-34)) every other day, and in the control group, PTH was replaced with 1 ml saline. The healing cartilages were assessed at postoperative days 7, 14, 21, and 28. Observation of gross specimens, hematoxylin eosin staining and Safranin O/fast green staining found that every-other-day subcutaneous injection of PTH at 20 µg/kg promoted healing of condylar cartilage and subchondral osteogenesis in the fracture site. Immunohistochemistry and polymerase chain reaction showed that PTH significantly upregulated the chondrogenic genes Sox9 and Col2a1 in the cartilage fracture site within 7-21 postoperative days in the experimental group than those in the control group, while it downregulated the cartilage inflammation gene matrix metalloproteinase-13 and chondrocyte terminal differentiation gene ColX. In summary, exogenous PTH can stimulate the formation of cartilage matrix by triggering Sox9 expression at the early stage of cartilage healing, and it provides a potential therapeutic protocol for high fractures of the mandibular condyle.
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Affiliation(s)
- Yuanyuan Jia
- Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Guizhou Medical University, Guiyang 550004, China
| | - Liuqin Xie
- Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Guizhou Medical University, Guiyang 550004, China
| | - Zhenglong Tang
- Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Guizhou Medical University, Guiyang 550004, China
| | - Dongxiang Wang
- Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Guizhou Medical University, Guiyang 550004, China
| | - Yun Hu
- Department of Oral Histopathology, School and Hospital of Stomatology, Guizhou Medical University, Guiyang 550004, China
| | - Guoxing Zhang
- Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Guizhou Medical University, Guiyang 550004, China
| | - Youli Chen
- Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Guizhou Medical University, Guiyang 550004, China
| | - Qiong Gao
- Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Guizhou Medical University, Guiyang 550004, China
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30
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Ping SH, Tian FM, Liu H, Sun Q, Shao LT, Lian QQ, Zhang L. Raloxifene inhibits the overexpression of TGF-β1 in cartilage and regulates the metabolism of subchondral bone in rats with osteoporotic osteoarthritis. Bosn J Basic Med Sci 2021; 21:284-293. [PMID: 33259777 PMCID: PMC8112563 DOI: 10.17305/bjbms.2020.5142] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 11/16/2020] [Indexed: 01/18/2023] Open
Abstract
Overexpression of transforming growth factor-beta 1 (TGF-β1) and subchondral bone remodelling play key roles in osteoarthritis (OA). Raloxifene (RAL) reduces the serum level of TGF-β1 in postmenopausal women. However, the effect of RAL on TGF-β1 expression in articular cartilage is still unclear. Therefore, we aimed to investigate the protective effect of RAL on osteoporotic osteoarthritis via affecting TGF-β1 expression in cartilage and the metabolism of subchondral bone. Osteoporotic osteoarthritis was induced by a combination of anterior cruciate transection (ACLT) and ovariectomy (OVX). Rats were divided into five groups (n = 12): The sham group, the ACLT group, the OVX group, the ACLT + OVX group, and the RAL group (ACLT + OVX + RAL, 6.25 mg/kg/day for 12 weeks). Assessment was performed by histomorphology, microcomputed tomography (micro-CT) scan, immunohistochemistry, and tartrate-resistant acid phosphatase (TRAP) staining. We found that severe cartilage degeneration was shown in the ACLT + OVX group. The histomorphological scores, the levels of TGF-β1, and its related catabolic enzymes and osteoclasts numbers in the ACLT + OVX group were higher than those in other groups (p < 0.05). Furthermore, structure model index (SMI) and trabecular spacing (Tb.Sp) were decreased (p < 0.05), while bone mineral density (BMD), bone volume fraction (BV/TV), and trabecular number (Tb.N) were increased by RAL compared with the ACLT + OVX group (p < 0.05). Our findings demonstrated that RAL in clinical doses retards the development of osteoporotic osteoarthritis by inhibiting the overexpression of TGF-β1 in cartilage and regulating the metabolism of subchondral bone. These results provide support for RAL in the expansion of clinical indication for prevention and treatment in postmenopausal osteoarthritis.
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Affiliation(s)
- Shao-Hua Ping
- Department of Orthopedic Surgery, Hebei Medical University, Shijiazhuang, China
| | - Fa-Ming Tian
- Medical Research Center, North China University of Science and Technology, Tangshan, China
| | - Hao Liu
- Department of Orthopedic Surgery, Affiliated Hospital of North China University of Science and Technology, Tangshan, China
| | - Qi Sun
- Department of Orthopedic Surgery, Hebei Medical University, Shijiazhuang, China
| | - Li-Tao Shao
- Department of Orthopedic Surgery, Hebei Medical University, Shijiazhuang, China
| | - Qiang-Qiang Lian
- Department of Orthopedic Surgery, the Affiliated Hospital of North China University of Science and Technology, Tangshan, China
| | - Liu Zhang
- Department of Orthopedic Surgery, Hebei Medical University, Shijiazhuang, China; Department of Orthopedic Surgery, Emergency General Hospital, Beijing, China
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31
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Fan X, Wu X, Crawford R, Xiao Y, Prasadam I. Macro, Micro, and Molecular. Changes of the Osteochondral Interface in Osteoarthritis Development. Front Cell Dev Biol 2021; 9:659654. [PMID: 34041240 PMCID: PMC8142862 DOI: 10.3389/fcell.2021.659654] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Accepted: 04/12/2021] [Indexed: 01/05/2023] Open
Abstract
Osteoarthritis (OA) is a long-term condition that causes joint pain and reduced movement. Notably, the same pathways governing cell growth, death, and differentiation during the growth and development of the body are also common drivers of OA. The osteochondral interface is a vital structure located between hyaline cartilage and subchondral bone. It plays a critical role in maintaining the physical and biological function, conveying joint mechanical stress, maintaining chondral microenvironment, as well as crosstalk and substance exchange through the osteochondral unit. In this review, we summarized the progress in research concerning the area of osteochondral junction, including its pathophysiological changes, molecular interactions, and signaling pathways that are related to the ultrastructure change. Multiple potential treatment options were also discussed in this review. A thorough understanding of these biological changes and molecular mechanisms in the pathologic process will advance our understanding of OA progression, and inform the development of effective therapeutics targeting OA.
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Affiliation(s)
- Xiwei Fan
- Faculty of Science and Engineering, School of Mechanical, Medical and Process Engineering, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia
| | - Xiaoxin Wu
- Faculty of Science and Engineering, School of Mechanical, Medical and Process Engineering, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia
| | - Ross Crawford
- Faculty of Science and Engineering, School of Mechanical, Medical and Process Engineering, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia
- Orthopaedic Department, The Prince Charles Hospital, Brisbane, QLD, Australia
| | - Yin Xiao
- Faculty of Science and Engineering, School of Mechanical, Medical and Process Engineering, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia
- Australia-China Centre for Tissue Engineering and Regenerative Medicine, Queensland University of Technology, Brisbane, QLD, Australia
| | - Indira Prasadam
- Faculty of Science and Engineering, School of Mechanical, Medical and Process Engineering, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia
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Danalache M, Beutler KR, Rolauffs B, Wolfgart JM, Bonnaire FC, Fischer S, Greving I, Hofmann UK. Exploration of changes in spatial chondrocyte organisation in human osteoarthritic cartilage by means of 3D imaging. Sci Rep 2021; 11:9783. [PMID: 33963289 PMCID: PMC8105369 DOI: 10.1038/s41598-021-89582-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Accepted: 04/28/2021] [Indexed: 12/11/2022] Open
Abstract
Using two-dimensional top-down view microscopy, researchers have recently described chondrocytes as being spatially arranged in distinct patterns such as strings, double strings, and small and large clusters. Because of the seeming association of these changes with tissue degeneration, they have been proposed as an image-based biomarker for early osteoarthritis (OA) staging. The aim of our study was to investigate the spatial arrangement of chondrocytes in human articular cartilage in a 3D fashion and to evaluate the 3D changes of these patterns in the context of local tissue destruction. Decalcified femoral condyle resections from the load-bearing area were analysed in 3D for their spatial chondrocyte organisation by means of fluorescence microscopy and synchrotron-radiation micro-computed tomography (SR-µCT). In intact cartilage chondrocyte strings can be found in the superficial, transitional and deep zones. The proposed pattern changes accompanying tissue destruction could be located not just along the surface but also through all layers of cartilage. Each spatial pattern was characterised by a different cellular density (the only exception being between single and double strings with p = 0.062), with cellular density significantly increasing alongside the increase in local tissue degeneration as defined by the chondrocyte patterns. We can thus corroborate that the proposed cellular spatial changes are a three-dimensional function of local tissue degeneration, underlining their relevance as an image-based biomarker for the early diagnosis and description of OA. Clinical trial registration number: Project number of the ethics committee of the University of Tübingen:171/2014BO2.
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Affiliation(s)
- Marina Danalache
- Department of Orthopaedic Surgery, University Hospital of Tübingen, Hoppe-Seyler-Strasse 3, 72076, Tübingen, Germany
| | - Kevin Ralf Beutler
- Medical Faculty of the University of Tübingen, 72076, Tübingen, Germany. .,Department of Orthopaedic Surgery and Traumatology, Spital Thurgau AG, Spitalcampus 1, 8596, Münsterlingen, Switzerland.
| | - Bernd Rolauffs
- G.E.R.N. Tissue Replacement, Regeneration and Neogenesis, Department of Orthopedics and Trauma Surgery, Medical Center - Albert-Ludwigs-University of Freiburg, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, 79108, Freiburg, Germany
| | | | - Florian Christof Bonnaire
- Department of Orthopaedic Surgery, University Hospital of Tübingen, Hoppe-Seyler-Strasse 3, 72076, Tübingen, Germany
| | - Stefan Fischer
- Department of Evolutionary Biology of Invertebrates, University of Tübingen, 72076, Tübingen, Germany.,Tübingen Structural Microscopy (TSM), Center for Applied Geoscience (ZAG), University of Tübingen, 72076, Tübingen, Germany
| | - Imke Greving
- Institute of Materials Research, Helmholtz-Zentrum Geesthacht, Geesthacht, Germany
| | - Ulf Krister Hofmann
- Department of Orthopaedic Surgery, University Hospital of Tübingen, Hoppe-Seyler-Strasse 3, 72076, Tübingen, Germany
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33
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Oral administration of hydrolysates of cartilage extract in the prevention of osteoarthritis. J Funct Foods 2021. [DOI: 10.1016/j.jff.2021.104376] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
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Houtman E, van Hoolwerff M, Lakenberg N, Suchiman EHD, van der Linden-van der Zwaag E, Nelissen RGHH, Ramos YFM, Meulenbelt I. Human Osteochondral Explants: Reliable Biomimetic Models to Investigate Disease Mechanisms and Develop Personalized Treatments for Osteoarthritis. Rheumatol Ther 2021; 8:499-515. [PMID: 33608843 PMCID: PMC7991015 DOI: 10.1007/s40744-021-00287-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 01/30/2021] [Indexed: 02/07/2023] Open
Abstract
Introduction Likely due to ignored heterogeneity in disease pathophysiology, osteoarthritis (OA) has become the most common disabling joint disease, without effective disease-modifying treatment causing a large social and economic burden. In this study we set out to explore responses of aged human osteochondral explants upon different OA-related perturbing triggers (inflammation, hypertrophy and mechanical stress) for future tailored biomimetic human models. Methods Human osteochondral explants were treated with IL-1β (10 ng/ml) or triiodothyronine (T3; 10 nM) or received 65% strains of mechanical stress (65% MS). Changes in chondrocyte signalling were determined by expression levels of nine genes involved in catabolism, anabolism and hypertrophy. Breakdown of cartilage was measured by sulphated glycosaminoglycans (sGAGs) release, scoring histological changes (Mankin score) and mechanical properties of cartilage. Results All three perturbations (IL-1β, T3 and 65% MS) resulted in upregulation of the catabolic genes MMP13 and EPAS1. IL-1β abolished COL2A1 and ACAN gene expression and increased cartilage degeneration, reflected by increased Mankin scores and sGAGs released. Treatment with T3 resulted in a high and significant upregulation of the hypertrophic markers COL1A1, COL10A1 and ALPL. However, 65% MS increased sGAG release and detrimentally altered mechanical properties of cartilage. Conclusion We present consistent and specific output on three different triggers of OA. Perturbation with the pro-inflammatory IL-1β mainly induced catabolic chondrocyte signalling and cartilage breakdown, while T3 initiated expression of hypertrophic and mineralization markers. Mechanical stress at a strain of 65% induced catabolic chondrocyte signalling and changed cartilage matrix integrity. The major strength of our ex vivo models was that they considered aged, preserved, human cartilage of a heterogeneous OA patient population. As a result, the explants may reflect a reliable biomimetic model prone to OA onset allowing for development of different treatment modalities. Supplementary Information The online version contains supplementary material available at 10.1007/s40744-021-00287-y.
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Affiliation(s)
- Evelyn Houtman
- Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands
| | - Marcella van Hoolwerff
- Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands
| | - Nico Lakenberg
- Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands
| | - Eka H D Suchiman
- Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands
| | | | - Rob G H H Nelissen
- Department of Orthopaedics, Leiden University Medical Center, Leiden, The Netherlands
| | - Yolande F M Ramos
- Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands
| | - Ingrid Meulenbelt
- Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands.
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35
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Anderson-Baron M, Liang Y, Kunze M, Mulet-Sierra A, Osswald M, Ansari K, Seikaly H, Adesida AB. Suppression of Hypertrophy During in vitro Chondrogenesis of Cocultures of Human Mesenchymal Stem Cells and Nasal Chondrocytes Correlates With Lack of in vivo Calcification and Vascular Invasion. Front Bioeng Biotechnol 2021; 8:572356. [PMID: 33469528 PMCID: PMC7813892 DOI: 10.3389/fbioe.2020.572356] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2020] [Accepted: 12/03/2020] [Indexed: 01/08/2023] Open
Abstract
Objective Human nasal septal chondrocytes (NC) are a promising minimally invasive derivable chondrogenic cell source for cartilage repair. However, the quality of NC-derived cartilage is variable between donors. Coculture of NC with mesenchymal stem cells (MSCs) mitigates the variability but with undesirable markers of chondrocyte hypertrophy, such as type X collagen, and the formation of unstable calcifying cartilage at ectopic sites. In contrast, monoculture NC forms non-calcifying stable cartilage. Formation of a stable NC-MSC coculture cartilage is crucial for clinical application. The aim of this study was to explore the utility of parathyroid hormone-related peptide (PTHrP) hormone to suppress chondrocyte hypertrophy in NC-MSC cocultures and form stable non-calcifying cartilage at ectopic sites. Methods Human NC and bone marrow MSCs, and cocultures of NC and MSC (1:3 ratio) were aggregated in pellet form and subjected to in vitro chondrogenesis for 3 weeks in chondrogenic medium in the presence and absence of PTHrP. Following in vitro chondrogenesis, the resulting pellets were implanted in immunodeficient athymic nude mice for 3 weeks. Results Coculture of NC and MSC resulted in synergistic cartilage matrix production. PTHrP suppressed the expression of hypertrophy marker, type X collagen (COL10A1), in a dose-dependent fashion without affecting the synergism in cartilage matrix synthesis, and in vivo calcification was eradicated with PTHrP. In contrast, cocultured control (CC) pellets without PTHrP treatment expressed COL10A1, calcified, and became vascularized in vivo.
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Affiliation(s)
- Matthew Anderson-Baron
- Division of Orthopaedic Surgery, Department of Surgery, Faculty of Medicine and Dentistry, Laboratory of Stem Cell Biology and Orthopaedic Tissue Engineering, University of Alberta, Edmonton, AB, Canada.,Division of Surgical Research, Department of Surgery, Faculty of Medicine and Dentistry, Laboratory of Stem Cell Biology and Orthopaedic Tissue Engineering, University of Alberta, Edmonton, AB, Canada
| | - Yan Liang
- Division of Orthopaedic Surgery, Department of Surgery, Faculty of Medicine and Dentistry, Laboratory of Stem Cell Biology and Orthopaedic Tissue Engineering, University of Alberta, Edmonton, AB, Canada.,Division of Surgical Research, Department of Surgery, Faculty of Medicine and Dentistry, Laboratory of Stem Cell Biology and Orthopaedic Tissue Engineering, University of Alberta, Edmonton, AB, Canada
| | - Melanie Kunze
- Division of Orthopaedic Surgery, Department of Surgery, Faculty of Medicine and Dentistry, Laboratory of Stem Cell Biology and Orthopaedic Tissue Engineering, University of Alberta, Edmonton, AB, Canada.,Division of Surgical Research, Department of Surgery, Faculty of Medicine and Dentistry, Laboratory of Stem Cell Biology and Orthopaedic Tissue Engineering, University of Alberta, Edmonton, AB, Canada
| | - Aillette Mulet-Sierra
- Division of Orthopaedic Surgery, Department of Surgery, Faculty of Medicine and Dentistry, Laboratory of Stem Cell Biology and Orthopaedic Tissue Engineering, University of Alberta, Edmonton, AB, Canada.,Division of Surgical Research, Department of Surgery, Faculty of Medicine and Dentistry, Laboratory of Stem Cell Biology and Orthopaedic Tissue Engineering, University of Alberta, Edmonton, AB, Canada
| | - Martin Osswald
- Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta Hospital, Edmonton, AB, Canada.,Institute for Reconstructive Sciences in Medicine, Misericordia Community Hospital, Edmonton, AB, Canada
| | - Khalid Ansari
- Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta Hospital, Edmonton, AB, Canada
| | - Hadi Seikaly
- Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta Hospital, Edmonton, AB, Canada
| | - Adetola B Adesida
- Division of Orthopaedic Surgery, Department of Surgery, Faculty of Medicine and Dentistry, Laboratory of Stem Cell Biology and Orthopaedic Tissue Engineering, University of Alberta, Edmonton, AB, Canada.,Division of Surgical Research, Department of Surgery, Faculty of Medicine and Dentistry, Laboratory of Stem Cell Biology and Orthopaedic Tissue Engineering, University of Alberta, Edmonton, AB, Canada.,Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta Hospital, Edmonton, AB, Canada
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Rellmann Y, Eidhof E, Dreier R. Review: ER stress-induced cell death in osteoarthritic cartilage. Cell Signal 2020; 78:109880. [PMID: 33307190 DOI: 10.1016/j.cellsig.2020.109880] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 12/03/2020] [Accepted: 12/04/2020] [Indexed: 12/16/2022]
Abstract
In cartilage, chondrocytes are responsible for the biogenesis and maintenance of the extracellular matrix (ECM) composed of proteins, glycoproteins and proteoglycans. Various cellular stresses, such as hypoxia, nutrient deprivation, oxidative stress or the accumulation of advanced glycation end products (AGEs) during aging, but also translational errors or mutations in cartilage components or chaperone proteins affect the synthesis and secretion of ECM proteins, causing protein aggregates to accumulate in the endoplasmic reticulum (ER). This condition, referred to as ER stress, interferes with cartilage cell homeostasis and initiates the unfolded protein response (UPR), a rescue mechanism to regain cell viability and function. Chronic or irreversible ER stress, however, triggers UPR-initiated cell death. Due to unresolved ER stress in chondrocytes, diseases of the skeletal system, such as chondrodysplasias, arise. ER stress has also been identified as a contributing factor to the pathogenesis of cartilage degeneration processes such as osteoarthritis (OA). This review provides current knowledge about the biogenesis of ECM components in chondrocytes, describes possible causes for the impairment of involved processes and focuses on the ER stress-induced cell death in articular cartilage during OA. Targeting of the ER stress itself or intervention in UPR signaling to reduce death of chondrocytes may be promising for future osteoarthritis therapy.
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Affiliation(s)
- Yvonne Rellmann
- Institute of Physiological Chemistry and Pathobiochemistry, Waldeyerstraße 15, 48149 Münster, Germany
| | - Elco Eidhof
- Institute of Physiological Chemistry and Pathobiochemistry, Waldeyerstraße 15, 48149 Münster, Germany
| | - Rita Dreier
- Institute of Physiological Chemistry and Pathobiochemistry, Waldeyerstraße 15, 48149 Münster, Germany.
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37
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Tonomura H, Nagae M, Takatori R, Ishibashi H, Itsuji T, Takahashi K. The Potential Role of Hepatocyte Growth Factor in Degenerative Disorders of the Synovial Joint and Spine. Int J Mol Sci 2020; 21:ijms21228717. [PMID: 33218127 PMCID: PMC7698933 DOI: 10.3390/ijms21228717] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 10/30/2020] [Accepted: 11/16/2020] [Indexed: 02/08/2023] Open
Abstract
This paper aims to provide a comprehensive review of the changing role of hepatocyte growth factor (HGF) signaling in the healthy and diseased synovial joint and spine. HGF is a multifunctional growth factor that, like its specific receptor c-Met, is widely expressed in several bone and joint tissues. HGF has profound effects on cell survival and proliferation, matrix metabolism, inflammatory response, and neurotrophic action. HGF plays an important role in normal bone and cartilage turnover. Changes in HGF/c-Met have also been linked to pathophysiological changes in degenerative joint diseases, such as osteoarthritis (OA) and intervertebral disc degeneration (IDD). A therapeutic role of HGF has been proposed in the regeneration of osteoarticular tissues. HGF also influences bone remodeling and peripheral nerve activity. Studies aimed at elucidating the changing role of HGF/c-Met signaling in OA and IDD at different pathophysiological stages, and their specific molecular mechanisms are needed. Such studies will contribute to safe and effective HGF/c-Met signaling-based treatments for OA and IDD.
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Kawashima K, Ogawa H, Komura S, Ishihara T, Yamaguchi Y, Akiyama H, Matsumoto K. Heparan sulfate deficiency leads to hypertrophic chondrocytes by increasing bone morphogenetic protein signaling. Osteoarthritis Cartilage 2020; 28:1459-1470. [PMID: 32818603 PMCID: PMC7606622 DOI: 10.1016/j.joca.2020.08.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 08/03/2020] [Accepted: 08/11/2020] [Indexed: 02/02/2023]
Abstract
OBJECTIVE Exostosin-1 (EXT1) and EXT2 are the major genetic etiologies of multiple hereditary exostoses and are essential for heparan sulfate (HS) biosynthesis. Previous studies investigating HS in several mouse models of multiple hereditary exostoses have reported that aberrant bone morphogenetic protein (BMP) signaling promotes osteochondroma formation in Ext1-deficient mice. This study examined the mechanism underlying the effects of HS deficiency on BMP/Smad signaling in articular cartilage in a cartilage-specific Ext-/- mouse model. METHOD We generated mice with a conditional Ext1 knockout in cartilage tissue (Ext1-cKO mice) using Prg4-Cre transgenic mice. Structural cartilage alterations were histologically evaluated and phospho-Smad1/5/9 (pSmad1/5/9) expression in mouse chondrocytes was analyzed. The effect of pharmacological intervention of BMP signaling using a specific inhibitor was assessed in the articular cartilage of Ext1-cKO mice. RESULTS Hypertrophic chondrocytes were significantly more abundant (P = 0.021) and cartilage thickness was greater in Ext1-cKO mice at 3 months postnatal than in control littermates (P = 0.036 for femur; and P < 0.001 for tibia). However, osteoarthritis did not spontaneously occur before the 1-year follow-up. matrix metalloproteinase (MMP)-13 and adamalysin-like metalloproteinases with thrombospondin motifs(ADAMTS)-5 were upregulated in hypertrophic chondrocytes of transgenic mice. Immunostaining and western blotting revealed that pSmad1/5/9-positive chondrocytes were more abundant in the articular cartilage of Ext1-cKO mice than in control littermates. Furthermore, the BMP inhibitor significantly decreased the number of hypertrophic chondrocytes in Ext1-cKO mice (P = 0.007). CONCLUSIONS HS deficiency in articular chondrocytes causes chondrocyte hypertrophy, wherein upregulated BMP/Smad signaling partially contributes to this phenotype. HS might play an important role in maintaining the cartilaginous matrix by regulating BMP signaling.
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Affiliation(s)
- K. Kawashima
- Department of Orthopaedic Surgery, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, Japan
| | - H. Ogawa
- Department of Orthopaedic Surgery, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, Japan
| | - S. Komura
- Department of Orthopaedic Surgery, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, Japan
| | - T. Ishihara
- Innovative and Clinical Research Promotion Center, Gifu University Hospital, 1-1 Yanagido, Gifu, Japan
| | - Y. Yamaguchi
- Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA, 92037, USA
| | - H. Akiyama
- Department of Orthopaedic Surgery, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, Japan
| | - K. Matsumoto
- Department of Orthopaedic Surgery, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, Japan,Address correspondence and reprint requests to: K. Matsumoto, Department of Orthopedic Surgery, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, 501-1194, Japan. Tel.: 81-58-230-6333; Fax: 81-58-230-6334. (K. Matsumoto)
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Arthritis and the role of endogenous glucocorticoids. Bone Res 2020; 8:33. [PMID: 32963891 PMCID: PMC7478967 DOI: 10.1038/s41413-020-00112-2] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 07/09/2020] [Accepted: 07/27/2020] [Indexed: 12/17/2022] Open
Abstract
Rheumatoid arthritis and osteoarthritis, the most common forms of arthritis, are chronic, painful, and disabling conditions. Although both diseases differ in etiology, they manifest in progressive joint destruction characterized by pathological changes in the articular cartilage, bone, and synovium. While the potent anti-inflammatory properties of therapeutic (i.e., exogenous) glucocorticoids have been heavily researched and are widely used in clinical practice, the role of endogenous glucocorticoids in arthritis susceptibility and disease progression remains poorly understood. Current evidence from mouse models suggests that local endogenous glucocorticoid signaling is upregulated by the pro-inflammatory microenvironment in rheumatoid arthritis and by aging-related mechanisms in osteoarthritis. Furthermore, these models indicate that endogenous glucocorticoid signaling in macrophages, mast cells, and chondrocytes has anti-inflammatory effects, while signaling in fibroblast-like synoviocytes, myocytes, osteoblasts, and osteocytes has pro-inflammatory actions in rheumatoid arthritis. Conversely, in osteoarthritis, endogenous glucocorticoid signaling in both osteoblasts and chondrocytes has destructive actions. Together these studies provide insights into the role of endogenous glucocorticoids in the pathogenesis of both inflammatory and degenerative joint disease.
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Lin D, Cai B, Wang L, Cai L, Wang Z, Xie J, Lv QX, Yuan Y, Liu C, Shen SGF. A viscoelastic PEGylated poly(glycerol sebacate)-based bilayer scaffold for cartilage regeneration in full-thickness osteochondral defect. Biomaterials 2020; 253:120095. [DOI: 10.1016/j.biomaterials.2020.120095] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 04/29/2020] [Accepted: 05/02/2020] [Indexed: 10/24/2022]
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Rahmani Del Bakhshayesh A, Babaie S, Tayefi Nasrabadi H, Asadi N, Akbarzadeh A, Abedelahi A. An overview of various treatment strategies, especially tissue engineering for damaged articular cartilage. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2020; 48:1089-1104. [DOI: 10.1080/21691401.2020.1809439] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
- Azizeh Rahmani Del Bakhshayesh
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Tissue Engineering, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Soraya Babaie
- Department of Nanotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hamid Tayefi Nasrabadi
- Department of Tissue Engineering, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nahideh Asadi
- Department of Nanotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Abolfazl Akbarzadeh
- Department of Nanotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Abedelahi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Tissue Engineering, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
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Severmann AC, Jochmann K, Feller K, Bachvarova V, Piombo V, Stange R, Holzer T, Brachvogel B, Esko J, Pap T, Hoffmann D, Vortkamp A. An altered heparan sulfate structure in the articular cartilage protects against osteoarthritis. Osteoarthritis Cartilage 2020; 28:977-987. [PMID: 32315715 PMCID: PMC8422443 DOI: 10.1016/j.joca.2020.04.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Revised: 04/05/2020] [Accepted: 04/09/2020] [Indexed: 02/02/2023]
Abstract
OBJECTIVE Osteoarthritis (OA) is a progressive degenerative disease of the articular cartilage caused by an unbalanced activity of proteases, cytokines and other secreted proteins. Since heparan sulfate (HS) determines the activity of many extracellular factors, we investigated its role in OA progression. METHODS To analyze the role of the HS level, OA was induced by anterior cruciate ligament transection (ACLT) in transgenic mice carrying a loss-of-function allele of Ext1 in clones of chondrocytes (Col2-rtTA-Cre;Ext1e2fl/e2fl). To study the impact of the HS sulfation pattern, OA was surgically induced in mice with a heterozygous (Ndst1+/-) or chondrocyte-specific (Col2-Cre;Ndst1fl/fl) loss-of-function allele of the sulfotransferase Ndst1. OA progression was evaluated using the OARSI scoring system. To investigate expression and activity of cartilage degrading proteases, femoral head explants of Ndst1+/- mutants were analyzed by qRT-PCR, Western Blot and gelatin zymography. RESULTS All investigated mouse strains showed reduced OA scores (Col2-rtTA-Cre;Ext1e2fl/e2fl: 0.83; 95% HDI 0.72-0.96; Ndst1+/-: 0.83, 95% HDI 0.74-0.9; Col2-Cre;Ndst1fl/fl: 0.87, 95% HDI 0.76-1). Using cartilage explant cultures of Ndst1 animals, we detected higher amounts of aggrecan degradation products in wildtype samples (NITEGE 4.24-fold, 95% HDI 1.05-18.55; VDIPEN 1.54-fold, 95% HDI 1.54-2.34). Accordingly, gelatin zymography revealed lower Mmp2 activity in mutant samples upon RA-treatment (0.77-fold, 95% HDI: 0.60-0.96). As expression of major proteases and their inhibitors was not altered, HS seems to regulate cartilage degeneration by affecting protease activity. CONCLUSION A decreased HS content or a reduced sulfation level protect against OA progression by regulating protease activity rather than expression.
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Affiliation(s)
- A-C Severmann
- Department of Developmental Biology, Center for Medical Biotechnology, Faculty Biology, University Duisburg-Essen, Germany.
| | - K Jochmann
- Department of Developmental Biology, Center for Medical Biotechnology, Faculty Biology, University Duisburg-Essen, Germany.
| | - K Feller
- Department of Developmental Biology, Center for Medical Biotechnology, Faculty Biology, University Duisburg-Essen, Germany.
| | - V Bachvarova
- Department of Developmental Biology, Center for Medical Biotechnology, Faculty Biology, University Duisburg-Essen, Germany.
| | - V Piombo
- Department of Developmental Biology, Center for Medical Biotechnology, Faculty Biology, University Duisburg-Essen, Germany.
| | - R Stange
- Zentrum für Muskuloskelettale Medizin, Westfälische Wilhelms-Universität Münster, Germany.
| | - T Holzer
- Center for Biochemistry, Department of Pediatrics and Adolescent Medicine, Experimental Neonatology, Medical Faculty, University of Cologne, Germany.
| | - B Brachvogel
- Center for Biochemistry, Department of Pediatrics and Adolescent Medicine, Experimental Neonatology, Medical Faculty, University of Cologne, Germany.
| | - J Esko
- Department of Cellular and Molecular Medicine, Glycobiology Research & Training Center, University of California, San Diego, La Jolla, CA, 92093-0687, USA.
| | - T Pap
- Zentrum für Muskuloskelettale Medizin, Westfälische Wilhelms-Universität Münster, Germany.
| | - D Hoffmann
- Department Bioinformatics and Computational Biophysics, Center for Medical Biotechnology, Faculty Biology, University Duisburg-Essen, Germany.
| | - A Vortkamp
- Department of Developmental Biology, Center for Medical Biotechnology, Faculty Biology, University Duisburg-Essen, Germany.
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Chaly Y, Hostager B, Smith S, Hirsch R. The Follistatin-like Protein 1 Pathway Is Important for Maintaining Healthy Articular Cartilage. ACR Open Rheumatol 2020; 2:407-414. [PMID: 32530126 PMCID: PMC7368136 DOI: 10.1002/acr2.11155] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2018] [Accepted: 05/11/2020] [Indexed: 12/19/2022] Open
Abstract
OBJECTIVE We sought to determine whether follistatin-like protein 1 (FSTL1), a protein produced by articular chondrocytes, promotes healthy articular cartilage and prevents chondrocytes from undergoing terminal differentiation to hypertrophic cells. METHODS In vitro experiments were performed with immortalized human articular chondrocytes. The cells were transduced with a lentivirus encoding human FSTL1 small hairpin RNA or with an adenovirus encoding FSTL1. A quantitative polymerase chain reaction was used for gene expression analysis. Protein expression was assessed by Western blotting. Co-immunoprecipitation was used to identify interacting partners of FSTL1. FSTL1 expression in human articular cartilage was analyzed using confocal microscopy. RESULTS Downregulation of FSTL1 expression in transforming growth factor β (TGFβ)-stimulated chondrocyte pellet cultures led to chondrocyte terminal differentiation characterized by poor production of cartilage extracellular matrix and altered expression of genes and proteins involved in cartilage homeostasis, including MMP13, COL10A1, RUNX2, COL2A1, ACAN, Sox9, and phospho-Smad3. We also showed that FSTL1 interacts with TGFβ receptor proteins, Alk1 and endoglin, suggesting a potential mechanism for its effects on chondrocytes. Transduction of chondrocytes with an FSTL1 transgene increased COL2A1 expression, whereas it did not affect MMP13 expression. FSTL1 protein expression was decreased in human osteoarthritic cartilage in situ. CONCLUSION Our data suggest that FSTL1 plays an important role in maintaining healthy articular cartilage and the FSTL1 pathway may represent a therapeutic target for degenerative diseases of cartilage.
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Affiliation(s)
- Yury Chaly
- University of Iowa Carver College of MedicineIowa City
| | | | - Sonja Smith
- University of Iowa Carver College of MedicineIowa City
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Tarquini C, Pucci S, Scioli MG, Doldo E, Agostinelli S, D'Amico F, Bielli A, Ferlosio A, Caredda E, Tarantino U, Orlandi A. Clusterin exerts a cytoprotective and antioxidant effect in human osteoarthritic cartilage. Aging (Albany NY) 2020; 12:10129-10146. [PMID: 32516132 PMCID: PMC7346069 DOI: 10.18632/aging.103310] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Accepted: 04/28/2020] [Indexed: 12/31/2022]
Abstract
Osteoarthritis (OA) is the most common joint disease characterized by destruction of articular cartilage. OA-induced cartilage degeneration causes inflammation, oxidative stress and the hypertrophic shift of quiescent chondrocytes. Clusterin (CLU) is a ubiquitous glycoprotein implicated in many cellular processes and its upregulation has been recently reported in OA cartilage. However, the specific role of CLU in OA cartilage injury has not been investigated yet. We analyzed CLU expression in human articular cartilage in vivo and in cartilage-derived chondrocytes in vitro. CLU knockdown in OA chondrocytes was also performed and its effect on proliferation, hypertrophic phenotype, apoptosis, inflammation and oxidative stress was investigated. CLU expression was upregulated in human OA cartilage and in cultured OA cartilage-derived chondrocytes compared with control group. CLU knockdown reduced cell proliferation and increased hypertrophic phenotype as well as apoptotic death. CLU-silenced OA chondrocytes showed higher MMP13 and COL10A1 as well as greater TNF-α, Nox4 and ROS levels. Our results indicate a possible cytoprotective role of CLU in OA chondrocytes promoting cell survival by its anti-apoptotic, anti-inflammatory and antioxidant properties and counteracting the hypertrophic phenotypic shift. Further studies are needed to deepen the role of CLU in order to identify a new potential therapeutic target for OA.
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Affiliation(s)
- Chiara Tarquini
- Anatomic Pathology, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy.,Orthopedics and Traumatology, Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Sabina Pucci
- Anatomic Pathology, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | - Maria Giovanna Scioli
- Anatomic Pathology, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | - Elena Doldo
- Anatomic Pathology, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | - Sara Agostinelli
- Anatomic Pathology, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | - Federico D'Amico
- Anatomic Pathology, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | - Alessandra Bielli
- Anatomic Pathology, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | - Amedeo Ferlosio
- Anatomic Pathology, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | - Emanuele Caredda
- Hygiene and Preventive Medicine, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | - Umberto Tarantino
- Orthopedics and Traumatology, Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Augusto Orlandi
- Anatomic Pathology, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy.,Department of Biomedical Sciences, Catholic University Our Lady of Good Counsel, Tirana, Albania
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Liu N, Fu D, Yang J, Liu P, Song X, Wang X, Li R, Fu Z, Chen J, Gong X, Chen C, Yang L. Asiatic acid attenuates hypertrophic and fibrotic differentiation of articular chondrocytes via AMPK/PI3K/AKT signaling pathway. Arthritis Res Ther 2020; 22:112. [PMID: 32398124 PMCID: PMC7218496 DOI: 10.1186/s13075-020-02193-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Accepted: 04/22/2020] [Indexed: 12/14/2022] Open
Abstract
Background Osteoarthritis (OA), the most common joint disorder, is characterized by a progressive degradation of articular cartilage. Increasing evidence suggests that OA is closely associated with cartilage pathologies including chondrocyte hypertrophy and fibrosis. Methods In this study, we showed that asiatic acid (AA) treatment reduced chondrocyte hypertrophy and fibrosis. First, the cytotoxicity of AA (0, 5, 10, and 20 μM) to chondrocytes was evaluated, and 5 μM was selected for subsequent experiments. Then, we detected the gene and protein level of chondrocyte hypertrophic markers including type X collagen (COL-X), matrix metalloproteinase-13 (MMP-13), alkaline phosphatase (ALP), and runt-related transcription factor 2 (Runx2); chondrocyte fibrosis markers including type I collagen (COL-Ι) and alpha-smooth muscle actin (α-SMA); and chondrogenic markers including SRY-related HMG box 9 (SOX9), type II collagen (COL-II), and aggrecan (ACAN). Further, we tested the mechanism of AA on inhibiting chondrocyte hypertrophy and fibrosis. Finally, we verified the results in an anterior cruciate ligament transection (ACLT) rat OA model. Results We found that AA treatment inhibited the hypertrophic and fibrotic phenotype of chondrocytes, without affecting the chondrogenic phenotype. Moreover, we found that AA treatment activated AMP-activated protein kinase (AMPK) and inhibited phosphoinositide-3 kinase/protein kinase B (PI3K/AKT) signaling pathway in vitro. The results in an ACLT rat OA model also indicated that AA significantly attenuated chondrocyte hypertrophy and fibrosis. Conclusion AA treatment could reduce hypertrophic and fibrotic differentiation and maintain the chondrogenic phenotype of articular chondrocytes by targeting the AMPK/PI3K/AKT signaling pathway. Our study suggested that AA might be a prospective drug component that targets hypertrophic and fibrotic chondrocytes for OA treatment.
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Affiliation(s)
- Na Liu
- Key Laboratory of Freshwater Fish Reproduction and Development, Ministry of Education, Laboratory of Molecular Developmental Biology, School of Life Sciences, Southwest University, Chongqing, China.,Center for Joint Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Dejie Fu
- Center for Joint Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Junjun Yang
- Center for Joint Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Pingju Liu
- Zunyi Traditional Chinese Medicine Hospital, Zunyi, China
| | - Xiongbo Song
- Center for Joint Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Xin Wang
- Center for Joint Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Rui Li
- Center for Joint Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Zhenlan Fu
- Center for Joint Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Jiajia Chen
- Biomedical Analysis Center, Third Military Medical University (Army Medical University), Chongqing, China
| | - Xiaoyuan Gong
- Center for Joint Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Cheng Chen
- College of Medical Informatics, Chongqing Medical University, Chongqing, China.
| | - Liu Yang
- Center for Joint Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China.
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Liu X, Shortt C, Zhang F, Bater MQ, Cowman MK, Kirsch T. Extracellular Vesicles Released From Articular Chondrocytes Play a Major Role in Cell-Cell Communication. J Orthop Res 2020; 38:731-739. [PMID: 31736104 PMCID: PMC7071989 DOI: 10.1002/jor.24525] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Accepted: 11/03/2019] [Indexed: 02/04/2023]
Abstract
The purpose of this investigation was to determine the role of extracellular vesicles (EVs), released from articular chondrocytes in a physiological or pathological state, in cell-cell communication with other articular chondrocytes or chondrocyte precursor cells. The conditioned medium from interleukin-1β (IL-1β)-treated human articular chondrocytes stimulated catabolic events and inhibited type II collagen expression in articular chondrocytes to a much greater degree than medium from IL-1β-treated chondrocytes after complete removal of EVs. The vehicle-treated and IL-1β-treated human articular chondrocytes released EVs of similar size; however, the number of EVs released by IL-1β-treated chondrocytes was markedly higher than the number of EVs released from the vehicle-treated cells. Furthermore, our findings demonstrate that similar to medium from IL-1β-treated chondrocytes containing EVs, EVs isolated from medium of IL-1β-treated chondrocytes stimulated catabolic events in articular chondrocytes, whereas EVs isolated from the medium of vehicle-treated chondrocytes inhibited catabolic events and increased messenger RNA levels of aggrecan and type II collagen in IL-1β-treated chondrocytes. Furthermore, the medium containing EVs from vehicle-treated articular chondrocytes or EVs isolated from this medium stimulated chondrogenesis of C3H10T1/2 cells, whereas medium containing EVs from IL-1β-treated chondrocytes or EVs isolated from this medium inhibited chondrogenesis. Our findings suggest that EVs released by articular chondrocytes play a key role in the communication between joint cells and ultimately in joint homeostasis, maintenance, pathology, and repair. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:731-739, 2020.
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Affiliation(s)
- Xiaoming Liu
- Musculoskeletal Research Center, Department of Orthopaedic Surgery, New York University School of Medicine, New York, NY, USA,Current addresses: Department of Spinal Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Claire Shortt
- Musculoskeletal Research Center, Department of Orthopaedic Surgery, New York University School of Medicine, New York, NY, USA,Current addresses: FoodMarble Digestive Health, Dublin 2, Ireland
| | - Fenglin Zhang
- Musculoskeletal Research Center, Department of Orthopaedic Surgery, New York University School of Medicine, New York, NY, USA
| | - Mariah Q. Bater
- Department of Biomedical Engineering, New York University Tandon School of Engineering, New York, NY, USA
| | - Mary K. Cowman
- Musculoskeletal Research Center, Department of Orthopaedic Surgery, New York University School of Medicine, New York, NY, USA,Department of Biomedical Engineering, New York University Tandon School of Engineering, New York, NY, USA
| | - Thorsten Kirsch
- Musculoskeletal Research Center, Department of Orthopaedic Surgery, New York University School of Medicine, New York, NY, USA,Department of Biomedical Engineering, New York University Tandon School of Engineering, New York, NY, USA
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Maturation of the equine medial femoral condyle osteochondral unit. OSTEOARTHRITIS AND CARTILAGE OPEN 2020; 2:100029. [DOI: 10.1016/j.ocarto.2020.100029] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Accepted: 01/16/2020] [Indexed: 12/15/2022] Open
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Mukherjee S, Nazemi M, Jonkers I, Geris L. Use of Computational Modeling to Study Joint Degeneration: A Review. Front Bioeng Biotechnol 2020; 8:93. [PMID: 32185167 PMCID: PMC7058554 DOI: 10.3389/fbioe.2020.00093] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Accepted: 01/31/2020] [Indexed: 12/13/2022] Open
Abstract
Osteoarthritis (OA), a degenerative joint disease, is the most common chronic condition of the joints, which cannot be prevented effectively. Computational modeling of joint degradation allows to estimate the patient-specific progression of OA, which can aid clinicians to estimate the most suitable time window for surgical intervention in osteoarthritic patients. This paper gives an overview of the different approaches used to model different aspects of joint degeneration, thereby focusing mostly on the knee joint. The paper starts by discussing how OA affects the different components of the joint and how these are accounted for in the models. Subsequently, it discusses the different modeling approaches that can be used to answer questions related to OA etiology, progression and treatment. These models are ordered based on their underlying assumptions and technologies: musculoskeletal models, Finite Element models, (gene) regulatory models, multiscale models and data-driven models (artificial intelligence/machine learning). Finally, it is concluded that in the future, efforts should be made to integrate the different modeling techniques into a more robust computational framework that should not only be efficient to predict OA progression but also easily allow a patient’s individualized risk assessment as screening tool for use in clinical practice.
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Affiliation(s)
- Satanik Mukherjee
- Prometheus, Division of Skeletal Tissue Engineering, KU Leuven, Leuven, Belgium.,Biomechanics Section, KU Leuven, Leuven, Belgium
| | - Majid Nazemi
- GIGA in silico Medicine, University of Liège, Liège, Belgium
| | - Ilse Jonkers
- Human Movement Biomechanics Research Group, Department of Movement Sciences, KU Leuven, Leuven, Belgium
| | - Liesbet Geris
- Prometheus, Division of Skeletal Tissue Engineering, KU Leuven, Leuven, Belgium.,Biomechanics Section, KU Leuven, Leuven, Belgium.,GIGA in silico Medicine, University of Liège, Liège, Belgium
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Kronemberger GS, Matsui RAM, Miranda GDASDCE, Granjeiro JM, Baptista LS. Cartilage and bone tissue engineering using adipose stromal/stem cells spheroids as building blocks. World J Stem Cells 2020; 12:110-122. [PMID: 32184936 PMCID: PMC7062040 DOI: 10.4252/wjsc.v12.i2.110] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Revised: 10/19/2019] [Accepted: 01/15/2020] [Indexed: 02/06/2023] Open
Abstract
Scaffold-free techniques in the developmental tissue engineering area are designed to mimic in vivo embryonic processes with the aim of biofabricating, in vitro, tissues with more authentic properties. Cell clusters called spheroids are the basis for scaffold-free tissue engineering. In this review, we explore the use of spheroids from adult mesenchymal stem/stromal cells as a model in the developmental engineering area in order to mimic the developmental stages of cartilage and bone tissues. Spheroids from adult mesenchymal stromal/stem cells lineages recapitulate crucial events in bone and cartilage formation during embryogenesis, and are capable of spontaneously fusing to other spheroids, making them ideal building blocks for bone and cartilage tissue engineering. Here, we discuss data from ours and other labs on the use of adipose stromal/stem cell spheroids in chondrogenesis and osteogenesis in vitro. Overall, recent studies support the notion that spheroids are ideal "building blocks" for tissue engineering by “bottom-up” approaches, which are based on tissue assembly by advanced techniques such as three-dimensional bioprinting. Further studies on the cellular and molecular mechanisms that orchestrate spheroid fusion are now crucial to support continued development of bottom-up tissue engineering approaches such as three-dimensional bioprinting.
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Affiliation(s)
- Gabriela S Kronemberger
- Laboratory of Tissue Bioengineering, Directory of Metrology Applied to Life Sciences, National Institute of Metrology, Quality and Technology (INMETRO), Duque de Caxias, RJ 25250-020, Brazil
- Post-graduate Program in Translational Biomedicine (Biotrans), Unigranrio, Campus I, Duque de Caxias, RJ 25250-020, Brazil
| | - Renata Akemi Morais Matsui
- Laboratory of Tissue Bioengineering, Directory of Metrology Applied to Life Sciences, National Institute of Metrology, Quality and Technology (INMETRO), Duque de Caxias, RJ 25250-020, Brazil
- Post-graduate Program in Biotechnology, National Institute of Metrology, Quality and Technology (INMETRO), Duque de Caxias, RJ 25250-020, Brazil
| | - Guilherme de Almeida Santos de Castro e Miranda
- Laboratory of Tissue Bioengineering, Directory of Metrology Applied to Life Sciences, National Institute of Metrology, Quality and Technology (INMETRO), Duque de Caxias, RJ 25250-020, Brazil
- Federal University of Rio de Janeiro (UFRJ), Campus Duque de Caxias, Duque de Caxias, RJ 25250-020, Brazil
| | - José Mauro Granjeiro
- Laboratory of Tissue Bioengineering, Directory of Metrology Applied to Life Sciences, National Institute of Metrology, Quality and Technology (INMETRO), Duque de Caxias, RJ 25250-020, Brazil
- Post-graduate Program in Biotechnology, National Institute of Metrology, Quality and Technology (INMETRO), Duque de Caxias, RJ 25250-020, Brazil
- Laboratory of Clinical Research in Odontology, Fluminense Federal University (UFF), Niterói 25255-030 Brazil
| | - Leandra Santos Baptista
- Laboratory of Tissue Bioengineering, Directory of Metrology Applied to Life Sciences, National Institute of Metrology, Quality and Technology (INMETRO), Duque de Caxias, RJ 25250-020, Brazil
- Post-graduate Program in Translational Biomedicine (Biotrans), Unigranrio, Campus I, Duque de Caxias, RJ 25250-020, Brazil
- Post-graduate Program in Biotechnology, National Institute of Metrology, Quality and Technology (INMETRO), Duque de Caxias, RJ 25250-020, Brazil
- Multidisciplinary Center for Biological Research (Numpex-Bio), Federal University of Rio de Janeiro (UFRJ) Campus Duque de Caxias, Duque de Caxias, RJ 25245-390, Brazil
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50
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Pathomechanisms of Posttraumatic Osteoarthritis: Chondrocyte Behavior and Fate in a Precarious Environment. Int J Mol Sci 2020; 21:ijms21051560. [PMID: 32106481 PMCID: PMC7084733 DOI: 10.3390/ijms21051560] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 02/18/2020] [Accepted: 02/21/2020] [Indexed: 02/07/2023] Open
Abstract
Traumatic injuries of the knee joint result in a wide variety of pathomechanisms, which contribute to the development of so-called posttraumatic osteoarthritis (PTOA). These pathogenetic processes include oxidative stress, excessive expression of catabolic enzymes, release of damage-associated molecular patterns (DAMPs), and synovial inflammation. The present review focuses on the underlying pathomechanisms of PTOA and in particular the behavior and fate of the surviving chondrocytes, comprising chondrocyte metabolism, regulated cell death, and phenotypical changes comprising hypertrophy and senescence. Moreover, possible therapeutic strategies, such as chondroanabolic stimulation, anti-oxidative and anti-inflammatory treatment, as well as novel therapeutic targets are discussed.
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