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Zhang HA, Zhang BY, Tang HB. Effects of macrophages on the osteogenic differentiation of adipose tissue-derived stem cells in two-dimensional and three-dimensional cocultures. World J Stem Cells 2025; 17:99326. [DOI: 10.4252/wjsc.v17.i2.99326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 11/24/2024] [Accepted: 01/23/2025] [Indexed: 02/24/2025] Open
Abstract
BACKGROUND Fracture is one of the most pervasive injuries in the musculoskeletal system, and there is a complex interaction between macrophages and adipose tissue-derived stem cells (ADSCs) in fracture healing. However, two-dimensional (2D) coculture of macrophages and ADSCs can not accurately mimic the in vivo cell microenvironment.
AIM To establish both 2D and 3D osteogenic coculture models to investigate the interaction between macrophages and ADSCs.
METHODS After obtaining ADSCs from surgery and inducing differentiation of the THP1 cell line, we established 2D and 3D osteogenic coculture models. To assess the level of osteogenic differentiation, we used alizarin red staining and measured the relative expression levels of osteogenic differentiation markers osteocalcin, Runt-related transcription factor 2, and alkaline phosphatase through polymerase chain reaction. Verification was conducted by analyzing the expression changes of N-cadherin and the activation of the Wnt/β-catenin signaling pathway using western blotting.
RESULTS In this study, it was discovered that macrophages in 3D culture inhibited osteogenic differentiation of ADSCs, contrary to the effect in 2D culture. This observation confirmed the significance of intricate intercellular connections in the 3D culture environment. Additionally, the 3D culture group exhibited significantly higher N-cadherin expression and showed reduced β-catenin and Wnt1 protein levels compared to the 2D culture group.
CONCLUSION Macrophages promoted ADSC osteogenic differentiation in 2D culture conditions but inhibited it in 3D culture. The 3D culture environment might inhibit the Wnt/β-catenin signaling pathway by upregulating N-cadherin expression, ultimately hindering the osteogenic differentiation of ADSCs. By investigating the process of osteogenesis in ADSCs, this study provides novel ideas for exploring 3D osteogenesis in ADSCs, fracture repair, and other bone trauma repair.
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Affiliation(s)
- He-Ao Zhang
- Department of Plastic and Cosmetic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Bo-Yu Zhang
- Department of Plastic and Cosmetic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Hong-Bo Tang
- Department of Plastic and Cosmetic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
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Burgan J, Rahmati M, Lee M, Saiz AM. Innate immune response to bone fracture healing. Bone 2025; 190:117327. [PMID: 39522707 DOI: 10.1016/j.bone.2024.117327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 11/05/2024] [Accepted: 11/07/2024] [Indexed: 11/16/2024]
Abstract
The field of osteoimmunology has primarily focused on fracture healing in isolated musculoskeletal injuries. The innate immune system is the initial response to fracture, with inflammatory macrophages, cytokines, and neutrophils arriving first at the fracture hematoma, followed by an anti-inflammatory phase to begin the process of new bone formation. This review aims to first discuss the current literature and knowledge gaps on the immune responses governing single fracture healing by encompassing the individual role of macrophages, neutrophils, cytokines, mesenchymal stem cells, bone cells, and other immune cells. This paper discusses the interactive effects of these cellular responses underscoring the field of osteoimmunology. The critical role of the metabolic environment in guiding the immune system properties will be highlighted along with some effective therapeutics for fracture healing in the context of osteoimmunology. However, compared to isolated fractures, which frequently heal well, long bone fractures in over 30 % of polytrauma patients exhibit impaired healing. Clinical evidence suggests there may be distinct physiologic and inflammatory pathways altered in polytrauma resulting in nonunion. Nonunion is associated with worse patient outcomes and increased societal healthcare costs. The dysregulated immunomodulatory/inflammatory response seen in polytrauma may lead to this increased nonunion rate. This paper will investigate the differences in immune response between isolated and polytrauma fractures. Finally, future directions for fracture studies are explored with consideration of the emerging roles of newly discovered immune cell functions in fracture healing, the existing challenges and conflicting results in the field, the translational potential of these studies in clinic, and the more complex nature of polytrauma fractures that can alter cell functions in different tissues.
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Affiliation(s)
- Jane Burgan
- Department of Orthopaedic Surgery, UC Davis Health, 4860 Y Street, Suite 3800, Sacramento, CA 95817, USA; Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA
| | - Maryam Rahmati
- Department of Orthopaedic Surgery, UC Davis Health, 4860 Y Street, Suite 3800, Sacramento, CA 95817, USA; Department of Biomaterials, Institute for Clinical Dentistry, University of Oslo, PO Box 1109, Blindern, NO-0317 Oslo, Norway
| | - Mark Lee
- Department of Orthopaedic Surgery, UC Davis Health, 4860 Y Street, Suite 3800, Sacramento, CA 95817, USA
| | - Augustine Mark Saiz
- Department of Orthopaedic Surgery, UC Davis Health, 4860 Y Street, Suite 3800, Sacramento, CA 95817, USA.
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Abstract
PURPOSE Dental implant osseointegration comprises two types of bone formation-contact and distance osteogenesis-which result in bone formation originating from the implant surface or bone edges, respectively. The physicochemical properties of the implant surface regulate initial contact osteogenesis by directly tuning the osteoprogenitor cells in the peri-implant environment. However, whether these implant surface properties can regulate osteoprogenitor cells distant from the implant remains unclear. Innate immune cells, including neutrophils and macrophages, govern bone metabolism, suggesting their involvement in osseointegration and distance osteogenesis. This narrative review discusses the role of innate immunity in osseointegration and the effects of implant surface properties on distant osteogenesis, focusing on innate immune regulation. STUDY SELECTION The role of innate immunity in bone formation and the effects of implant surface properties on innate immune function were reviewed based on clinical, animal, and in vitro studies. RESULTS Neutrophils and macrophages are responsible for bone formation during osseointegration, via inflammatory mediators. The microroughness and hydrophilic status of titanium implants have the potential to alleviate this inflammatory response of neutrophils, and induce an anti-inflammatory response in macrophages, to tune both contact and distance osteogenesis through the activation of osteoblasts. Thus, the surface micro-roughness and hydrophilicity of implants can regulate the function of distant osteoprogenitor cells through innate immune cells. CONCLUSIONS Surface modification of implants aimed at regulating innate immunity may be useful in promoting further osteogenesis and overcoming the limitations encountered in severe situations, such as early loading protocol application.
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Affiliation(s)
- Takeru Kondo
- Division of Molecular and Regenerative Prosthodontics, Tohoku University Graduate School of Dentistry, Sendai, Japan
| | - Masahiro Yamada
- Division of Molecular and Regenerative Prosthodontics, Tohoku University Graduate School of Dentistry, Sendai, Japan
| | - Hiroshi Egusa
- Division of Molecular and Regenerative Prosthodontics, Tohoku University Graduate School of Dentistry, Sendai, Japan
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Vu EK, Karkache IY, Pham A, Koroth J, Bradley EW. Hdac3 deficiency limits periosteal reaction associated with Western diet feeding in female mice. J Cell Mol Med 2024; 28:e70081. [PMID: 39261913 PMCID: PMC11390340 DOI: 10.1111/jcmm.70081] [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: 07/03/2024] [Revised: 08/25/2024] [Accepted: 09/01/2024] [Indexed: 09/13/2024] Open
Abstract
Diet-induced obesity is associated with enhanced systemic inflammation that limits bone regeneration. HDAC inhibitors are currently being explored as anti-inflammatory agents. Prior reports show that myeloid progenitor-directed Hdac3 ablation enhances intramembranous bone healing in female mice. In this study, we determined if Hdac3 ablation increased intramembranous bone regeneration in mice fed a high-fat/high-sugar (HFD) diet. Micro-CT analyses demonstrated that HFD-feeding enhanced the formation of periosteal reaction tissue of control littermates, reflective of suboptimal bone healing. We confirmed enhanced bone volume within the defect of Hdac3-ablated females and showed that Hdac3 ablation reduced the amount of periosteal reaction tissue following HFD feeding. Osteoblasts cultured in a conditioned medium derived from Hdac3-ablated cells exhibited a four-fold increase in mineralization and enhanced osteogenic gene expression. We found that Hdac3 ablation elevated the secretion of several chemokines, including CCL2. We then confirmed that Hdac3 deficiency increased the expression of Ccl2. Lastly, we show that the proportion of CCL2-positve cells within bone defects was significantly higher in Hdac3-deficient mice and was further enhanced by HFD. Overall, our studies demonstrate that Hdac3 deletion enhances intramembranous bone healing in a setting of diet-induced obesity, possibly through increased production of CCL2 by macrophages within the defect.
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Affiliation(s)
- Elizabeth K. Vu
- Department of Orthopedic SurgeryMedical School, University of MinnesotaMinneapolisMNUSA
| | - Ismael Y. Karkache
- Comparative Molecular BiosciencesSchool of Veterinary MedicineSt. PaulMNUSA
| | - Anthony Pham
- Department of Orthopedic SurgeryMedical School, University of MinnesotaMinneapolisMNUSA
| | - Jinsha Koroth
- Department of Orthopedic SurgeryMedical School, University of MinnesotaMinneapolisMNUSA
| | - Elizabeth W. Bradley
- Department of Orthopedic SurgeryMedical School, University of MinnesotaMinneapolisMNUSA
- Comparative Molecular BiosciencesSchool of Veterinary MedicineSt. PaulMNUSA
- Stem Cell Institute, University of MinnesotaMinneapolisMNUSA
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Batoon L, Koh AJ, Millard SM, Grewal J, Choo FM, Kannan R, Kinnaird A, Avey M, Teslya T, Pettit AR, McCauley LK, Roca H. Induction of osteoblast apoptosis stimulates macrophage efferocytosis and paradoxical bone formation. Bone Res 2024; 12:43. [PMID: 39103355 DOI: 10.1038/s41413-024-00341-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2023] [Revised: 04/03/2024] [Accepted: 05/09/2024] [Indexed: 08/07/2024] Open
Abstract
Apoptosis is crucial for tissue homeostasis and organ development. In bone, apoptosis is recognized to be a main fate of osteoblasts, yet the relevance of this process remains underexplored. Using our murine model with inducible Caspase 9, the enzyme that initiates intrinsic apoptosis, we triggered apoptosis in a proportion of mature osteocalcin (OCN+) osteoblasts and investigated the impact on postnatal bone development. Osteoblast apoptosis stimulated efferocytosis by osteal macrophages. A five-week stimulation of OCN+ osteoblast apoptosis in 3-week-old male and female mice significantly enhanced vertebral bone formation while increasing osteoblast precursors. A similar treatment regimen to stimulate osterix+ cell apoptosis had no impact on bone volume or density. The vertebral bone accrual following stimulation of OCN+ osteoblast apoptosis did not translate in improved mechanical strength due to disruption of the lacunocanalicular network. The observed bone phenotype was not influenced by changes in osteoclasts but was associated with stimulation of macrophage efferocytosis and vasculature formation. Phenotyping of efferocytic macrophages revealed a unique transcriptomic signature and expression of factors including VEGFA. To examine whether macrophages participated in the osteoblast precursor increase following osteoblast apoptosis, macrophage depletion models were employed. Depletion of macrophages via clodronate-liposomes and the CD169-diphtheria toxin receptor mouse model resulted in marked reduction in leptin receptor+ and osterix+ osteoblast precursors. Collectively, this work demonstrates the significance of osteoblast turnover via apoptosis and efferocytosis in postnatal bone formation. Importantly, it exposes the potential of targeting this mechanism to promote bone anabolism in the clinical setting.
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Affiliation(s)
- Lena Batoon
- Department of Periodontics and Oral Medicine, University of Michigan, School of Dentistry, Ann Arbor, MI, 48109, USA
| | - Amy Jean Koh
- Department of Periodontics and Oral Medicine, University of Michigan, School of Dentistry, Ann Arbor, MI, 48109, USA
| | - Susan Marie Millard
- Mater Research Institute, The University of Queensland, Brisbane, QLD, 4102, Australia
| | - Jobanpreet Grewal
- Department of Periodontics and Oral Medicine, University of Michigan, School of Dentistry, Ann Arbor, MI, 48109, USA
| | - Fang Ming Choo
- Mater Research Institute, The University of Queensland, Brisbane, QLD, 4102, Australia
| | - Rahasudha Kannan
- Department of Periodontics and Oral Medicine, University of Michigan, School of Dentistry, Ann Arbor, MI, 48109, USA
| | - Aysia Kinnaird
- Department of Periodontics and Oral Medicine, University of Michigan, School of Dentistry, Ann Arbor, MI, 48109, USA
| | - Megan Avey
- Department of Periodontics and Oral Medicine, University of Michigan, School of Dentistry, Ann Arbor, MI, 48109, USA
| | - Tatyana Teslya
- Department of Periodontics and Oral Medicine, University of Michigan, School of Dentistry, Ann Arbor, MI, 48109, USA
| | - Allison Robyn Pettit
- Mater Research Institute, The University of Queensland, Brisbane, QLD, 4102, Australia
| | - Laurie K McCauley
- Department of Periodontics and Oral Medicine, University of Michigan, School of Dentistry, Ann Arbor, MI, 48109, USA.
- Department of Pathology, University of Michigan, Medical School, Ann Arbor, MI, 48109, USA.
| | - Hernan Roca
- Department of Periodontics and Oral Medicine, University of Michigan, School of Dentistry, Ann Arbor, MI, 48109, USA.
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Li L, Zhai M, Cheng C, Cui S, Wang J, Zhang Z, Liu J, Wei F. Mechanically induced M2 macrophages are involved in bone remodeling of the midpalatal suture during palatal expansion. Prog Orthod 2024; 25:30. [PMID: 39098934 PMCID: PMC11298508 DOI: 10.1186/s40510-024-00529-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Accepted: 05/30/2024] [Indexed: 08/06/2024] Open
Abstract
BACKGROUND Palatal expansion is a common way of treating maxillary transverse deficiency. Under mechanical force, the midpalatal suture is expanded, causing local immune responses. This study aimed to determine whether macrophages participate in bone remodeling of the midpalatal suture during palatal expansion and the effects on bone remodeling. METHODS Palatal expansion model and macrophage depletion model were established. Micro-CT, histological staining, and immunohistochemical staining were used to investigate the changes in the number and phenotype of macrophages during palatal expansion as well as the effects on bone remodeling of the midpalatal suture. Additionally, the effect of mechanically induced M2 macrophages on palatal osteoblasts was also elucidated in vitro. RESULTS The number of macrophages increased significantly and polarized toward M2 phenotype with the increase of the expansion time, which was consistent with the trend of bone remodeling. After macrophage depletion, the function of osteoblasts and bone formation at the midpalatal suture were impaired during palatal expansion. In vitro, conditioned medium derived from M2 macrophages facilitated osteogenic differentiation of osteoblasts and decreased the RANKL/OPG ratio. CONCLUSIONS Macrophages through polarizing toward M2 phenotype participated in midpalatal suture bone remodeling during palatal expansion, which may provide a new idea for promoting bone remodeling from the perspective of regulating macrophage polarization.
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Affiliation(s)
- Lan Li
- Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Shandong University, No.44-1 Wenhua Road West, Shandong, Jinan, 250012, China
| | - Mingrui Zhai
- Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Shandong University, No.44-1 Wenhua Road West, Shandong, Jinan, 250012, China
| | - Chen Cheng
- Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Shandong University, No.44-1 Wenhua Road West, Shandong, Jinan, 250012, China
| | - Shuyue Cui
- Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Shandong University, No.44-1 Wenhua Road West, Shandong, Jinan, 250012, China
| | - Jixiao Wang
- Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Shandong University, No.44-1 Wenhua Road West, Shandong, Jinan, 250012, China
| | - Zijie Zhang
- Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Shandong University, No.44-1 Wenhua Road West, Shandong, Jinan, 250012, China
| | - Jiani Liu
- Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Shandong University, No.44-1 Wenhua Road West, Shandong, Jinan, 250012, China
| | - Fulan Wei
- Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Shandong University, No.44-1 Wenhua Road West, Shandong, Jinan, 250012, China.
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7
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Huang R, Kang T, Chen S. The role of tumor-associated macrophages in tumor immune evasion. J Cancer Res Clin Oncol 2024; 150:238. [PMID: 38713256 PMCID: PMC11076352 DOI: 10.1007/s00432-024-05777-4] [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: 03/01/2024] [Accepted: 05/03/2024] [Indexed: 05/08/2024]
Abstract
BACKGROUND Tumor growth is closely linked to the activities of various cells in the tumor microenvironment (TME), particularly immune cells. During tumor progression, circulating monocytes and macrophages are recruited, altering the TME and accelerating growth. These macrophages adjust their functions in response to signals from tumor and stromal cells. Tumor-associated macrophages (TAMs), similar to M2 macrophages, are key regulators in the TME. METHODS We review the origins, characteristics, and functions of TAMs within the TME. This analysis includes the mechanisms through which TAMs facilitate immune evasion and promote tumor metastasis. Additionally, we explore potential therapeutic strategies that target TAMs. RESULTS TAMs are instrumental in mediating tumor immune evasion and malignant behaviors. They release cytokines that inhibit effector immune cells and attract additional immunosuppressive cells to the TME. TAMs primarily target effector T cells, inducing exhaustion directly, influencing activity indirectly through cellular interactions, or suppressing through immune checkpoints. Additionally, TAMs are directly involved in tumor proliferation, angiogenesis, invasion, and metastasis. Developing innovative tumor-targeted therapies and immunotherapeutic strategies is currently a promising focus in oncology. Given the pivotal role of TAMs in immune evasion, several therapeutic approaches have been devised to target them. These include leveraging epigenetics, metabolic reprogramming, and cellular engineering to repolarize TAMs, inhibiting their recruitment and activity, and using TAMs as drug delivery vehicles. Although some of these strategies remain distant from clinical application, we believe that future therapies targeting TAMs will offer significant benefits to cancer patients.
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Affiliation(s)
- Ruizhe Huang
- Department of Oncology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
| | - Ting Kang
- Department of Oncology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
| | - Siyu Chen
- Department of Oncology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.
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8
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Mou K, Chan SMH, Vlahos R. Musculoskeletal crosstalk in chronic obstructive pulmonary disease and comorbidities: Emerging roles and therapeutic potentials. Pharmacol Ther 2024; 257:108635. [PMID: 38508342 DOI: 10.1016/j.pharmthera.2024.108635] [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: 11/06/2023] [Revised: 02/13/2024] [Accepted: 03/11/2024] [Indexed: 03/22/2024]
Abstract
Chronic Obstructive Pulmonary Disease (COPD) is a multifaceted respiratory disorder characterized by progressive airflow limitation and systemic implications. It has become increasingly apparent that COPD exerts its influence far beyond the respiratory system, extending its impact to various organ systems. Among these, the musculoskeletal system emerges as a central player in both the pathogenesis and management of COPD and its associated comorbidities. Muscle dysfunction and osteoporosis are prevalent musculoskeletal disorders in COPD patients, leading to a substantial decline in exercise capacity and overall health. These manifestations are influenced by systemic inflammation, oxidative stress, and hormonal imbalances, all hallmarks of COPD. Recent research has uncovered an intricate interplay between COPD and musculoskeletal comorbidities, suggesting that muscle and bone tissues may cross-communicate through the release of signalling molecules, known as "myokines" and "osteokines". We explored this dynamic relationship, with a particular focus on the role of the immune system in mediating the cross-communication between muscle and bone in COPD. Moreover, we delved into existing and emerging therapeutic strategies for managing musculoskeletal disorders in COPD. It underscores the development of personalized treatment approaches that target both the respiratory and musculoskeletal aspects of COPD, offering the promise of improved well-being and quality of life for individuals grappling with this complex condition. This comprehensive review underscores the significance of recognizing the profound impact of COPD on the musculoskeletal system and its comorbidities. By unravelling the intricate connections between these systems and exploring innovative treatment avenues, we can aspire to enhance the overall care and outcomes for COPD patients, ultimately offering hope for improved health and well-being.
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Affiliation(s)
- Kevin Mou
- Centre for Respiratory Science and Health, School of Health & Biomedical Sciences, RMIT University, Melbourne, VIC, Australia
| | - Stanley M H Chan
- Centre for Respiratory Science and Health, School of Health & Biomedical Sciences, RMIT University, Melbourne, VIC, Australia
| | - Ross Vlahos
- Centre for Respiratory Science and Health, School of Health & Biomedical Sciences, RMIT University, Melbourne, VIC, Australia.
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Yuan R, Li J. Role of macrophages and their exosomes in orthopedic diseases. PeerJ 2024; 12:e17146. [PMID: 38560468 PMCID: PMC10979751 DOI: 10.7717/peerj.17146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Accepted: 03/01/2024] [Indexed: 04/04/2024] Open
Abstract
Exosomes are vesicles with a lipid bilayer structure that carry various active substances, such as proteins, DNA, non-coding RNA, and nucleic acids; these participate in the immune response, tissue formation, and cell communication. Owing to their low immunogenicity, exosomes play a key role in regulating the skeletal immune environment. Macrophages are important immune cells that swallow various cellular and tissue fragments. M1-like and M2-like macrophages differentiate to play pro-inflammatory, anti-inflammatory, and repair roles following stimulation. In recent years, the increase in the population base and the aging of the population have led to a gradual rise in orthopedic diseases, placing a heavy burden on the social medical system and making it urgent to find effective solutions. Macrophages and their exosomes have been demonstrated to be closely associated with the pathogenesis and prognosis of orthopedic diseases. An in-depth understanding of their mechanisms of action and the interaction between them will be helpful for the future clinical treatment of orthopedic diseases. This review focuses on the mechanisms of action, diagnosis, and treatment of orthopedic diseases involving macrophages and their exosomes, including fracture healing, diabetic bone damage, osteosarcoma, and rheumatoid arthritis. In addition, we discuss the prospects and major challenges faced by macrophages and their exosomes in clinical practice.
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Affiliation(s)
- Riming Yuan
- Shengjing Hospital, China Medical University, Shenyang, China
| | - Jianjun Li
- Shengjing Hospital, China Medical University, Shenyang, China
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10
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Sims NA, Lévesque JP. Oncostatin M: Dual Regulator of the Skeletal and Hematopoietic Systems. Curr Osteoporos Rep 2024; 22:80-95. [PMID: 38198032 PMCID: PMC10912291 DOI: 10.1007/s11914-023-00837-z] [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] [Accepted: 10/30/2023] [Indexed: 01/11/2024]
Abstract
PURPOSE OF THE REVIEW The bone and hematopoietic tissues coemerge during development and are functionally intertwined throughout mammalian life. Oncostatin M (OSM) is an inflammatory cytokine of the interleukin-6 family produced by osteoblasts, bone marrow macrophages, and neutrophils. OSM acts via two heterodimeric receptors comprising GP130 with either an OSM receptor (OSMR) or a leukemia inhibitory factor receptor (LIFR). OSMR is expressed on osteoblasts, mesenchymal, and endothelial cells and mice deficient for the Osm or Osmr genes have both bone and blood phenotypes illustrating the importance of OSM and OSMR in regulating these two intertwined tissues. RECENT FINDINGS OSM regulates bone mass through signaling via OSMR, adaptor protein SHC1, and transducer STAT3 to both stimulate osteoclast formation and promote osteoblast commitment; the effect on bone formation is also supported by action through LIFR. OSM produced by macrophages is an important inducer of neurogenic heterotopic ossifications in peri-articular muscles following spinal cord injury. OSM produced by neutrophils in the bone marrow induces hematopoietic stem and progenitor cell proliferation in an indirect manner via OSMR expressed by bone marrow stromal and endothelial cells that form hematopoietic stem cell niches. OSM acts as a brake to therapeutic hematopoietic stem cell mobilization in response to G-CSF and CXCR4 antagonist plerixafor. Excessive OSM production by macrophages in the bone marrow is a key contributor to poor hematopoietic stem cell mobilization (mobilopathy) in people with diabetes. OSM and OSMR may also play important roles in the progression of several cancers. It is increasingly clear that OSM plays unique roles in regulating the maintenance and regeneration of bone, hematopoietic stem and progenitor cells, inflammation, and skeletal muscles. Dysregulated OSM production can lead to bone pathologies, defective muscle repair and formation of heterotopic ossifications in injured muscles, suboptimal mobilization of hematopoietic stem cells, exacerbated inflammatory responses, and anti-tumoral immunity. Ongoing research will establish whether neutralizing antibodies or cytokine traps may be useful to correct pathologies associated with excessive OSM production.
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Affiliation(s)
- Natalie A Sims
- St. Vincent's Institute of Medical Research, 9 Princes St, Fitzroy, VIC, Australia
- Melbourne Medical School, The University of Melbourne, Melbourne, VIC, Australia
| | - Jean-Pierre Lévesque
- Translational Research Institute, Mater Research Institute - The University of Queensland, 37 Kent Street, Woolloongabba, QLD, Australia.
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11
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Pappert M, Khosla S, Doolittle M. Influences of Aged Bone Marrow Macrophages on Skeletal Health and Senescence. Curr Osteoporos Rep 2023; 21:771-778. [PMID: 37688671 PMCID: PMC10724341 DOI: 10.1007/s11914-023-00820-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/25/2023] [Indexed: 09/11/2023]
Abstract
PURPOSE OF REVIEW The purpose of this review is to discuss the role of macrophages in the regulation of skeletal health with age, particularly in regard to both established and unexplored mechanisms in driving inflammation and senescence. RECENT FINDINGS A multitude of research has uncovered mechanisms of intrinsic aging in macrophages, detrimental factors released by these immune cells, and crosstalk from senescent mesenchymal cell types, which altogether drive age-related bone loss. Furthermore, bone marrow macrophages were recently proposed to be responsible for the megakaryocytic shift during aging and overall maintenance of the hematopoietic niche. Studies on extra-skeletal macrophages have shed light on possible conserved mechanisms within bone and highlight the importance of these cells in systemic aging. Macrophages are a critically important cell type in maintaining skeletal homeostasis with age. New discoveries in this area are of utmost importance in fully understanding the pathogenesis of osteoporosis in aged individuals.
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Affiliation(s)
- Moritz Pappert
- Division of Endocrinology, Diabetes and Metabolism, Mayo Clinic, Rochester, MN, USA
- Robert and Arlene Kogod Center On Aging, Mayo Clinic, Rochester, MN, USA
- Department of Medicine, Paracelsus Medical University, Salzburg, Austria
| | - Sundeep Khosla
- Division of Endocrinology, Diabetes and Metabolism, Mayo Clinic, Rochester, MN, USA
- Robert and Arlene Kogod Center On Aging, Mayo Clinic, Rochester, MN, USA
| | - Madison Doolittle
- Division of Endocrinology, Diabetes and Metabolism, Mayo Clinic, Rochester, MN, USA.
- Robert and Arlene Kogod Center On Aging, Mayo Clinic, Rochester, MN, USA.
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12
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Liu X, Li F, Dong Z, Gu C, Mao D, Chen J, Luo L, Huang Y, Xiao J, Li Z, Liu Z, Yang Y. Metal-polyDNA nanoparticles reconstruct osteoporotic microenvironment for enhanced osteoporosis treatment. SCIENCE ADVANCES 2023; 9:eadf3329. [PMID: 37531423 PMCID: PMC10396296 DOI: 10.1126/sciadv.adf3329] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 06/29/2023] [Indexed: 08/04/2023]
Abstract
Current clinical approaches to osteoporosis primarily target osteoclast biology, overlooking the synergistic role of bone cells, immune cells, cytokines, and inorganic components in creating an abnormal osteoporotic microenvironment. Here, metal-polyDNA nanoparticles (Ca-polyCpG MDNs) composed of Ca2+ and ultralong single-stranded CpG sequences were developed to reconstruct the osteoporotic microenvironment and suppress osteoporosis. Ca-polyCpG MDNs can neutralize osteoclast-secreted hydrogen ions, provide calcium repletion, promote remineralization, and repair bone defects. Besides, the immune-adjuvant polyCpG in MDNs could induce the secretion of osteoclastogenesis inhibitor interleukin-12 and reduce the expression of osteoclast function effector protein to inhibit osteoclast differentiation, further reducing osteoclast-mediated bone resorption. PPi4- generated during the rolling circle amplification reaction acts as bisphosphonate analog and enhances bone targeting of Ca-polyCpG MDNs. In ovariectomized mouse and rabbit models, Ca-polyCpG MDNs prevented bone resorption and promoted bone repair by restoring the osteoporotic microenvironment, providing valuable insights into osteoporosis therapy.
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Affiliation(s)
- Xueliang Liu
- Institute of Molecular Medicine (IMM), Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Fan Li
- Institute of Functional Nano & Soft Materials Laboratory (FUNSOM), Soochow University, Suzhou, Jiangsu 215123, China
| | - Ziliang Dong
- Department of Orthopaedic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Chao Gu
- Institute of Molecular Medicine (IMM), Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, China
- Department of Anesthesiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Dongsheng Mao
- Institute of Molecular Medicine (IMM), Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Jingqi Chen
- Institute of Molecular Medicine (IMM), Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Lei Luo
- Institute of Molecular Medicine (IMM), Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Yuting Huang
- Institute of Molecular Medicine (IMM), Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Jie Xiao
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China
| | - Zhanchun Li
- Institute of Functional Nano & Soft Materials Laboratory (FUNSOM), Soochow University, Suzhou, Jiangsu 215123, China
| | - Zhuang Liu
- Department of Orthopaedic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Yu Yang
- Institute of Molecular Medicine (IMM), Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, China
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13
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Xu J, Yu L, Liu F, Wan L, Deng Z. The effect of cytokines on osteoblasts and osteoclasts in bone remodeling in osteoporosis: a review. Front Immunol 2023; 14:1222129. [PMID: 37475866 PMCID: PMC10355373 DOI: 10.3389/fimmu.2023.1222129] [Citation(s) in RCA: 64] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Accepted: 06/12/2023] [Indexed: 07/22/2023] Open
Abstract
The complicated connections and cross talk between the skeletal system and the immune system are attracting more attention, which is developing into the field of Osteoimmunology. In this field, cytokines that are among osteoblasts and osteoclasts play a critical role in bone remodeling, which is a pathological process in the pathogenesis and development of osteoporosis. Those cytokines include the tumor necrosis factor (TNF) family, the interleukin (IL) family, interferon (IFN), chemokines, and so on, most of which influence the bone microenvironment, osteoblasts, and osteoclasts. This review summarizes the effect of cytokines on osteoblasts and osteoclasts in bone remodeling in osteoporosis, aiming to providing the latest reference to the role of immunology in osteoporosis.
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Affiliation(s)
- Jie Xu
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, China
| | - Linxin Yu
- Renmin Hospital of Wuhan University, Wuhan, China
| | - Feng Liu
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, China
| | - Longbiao Wan
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zhenhua Deng
- Hubei Provincial Hospital of Traditional Chinese Medicine (TCM), Wuhan, China
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14
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Mishra AK, Malonia SK. Advancing cellular immunotherapy with macrophages. Life Sci 2023:121857. [PMID: 37307965 DOI: 10.1016/j.lfs.2023.121857] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Revised: 06/01/2023] [Accepted: 06/09/2023] [Indexed: 06/14/2023]
Abstract
Cell-based immunotherapies have become an exciting avenue for cancer treatment, particularly CAR T cells, which have shown great success in treating hematological malignancies. However, the limited success of T cell-based approaches in treating solid tumors has sparked interest in alternative cell types that could be used for solid tumor immunotherapy. Recent research has pointed to macrophages as a potential solution, given their ability to infiltrate solid tumors, exhibit a strong anti-tumor response, and persist long-term in the tumor microenvironment. Although early attempts with ex-vivo activated macrophage-based therapies failed to translate into clinical success, the field has revolutionized with the recent development of chimeric antigen receptor-expressing macrophages (CAR-M). While CAR-M therapy has reached the clinical trial stage, several challenges still need to be overcome before the therapy can become a reality. Here we review the evolution of macrophage-based cell therapy and evaluate recent studies and developments, emphasizing the potential of macrophages as cellular therapeutics. Furthermore, we also discuss the challenges and opportunities associated with using macrophages as a basis for therapeutic interventions.
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Affiliation(s)
- Alok K Mishra
- Department of Molecular, Cell, and Cancer Biology, UMass Chan Medical School, Worcester, MA 01605, USA.
| | - Sunil K Malonia
- Department of Molecular, Cell, and Cancer Biology, UMass Chan Medical School, Worcester, MA 01605, USA.
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15
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Cao G, Zhang S, Wang Y, Quan S, Yue C, Yao J, Alexander PG, Tan H. Pathogenesis of acquired heterotopic ossification: Risk factors, cellular mechanisms, and therapeutic implications. Bone 2023; 168:116655. [PMID: 36581258 DOI: 10.1016/j.bone.2022.116655] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Revised: 12/14/2022] [Accepted: 12/22/2022] [Indexed: 12/27/2022]
Abstract
Heterotopic ossification (HO), including hereditary and acquired HO, is the formation of extraskeletal bone in skeletal muscle and surrounding soft tissues. Acquired HO is often caused by range of motion, explosion injury, nerve injury or burns. Severe HO can lead to pain and limited joint activity, affecting functional rehabilitation and quality of life. Increasing evidence shows that inflammatory processes and mesenchymal stem cells (MSCs) can drive HO. However, explicit knowledge about the specific mechanisms that result in HO and related cell precursors is still limited. Moreover, there are no effective methods to prevent or reduce HO formation. In this review, we provide an update of known risk factors and relevant cellular origins for HO. In particular, we focus on the underlying mechanisms of MSCs in acquired HO, which follow the osteogenic program. We also discuss the latest therapeutic value and implications for acquired HO. Our review highlights the current gaps in knowledge regarding the pathogenesis of acquired HO and identifies potential targets for the prevention and treatment of HO.
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Affiliation(s)
- Guorui Cao
- Department of Knee Surgery, Luoyang Orthopedic Hospital of Henan Province, Orthopedic Hospital of Henan Province, Luoyang, Henan Province, People's Republic of China.
| | - Shaoyun Zhang
- Department of Orthopedics, The Third Hospital of Mianyang, Sichuan Mental Health Center, Mianyang, Sichuan Province, People's Republic of China
| | - Yixuan Wang
- Hunan University of Chinese Medicine, Changsha, Hunan Province, People's Republic of China
| | - Songtao Quan
- Department of Knee Surgery, Luoyang Orthopedic Hospital of Henan Province, Orthopedic Hospital of Henan Province, Luoyang, Henan Province, People's Republic of China
| | - Chen Yue
- Department of Knee Surgery, Luoyang Orthopedic Hospital of Henan Province, Orthopedic Hospital of Henan Province, Luoyang, Henan Province, People's Republic of China
| | - Junna Yao
- Department of Knee Surgery, Luoyang Orthopedic Hospital of Henan Province, Orthopedic Hospital of Henan Province, Luoyang, Henan Province, People's Republic of China
| | - Peter G Alexander
- Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, United States of America.
| | - Honglue Tan
- Department of Knee Surgery, Luoyang Orthopedic Hospital of Henan Province, Orthopedic Hospital of Henan Province, Luoyang, Henan Province, People's Republic of China.
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16
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Weivoda MM, Bradley EW. Macrophages and Bone Remodeling. J Bone Miner Res 2023; 38:359-369. [PMID: 36651575 PMCID: PMC10023335 DOI: 10.1002/jbmr.4773] [Citation(s) in RCA: 53] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 01/05/2023] [Accepted: 01/10/2023] [Indexed: 01/19/2023]
Abstract
Bone remodeling in the adult skeleton facilitates the removal and replacement of damaged and old bone to maintain bone quality. Tight coordination of bone resorption and bone formation during remodeling crucially maintains skeletal mass. Increasing evidence suggests that many cell types beyond osteoclasts and osteoblasts support bone remodeling, including macrophages and other myeloid lineage cells. Herein, we discuss the origin and functions for macrophages in the bone microenvironment, tissue resident macrophages, osteomacs, as well as newly identified osteomorphs that result from osteoclast fission. We also touch on the role of macrophages during inflammatory bone resorption. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
| | - Elizabeth W. Bradley
- Department of Orthopedics and Stem Cell Institute, University of Minnesota, Minneapolis, MN
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17
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Zhang D, Dang Y, Deng R, Ma Y, Wang J, Ao J, Wang X. Research Progress of Macrophages in Bone Regeneration. J Tissue Eng Regen Med 2023; 2023:1512966. [PMID: 40226416 PMCID: PMC11919137 DOI: 10.1155/2023/1512966] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 12/07/2022] [Accepted: 12/17/2022] [Indexed: 04/15/2025]
Abstract
Bone tissue regeneration plays an increasingly important role in contemporary clinical treatment. The reconstruction of bone defects remains a huge challenge for clinicians. Bone regeneration is regulated by the immune system, in which inflammation is an important regulating factor in bone formation and remodeling. As the main cells involved in inflammation, macrophages play a key role in osteogenesis by polarizing into different phenotypes during different stages of bone regeneration. Considering this, this review mainly summarizes the function of macrophage in bone regeneration based on mesenchymal stem cells (MSCs), osteoblasts, osteoclasts, and vascular cells. In conclusion, anti-inflammatory macrophages (M2) have a greater potentiality to promote bone regeneration than M0 and classically activated proinflammatory macrophages (M1). In the fracture and bone defect models, tissue engineering materials can induce the transition from M1 to M2, alter the bone microenvironment, and promote bone regeneration through interactions with bone-related cells and blood vessels. The review provides a further understanding of macrophage polarization behavior in the evolving field of bone immunology.
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Affiliation(s)
- Dingmei Zhang
- Department of Orthopaedic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, China
| | - Yi Dang
- Department of Orthopaedic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, China
| | - Renli Deng
- Nurse Department, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, China
| | - Yaping Ma
- Department of Orthopaedic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, China
| | - Jing Wang
- Department of Orthopaedic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, China
| | - Jun Ao
- Department of Orthopaedic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, China
| | - Xin Wang
- Department of Orthopaedic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, China
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18
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Abstract
Osteoclasts are the only cells that can efficiently resorb bone. They do so by sealing themselves on to bone and removing the mineral and organic components. Osteoclasts are essential for bone homeostasis and are involved in the development of diseases associated with decreased bone mass, like osteoporosis, or abnormal bone turnover, like Paget's disease of bone. In addition, compromise of their development or resorbing machinery is pathogenic in multiple types of osteopetrosis. However, osteoclasts also have functions other than bone resorption. Like cells of the innate immune system, they are derived from myeloid precursors and retain multiple immune cell properties. In addition, there is now strong evidence that osteoclasts regulate osteoblasts through a process known as coupling, which coordinates rates of bone resorption and bone formation during bone remodeling. In this article we review the non-resorbing functions of osteoclasts and highlight their importance in health and disease.
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Affiliation(s)
- Kyung-Hyun Park-Min
- Arthritis and Tissue Degeneration Program, David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY 10021, USA; Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
| | - Joseph Lorenzo
- The Departments of Medicine and Orthopaedics, UConn Health, Farmington, CT 06030, USA.
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19
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Rankouhi TR, Keulen DV, Tempel D, Venhorst J. Oncostatin M: Risks and Benefits of a Novel Therapeutic Target for Atherosclerosis. Curr Drug Targets 2022; 23:1345-1369. [PMID: 35959619 DOI: 10.2174/1389450123666220811101032] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 05/30/2022] [Accepted: 06/03/2022] [Indexed: 01/25/2023]
Abstract
BACKGROUND Cardiovascular disease (CVD) is a leading cause of death worldwide. It is predicted that approximately 23.6 million people will die from CVDs annually by 2030. Therefore, there is a great need for an effective therapeutic approach to combat this disease. The European Cardiovascular Target Discovery (CarTarDis) consortium identified Oncostatin M (OSM) as a potential therapeutic target for atherosclerosis. The benefits of modulating OSM - an interleukin (IL)-6 family cytokine - have since been studied for multiple indications. However, as decades of high attrition rates have stressed, the success of a drug target is determined by the fine balance between benefits and the risk of adverse events. Safety issues should therefore not be overlooked. OBJECTIVE In this review, a risk/benefit analysis is performed on OSM inhibition in the context of atherosclerosis treatment. First, OSM signaling characteristics and its role in atherosclerosis are described. Next, an overview of in vitro, in vivo, and clinical findings relating to both the benefits and risks of modulating OSM in major organ systems is provided. Based on OSM's biological function and expression profile as well as drug intervention studies, safety concerns of inhibiting this target have been identified, assessed, and ranked for the target population. CONCLUSION While OSM may be of therapeutic value in atherosclerosis, drug development should also focus on de-risking the herein identified major safety concerns: tissue remodeling, angiogenesis, bleeding, anemia, and NMDA- and glutamate-induced neurotoxicity. Close monitoring and/or exclusion of patients with various comorbidities may be required for optimal therapeutic benefit.
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Affiliation(s)
- Tanja Rouhani Rankouhi
- Department of Risk Analysis for Products in Development, TNO, Utrechtseweg 48, 3704 HE, Zeist, The Netherlands
| | - Daniëlle van Keulen
- SkylineDx BV, Science and Clinical Development, 3062 ME Rotterdam, The Netherlands
| | - Dennie Tempel
- SkylineDx BV, Science and Clinical Development, 3062 ME Rotterdam, The Netherlands
| | - Jennifer Venhorst
- Department of Risk Analysis for Products in Development, TNO, Utrechtseweg 48, 3704 HE, Zeist, The Netherlands
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20
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Isojima T, Walker EC, Poulton IJ, McGregor NE, Wicks IP, Gooi JH, Martin TJ, Sims NA. G-CSF Receptor Deletion Amplifies Cortical Bone Dysfunction in Mice With STAT3 Hyperactivation in Osteocytes. J Bone Miner Res 2022; 37:1876-1890. [PMID: 35856245 DOI: 10.1002/jbmr.4654] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 06/27/2022] [Accepted: 07/16/2022] [Indexed: 11/09/2022]
Abstract
Bone strength is determined by the structure and composition of its thickened outer shell (cortical bone), yet the mechanisms controlling cortical consolidation are poorly understood. Cortical bone maturation depends on SOCS3-mediated suppression of IL-6 cytokine-induced STAT3 phosphorylation in osteocytes, the cellular network embedded in bone matrix. Because SOCS3 also suppresses granulocyte-colony-stimulating factor receptor (G-CSFR) signaling, we here tested whether global G-CSFR (Csf3r) ablation altereed bone structure in male and female mice lacking SOCS3 in osteocytes, (Dmp1Cre :Socs3f/f mice). Dmp1Cre :Socs3f/f :Csf3r-/- mice were generated by crossing Dmp1Cre :Socs3f/f mice with Csf3r-/- mice. Although G-CSFR is not expressed in osteocytes, Csf3r deletion further delayed cortical consolidation in Dmp1Cre :Socs3f/f mice. Micro-CT images revealed extensive, highly porous low-density bone, with little true cortex in the diaphysis, even at 26 weeks of age; including more low-density bone and less high-density bone in Dmp1Cre :Socs3f/f :Csf3r-/- mice than controls. By histology, the area where cortical bone would normally be found contained immature compressed trabecular bone in Dmp1Cre :Socs3f/f :Csf3r-/- mice and greater than normal levels of intracortical osteoclasts, extensive new woven bone formation, and the presence of more intracortical blood vessels than the already high levels observed in Dmp1Cre :Socs3f/f controls. qRT-PCR of cortical bone from Dmp1Cre :Socs3f/f :Csf3r-/- mice also showed more than a doubling of mRNA levels for osteoclasts, osteoblasts, RANKL, and angiogenesis markers. The further delay in cortical bone maturation was associated with significantly more phospho-STAT1 and phospho-STAT3-positive osteocytes, and a threefold increase in STAT1 and STAT3 target gene mRNA levels, suggesting G-CSFR deletion further increases STAT signaling beyond that of Dmp1Cre :Socs3f/f bone. G-CSFR deficiency therefore promotes STAT1/3 signaling in osteocytes, and when SOCS3 negative feedback is absent, elevated local angiogenesis, bone resorption, and bone formation delays cortical bone consolidation. This points to a critical role of G-CSF in replacing condensed trabecular bone with lamellar bone during cortical bone formation. © 2022 American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
- Tsuyoshi Isojima
- St. Vincent's Institute of Medical Research, Fitzroy, Australia.,Department of Pediatrics, Teikyo University School of Medicine, Tokyo, Japan
| | - Emma C Walker
- St. Vincent's Institute of Medical Research, Fitzroy, Australia
| | | | | | - Ian P Wicks
- Walter and Eliza Hall Institute, Parkville, Australia
| | - Jonathan H Gooi
- St. Vincent's Institute of Medical Research, Fitzroy, Australia.,Bio21 Molecular Science and Biotechnology Institute, Parkville, Australia
| | - T John Martin
- St. Vincent's Institute of Medical Research, Fitzroy, Australia.,The University of Melbourne, Department of Medicine at St. Vincent's Hospital, Fitzroy, Australia
| | - Natalie A Sims
- St. Vincent's Institute of Medical Research, Fitzroy, Australia.,The University of Melbourne, Department of Medicine at St. Vincent's Hospital, Fitzroy, Australia
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21
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Nadine S, Fernandes I, Patrício SG, Correia CR, Mano JF. Liquefied Microcapsules Compartmentalizing Macrophages and Umbilical Cord-Derived Cells for Bone Tissue Engineering. Adv Healthc Mater 2022; 11:e2200651. [PMID: 35904030 DOI: 10.1002/adhm.202200651] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 07/22/2022] [Indexed: 01/28/2023]
Abstract
Extraordinary capabilities underlie the potential use of immune cells, particularly macrophages, in bone tissue engineering. Indeed, the depletion of macrophages during bone repair often culminates in disease scenarios. Inspired by the native dynamics between immune and skeletal systems, this work proposes a straightforward in vitro method to bioengineer biomimetic bone niches using biological waste. For that, liquefied and semipermeable reservoirs generated by electrohydrodynamic atomization and layer-by-layer techniques are developed to coculture umbilical cord-derived human cells, namely monocyte-derived macrophages, mesenchymal-derived stromal cells (MSCs), and human umbilical vein endothelial cells (HUVECs). Poly(ε-caprolactone) microparticles are also added to the liquefied core to act as cell carriers. The fabricated microcapsules grant the successful development of viable microtissues, ensuring the high diffusion of bioactive factors. Interestingly, macrophages within the bioengineered microcapsules increase the release of osteocalcin, osteoprotegerin, and vascular endothelial growth factor. The cytokines profile variation indicates macrophages' polarization into a prohealing phenotype. Altogether, the incorporation of macrophages within the fabricated microcapsules allows to recreate an appropriate bone microenvironment for developing new bone mineralized microtissues. The proposed bioencapsulation protocol is a powerful self-regulated system, which might find great applicability in bone tissue engineering based on bottom-up approaches or disease modeling.
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Affiliation(s)
- Sara Nadine
- CICECO - Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, Campus Universitário de Santiago, Aveiro, 3810-193, Portugal
| | - Inês Fernandes
- CICECO - Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, Campus Universitário de Santiago, Aveiro, 3810-193, Portugal
| | - Sónia G Patrício
- CICECO - Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, Campus Universitário de Santiago, Aveiro, 3810-193, Portugal
| | - Clara R Correia
- CICECO - Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, Campus Universitário de Santiago, Aveiro, 3810-193, Portugal
| | - João F Mano
- CICECO - Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, Campus Universitário de Santiago, Aveiro, 3810-193, Portugal
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22
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Wang W, Liu H, Liu T, Yang H, He F. Insights into the Role of Macrophage Polarization in the Pathogenesis of Osteoporosis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:2485959. [PMID: 35707276 PMCID: PMC9192196 DOI: 10.1155/2022/2485959] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 05/01/2022] [Accepted: 05/11/2022] [Indexed: 12/12/2022]
Abstract
Millions of people worldwide suffer from osteoporosis, which causes bone fragility and increases the risk of fractures. Osteoporosis is closely related to the inhibition of osteogenesis and the enhancement of osteoclastogenesis. In addition, chronic inflammation and macrophage polarization may contribute to osteoporosis as well. Macrophages, crucial to inflammatory responses, display different phenotypes under the control of microenvironment. There are two major phenotypes, classically activated macrophages (M1) and alternatively activated macrophages (M2). Generally, M1 macrophages mainly lead to bone resorption, while M2 macrophages result in osteogenesis. M1/M2 ratio reflects the "fluid" state of macrophage polarization, and the imbalance of M1/M2 ratio may cause disease such as osteoporosis. Additionally, antioxidant drugs, such as melatonin, are applied to change the state of macrophage polarization and to treat osteoporosis. In this review, we introduce the mechanisms of macrophage polarization-mediated bone resorption and bone formation and the contribution to the clinical strategies of osteoporosis treatment.
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Affiliation(s)
- Wenhao Wang
- Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
- Orthopaedic Institute, Medical College, Soochow University, Suzhou 215000, China
| | - Hao Liu
- Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
- Orthopaedic Institute, Medical College, Soochow University, Suzhou 215000, China
| | - Tao Liu
- Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Huilin Yang
- Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
- Orthopaedic Institute, Medical College, Soochow University, Suzhou 215000, China
| | - Fan He
- Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
- Orthopaedic Institute, Medical College, Soochow University, Suzhou 215000, China
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23
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Durdan MM, Azaria RD, Weivoda MM. Novel insights into the coupling of osteoclasts and resorption to bone formation. Semin Cell Dev Biol 2022; 123:4-13. [PMID: 34756783 PMCID: PMC8840962 DOI: 10.1016/j.semcdb.2021.10.008] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 10/16/2021] [Accepted: 10/18/2021] [Indexed: 12/17/2022]
Abstract
Bone remodeling consists of resorption by osteoclasts (OCs) and formation by osteoblasts (OBs). Precise coordination of these activities is required for the resorbed bone to be replaced with an equal amount of new bone in order to maintain skeletal mass throughout the lifespan. This coordination of remodeling processes is referred to as the "coupling" of resorption to bone formation. In this review, we discuss the essential role for OCs in coupling resorption to bone formation, mechanisms for this coupling, and how coupling becomes less efficient or disrupted in conditions of bone loss. Lastly, we provide perspectives on targeting coupling to treat human bone disease.
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Affiliation(s)
- Margaret M. Durdan
- Cell and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA,Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA
| | - Ruth D. Azaria
- Cell and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA,Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA
| | - Megan M. Weivoda
- Cell and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA,Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA,Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA
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24
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Wang Q, Xu L, Willumeit-Römer R, Luthringer-Feyerabend BJC. Macrophage-derived oncostatin M/bone morphogenetic protein 6 in response to Mg-based materials influences pro-osteogenic activity of human umbilical cord perivascular cells. Acta Biomater 2021; 133:268-279. [PMID: 33321219 DOI: 10.1016/j.actbio.2020.12.016] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2020] [Revised: 11/26/2020] [Accepted: 12/08/2020] [Indexed: 01/08/2023]
Abstract
Macrophages are the central immune cell involved in the foreign body reaction to the implants. Furthermore, the magnesium-based materials could modulate macrophage functions, and subsequently influence bone formation via not clearly understood mechanisms. To analysis the roles of materials (magnesium and its gadolinium-based alloy; Mg and Mg-10Gd) on secretion of macrophages and their effects on pro-osteogenic activity, human mesenchymal stem cells (MSC) and macrophages were cocultured directly on the materials surface. Here, oncostatin M (OSM) - glycoprotein 130 (gp130) signaling complex as well as BMP6/SMAD were found to be involved in the Mg and Mg-10Gd multifactorial modulating osteogenic differentiation. Furthermore, materials upregulated the gene expression of bone morphogenetic protein 6 (BMP6) in macrophages, as well as its protein receptors and mothers against decapentaplegic homolog (SMAD) 1/4/5 in cocultured MSC. Besides, both materials could reduce the secretion of tumour necrosis factor alpha (TNFα) and interleukin 1 beta (IL1β) in macrophages and cocultures. These results collectively imply that Mg and Mg-10Gd could create a beneficial microenvironment for osteogenic differentiation and further support Mg-based biomaterial immunomodulatory properties by modulating the interactions of macrophages and MSC for bone regeneration. STATEMENT OF SIGNIFICANCE: Mg-activated macrophages could regulate the pro-osteogenic activity via OSM/gp130 and Smad-related signalling. The neutralisation assay was utilised to confirm the hypothesis of inductive osteoblastic differentiation of human MSC via OSM/gp130 signalling. Current study are essential to evidence that the coordinated communication between macrophages and MSC (OSM/gp130/BMP6/TNFα/IL1β), which could be utilised for improving magnesium-based bone biomaterials and therapeutic applications.
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Affiliation(s)
- Qian Wang
- Institute of Materials Research, Division for Metallic Biomaterials, Helmholtz-Zentrum Geesthacht (HZG), Geesthacht, Germany
| | - Lei Xu
- Institute of Materials Research, Division for Metallic Biomaterials, Helmholtz-Zentrum Geesthacht (HZG), Geesthacht, Germany
| | - Regine Willumeit-Römer
- Institute of Materials Research, Division for Metallic Biomaterials, Helmholtz-Zentrum Geesthacht (HZG), Geesthacht, Germany
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Ping J, Zhou C, Dong Y, Wu X, Huang X, Sun B, Zeng B, Xu F, Liang W. Modulating immune microenvironment during bone repair using biomaterials: Focusing on the role of macrophages. Mol Immunol 2021; 138:110-120. [PMID: 34392109 DOI: 10.1016/j.molimm.2021.08.003] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 07/09/2021] [Accepted: 08/03/2021] [Indexed: 12/16/2022]
Abstract
Bone is a self-regenerative tissue that can repair small defects and fractures. In large defects, bone tissue is unable to provide nutrients and oxygen for repair, and autologous grafting is used as the gold standard. As an alternative method, the bone tissue regeneration approach uses osteoconductive biomaterials to overcome bone graft disadvantages. However, biomaterials are considered as foreign components that can stimulate host immune responses. Although traditional principles have been aimed to minimize immune reactions, the design of biomaterials has steadily shifted toward creating an immunomodulatory microenvironment to harness immune cells and responses to repair damaged tissue. Among immune cells, macrophages secrete various immunomodulatory mediators and crosstalk with bone-forming cells and play key roles in bone tissue engineering. Macrophage polarization toward M1 and M2 subtypes mediate pro-inflammatory and anti-inflammatory responses, respectively, which are crucial for bone repairing at different stages. This review provides an overview of the crosstalk between various immune cells and biomaterials, macrophage polarization, and the effect of physicochemical properties of biomaterials on the immune responses, especially macrophages, in bone tissue engineering.
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Affiliation(s)
- Jianfeng Ping
- Department of Orthopaedics, Shaoxing People's Hospital, Shaoxing Hospital, Zhejiang University School of Medicine, Shaoxing 312000, Zhejiang Province, PR China
| | - Chao Zhou
- Department of Orthopedics, Zhoushan Guanghua Hospital, Zhoushan 316000, Zhejiang Province, PR China
| | - Yongqiang Dong
- Department of Orthopaedics, Xinchang People's Hospital, Shaoxing 312500, Zhejiang Province, PR China
| | - Xudong Wu
- Department of Orthopedics, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Zhoushan 316000, Zhejiang Province, PR China
| | - Xiaogang Huang
- Department of Orthopedics, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Zhoushan 316000, Zhejiang Province, PR China
| | - Bin Sun
- Department of Orthopedics, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Zhoushan 316000, Zhejiang Province, PR China
| | - Bin Zeng
- Department of Orthopedics, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Zhoushan 316000, Zhejiang Province, PR China
| | - Fangming Xu
- Department of Orthopedics, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Zhoushan 316000, Zhejiang Province, PR China.
| | - Wenqing Liang
- Department of Orthopedics, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Zhoushan 316000, Zhejiang Province, PR China.
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Influences of the IL-6 cytokine family on bone structure and function. Cytokine 2021; 146:155655. [PMID: 34332274 DOI: 10.1016/j.cyto.2021.155655] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 07/08/2021] [Accepted: 07/12/2021] [Indexed: 01/12/2023]
Abstract
The IL-6 family of cytokines comprises a large group of cytokines that all act via the formation of a signaling complex that includes the glycoprotein 130 (gp130) receptor. Despite this, many of these cytokines have unique roles that regulate the activity of bone forming osteoblasts, bone resorbing osteoclasts, bone-resident osteocytes, and cartilage cells (chondrocytes). These include specific functions in craniofacial development, longitudinal bone growth, and the maintenance of trabecular and cortical bone structure, and have been implicated in musculoskeletal pathologies such as craniosynostosis, osteoporosis, rheumatoid arthritis, osteoarthritis, and heterotopic ossifications. This review will work systematically through each member of this family and provide an overview and an update on the expression patterns and functions of each of these cytokines in the skeleton, as well as their negative feedback pathways, particularly suppressor of cytokine signaling 3 (SOCS3). The specific cytokines described are interleukin 6 (IL-6), interleukin 11 (IL-11), oncostatin M (OSM), leukemia inhibitory factor (LIF), cardiotrophin 1 (CT-1), ciliary neurotrophic factor (CNTF), cardiotrophin-like cytokine factor 1 (CLCF1), neuropoietin, humanin and interleukin 27 (IL-27).
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Chen M, Hu J, Zhang E, Hu J, Wang X, Qin G. The osteoimmunomodulatory effect of nanostructured TiF x/TiO xcoating on osteogenesis induction. Biomed Mater 2021; 16. [PMID: 34087809 DOI: 10.1088/1748-605x/ac0863] [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: 04/01/2021] [Accepted: 06/04/2021] [Indexed: 11/12/2022]
Abstract
Macrophages play a central role in the host response and the integration of implant materials. The nanostructured TiFx/TiOxcoating (FOTi) on titanium surfaces has shown multiple properties, including antibacterial properties and bioactivity. However, little is known about the effects of these coatings on the regulation of macrophage activity and the subsequent immunomodulatory effects on osteogenesis. In this study, the behavior of macrophages on the FOTi samples was evaluated, and conditioned medium was collected and used to stimulate MC3T3-E1 cellsin vitro. The results showed that the FOTi samples stimulated macrophage elongation and promoted the production of proinflammatory cytokines at 24 h, while induced macrophage polarization to the anti-inflammatory M2 phenotype at 72 h. Furthermore, the immune microenvironment generated by macrophage/ FOTi samples interactions effectively promoted the osteogenic differentiation of MC3T3-E1 cells, as evidenced by improved cell adhesion, enhanced alkaline phosphatase activity and extracellular matrix mineralization, and upregulated osteogenesis-related gene expression. In summary, the FOTi samples mediated macrophage phenotype behaviors and induced beneficial immunomodulatory effects on osteogenesis, which could be a potential strategy for the surface modification of bone biomaterials.
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Affiliation(s)
- Mian Chen
- Jiangxi Key Laboratory of Nanobiomaterials, Institute of Advanced Materials, East China Jiaotong University, Nanchang 330013, People's Republic of China
| | - Jian Hu
- Jiangxi Key Laboratory of Nanobiomaterials, Institute of Advanced Materials, East China Jiaotong University, Nanchang 330013, People's Republic of China
| | - Erlin Zhang
- Key Laboratory for Anisotropy and Texture of Materials (ATM), Ministry of Education (MoE), School of Material Science and Engineering, Northeastern University, Shenyang 110819, People's Republic of China
| | - Jiali Hu
- Key Laboratory for Anisotropy and Texture of Materials (ATM), Ministry of Education (MoE), School of Material Science and Engineering, Northeastern University, Shenyang 110819, People's Republic of China
| | - Xiaoyan Wang
- School of Metallurgy, Northeastern University, Shenyang 110819, People's Republic of China
| | - Gaowu Qin
- Key Laboratory for Anisotropy and Texture of Materials (ATM), Ministry of Education (MoE), School of Material Science and Engineering, Northeastern University, Shenyang 110819, People's Republic of China
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Liu W, Liang L, Liu B, Zhao D, Tian Y, Huang Q, Wu H. The response of macrophages and their osteogenic potential modulated by micro/nano-structured Ti surfaces. Colloids Surf B Biointerfaces 2021; 205:111848. [PMID: 34022707 DOI: 10.1016/j.colsurfb.2021.111848] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 05/10/2021] [Accepted: 05/11/2021] [Indexed: 01/05/2023]
Abstract
Current understanding on the interactions between micro/nano-structured Ti surfaces and macrophages is still limited. In this work, TiO2 nano-structures were introduced onto acid-etched Ti surfaces by alkali-heat treatment, ion exchange and subsequent heat treatment. By adjusting the concentration of NaOH during alkali-heat treatment, nano-flakes, nano-flakes mixed with nano-wires or nano-wires could formed on acid-etched Ti surfaces. The micro- and micro/nano-structured Ti surfaces possessed similar surface chemical and phase compositions. In vitro results indicate that the morphology of macrophages was highly dependent on the morphological features of nano-structures. Nano-flakes and nano-wires were favorable to induce the formation of lamellipodia and filopodia, respectively. Compared to micro-structured Ti surface, micro/nano-structured Ti surfaces polarized macrophages to their M2 phenotype and enhanced the gene expressions of osteogenic growth factors in macrophages. The M2 polarized macrophages promoted the maturation of osteoblasts. Compared to that with nano-flakes or nano-wires, the surface with mixed features of nano-flakes and nano-wires exhibited stronger anti-inflammatory and osteo-immunomodulatory effects. The findings presented in the current work suggest that introducing micro/nano-topographies onto Ti-based implant surfaces is a promising strategy to modulate the inflammatory response and mediate osteogenesis.
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Affiliation(s)
- Wentao Liu
- State Key Laboratory of Powder Metallurgy, Central South University, Changsha, 410083, PR China
| | - Luxin Liang
- State Key Laboratory of Powder Metallurgy, Central South University, Changsha, 410083, PR China
| | - Bo Liu
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, 410011, PR China.
| | - Dapeng Zhao
- College of Biology, Hunan University, Changsha, 410082, PR China
| | - Yingtao Tian
- Engineering Department, Lancaster University, Lancaster, UK
| | - Qianli Huang
- State Key Laboratory of Powder Metallurgy, Central South University, Changsha, 410083, PR China; Foshan (Southern China) Institute for New Materials, Foshan, 528200, PR China.
| | - Hong Wu
- State Key Laboratory of Powder Metallurgy, Central South University, Changsha, 410083, PR China.
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Kreps LM, Addison CL. Targeting Intercellular Communication in the Bone Microenvironment to Prevent Disseminated Tumor Cell Escape from Dormancy and Bone Metastatic Tumor Growth. Int J Mol Sci 2021; 22:ijms22062911. [PMID: 33805598 PMCID: PMC7998601 DOI: 10.3390/ijms22062911] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 03/06/2021] [Accepted: 03/11/2021] [Indexed: 02/07/2023] Open
Abstract
Metastasis to the bone is a common feature of many cancers including those of the breast, prostate, lung, thyroid and kidney. Once tumors metastasize to the bone, they are essentially incurable. Bone metastasis is a complex process involving not only intravasation of tumor cells from the primary tumor into circulation, but extravasation from circulation into the bone where they meet an environment that is generally suppressive of their growth. The bone microenvironment can inhibit the growth of disseminated tumor cells (DTC) by inducing dormancy of the DTC directly and later on following formation of a micrometastatic tumour mass by inhibiting metastatic processes including angiogenesis, bone remodeling and immunosuppressive cell functions. In this review we will highlight some of the mechanisms mediating DTC dormancy and the complex relationships which occur between tumor cells and bone resident cells in the bone metastatic microenvironment. These inter-cellular interactions may be important targets to consider for development of novel effective therapies for the prevention or treatment of bone metastases.
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Affiliation(s)
- Lauren M. Kreps
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada;
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8L6, Canada
| | - Christina L. Addison
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada;
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8L6, Canada
- Department of Medicine, University of Ottawa, Ottawa, ON K1H 8L6, Canada
- Correspondence: ; Tel.: +1-613-737-7700
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Molstad DHH, Zars E, Norton A, Mansky KC, Westendorf JJ, Bradley EW. Hdac3 deletion in myeloid progenitor cells enhances bone healing in females and limits osteoclast fusion via Pmepa1. Sci Rep 2020; 10:21804. [PMID: 33311522 PMCID: PMC7733476 DOI: 10.1038/s41598-020-78364-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Accepted: 11/06/2020] [Indexed: 12/18/2022] Open
Abstract
Previous studies examining the role of the histone deacetylase Hdac3 within myeloid cells demonstrated that Hdac3 promotes M2 activation and tissue healing in inflammatory conditions. Since myeloid lineage cells are required for proper bone formation and regeneration, in this study we examined the functions of Hdac3 during bone healing. Conditional deletion of Hdac3 within myeloid progenitors accelerates healing of cortical bone defects. Moreover, reduced osteoclast numbers within the defect site are correlated with Hdac3 suppression. Ex vivo osteoclastogenesis assays further demonstrate that Hdac3 deficiency limits osteoclastogenesis, the number of nuclei per cell and bone resorption, suggesting a defect in cell fusion. High throughput RNA sequencing identified the transmembrane protein Pmepa1 as a differentially expressed gene within osteoclast progenitor cells. Knockdown of Pmepa1 partially restores defects in osteoclastogenesis induced by Hdac3 deficiency. These results show that Hdac3 is required for optimal bone healing and osteoclast fusion, potentially via its regulation of Pmepa1 expression.
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Affiliation(s)
- David H H Molstad
- Department of Orthopedics, University of Minnesota, Elizabeth W. Bradley, 100 Church St. S.E., Minneapolis, MN, 55455, USA
| | - Elizabeth Zars
- Departments of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
| | - Andrew Norton
- Developmental and Surgical Sciences, University of Minnesota, Minneapolis, MN, USA
| | - Kim C Mansky
- Developmental and Surgical Sciences, University of Minnesota, Minneapolis, MN, USA
| | - Jennifer J Westendorf
- Departments of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
- Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA
| | - Elizabeth W Bradley
- Department of Orthopedics, University of Minnesota, Elizabeth W. Bradley, 100 Church St. S.E., Minneapolis, MN, 55455, USA.
- Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA.
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Zhou P, Xia D, Ni Z, Ou T, Wang Y, Zhang H, Mao L, Lin K, Xu S, Liu J. Calcium silicate bioactive ceramics induce osteogenesis through oncostatin M. Bioact Mater 2020; 6:810-822. [PMID: 33024901 PMCID: PMC7528055 DOI: 10.1016/j.bioactmat.2020.09.018] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 09/18/2020] [Accepted: 09/18/2020] [Indexed: 12/13/2022] Open
Abstract
Immune reactions are a key factor in determining the destiny of bone substitute materials after implantation. Macrophages, the most vital factor in the immune response affecting implants, are critical in bone formation, as well as bone biomaterial-mediated bone repair. Therefore, it is critical to design materials with osteoimmunomodulatory properties to reduce host-to-material inflammatory responses by inducing macrophage polarization. Our previous study showed that calcium silicate (CS) bioceramics could significantly promote osteogenesis. Herein, we further investigated the effects of CS on the behavior of macrophages and how macrophages regulated osteogenesis. Under CS extract stimulation, the macrophage phenotype was converted to the M2 extreme. Stimulation by a macrophage-conditioned medium that was pretreated by CS extracts resulted in a significant enhancement of osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), indicating the important role of macrophage polarization in biomaterial-induced osteogenesis. Mechanistically, oncostatin M (OSM) in the macrophage-conditioned medium promoted osteogenic differentiation of BMSCs through the ERK1/2 and JAK3 pathways. This in vivo study further demonstrated that CS bioceramics could stimulate osteogenesis better than β-TCP implants by accelerating new bone formation at defective sites in the femur. These findings improve our understanding of immune modulation of CS bioactive ceramics and facilitate strategies to improve the in vitro osteogenesis capability of bone substitute materials.
Calcium silicate (CS) bioceramics significantly promoted osteogenesis by the regulating of macrophage polarization. ERK1/2 and JAK3 pathways mediated the osteogenic differentiation stimulated by CS. CS played a promising osteoimmunomodulatory agent for bone induction.
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Affiliation(s)
- Panyu Zhou
- Department of Emergency, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Demeng Xia
- Department of Emergency, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Zhexin Ni
- Department of Gynecology of Traditional Chinese Medicine, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Tianle Ou
- Department of Clinical Medicine, the Naval Medical University, Shanghai, China
| | - Yang Wang
- Department of Emergency, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Hongyue Zhang
- Department of Emergency, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Lixia Mao
- Department of Oral & Cranio-Maxillofacial Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China
| | - Kaili Lin
- Department of Oral & Cranio-Maxillofacial Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China
- Corresponding author.
| | - Shuogui Xu
- Department of Emergency, Changhai Hospital, Naval Medical University, Shanghai, China
- Corresponding author.
| | - Jiaqiang Liu
- Department of Oral & Cranio-Maxillofacial Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China
- Corresponding author.
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Cersosimo F, Lonardi S, Bernardini G, Telfer B, Mandelli GE, Santucci A, Vermi W, Giurisato E. Tumor-Associated Macrophages in Osteosarcoma: From Mechanisms to Therapy. Int J Mol Sci 2020; 21:E5207. [PMID: 32717819 PMCID: PMC7432207 DOI: 10.3390/ijms21155207] [Citation(s) in RCA: 152] [Impact Index Per Article: 30.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 07/20/2020] [Accepted: 07/21/2020] [Indexed: 12/20/2022] Open
Abstract
Osteosarcomas (OSs) are bone tumors most commonly found in pediatric and adolescent patients characterized by high risk of metastatic progression and recurrence after therapy. Effective therapeutic management of this disease still remains elusive as evidenced by poor patient survival rates. To achieve a more effective therapeutic management regimen, and hence patient survival, there is a need to identify more focused targeted therapies for OSs treatment in the clinical setting. The role of the OS tumor stroma microenvironment plays a significant part in the development and dissemination of this disease. Important components, and hence potential targets for treatment, are the tumor-infiltrating macrophages that are known to orchestrate many aspects of OS stromal signaling and disease progression. In particular, increased infiltration of M2-like tumor-associated macrophages (TAMs) has been associated with OS metastasis and poor patient prognosis despite currently used aggressive therapies regimens. This review aims to provide a summary update of current macrophage-centered knowledge and to discuss the possible roles that macrophages play in the process of OS metastasis development focusing on the potential influence of stromal cross-talk signaling between TAMs, cancer-stem cells and additional OSs tumoral microenvironment factors.
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Affiliation(s)
- Francesca Cersosimo
- Department of Biotechnology Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy; (F.C.); (G.B.); (A.S.)
| | - Silvia Lonardi
- Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; (S.L.); (G.E.M.); (W.V.)
| | - Giulia Bernardini
- Department of Biotechnology Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy; (F.C.); (G.B.); (A.S.)
| | - Brian Telfer
- Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PL, UK;
| | - Giulio Eugenio Mandelli
- Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; (S.L.); (G.E.M.); (W.V.)
| | - Annalisa Santucci
- Department of Biotechnology Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy; (F.C.); (G.B.); (A.S.)
| | - William Vermi
- Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; (S.L.); (G.E.M.); (W.V.)
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Emanuele Giurisato
- Department of Biotechnology Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy; (F.C.); (G.B.); (A.S.)
- Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PL, UK
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Wang J, Zheng Z, Huang B, Wu H, Zhang X, Chen Y, Liu J, Shan Z, Fan S, Chen J, Zhao F. Osteal Tissue Macrophages Are Involved in Endplate Osteosclerosis through the OSM-STAT3/YAP1 Signaling Axis in Modic Changes. THE JOURNAL OF IMMUNOLOGY 2020; 205:968-980. [PMID: 32690652 DOI: 10.4049/jimmunol.1901001] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Accepted: 06/22/2020] [Indexed: 11/19/2022]
Abstract
Modic changes (MCs) are radiographic manifestations of lumbar degenerative diseases. Various types of MCs are often associated with endplate osteosclerosis. Osteal tissue macrophages (Osteomacs) were reported to be crucial for bone homeostasis and bone repair, but whether osteomacs participate in the endplate osteosclerosis in MCs remained unclear. In this study, we tried to explore the critical role of osteomacs in regulating osteogenesis in MCs. We collected MCs from patient samples and developed a Propionibacterium acnes-induced rat MCs model, using microcomputed tomography and immunohistochemistry to detect the endplate bone mass and distribution of osteomacs. In patients' MCs, osteomacs increased in endplate subchondral bone, especially in Modic type II. Endplate in Modic type III presented a stable osteosclerosis. In rat MCs model, osteomacs increased in the bone hyperplasia area but not in the inflammation area of the endplate region, whereas the distribution of osteomacs was consistent with the area of osteosclerosis. To further explore the functions of osteomacs in vitro, we isolated osteomacs using MACS technology and found osteomacs secreted oncostatin M (OSM) and strongly promoted osteoblast differentiation rather than osteoclast through the mechanism of OSM-mediated tyrosine phosphorylation and interaction of STAT3 and Yes-associated protein 1 (YAP1). STAT3 phosphorylation inhibition or YAP1 knockdown attenuated OSM-mediated osteoblast differentiation. Finally, we confirmed that blockade of OSM in vivo using anti-OSM-neutralizing Ab prevented endplate osteosclerosis in rat MCs model. Taken together, these findings confirmed that endplate osteosclerosis in MCs was accompanied by an increased number of osteomacs, which regulated osteogenesis via the OSM-STAT3/YAP1 signaling axis.
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Affiliation(s)
- Jiasheng Wang
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China; and Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou 310016, China
| | - Zeyu Zheng
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China; and Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou 310016, China
| | - Bao Huang
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China; and Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou 310016, China
| | - Hao Wu
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China; and Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou 310016, China
| | - Xuyang Zhang
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China; and Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou 310016, China
| | - Yilei Chen
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China; and Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou 310016, China
| | - Junhui Liu
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China; and Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou 310016, China
| | - Zhi Shan
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China; and Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou 310016, China
| | - Shunwu Fan
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China; and Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou 310016, China
| | - Jian Chen
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China; and Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou 310016, China
| | - Fengdong Zhao
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China; and Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou 310016, China
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Li X, Huang Q, Hu X, Wu D, Li N, Liu Y, Li Q, Wu H. Evaluating the osteoimmunomodulatory properties of micro-arc oxidized titanium surface at two different biological stages using an optimized in vitro cell culture strategy. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2020; 110:110722. [DOI: 10.1016/j.msec.2020.110722] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Revised: 12/31/2019] [Accepted: 02/03/2020] [Indexed: 12/12/2022]
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Macrophage Transplantation Fails to Improve Repair of Critical-Sized Calvarial Defects. J Craniofac Surg 2020; 30:2640-2645. [PMID: 31609958 DOI: 10.1097/scs.0000000000005797] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
INTRODUCTION Over 500,000 bone grafting procedures are performed every year in the United States for neoplastic and traumatic lesions of the craniofacial skeleton, costing $585 million in medical care. Current bone grafting procedures are limited, and full-thickness critical-sized defects (CSDs) of the adult human skull thus pose a substantial reconstructive challenge for the craniofacial surgeon. Cell-based strategies have been shown to safely and efficaciously accelerate the rate of bone formation in CSDs in animals. The authors recently demonstrated that supraphysiological transplantation of macrophages seeded in pullalan-collagen composite hydrogels significantly accelerated wound healing in wild type and diabetic mice, an effect mediated in part by enhancing angiogenesis. In this study, the authors investigated the bone healing effects of macrophage transplantation into CSDs of mice. METHODS CD1 athymic nude mice (60 days of age) were anesthetized, and unilateral full-thickness critical-sized (4 mm in diameter) cranial defects were created in the right parietal bone, avoiding cranial sutures. Macrophages were isolated from FVB-L2G mice and seeded onto hydroxyapatite-poly (lactic-co-glycolic acid) (HA-PLGA) scaffolds (1.0 × 10 cells per CSD). Scaffolds were incubated for 24 hours before they were placed into the CSDs. Macrophage survival was assessed using three-dimensional in vivo imaging system (3D IVIS)/micro-CT. Micro-CT at 0, 2, 4, 6, and 8 weeks was performed to evaluate gross bone formation, which was quantified using Adobe Photoshop. Microscopic evidence of bone regeneration was assessed at 8 weeks by histology. Bone formation and macrophage survival were compared at each time point using independent samples t tests. RESULTS Transplantation of macrophages at supraphysiological concentration had no effect on the formation of bones in CSDs as assessed by either micro-CT data at any time point analyzed (all P > 0.05). These results were corroborated by histology. 3D IVIS/micro-CT demonstrated survival of macrophages through 8 weeks. CONCLUSION Supraphysiologic delivery of macrophages to CSDs of mice had no effect on bone formation despite survival of transplanted macrophages through to 8 weeks posttransplantation. Further research into the physiological effects of macrophages on bone regeneration is needed to assess whether recapitulation of these conditions in macrophage-based therapy can promote the healing of large cranial defects.
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Bordoni V, Reina G, Orecchioni M, Furesi G, Thiele S, Gardin C, Zavan B, Cuniberti G, Bianco A, Rauner M, Delogu LG. Stimulation of bone formation by monocyte-activator functionalized graphene oxide in vivo. NANOSCALE 2019; 11:19408-19421. [PMID: 31386739 DOI: 10.1039/c9nr03975a] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/18/2023]
Abstract
Nanosystems are able to enhance bone regeneration, a complex process requiring the mutual interplay between immune and skeletal cells. Activated monocytes can communicate pro-osteogenic signals to mesenchymal stem cells and promote osteogenesis. Thus, the activation of monocytes is a promising strategy to improve bone regeneration. Nanomaterials specifically selected to provoke immune-mediated bone formation are still missing. As a proof of concept, we apply here the intrinsic immune-characteristics of graphene oxide (GO) with the well-recognized osteoinductive capacity of calcium phosphate (CaP) in a biocompatible nanomaterial called maGO-CaP (monocytes activator GO complexed with CaP). In the presence of monocytes, the alkaline phosphatase activity and the expression of osteogenic markers increased. Studying the mechanisms of action, we detected an up-regulation of Wnt and BMP signaling, two key osteogenic pathways. The role of the immune activation was evidenced by the over-production of oncostatin M, a pro-osteogenic factor produced by monocytes. Finally, we tested the pro-osteogenic effects of maGO-CaP in vivo. maGO-CaP injected into the tibia of mice enhanced local bone mass and the bone formation rate. Our study suggests that maGO-CaP can activate monocytes to enhance osteogenesis ex vivo and in vivo.
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Affiliation(s)
| | - Giacomo Reina
- University of Strasbourg, CNRS, Immunology, Immunopathology and Therapeutic Chemistry, UPR 3572 Strasbourg, France.
| | | | - Giulia Furesi
- University of Sassari, Sassari, Italy. and TU Dresden Medical Center, Dresden, Germany.
| | | | - Chiara Gardin
- Department of Biomedical Sciences University of Padova, Padova, Italy
| | - Barbara Zavan
- Department of Biomedical Sciences University of Padova, Padova, Italy
| | - Gianaurelio Cuniberti
- Max Bergmann Center of Biomaterials and Institute for Materials Science, Dresden University of Technology, Dresden, Germany
| | - Alberto Bianco
- University of Strasbourg, CNRS, Immunology, Immunopathology and Therapeutic Chemistry, UPR 3572 Strasbourg, France.
| | | | - Lucia G Delogu
- University of Sassari, Sassari, Italy. and Department of Biomedical Sciences, University of Padova, Padova, Italy and Fondazione Istituto di Ricerca Pediatrica Città della Speranza, Padova, Italy
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Sims NA, Martin TJ. Osteoclasts Provide Coupling Signals to Osteoblast Lineage Cells Through Multiple Mechanisms. Annu Rev Physiol 2019; 82:507-529. [PMID: 31553686 DOI: 10.1146/annurev-physiol-021119-034425] [Citation(s) in RCA: 174] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Bone remodeling is essential for the repair and replacement of damaged and old bone. The major principle underlying this process is that osteoclast-mediated resorption of a quantum of bone is followed by osteoblast precursor recruitment; these cells differentiate to matrix-producing osteoblasts, which form new bone to replace what was resorbed. Evidence from osteopetrotic syndromes indicate that osteoclasts not only resorb bone, but also provide signals to promote bone formation. Osteoclasts act upon osteoblast lineage cells throughout their differentiation by facilitating growth factor release from resorbed matrix, producing secreted proteins and microvesicles, and expressing membrane-bound factors. These multiple mechanisms mediate the coupling of bone formation to resorption in remodeling. Additional interactions of osteoclasts with osteoblast lineage cells, including interactions with canopy and reversal cells, are required to achieve coordination between bone formation and resorption during bone remodeling.
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Affiliation(s)
- Natalie A Sims
- Bone Cell Biology and Disease Unit, St. Vincent's Institute of Medical Research, Melbourne, Victoria 3065, Australia; , .,Department of Medicine, The University of Melbourne, St. Vincent's Hospital, Melbourne, Victoria 3065, Australia
| | - T John Martin
- Bone Cell Biology and Disease Unit, St. Vincent's Institute of Medical Research, Melbourne, Victoria 3065, Australia; , .,Department of Medicine, The University of Melbourne, St. Vincent's Hospital, Melbourne, Victoria 3065, Australia
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West NR. Coordination of Immune-Stroma Crosstalk by IL-6 Family Cytokines. Front Immunol 2019; 10:1093. [PMID: 31156640 PMCID: PMC6529849 DOI: 10.3389/fimmu.2019.01093] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Accepted: 04/29/2019] [Indexed: 12/15/2022] Open
Abstract
Stromal cells are a subject of rapidly growing immunological interest based on their ability to influence virtually all aspects of innate and adaptive immunity. Present in every bodily tissue, stromal cells complement the functions of classical immune cells by sensing pathogens and tissue damage, coordinating leukocyte recruitment and function, and promoting immune response resolution and tissue repair. These diverse roles come with a price: like classical immune cells, inappropriate stromal cell behavior can lead to various forms of pathology, including inflammatory disease, tissue fibrosis, and cancer. An important immunological function of stromal cells is to act as information relays, responding to leukocyte-derived signals and instructing leukocyte behavior in kind. In this regard, several members of the interleukin-6 (IL-6) cytokine family, including IL-6, IL-11, oncostatin M (OSM), and leukemia inhibitory factor (LIF), have gained recognition as factors that mediate crosstalk between stromal and immune cells, with diverse roles in numerous inflammatory and homeostatic processes. This review summarizes our current understanding of how IL-6 family cytokines control stromal-immune crosstalk in health and disease, and how these interactions can be leveraged for clinical benefit.
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Affiliation(s)
- Nathaniel R West
- Department of Cancer Immunology, Genentech, South San Francisco, CA, United States
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Tang H, Husch JFA, Zhang Y, Jansen JA, Yang F, van den Beucken JJJP. Coculture with monocytes/macrophages modulates osteogenic differentiation of adipose-derived mesenchymal stromal cells on poly(lactic-co-glycolic) acid/polycaprolactone scaffolds. J Tissue Eng Regen Med 2019; 13:785-798. [PMID: 30771241 PMCID: PMC6594112 DOI: 10.1002/term.2826] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2017] [Revised: 11/17/2018] [Accepted: 02/13/2019] [Indexed: 12/18/2022]
Abstract
The effects of immune cells, in particular macrophages, on the behaviour of mesenchymal stromal cells (MSCs) have recently gained much attention for MSCs‐based tissue‐engineered constructs. This study aimed to evaluate the effect of monocytes/macrophages on the osteogenic differentiation of adipose‐derived mesenchymal stromal cells (ADMSCs) in three‐dimensional (3D) cocultures. For this, we cocultured THP‐1 monocytes, M1 macrophages, or M2 macrophages with ADMSCs on 3D poly(lactic‐co‐glycolic) acid (PLGA)/polycaprolactone (PCL) scaffolds using osteogenic medium for up to 42 days. We found that osteogenic differentiation of ADMSCs was inhibited by monocytes and both macrophage subtypes in 3D scaffolds. Furthermore, coculture of monocytes/macrophages with ADMSCs resulted in downregulated secretion of oncostatin M (OSM) and bone morphogenetic protein 2 (BMP‐2) and inhibited expression of osteogenic markers alkaline phosphatase (ALP), bone sialoprotein (BSP), and runt‐related transcription factor 2 (RUNX2). Compared with both macrophage subtypes, monocytes inhibited osteogenic differentiation of ADMSCs more significantly. These data suggest that the mutual interactions between monocytes/macrophages and ADMSCs negatively affect MSC osteogenic differentiation and thus possibly bone healing capacity, which highlights the importance of the micro‐environment in influencing cell‐based constructs to treat bone defects and the potential to improve their performance by resolving the inflammation ahead of treatment.
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Affiliation(s)
- Hongbo Tang
- Department of Biomaterials, Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen, The Netherlands.,Department of Plastic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Johanna F A Husch
- Department of Biomaterials, Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen, The Netherlands
| | - Yang Zhang
- Department of Biomaterials, Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen, The Netherlands
| | - John A Jansen
- Department of Biomaterials, Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen, The Netherlands
| | - Fang Yang
- Department of Biomaterials, Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen, The Netherlands
| | - Jeroen J J P van den Beucken
- Department of Biomaterials, Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen, The Netherlands
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Xie J, Huang Z, Yu X, Zhou L, Pei F. Clinical implications of macrophage dysfunction in the development of osteoarthritis of the knee. Cytokine Growth Factor Rev 2019; 46:36-44. [PMID: 30910350 DOI: 10.1016/j.cytogfr.2019.03.004] [Citation(s) in RCA: 86] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Accepted: 03/12/2019] [Indexed: 02/06/2023]
Abstract
Osteoarthritis (OA) is the most common form of arthritic disease, leading to disability and impaired quality of life and no curative treatments exist. Increasing evidence indicates that low-grade inflammation plays a pivotal role in the onset and progression of OA. In this review, we summarize emerging findings on the pathological roles of synovial macrophages, adipose tissue macrophages, and osteoclasts in OA and their potential clinical implications from cell biology to preclinical and preliminary clinical trials. The failure of synovial macrophages to transition from pro-inflammatory M1 to anti-inflammatory M2 subtypes may contribute to the initiation and maintenance of synovitis in OA. M1 macrophages promote the inflammatory microenvironment and progression of OA through interactions with synovial fibroblasts and chondrocytes, thus increasing the secretion of matrix metalloproteinases. Direct inhibition of M1 or promotion of M2 polarization may be useful therapeutic interventions. Adipose tissue macrophages present in the infrapatella fat pad (IPFP) were involved in the progression of obesity-induced OA, which contributed to changes in the integrity of the IPFP. Furthermore, macrophages and osteoclasts in the subchondral bone were involved in bone remodeling and pain through uncoupled osteoclast/osteoblast activity and increased nociceptive signaling. Growing evidence has indicated an important role for macrophage-mediated low-grade inflammation in OA. Fully understanding the link between macrophages and other cells in joints will provide new insights into OA disease modification.
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Affiliation(s)
- Jinwei Xie
- Department of Orthopaedics Surgery, Laboratory of Endocrinology and Metabolism, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, Sichuan Province, China
| | - Zeyu Huang
- Department of Orthopaedics Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Xijie Yu
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
| | - Li Zhou
- Core Facility of West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Fuxing Pei
- Department of Orthopaedics Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
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Pajarinen J, Lin T, Gibon E, Kohno Y, Maruyama M, Nathan K, Lu L, Yao Z, Goodman SB. Mesenchymal stem cell-macrophage crosstalk and bone healing. Biomaterials 2019; 196:80-89. [PMID: 29329642 PMCID: PMC6028312 DOI: 10.1016/j.biomaterials.2017.12.025] [Citation(s) in RCA: 594] [Impact Index Per Article: 99.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Revised: 12/25/2017] [Accepted: 12/31/2017] [Indexed: 12/12/2022]
Abstract
Recent research has brought about a clear understanding that successful fracture healing is based on carefully coordinated cross-talk between inflammatory and bone forming cells. In particular, the key role that macrophages play in the recruitment and regulation of the differentiation of mesenchymal stem cells (MSCs) during bone regeneration has been brought to focus. Indeed, animal studies have comprehensively demonstrated that fractures do not heal without the direct involvement of macrophages. Yet the exact mechanisms by which macrophages contribute to bone regeneration remain to be elucidated. Macrophage-derived paracrine signaling molecules such as Oncostatin M, Prostaglandin E2 (PGE2), and Bone Morphogenetic Protein-2 (BMP2) have been shown to play critical roles; however the relative importance of inflammatory (M1) and tissue regenerative (M2) macrophages in guiding MSC differentiation along the osteogenic pathway remains poorly understood. In this review, we summarize the current understanding of the interaction of macrophages and MSCs during bone regeneration, with the emphasis on the role of macrophages in regulating bone formation. The potential implications of aging to this cellular cross-talk are reviewed. Emerging treatment options to improve facture healing by utilizing or targeting MSC-macrophage crosstalk are also discussed.
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Affiliation(s)
- Jukka Pajarinen
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Tzuhua Lin
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Emmanuel Gibon
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Yusuke Kohno
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Masahiro Maruyama
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Karthik Nathan
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Laura Lu
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Zhenyu Yao
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Stuart B Goodman
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, USA.
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West NR, Owens BMJ, Hegazy AN. The oncostatin M-stromal cell axis in health and disease. Scand J Immunol 2018; 88:e12694. [DOI: 10.1111/sji.12694] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2018] [Accepted: 06/15/2018] [Indexed: 12/17/2022]
Affiliation(s)
- Nathaniel R. West
- Department of Cancer Immunology; Genentech; South San Francisco California
| | - Benjamin M. J. Owens
- Somerville College; University of Oxford; Oxford UK
- EUSA Pharma; Hemel Hempstead UK
| | - Ahmed N. Hegazy
- Division of Gastroenterology, Infectiology, and Rheumatology; Charité Universitätsmedizin; Berlin Germany
- Deutsches Rheuma-Forschungszentrum; ein Institut der Leibniz-Gemeinschaft; Berlin Germany
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Scutera S, Salvi V, Lorenzi L, Piersigilli G, Lonardi S, Alotto D, Casarin S, Castagnoli C, Dander E, D'Amico G, Sozzani S, Musso T. Adaptive Regulation of Osteopontin Production by Dendritic Cells Through the Bidirectional Interaction With Mesenchymal Stromal Cells. Front Immunol 2018; 9:1207. [PMID: 29910810 PMCID: PMC5992779 DOI: 10.3389/fimmu.2018.01207] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Accepted: 05/14/2018] [Indexed: 12/11/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) exert immunosuppressive effects on immune cells including dendritic cells (DCs). However, many details of the bidirectional interaction of MSCs with DCs are still unsolved and information on key molecules by which DCs can modulate MSC functions is limited. Here, we report that osteopontin (OPN), a cytokine involved in homeostatic and pathophysiologic responses, is constitutively expressed by DCs and regulated in the DC/MSC cocultures depending on the activation state of MSCs. Resting MSCs promoted OPN production, whereas the production of OPN was suppressed when MSCs were activated by proinflammatory cytokines (i.e., TNF-α, IL-6, and IL-1β). OPN induction required cell-to-cell contact, mediated at least in part, by β1 integrin (CD29). Conversely, activated MSCs inhibited the release of OPN via the production of soluble factors with a major role played by Prostaglandin E2 (PGE2). Accordingly, pretreatment with indomethacin significantly abrogated the MSC-mediated suppression of OPN while the direct addition of exogenous PGE2 inhibited OPN production by DCs. Furthermore, DC-conditioned medium promoted osteogenic differentiation of MSCs with a concomitant inhibition of adipogenesis. These effects were paralleled by the repression of the adipogenic markers PPARγ, adiponectin, and FABP4, and induction of the osteogenic markers alkaline phosphatase, RUNX2, and of the bone-anabolic chemokine CCL5. Notably, blocking OPN activity with RGD peptides or with an antibody against CD29, one of the OPN receptors, prevented the effects of DC-conditioned medium on MSC differentiation and CCL5 induction. Because MSCs have a key role in maintenance of bone marrow (BM) hematopoietic stem cell niche through reciprocal regulation with immune cells, we investigated the possible MSC/DC interaction in human BM by immunohistochemistry. Although DCs (CD1c+) are a small percentage of BM cells, we demonstrated colocalization of CD271+ MSCs with CD1c+ DCs in normal and myelodysplastic BM. OPN reactivity was observed in occasional CD1c+ cells in the proximity of CD271+ MSCs. Altogether, these results candidate OPN as a signal modulated by MSCs according to their activation status and involved in DC regulation of MSC differentiation.
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Affiliation(s)
- Sara Scutera
- Department of Public Health and Pediatric Sciences, University of Turin, Turin, Italy
| | - Valentina Salvi
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Luisa Lorenzi
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Giorgia Piersigilli
- Department of Public Health and Pediatric Sciences, University of Turin, Turin, Italy
| | - Silvia Lonardi
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Daniela Alotto
- Skin Bank, Department of General and Specialized Surgery, A.O.U. Citta della Salute e della Scienza di Torino, Turin, Italy
| | - Stefania Casarin
- Skin Bank, Department of General and Specialized Surgery, A.O.U. Citta della Salute e della Scienza di Torino, Turin, Italy
| | - Carlotta Castagnoli
- Skin Bank, Department of General and Specialized Surgery, A.O.U. Citta della Salute e della Scienza di Torino, Turin, Italy
| | - Erica Dander
- "M. Tettamanti" Research Center, Pediatric Department, University of Milano-Bicocca, Monza, Italy
| | - Giovanna D'Amico
- "M. Tettamanti" Research Center, Pediatric Department, University of Milano-Bicocca, Monza, Italy
| | - Silvano Sozzani
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Tiziana Musso
- Department of Public Health and Pediatric Sciences, University of Turin, Turin, Italy
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Geurtzen K, Vernet A, Freidin A, Rauner M, Hofbauer LC, Schneider JE, Brand M, Knopf F. Immune Suppressive and Bone Inhibitory Effects of Prednisolone in Growing and Regenerating Zebrafish Tissues. J Bone Miner Res 2017; 32:2476-2488. [PMID: 28771888 DOI: 10.1002/jbmr.3231] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Revised: 07/19/2017] [Accepted: 07/31/2017] [Indexed: 01/15/2023]
Abstract
Glucocorticoids are widely used as therapeutic agents to treat immune-mediated diseases in humans because of their anti-inflammatory and immunosuppressive effects. However, glucocorticoids have various adverse effects, in particular rapid and pronounced bone loss associated with fractures in glucocorticoid-induced osteoporosis, a common form of secondary osteoporosis. In zebrafish, which are increasingly used to study processes of bone regeneration and disease, glucocorticoids show detrimental effects on bone tissue; however, the underlying cellular mechanisms are incompletely understood. Here, we show that treatment with the glucocorticoid prednisolone impacts on the number, activity and differentiation of osteoblasts, osteoclasts, and immune cells during ontogenetic growth, homeostasis, and regeneration of zebrafish bone. Macrophage numbers are reduced in both larval and adult tissues, correlating with decreased generation of myelomonocytes and enhanced apoptosis of these cells. In contrast, osteoblasts fail to proliferate, show decreased activity, and undergo incomplete differentiation. In addition, prednisolone treatment mitigates the number and recruitment of osteoclasts to sites of bone regeneration in adult fish. In combination, these effects delay bone growth and impair bone regeneration. Our study demonstrates the many-faceted effects of glucocorticoids in non-mammalian vertebrates and helps to further establish the zebrafish as a model to study glucocorticoid-induced osteoporosis. © 2017 American Society for Bone and Mineral Research.
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Affiliation(s)
- Karina Geurtzen
- Center for Regenerative Therapies Dresden (CRTD) and Biotechnology Center, Technische Universität Dresden, Dresden, Germany
| | - Aude Vernet
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
| | - Andrew Freidin
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
| | - Martina Rauner
- Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany
- Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
| | - Lorenz C Hofbauer
- Center for Regenerative Therapies Dresden (CRTD) and Biotechnology Center, Technische Universität Dresden, Dresden, Germany
- Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany
- Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
| | - Jürgen E Schneider
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
- Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK
| | - Michael Brand
- Center for Regenerative Therapies Dresden (CRTD) and Biotechnology Center, Technische Universität Dresden, Dresden, Germany
| | - Franziska Knopf
- Center for Regenerative Therapies Dresden (CRTD) and Biotechnology Center, Technische Universität Dresden, Dresden, Germany
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
- Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
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Torossian F, Guerton B, Anginot A, Alexander KA, Desterke C, Soave S, Tseng HW, Arouche N, Boutin L, Kulina I, Salga M, Jose B, Pettit AR, Clay D, Rochet N, Vlachos E, Genet G, Debaud C, Denormandie P, Genet F, Sims NA, Banzet S, Levesque JP, Lataillade JJ, Le Bousse-Kerdilès MC. Macrophage-derived oncostatin M contributes to human and mouse neurogenic heterotopic ossifications. JCI Insight 2017; 2:96034. [PMID: 29093266 DOI: 10.1172/jci.insight.96034] [Citation(s) in RCA: 81] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2017] [Accepted: 09/26/2017] [Indexed: 02/04/2023] Open
Abstract
Neurogenic heterotopic ossification (NHO) is the formation of ectopic bone generally in muscles surrounding joints following spinal cord or brain injury. We investigated the mechanisms of NHO formation in 64 patients and a mouse model of spinal cord injury-induced NHO. We show that marrow from human NHOs contains hematopoietic stem cell (HSC) niches, in which mesenchymal stromal cells (MSCs) and endothelial cells provide an environment supporting HSC maintenance, proliferation, and differentiation. The transcriptomic signature of MSCs from NHOs shows a neuronal imprinting associated with a molecular network required for HSC support. We demonstrate that oncostatin M (OSM) produced by activated macrophages promotes osteoblastic differentiation and mineralization of human muscle-derived stromal cells surrounding NHOs. The key role of OSM was confirmed using an experimental model of NHO in mice defective for the OSM receptor (OSMR). Our results provide strong evidence that macrophages contribute to NHO formation through the osteogenic action of OSM on muscle cells within an inflammatory context and suggest that OSM/OSMR could be a suitable therapeutic target. Altogether, the evidence of HSCs in ectopic bones growing at the expense of soft tissue in spinal cord/brain-injured patients indicates that inflammation and muscle contribute to HSC regulation by the brain-bone-blood triad.
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Affiliation(s)
- Frédéric Torossian
- Inserm UMR-S-MD1197, Paris 11 University, Paul Brousse Hospital, Villejuif, France
| | - Bernadette Guerton
- Inserm UMR-S-MD1197, Paris 11 University, Paul Brousse Hospital, Villejuif, France
| | - Adrienne Anginot
- Inserm UMR-S-MD1197, Paris 11 University, Paul Brousse Hospital, Villejuif, France
| | - Kylie A Alexander
- Mater Research Institute, The University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia
| | | | - Sabrina Soave
- Inserm UMR-S-MD1197, Paris 11 University, Paul Brousse Hospital, Villejuif, France
| | - Hsu-Wen Tseng
- Mater Research Institute, The University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia
| | - Nassim Arouche
- Inserm UMR-S-MD1197, Paris 11 University, Paul Brousse Hospital, Villejuif, France
| | - Laetitia Boutin
- Inserm UMR-S-MD1197, Paris 11 University, Paul Brousse Hospital, Villejuif, France
| | - Irina Kulina
- Mater Research Institute, The University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia
| | - Marjorie Salga
- Mater Research Institute, The University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia.,Université de Versailles Saint-Quentin-en-Yvelines, Evolution of neuromuscular diseases: innovative concepts and practices, Inserm U1179, Montigny le Bretonneux, France
| | - Beulah Jose
- Mater Research Institute, The University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia
| | - Allison R Pettit
- Mater Research Institute, The University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia
| | - Denis Clay
- UMS33, Paris 11 University, Paul Brousse Hospital, Villejuif, France
| | - Nathalie Rochet
- Université Côte d'Azur, CNRS, Inserm, Institut de Biologie Valrose, Nice, France
| | - Erica Vlachos
- Service de Médecine Physique et de Réadaptation, Paris 12 University, Garches, France
| | - Guillaume Genet
- Service de Médecine Physique et de Réadaptation, Paris 12 University, Garches, France
| | - Charlotte Debaud
- Université de Versailles Saint-Quentin-en-Yvelines, Evolution of neuromuscular diseases: innovative concepts and practices, Inserm U1179, Montigny le Bretonneux, France.,Service de Médecine Physique et de Réadaptation, Paris 12 University, Garches, France
| | - Philippe Denormandie
- Service de Médecine Physique et de Réadaptation, Paris 12 University, Garches, France
| | - François Genet
- Université de Versailles Saint-Quentin-en-Yvelines, Evolution of neuromuscular diseases: innovative concepts and practices, Inserm U1179, Montigny le Bretonneux, France.,Service de Médecine Physique et de Réadaptation, Paris 12 University, Garches, France
| | - Natalie A Sims
- St. Vincent's Institute of Medical Research and Department of Medicine, St. Vincent's Hospital, The University of Melbourne, Fitzroy, Victoria, Australia
| | - Sébastien Banzet
- Inserm UMR-S-MD1197, Paris 11 University, Paul Brousse Hospital, Villejuif, France.,Centre de Transfusion Sanguine des Armées, L'Institut de Recherche Biomédicale des Armées, Clamart, France
| | - Jean-Pierre Levesque
- Mater Research Institute, The University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia
| | - Jean-Jacques Lataillade
- Inserm UMR-S-MD1197, Paris 11 University, Paul Brousse Hospital, Villejuif, France.,Centre de Transfusion Sanguine des Armées, L'Institut de Recherche Biomédicale des Armées, Clamart, France
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CD169 + macrophages are critical for osteoblast maintenance and promote intramembranous and endochondral ossification during bone repair. Biomaterials 2017; 196:51-66. [PMID: 29107337 DOI: 10.1016/j.biomaterials.2017.10.033] [Citation(s) in RCA: 134] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2017] [Revised: 09/06/2017] [Accepted: 10/17/2017] [Indexed: 12/23/2022]
Abstract
Osteal macrophages (osteomacs) contribute to bone homeostasis and regeneration. To further distinguish their functions from osteoclasts, which share many markers and growth factor requirements, we developed a rapid, enzyme-free osteomac enrichment protocol that permitted characterization of minimally manipulated osteomacs by flow cytometry. Osteomacs differ from osteoclasts in expression of Siglec1 (CD169). This distinction was confirmed using the CD169-diphtheria toxin (DT) receptor (DTR) knock-in model. DT treatment of naïve CD169-DTR mice resulted in selective and striking loss of osteomacs, whilst osteoclasts and trabecular bone area were unaffected. Consistent with a previously-reported trophic interaction, osteomac loss was accompanied by a concomitant and proportionately striking reduction in osteoblasts. The impact of CD169+ macrophage depletion was assessed in two models of bone injury that heal via either intramembranous (tibial injury) or endochondral (internally-plated femoral fracture model) ossification. In both models, CD169+ macrophage, including osteomac depletion compromised bone repair. Importantly, DT treatment in CD169-DTR mice did not affect osteoclast frequency in either model. In the femoral fracture model, the magnitude of callus formation correlated with the number of F4/80+ macrophages that persisted within the callus. Overall these observations provide compelling support that CD169+ osteomacs, independent of osteoclasts, provide vital pro-anabolic support to osteoblasts during both bone homeostasis and repair.
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Abstract
PURPOSE OF REVIEW Mounting evidence supporting the critical contribution of macrophages, in particular osteal macrophages, to bone regeneration is reviewed. We specifically examine the potential role of macrophages in the basic multicellular units coordinating lifelong bone regeneration via remodelling and bone regeneration in response to injury. We review and discuss the distinctions between macrophage and osteoclast contributions to bone homeostasis, particularly the dichotomous role of the colony-stimulating factor 1-colony-stimulating factor 1 receptor axis. RECENT FINDINGS The impact of inflammation associated with aging and other hallmarks of aging, including senescence, on macrophage function is addressed in the context of osteoporosis and delayed fracture repair. Resident macrophages versus recruited macrophage contributions to fracture healing are also discussed. We identify some of the remaining knowledge gaps that will need to be closed in order to maximise benefits from therapeutically modulating or mimicking the function of macrophages to improve bone health and regeneration over a lifetime.
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Affiliation(s)
- Lena Batoon
- Bones and Immunology Laboratory, Cancer Biology and Care Program, Mater Research Institute - The University of Queensland, Translational Research Institute, 37 Kent Street, Woolloongabba, QLD, 4102, Australia
| | - Susan Marie Millard
- Bones and Immunology Laboratory, Cancer Biology and Care Program, Mater Research Institute - The University of Queensland, Translational Research Institute, 37 Kent Street, Woolloongabba, QLD, 4102, Australia
| | - Liza Jane Raggatt
- Bones and Immunology Laboratory, Cancer Biology and Care Program, Mater Research Institute - The University of Queensland, Translational Research Institute, 37 Kent Street, Woolloongabba, QLD, 4102, Australia
- Faculty of Medicine, The University of Queensland, Herston, QLD, 4092, Australia
| | - Allison Robyn Pettit
- Bones and Immunology Laboratory, Cancer Biology and Care Program, Mater Research Institute - The University of Queensland, Translational Research Institute, 37 Kent Street, Woolloongabba, QLD, 4102, Australia.
- Faculty of Medicine, The University of Queensland, Herston, QLD, 4092, Australia.
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Crosstalk between mesenchymal stem cells and macrophages in inflammatory bowel disease and associated colorectal cancer. Contemp Oncol (Pozn) 2017; 21:91-97. [PMID: 28947877 PMCID: PMC5611497 DOI: 10.5114/wo.2017.68616] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Accepted: 05/17/2017] [Indexed: 12/19/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are attractive seed cells for immunotherapy, tissue engineering and regenerative medicine due to their self-renewal and multidirectional differentiation abilities, diverse immunoregulatory functions and ease of isolation from a wide range of tissues. MSCs exert their immunoregulatory effect on immune cells via cell-to-cell contact and paracrine mechanisms. In turn, MSCs can also be modulated by immune cells. Macrophages are constantly present in the mucosa of the intestinal tract of mammals and play an important role in the development and progression of inflammatory bowel disease (IBD), a chronic and recurrent inflammatory disease of the gastrointestinal tract characterized by idiopathic mucosal inflammation. The increased morbidity and mortality of IBD have made it a disease hard to cure in the clinic. MSCs have emerged as an important tool for IBD therapy due to their abilities to differentiate into enterocyte-like cells and regulate inflammatory cells, especially macrophages. In this review, we discuss the recent advances in the interaction between MSCs and macrophages in diseases, with an emphasis on IBD. We propose that an optimized MSC-based therapy would provide a novel strategy for the treatment of IBD and the prevention of IBD-associated colorectal cancer (CRC).
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Tang H, Zhang Y, Jansen JA, van den Beucken JJJP. Effect of monocytes/macrophages on the osteogenic differentiation of adipose-derived mesenchymal stromal cells in 3D co-culture spheroids. Tissue Cell 2017; 49:461-469. [PMID: 28684045 DOI: 10.1016/j.tice.2017.06.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Revised: 06/02/2017] [Accepted: 06/06/2017] [Indexed: 02/08/2023]
Abstract
This study aimed to investigate the distinctive roles of the monocytes and macrophages on osteogenic differentiation of adipose-derived mesenchymal stromal cells (ADMSCs) in 3D spheroid co-cultures. We hypothesized that monocytes or macrophages (subtypes pro-inflammatory M1 and pro-wound healing M2) would affect the osteogenic differentiation of ADMSCs in 3D spheroids and that cell-cell interactions between monocytes/macrophages and ADMSCs play an important role in the osteogenic differentiation process of ADMSCs. The obtained results indicated that the osteogenic differentiation of ADMSCs was inhibited by monocytes and both macrophage subtypes in 3D spheroids. Monocytes and M2 macrophages had a stronger inhibiting effect than M1 macrophages. Cell-cell interactions mediated by N-cadherin likely played a role in the inhibiting effect of monocytes/macrophages on the osteogenic differentiation of ADMSCs.
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Affiliation(s)
- Hongbo Tang
- Department of Biomaterials, Radboudumc, Nijmegen, the Netherlands; Department of Plastic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yang Zhang
- Department of Biomaterials, Radboudumc, Nijmegen, the Netherlands
| | - John A Jansen
- Department of Biomaterials, Radboudumc, Nijmegen, the Netherlands
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50
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Abstract
Bone is in a constant state of remodeling, a process which was once attributed solely to osteoblasts and osteoclasts. Decades of research has identified many other populations of cells in the bone that participate and mediate skeletal homeostasis. Recently, osteal macrophages emerged as vital participants in skeletal remodeling and osseous repair. The exact mechanistic roles of these tissue-resident macrophages are currently under investigation. Macrophages are highly plastic in response to their micro-environment and are typically classified as being pro- or anti-inflammatory (pro-resolving) in nature. Given that inflammatory states result in decreased bone mass, proinflammatory macrophages may be negative regulators of bone turnover. Pro-resolving macrophages have been shown to release anabolic factors and may present a target for therapeutic intervention in inflammation-induced bone loss and fracture healing. The process of apoptotic cell clearance, termed efferocytosis, is mediated by pro-resolving macrophages and may contribute to steady-state bone turnover as well as fracture healing and anabolic effects of osteoporosis therapies. Parathyroid hormone is an anabolic agent in bone that is more effective in the presence of mature phagocytic macrophages, further supporting the hypothesis that efferocytic macrophages are positive contributors to bone turnover. Therapies which alter macrophage plasticity in tissues other than bone should be explored for their potential to treat bone loss either alone or in conjunction with current bone therapeutics. A better understanding of the exact mechanisms by which macrophages mediate bone homeostasis will lead to an expansion of pharmacologic targets for the treatment of osteoporosis and inflammation-induced bone loss.
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Affiliation(s)
- Megan N Michalski
- Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109, United States
| | - Laurie K McCauley
- Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109, United States; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, United States.
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