摘要：

Background Osteoarthritis is leading cause of disability, and its prevalence is rising due to the aging population and obesity epidemic 1 . Despite the substantial morbidity and health costs attributed to osteoarthritis, no treatment has been approved to prevent or slow disease progression, largely because the underlying pathogenic mechanism remains elusive. Both integrin αVβ3 and the integrin-associated receptor CD47 are considered important therapeutic targets for a number of diseases, but the potential involvement of these receptors in osteoarthritis remains unclear 2 . Objectives Our study aimed at assessing the role of integrin αVβ3 and the integrin-associated receptor CD47 signaling pathways in the pathogenesis of osteoarthritis, and identifying potential targets for disease-modifying therapy. Methods We performed transcriptomic and proteomic analyses of human and murine osteoarthritic tissues to examine the involvement of integrin αVβ3 and CD47 with osteoarthritis. Further, we evaluated the effects of genetic deficiency in and pharmacological modulations of integrin αVβ3 subunits, CD47, and their downstream signaling molecules Fyn and FAK on the destabilization of the medial meniscus (DMM) mouse model. Additionally, we used microPET/CT imaging of the DMM mouse model to assess the ligand-binding capacities of integrin αVβ3 and CD47 in osteoarthritic joints. Finally, we carried out multiple in vitro assays to determine how integrin αVβ3 and CD47 signaling might become activated in osteoarthritis, and what the molecular consequences of such activation might be. Results Our transcriptomic and proteomic analyses revealed the involvement of dysregulated integrin αVβ3 and CD47 signaling in osteoarthritis. Data from investigations of genetically deficient mice and pharmacological modulations showed that αVβ3, CD47, Fyn, and FAK are crucial to the pathogenesis of arthritis. We detected elevated ligand-binding capacities of integrin αVβ3 and CD47 in osteoarthritic joints by microPET/CT imaging of mice subjected to DMM. Our in vitro studies demonstrated that chondrocyte breakdown products, derived from the articular cartilage of individuals with osteoarthritis, induced αVβ3/CD47-dependent expression of inflammatory and degradative mediators, and revealed that the signaling network involved the Ras-CRAF-MEK-ERK pathways. Conclusions Our findings identify a central role of deregulated αVβ3 and CD47 signaling in the pathogenesis of osteoarthritis, and provide a rationale for targeting these signaling pathways as a disease-modifying therapy. References Lawrence, R. C. et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum 58, 26–35, doi:10.1002/art.23176 (2008). Tian, J., Zhang, F. J. And Lei, G. H. Role of integrins and their ligands in osteoarthritic cartilage. Rheumatology international 35, 787–798, doi: 10.1007/s00296–014–3137–5 (2015). Acknowledgements We thank Tamsin M. Lindstrom for her scientific input. Our research is supported by VA I01BX002345, I01RX000934, and I01RX000588. Disclosure of Interest None declared

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