Abstract
Osteoarthritis (OA) is believed to be linked with cartilage degeneration, subchondral bone sclerosis, and synovial inflammation that lead to joint failure, and yet treatment that can effectively reverse the pathological process of the disease still not exists. Recent evidence suggests excessive mechanical stress (eMS) as an essential role in the pathogenesis of OA. Increased levels of integrin αVβ3 have been detected in osteoarthritic cartilage and were previously implicated in OA pathogenesis. However, the role of integrin αVβ3 in the process of eMS-induced OA remains unclear. Here, histologic and proteomic analyses of osteoarthritic cartilage in a rat destabilization of the medial meniscus model demonstrated elevated expression of integrin αVβ3 as well as more serious cartilage degeneration in the medial weight-bearing area. Furthermore, results of in vitro study demonstrated that eMS led to a significant increase of integrin αVβ3 expression and phosphorylation of downstream signaling molecules such as FAK and ERK, as well as upregulated expressions of inflammatory and degradative mediators. In addition, we found that inhibition of integrin αVβ3 could alleviate chondrocyte inflammation triggered by eMS both in vivo and in vitro. Our findings suggest a central role for upregulation of integrin αVβ3 signaling in OA pathogenesis and demonstrate that activation of integrin αVβ3 signaling in cartilage contributes to inflammation and joint destruction in eMS-induced OA. Taken together, our data presented here provide a possibility for targeting integrin αVβ3 signaling pathway as a disease-modifying therapy.