Dysregulated integrin αVβ3 and CD47 signaling promotes joint inflammation, cartilage breakdown, and progression of osteoarthritis

Osteoarthritis (OA) is the leading cause of joint failure, yet the underlying mechanisms remain elusive, and no approved therapies that slow progression exist. Dysregulated integrin function was previously implicated in OA pathogenesis. However, the roles of integrin alpha(V)beta(3) and the integrin-associated receptor CD47 in OA remain largely unknown. Here, transcriptomic and proteomic analyses of human and murine osteoarthritic tissues revealed dysregulated expression of alpha(V)beta(3), CD47, and their ligands. Using genetically deficient mice and pharmacologic inhibitors, we showed that alpha(V)beta(3), CD47, and the downstream signaling molecules Fyn and FAK are crucial to OA pathogenesis. MicroPET/CT imaging of a mouse model showed elevated ligand-binding capacities of integrin alpha(V)beta(3) and CD47 in osteoarthritic joints. Further, our in vitro studies demonstrated that chondrocyte breakdown products, derived from articular cartilage of individuals with OA, induced alpha(V)beta(3)/CD47-dependent expression of inflammatory and degradative mediators, and revealed the downstream signaling network, Our findings identify a central role for dysregulated alpha(V)beta(3)( )and CD47 signaling in OA pathogenesis and suggest that activation of alpha(V)beta(3) and CD47 signaling in many articular cell types contributes to inflammation and joint destruction in OA. Thus, the data presented here provide a rationale for targeting alpha(V)beta(3), CD47, and their signaling pathways as a disease-modifying therapy.