Integrin inhibition facilitates fibrocartilaginous transformation in connective tissue in osteoarthritis

Osteoarthritis (OA) is a disabling condition with pathological remodeling of different joints, resulting in impaired function of the whole musculoskeletal system in vertebrates. Fibrocartilage has poor self-repair capacity after OA, leading to restricted treatment strategies and unsatisfying clinical efficacy. Recently, we constructed the spatiotemporal multiomic landscape of fibrocartilage and connective tissue in human temporomandibular joint (TMJ)-OA, observing that adjacent connective tissue could transform to fibrocartilage in TMJ-OA. We found that the <i>COL5A1</i>⁺ fibroblast population, derived from perivascular niche, contributes to fibrocartilaginous extracellular matrix (ECM) transformation. Multijoint analysis showed that integrin α_V/β₅ was universally activated in OA joints, which led to increased fibrocartilaginous transcription but disarranged ECM transformation in connective tissues. In OA mouse models and a TMJ-OA miniature pig model, inhibition of integrin α_V/β₅ activity using cilengitide facilitated the transcriptional reprogramming of <i>C</i>o<i>l5a1</i>⁺ fibroblast and functional remodeling of the connective tissues. Our findings verified the effectiveness of cilengitide and provided a clinical route for fibrocartilage injury repair in OA.