Integrin inhibition facilitates fibrocartilaginous transformation in connective tissue in osteoarthritis

Abstract

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 COL5A1+ fibroblast population, derived from perivascular niche, contributes to fibrocartilaginous extracellular matrix (ECM) transformation. Multijoint analysis showed that integrin αV/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 αV/β5 activity using cilengitide facilitated the transcriptional reprogramming of Col5a1+ 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.