Matrix Stiffening‐Induced SLIT3 Activation in Chondrocytes Drives Cartilage Degradation and Angiogenesis in Temporomandibular Joint Osteoarthritis

Cartilage degeneration and subchondral angiogenesis are key pathological features of temporomandibular joint osteoarthritis (TMJOA). This study aims to investigate the role and regulatory mechanism of SLIT3, a potent pro-angiogenic factor, in driving these processes. Male C57BL/6 mice underwent either sham surgery or unilateral anterior crossbite (UAC) surgery to induce TMJOA. Bilateral temporomandibular joints were harvested at 3 and 6 weeks post-surgery for radiographic, histological, and molecular analyses. Rat primary condylar chondrocytes were isolated for in vitro studies, including loss-of-function experiments to elucidate the role of chondrocyte-derived SLIT3. Early-stage TMJOA was characterized by progressive cartilage degradation and increased subchondral type H vessel formation, accompanied by increased SLIT3 expression in chondrocytes. We identified a previously unrecognized dual function of SLIT3: it not only promoted endothelial tube formation but also suppressed cartilage matrix synthesis. Mechanistically, SLIT3 secretion in chondrocytes was regulated by the Plexin-B2/YAP pathway in response to extracellular matrix (ECM) stiffening. Our findings reveal a novel mechano-driven pathological axis in TMJOA, wherein ECM stiffening activates the Plexin-B2/YAP/SLIT3 axis in chondrocytes, simultaneously driving both type H angiogenesis and cartilage degradation. This study uncovers a critical link between mechanical stimuli, chondrocyte signaling, and vascular invasion, offering new therapeutic targets for TMJOA intervention.