Cross-talk between GLI2 and FOXC1 promotes osteoarthritis-like cartilage catabolism and in vivo joint degeneration.

Osteoarthritis (OA) is a degenerative joint disease with limited disease-modifying therapies. This study investigated the roles of GLI family zinc finger 2 (GLI2) and Forkhead box C1 (FOXC1) in OA pathogenesis. Synovial fluid and cartilage were obtained from patients with knee OA who underwent total knee arthroplasty. The human chondrosarcoma cell line SW1353 was stimulated with OA synovial fluid to establish an in vitro model. Gain- and loss-of-function studies were performed using short hairpin RNA and overexpression plasmids. A rat papain-induced model was used for in vivo validation. OARSI scoring was performed by three observers on three sections per animal. GLI1, GLI2, and FOXC1 expression positively correlated with OA severity. In SW1353 cells, GLI2 and FOXC1 promoted catabolic changes and activated Wnt/β-catenin and BMP signaling. Silencing GLI2 or FOXC1 attenuated these phenotypes. Mechanistically, FOXC1 inhibited GLI2 ubiquitination by promoting JNK phosphorylation. Rescue experiments confirmed that FOXC1 exerted its effects primarily through GLI2. In vivo, sonic hedgehog inhibition or GLI2 knockdown ameliorated cartilage degeneration, as quantified by OARSI scoring. FOXC1 stabilizes GLI2 by suppressing its ubiquitination via enhanced JNK phosphorylation. The FOXC1-GLI2 axis forms a positive feedback loop that activates Wnt/β-catenin and BMP signaling, therefore representing a candidate molecular target for OA.