Fibroblast growth factor 18 stimulates chondrocyte proliferation by modulating FOXN2 to mitigate post-traumatic osteoarthritis in a mouse model.

INTRODUCTION: FGF18 is linked to osteoarthritis (OA) progression, but its relationship with FOXN2 and its roles in post-traumatic osteoarthritis (PTOA) remain unclear. METHODS: We conducted comparative screening between PTOA and normal controls to assess FGF18 expression in articular cartilage. Functional studies examined FGF18 overexpression effects on chondrocyte proliferation and cartilage degradation. Intra-articular FGF18 delivery was performed in destabilized medial meniscus (DMM)-induced PTOA mice models. RESULTS: FGF18 expression was significantly downregulated in articular cartilage of PTOA patients compared to normal cases. FGF18 overexpression enhanced chondrocyte proliferation through BMP2 upregulation and attenuated cartilage degradation by suppressing CTX-II and catabolic factors (MMP13 and ADAMTS-5), while substantially promoting aggrecan synthesis. Intra-articular FGF18 delivery in DMM mice significantly reduced cartilage erosion and markedly decreased synovial thickening compared to saline-treated controls, with improved cartilage matrix integrity. FOXN2 expression was significantly upregulated in FGF18-knockout chondrocytes but restored upon FGF18 overexpression. DISCUSSION: These findings highlight that FGF18 mitigates PTOA progression by targeting FOXN2, promoting robust aggrecan synthesis, and substantially suppressing cartilage-degrading enzymes. Our study delineates a novel therapeutic axis for PTOA, emphasizing the distinct molecular mechanisms underlying trauma-driven cartilage pathology.