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

FGF18 is linked to osteoarthritis (OA) progression, but its relationship with FOXN2 and its roles in post-traumatic osteoarthritis (PTOA) remain unclear. Here, we conducted comparative screening between PTOA and normal controls, revealing that FGF18 expression was significantly downregulated in articular cartilage of PTOA patients compared to normal cases. Functional studies demonstrated that FGF18 overexpression enhanced chondrocyte proliferation through Bone Morphogenetic Protein 2 (BMP2) upregulation and attenuated cartilage degradation by suppressing CTX-II (a cartilage degradation biomarker) and catabolic factors (MMP13 and ADAMTS-5), while substantially promoting aggrecan synthesis in PTOA models. Intra-articular delivery of FGF18 in destabilized medial meniscus (DMM)-induced PTOA mice significantly reduced cartilage erosion and markedly decreased synovial thickening compared to saline-treated controls, with improved cartilage matrix integrity. Intriguingly, FOXN2 expression was significantly upregulated in FGF18-knockout chondrocytes but restored upon FGF18 overexpression, identifying FOXN2 as a downstream mediator of FGF18 in PTOA pathophysiology. 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.