MFAP5⁺ synovial fibroblasts drive LOX upregulation to promote osteoarthritis progression

Synovial fibroblasts (SFs), the predominant synovial cell population, drive osteoarthritis (OA) pathogenesis. Understanding SF reprogramming in OA progression may reveal potential targets. Transcriptomic analysis identified preferential infiltration of MFAP5 ⁺ SFs in end-stage OA. Immunohistochemistry, quantitative real-time PCR, and immunofluorescence demonstrated MFAP5 upregulation in end-stage OA synovium from rats and patients compared with early-stage OA and controls. Increased MFAP5 and vimentin colocalization was observed in the synovium of end-stage OA patients. MFAP5⁺ SFs showed elevated LOX expression, and both MFAP5 and LOX were upregulated in lipopolysaccharide (LPS)-stimulated rat SF cell line (iCell-0135a). MFAP5 knockdown attenuated LPS-induced LOX upregulation in iCell-0135a cells, while overexpression enhanced LOX expression. Reduced LOX expression reduced LPS-induced IL-1β upregulation. In vivo, intra-articular administration of a LOX inhibitor alleviated joint damage in OA-model rats. These findings indicate that MFAP5 ⁺ SFs with high LOX expression characterize end-stage OA, and pharmacological LOX inhibition offers therapeutic potential for OA.