TNFSF4 Promotes Bone Erosion in Rheumatoid Arthritis by Enhancing the Inflammatory Response of Synovial Macrophages

Tumor necrosis factor superfamily member 4 (TNFSF4), also known as OX40L, is implicated in autoimmune diseases, but its role in rheumatoid arthritis (RA) remains poorly understood. This study reveals that TNFSF4 expression is elevated in RA synovial tissue and correlates with disease activity markers. Using a collagen-induced arthritis (CIA) mouse model, we demonstrate that TNFSF4 exacerbates synovial inflammation and promotes bone erosion by skewing macrophage polarization toward the pro-inflammatory M1 phenotype. TNFSF4 knockout reduces M1 macrophages, increases M2 macrophages, and attenuates cytokine-driven inflammation and osteoclast activity. Importantly, TNFSF4 does not directly modulate macrophage polarization but requires CD4⁺ T cell involvement. These findings uncover a novel mechanism by which TNFSF4 contributes to RA pathogenesis and highlight its potential as a therapeutic target for modulating immune responses and preventing joint damage in RA.