GDF15 ameliorates inflammatory arthritis-associated bone destruction and pain through inhibition of osteoclastogenesis and modulation of osteoclast-derived Netrin-1/CGRP+ nerve remodeling.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation, progressive bone erosion, and persistent pain, with limited therapeutic options for comprehensive disease control. Growth differentiation factor 15 (GDF15), a stress-responsive cytokine, has been implicated in inflammation and pain regulation, but its role in RA is not fully understood. Here, we investigated the expression, function, and underlying mechanisms of GDF15 in RA. We found that GDF15 was significantly upregulated in the serum and synovial tissues of patients with RA and in collagen-induced arthritis (CIA) mice. Functional studies showed that Gdf15 deficiency exacerbated arthritis severity, synovial inflammation, pannus formation, bone destruction, and mechanical hypersensitivity in collagen antibody-induced arthritis (CAIA) mice, whereas administration of recombinant GDF15 alleviated disease progression, reduced joint inflammation and bone loss, and improved pain-related behaviors in CIA mice. Mechanistically, GDF15 inhibited osteoclast differentiation and resorptive activity without affecting precursor viability, through suppression of NF-κB signaling and attenuation of calcium-dependent NFATc1 activation. In addition, GDF15 decreased osteoclast-derived Netrin-1 expression and reduced CGRP+ sensory nerve fiber density in the synovium. Rescue experiments demonstrated that exogenous Netrin-1 supplementation partially counteracted the beneficial effects of GDF15 on pain-related behaviors and CGRP+ sensory nerve remodeling in CAIA mice, further supporting the involvement of the osteoclast-derived Netrin-1/CGRP+ sensory nerve axis in GDF15-mediated pain regulation. Collectively, these findings identify GDF15 as an endogenous protective factor in inflammatory arthritis that limits osteoclastogenesis, bone destruction, and pain-related nerve remodeling, highlighting its potential as a therapeutic target for RA.