Adipose-derived leptin and complement factor D mediate osteoarthritis severity and pain.

Obesity is a risk factor for osteoarthritis (OA), and leptin is among the adipokines implicated in obesity-induced OA. However, the specific role of leptin in OA severity and pain is not known. Using lipodystrophic (LD) mice, we show that fat-secreted factors are required for knee OA development, implicating a fat-cartilage cross-talk. Fat pad implantation or systemic leptin restoration in LD mice reintroduced structural OA and pain, whereas implantation of leptin-deficient fat pad did not change OA susceptibility. Isochronic parabiosis and spatial transcriptomics confirmed that a fat-joint cross-talk likely occurred via soluble mediators. Global unsupervised multiomics of conditioned media from fat implants revealed that leptin exerts a regulatory effect on adipsin (or complement factor D), the activity of which modulates the contrastive OA structural and pain phenotype. These findings suggest that adipokines influence OA pathogenesis, providing conclusive evidence of a fat-joint cross-talk and implicating OA as a systemic disease of adipose tissue.