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 fat-secreted factors are required for knee OA development, implicating a fat-cartilage crosstalk. 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 fat-joint crosstalk 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 contrastive OA structural and pain phenotype. These findings suggest adipokines influence OA pathogenesis, providing conclusive evidence of a fat-joint crosstalk and implicating OA as a systemic disease of adipose tissue.