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. Male LD mice received either a MEF transplant (MEF-rescue) from WT, leptin heterozygous (MEF-HET) or leptin homozygous knockout (MEF-KO) pups as previously described, which developed into adipose-like tissue between 3 and 5 weeks of age. The injection was delivered subcutaneously to the sternal aspect of a donor LD mouse (3–5 weeks old) under 2% isoflurane with a 27 gauge needle. At 16 weeks of age, surgical animals underwent destabilization of the medial meniscus surgery in their left knee joints, and the right limb served as a nonsurgical contralateral control. Mice were sacrificed at 28 weeks of age to assess OA severity, bone microstructure, and serum and SF inflammatory profiles. Genotype: Vis (Visceral), KO (Leptin Knockout), Sub (Subcutaneous), and WT (Wildtype). Treatment: EVFN (endogenous visceral fat nonsurgical), MKM (MEF knockout fat males + surgery), ESM (endogenous subcutaneous fat + male surgery), MKF (MEF knockout fat + surgery female), EVM (endogenous visceral fat + surgery), MWF (MEF WT fat females + surgery), MWM (MEF WT fat males + surgery), and ESF (endogenous subcutaneous fat + female surgery)