Adipose-cartilage communication via EV-Mito-mtDNA signaling promotes osteoarthritis progression.

Obesity is a major risk factor for osteoarthritis (OA), yet the mechanisms linking excess adiposity to joint degeneration remain incompletely understood. Here, we identify adipocyte-derived extracellular vesicles enriched in mitochondrial components (EV-Mito) as pathogenic mediators that transfer mitochondrial DNA (mtDNA) to chondrocytes. The internalized mtDNA activates the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) cytosolic DNA-sensing pathway, inducing inflammatory signaling, metabolic dysfunction, senescence, and cartilage degeneration in murine and human models. Genetic and pharmacological inhibition of cGAS-STING signaling attenuates cartilage damage, pain behaviors, and gait abnormalities. Population-level and interventional data further show that body fat percentage, rather than body mass index, is more closely associated with OA risk and severity. In an exercise cohort, high-intensity interval training selectively reduced adiposity and was associated with lower mtDNA abundance in synovial EV fractions enriched for adipose-associated EV markers, reduced synovial 2',3'-cyclic GMP-AMP levels, and superior improvement in OA symptoms. These findings define a conserved EV-Mito-mtDNA-cGAS-STING axis linking adipose tissue to joint pathology and highlight fat-targeted interventions as mechanistically informed strategies for preventing and treating obesity-associated OA.