Authors
Cheng Gu, Fawei Liao, Ganggang Kong, Shiyi Yin, Yifei Jiang, Runtao Zhou, Jingguang Zeng, Yixun Wu, Xubo Li, Bo Wang, Qiguang Pang, Ming Fu, Qingtang Zhu, Canbin Zheng
Published in
Science advances. Volume 12. Issue 35. Pages eaee6780. Aug 28, 2026. Epub Aug 28, 2026.
Abstract
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.
PMID:
42664348
Bibliographic data and abstract were imported from PubMed on 29 Aug 2026.
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