Adipose-cartilage communication via EV-Mito-mtDNA signaling promotes osteoarthritis progression
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.
How strong is the evidence?
Evidence Hub reads this as a cohort study, done in people. Its evidence level is 3 of 5 (Moderate · trial / cohort / secondary analysis). Trials without a large randomized design, cohorts and secondary analyses give moderate evidence.
Read the paper
Related studies
- A Coupled SYSTEM of Intracellular Ca 2+ Clocks and Surface Membrane Voltage Clocks Controls the Timekeeping Mechanism of the Heart’s Pacemaker
- A Comprehensive Review on the Therapeutic Potential of Curcuma longa Linn. in Relation to its Major Active Constituent Curcumin
- Cancer epigenetics: Moving forward
- Current developments in LC-MS for pharmaceutical analysis
- Myricetin: A comprehensive review on its biological potentials
- A Computational Systems Biology Software Platform for Multiscale Modeling and Simulation: Integrating Whole-Body Physiology, Disease Biology, and Molecular Reaction Networks
Go deeper in Evidence Hub
Evidence Hub adds a study data sheet (design, sample size, evidence level, key numbers), an AI summary and a chat grounded in the paper's text.