Dysfunctional autophagy triggers STING1 activation to exacerbate cartilage degeneration in obesity-associated...

Obesity, a major risk factor for osteoarthritis (OA), is related to increased circulating levels of free fatty acids (FFAs). However, the molecular mechanism underlying this metabolic OA phenotype remains unknown. We found that mice fed a high-fat diet (HFD) became obese and developed OA in their knee joints. Macroautophagy/autophagy activity was significantly reduced in articular cartilage of mice fed an HFD or in chondrocytes exposed to FFAs. Using conditional knockout (cKO) mice with cartilage-specific deletion of Atg7 to inhibit autophagy in vivo and shAtg7-lentiviral-transduced chondrocytes in vitro, we showed that autophagy deficiency aggravated HFD-induced OA progression and chondrocyte extracellular matrix (ECM) degradation. Mechanistically, STING1 was degraded in an autophagy-dependent manner. Autophagy deficiency increased STING1 levels, in turn activating the STING1-TBK1-IRF3 and MAP2K3/MKK3-MAPK/p38 signaling pathways, thereby triggering cartilage ECM degradation. These findings suggested that the HFD-autophagy-STING1 axis played a pivotal role in OA development, providing a potential therapeutic strategy for obesity-associated OA.Abbreviation: 3-MA: 3-methyladenine; ACAN: aggrecan; AOD: average optical density; ATG7: autophagy related 7; BafA1: bafilomycin A1; CGAS: cyclic GMP-AMP synthase; cKO: conditional knockout; COL2A1: collagen, type II, alpha 1; DMM: destabilizing the medial meniscus; DMXAA: 5.