cGAS-STING Aggravates Cartilage Degradation by Promoting Glycolysis in TMJOA

Abstract The abnormal mechanical stress has been considered as a major contributor of temporomandibular joint osteoarthritis (TMJOA), but the mechanism by which it leads to the degeneration of condylar cartilage remains elusive. The double-stranded (dsDNA)-sensing cGAS/STING pathway serves as a response mechanism in many sterile inflammatory responses. In the present study, we found that mechanical stress exerted on condyle chondrocytes induced dsDNA leakage from mitochondria to cytoplasm to activate STING. Upon activation, STING exacerbated cartilage degradation by suppressing the anabolism of cartilage extracellular matrix (ECM) and accelerating the catabolic activity. Furthermore, the promoted glycolysis in chondrocytes was identified as a central mechanism in the onset of TMJOA, with critical rate-limiting enzymes downstream of STING. Our study not only establishes an important link between the intrinsic TMJOA suppressor activity of STING and chondrocyte metabolism, but also has critical implications for the development of STING-targeted therapeutic modalities of TMJOA.