The cross-talk between the cGAS-STING signaling pathway and chronic inflammation in the development of musculoskeletal disorders

Musculoskeletal disorders (MSDs) comprise diverse conditions affecting bones, joints, and muscles, leading to pain and loss of function, and are one of the most prevalent and major global health concerns. One of the hallmarks of MSDs is DNA damage. Once accumulated in the cytoplasm, the damaged DNA is sensed by the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway, which triggers the induction of type I interferons and inflammatory cytokines. Thus, this pathway connects the musculoskeletal and immune systems. Inhibitors of cGAS or STING have shown promising therapeutic effects in the pre-clinical models of several MSDs. Systemic, chronic, low-grade inflammation (SCLGI) underlies the development and maintenance of many MSDs. Failure to resolve SCLGI has been hypothesized to play a critical role in the development of chronic diseases, suggesting that the successful resolution of SCLGI will result in the alleviation of their related symptomatology. The process of inflammation resolution is feasible by specialized pro-resolving mediators (SPMs), which are enzymatically generated from dietary essential polyunsaturated fatty acids (PUFAs). The supplementation of SPMs or their stable, small-molecule mimetics and receptor agonists has revealed beneficial effects in inflammation-related animal models, including arthropathies, osteoporosis, and muscle dystrophy, suggesting a translational potential in MSDs. In this review, we substantiate the hypothesis that the use of cGAS-STING signaling pathway inhibitors together with SCLG-resolving compounds may serve as a promising new therapeutic approach for MSDs.