Therapeutic senescence via GPCR activation in synovial fibroblasts facilitates resolution of arthritis

Rheumatoid arthritis affects individuals commonly during the most productive years of adulthood. Poor response rates and the high costs associated mandate the search for new therapies. Here we show that targeting a specific GPCR promotes senescence in synovial fibroblasts enabling amelioration of joint inflammation. Following activation of the melanocortin type 1 receptor (MC1) synovial fibroblasts acquired a senescence phenotype characterized by arrested proliferation, metabolic re-programming and marked gene alteration resembling the remodeling phase of wound healing, with increased MMP expression and reduction in collagen production. This biological response was i) attained by selective agonism of MC1, not shared by non-selective ligands, and iii) dependent on downstream ERK1/2 phosphorylation. In vivo, activation of MC1 afforded anti-arthritic effects associated with induction of senescence in the synovial tissue and cartilage protection. Altogether,selective activation of MC1 is a viable strategy to induce cellular senescence affording a novel way to control joint inflammation and arthritis.