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Abstract
Rheumatoid arthritis affects individuals commonly during the most productive years of adulthood. Poor response rates and high costs associated with treatment mandate the search for new therapies. Here we show that targeting a specific G-protein coupled receptor promotes senescence in synovial fibroblasts, enabling amelioration of joint inflammation. Following activation of the melanocortin type 1 receptor (MC1), synovial fibroblasts acquire a senescence phenotype characterized by arrested proliferation, metabolic re-programming and marked gene alteration resembling the remodeling phase of wound healing, with increased matrix metalloproteinase expression and reduced collagen production. This biological response is attained by selective agonism of MC1, not shared by non-selective ligands, and dependent on downstream ERK1/2 phosphorylation. In vivo, activation of MC1 leads to 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 distinct way to control joint inflammation and arthritis.
Highlights
Rheumatoid arthritis affects individuals commonly during the most productive years of adulthood
The synovial layer transforms into a hyperplastic invasive tissue, expanding up to 10–20 cells thick in which synovial fibroblasts (SFs) acquire an aggressive proliferative phenotype turning into cytokines factories, driving cartilage and bone destruction, and promoting sustained recruitment and retention of immune cells
With respect to receptor activation, the natural panagonist αMSH and the melanocortin type 1 receptor (MC1)-selective compound BMS-470539 (BMS)[24] induced ERK-phosphorylation (Fig. 1d), they did not elevate cAMP, the canonical pathway described for this family of GPCRs25 (Fig. 1e)
Summary
Rheumatoid arthritis affects individuals commonly during the most productive years of adulthood. Following activation of the melanocortin type 1 receptor (MC1), synovial fibroblasts acquire a senescence phenotype characterized by arrested proliferation, metabolic re-programming and marked gene alteration resembling the remodeling phase of wound healing, with increased matrix metalloproteinase expression and reduced collagen production. MC1-mediated senescence leads to remarkable therapeutic consequences: cessation of SF proliferation and acquisition of a pro-repair phenotype that highly resembles that observed during senescence-driven wound healing[3,4,5] This effect is achieved by activation of the receptor by a small-molecule agonist, and it is the first reported evidence of cellular senescence induced through direct activation of a G-protein coupled receptor (GPCR)
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