New research shows that inducing senescence of synovial fibroblasts via activation of melanocortin type 1 receptor (MC1), a G protein-coupled receptor, could offer a novel approach to promote resolution of inflammation in joints affected by rheumatoid arthritis (RA). In the study, administration of a small-molecule MC1 agonist to synovial fibroblasts from patients with RA not only arrested proliferation of the cells, but also induced a pro-repair phenotype resembling that seen during the remodelling phase of wound healing.

Credit: DAVID HERRAEZ/Alamy Stock Photo

The researchers had previously demonstrated that drugs targeting the pro-resolving melanocortin system had anti-arthritic effects in mouse models of inflammatory arthritis. “In the present work we aimed to translate those findings into human arthritis by studying the effects of melanocortin drugs on human synovial fibroblasts from patients with RA, which are largely responsible for the sustained inflammation and hence lack of resolution within the arthritic joints,” explains lead author Trinidad Montero-Melendez.

In the study, treatment of RA synovial fibroblasts with the selective MC1 agonist BMS-470539, but not with non-selective ligands, induced senescence via phosphorylation of ERK. MC1 activation modulated processes related to cell cycle regulation, lysosomal function and metabolic processes. BMS-470539-treated cells were also characterized by downregulation of collagens and increased expression of matrix metalloproteinases.

In vivo, in mice with K/B × N serum transfer-induced arthritis, BMS-470539 had anti-arthritic effects in association with synovial fibroblast senescence. Notably, co-administration of senolytic drugs abrogated these anti-arthritic effects.

BMS-470539 had anti-arthritic effects in association with synovial fibroblast senescence

“Our study shows for the first time that senescence can be induced via the direct activation of a membrane receptor,” highlights Montero-Melendez. The results suggest a route to restoring homeostasis to joints affected by RA by directly targeting synovial fibroblasts.