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

Montero-Melendez, Trinidad and Nagano, Ai and Chelala, Claude and Filer, Andrew and Buckley, Christopher D and Perretti, Mauro (2020) Therapeutic senescence via GPCR activation in synovial fibroblasts facilitates resolution of arthritis. Nature communications, 11 (1). p. 745. ISSN 2041-1723. This article is available to all UHB staff and students via ASK Discovery tool http://tinyurl.com/z795c8c by using their UHB Athens login IDs

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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 (MC), 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 MC, not shared by non-selective ligands, and dependent on downstream ERK1/2 phosphorylation. In vivo, activation of MC leads to anti-arthritic effects associated with induction of senescence in the synovial tissue and cartilage protection. Altogether, selective activation of MC is a viable strategy to induce cellular senescence, affording a distinct way to control joint inflammation and arthritis.

Item Type: Article
Additional Information: This article is available to all UHB staff and students via ASK Discovery tool http://tinyurl.com/z795c8c by using their UHB Athens login IDs
Subjects: WD Diseases and disorders of systemic, metabolic or environmental origin
WD Diseases and disorders of systemic, metabolic or environmental origin > WD811 Rheumatology
Divisions: Ambulatory Care > Rheumatology
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Depositing User: Jamie Edgar
Date Deposited: 14 Feb 2020 13:57
Last Modified: 14 Feb 2020 13:57
URI: http://www.repository.uhblibrary.co.uk/id/eprint/2848

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