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 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 fibrob...
| Main Authors: | , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Nature Research
2020
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| _version_ | 1826270375096352768 |
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| author | Montero-Melendez, T Nagano, A Chelala, C Filer, A Buckley, CD Perretti, M |
| author_facet | Montero-Melendez, T Nagano, A Chelala, C Filer, A Buckley, CD Perretti, M |
| author_sort | Montero-Melendez, T |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T21:39:50Z |
| format | Journal article |
| id | oxford-uuid:4788a6bb-552d-4382-8b35-53f682facb96 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T21:39:50Z |
| publishDate | 2020 |
| publisher | Nature Research |
| record_format | dspace |
| spelling | oxford-uuid:4788a6bb-552d-4382-8b35-53f682facb962022-03-26T15:20:40ZTherapeutic senescence via GPCR activation in synovial fibroblasts facilitates resolution of arthritisJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:4788a6bb-552d-4382-8b35-53f682facb96EnglishSymplectic ElementsNature Research2020Montero-Melendez, TNagano, AChelala, CFiler, ABuckley, CDPerretti, MRheumatoid 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. |
| spellingShingle | Montero-Melendez, T Nagano, A Chelala, C Filer, A Buckley, CD Perretti, M Therapeutic senescence via GPCR activation in synovial fibroblasts facilitates resolution of arthritis |
| title | Therapeutic senescence via GPCR activation in synovial fibroblasts facilitates resolution of arthritis |
| title_full | Therapeutic senescence via GPCR activation in synovial fibroblasts facilitates resolution of arthritis |
| title_fullStr | Therapeutic senescence via GPCR activation in synovial fibroblasts facilitates resolution of arthritis |
| title_full_unstemmed | Therapeutic senescence via GPCR activation in synovial fibroblasts facilitates resolution of arthritis |
| title_short | Therapeutic senescence via GPCR activation in synovial fibroblasts facilitates resolution of arthritis |
| title_sort | therapeutic senescence via gpcr activation in synovial fibroblasts facilitates resolution of arthritis |
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