Therapeutic senescence via GPCR activation in synovial fibroblasts facilitates resolution of arthritis
Therapeutic senescence via GPCR activation in synovial fibroblasts facilitates resolution of arthritis
复制标题
通过激活滑膜成纤维细胞的GPCR治疗衰老有助于关节炎的解决
DOI：
10.1038/s41467-020-14421-x
复制
发表时间：
2020-02-06
影响因子：
16.6
通讯作者：
Perretti, Mauro
中科院分区：
文献类型：
--
作者：
Montero-Melendez, Trinidad;Nagano, Ai;Perretti, Mauro
风湿性关节炎通常影响成年期最具生产力的几年。与治疗相关的低反应率和高成本要求寻找新的治疗方法。在这里，我们表明，针对特定的G蛋白偶联受体促进滑膜成纤维细胞衰老，使关节炎症的改善。在黑皮质素1型受体（MC 1）活化后，滑膜成纤维细胞获得衰老表型，其特征在于增殖停滞、代谢重编程和类似于伤口愈合的重塑阶段的显著基因改变，具有增加的基质金属蛋白酶表达和减少的胶原蛋白产生。这种生物学反应是通过选择性激动MC 1来实现的，不被非选择性配体共享，并且依赖于下游ERK 1/2磷酸化。在体内，MC 1的激活导致与诱导滑膜组织衰老和软骨保护相关的抗关节炎作用。总之，选择性激活MC 1是诱导细胞衰老的可行策略，提供了控制关节炎症和关节炎的独特方法。
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.