Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, China; Department of Orthopedics, Jiangyin Hospital Affiliated to Southeast University, Wuxi 214400, China.
Department of Orthopedics, Jiangyin Hospital Affiliated to Southeast University, Wuxi 214400, China.
Int Immunopharmacol. 2019 Oct;75:105732. doi: 10.1016/j.intimp.2019.105732. Epub 2019 Jul 20.
Rheumatoid arthritis (RA) is a major debilitating systemic disease characterized by chronic inflammation of the synovium and joint destruction. Despite major advancements in our understanding of RA in recent decades, it remains a disease of unknown etiology. To our knowledge, this is the first study exploring the effects of agonism of the glucagon-like peptide-1 (GLP-1) receptor using lixisenatide, a licensed drug used for the treatment of type II diabetes, on the pathological characteristics of RA in human fibroblast-like synoviocytes. Our findings indicate that lixisenatide inhibited the inflammatory response through downregulation of proinflammatory cytokines, such as tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), and interleukin-8 (IL-8); inhibition of matrix metalloproteinases (MMPs); and blockade of cellular signaling pathways, including the c-Jun N-terminal kinase (JNK), activator protein 1 (AP-1), and nuclear factor κ B (NF-κB) pathways. Furthermore, lixisenatide improved oxidative stress, rescued mitochondrial membrane potential (ΔΨm), and prevented cell death in fibroblast-like synoviocytes. These findings suggest that agonism of the GLP-1 receptor using lixisenatide may serve as a novel therapeutic option for the treatment and prevention of RA.
类风湿关节炎（RA）是一种主要的致残性系统性疾病，其特征为滑膜和关节的慢性炎症及破坏。尽管近几十年来我们对 RA 的认识有了重大进展，但它仍然是一种病因不明的疾病。据我们所知，这是第一项研究探索使用利西那肽（一种用于治疗 2 型糖尿病的已上市药物）激动胰高血糖素样肽-1（GLP-1）受体对人成纤维样滑膜细胞中 RA 的病理特征的影响。我们的研究结果表明，利西那肽通过下调促炎细胞因子（如肿瘤坏死因子 α（TNF-α）、白细胞介素-6（IL-6）和白细胞介素-8（IL-8））、抑制基质金属蛋白酶（MMPs）和阻断细胞信号通路（包括 c-Jun N 末端激酶（JNK）、激活蛋白 1（AP-1）和核因子 κ B（NF-κB）通路）来抑制炎症反应。此外，利西那肽还改善了成纤维样滑膜细胞中的氧化应激，挽救了线粒体膜电位（ΔΨm），并防止了细胞死亡。这些发现表明，使用利西那肽激动 GLP-1 受体可能成为治疗和预防 RA 的一种新的治疗选择。
