Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka City, Fukuoka, 812-8582, Japan.
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA.
Sci Rep. 2021 May 18;11(1):10481. doi: 10.1038/s41598-021-90020-0.
G protein-coupled receptor kinase 5 (GRK5) regulates inflammatory responses via the nuclear factor-kappa B (NF-κB) pathway. This study investigated the functional involvement of GRK5 in the pathogenesis of inflammatory arthritis. Immunohistochemically, rheumatoid arthritis (RA) synovium had a significantly higher proportion of GRK5-positive cells in the synovial lining layer than healthy control synovium. Gene expression and NF-κB activation in lipopolysaccharide-stimulated human SW982 synovial cells were significantly suppressed by silencing of the GRK5 gene. Similarly, GRK5 kinase activity inhibition in human primary RA synovial cells attenuated gene expressions of inflammatory factors. In a murine model of collagen antibody-induced arthritis, arthritis scores and serum IL6 production of GRK5 knockout (GRK5) mice were significantly lower than those of wild-type mice. Histologically, the degree of synovitis and cartilage degeneration in GRK5 mice was significantly lower than in wild-type mice. In in vitro analyses using activated murine macrophages and fibroblast-like synoviocytes, gene expression of inflammatory factors and p65 nuclear translocation were significantly lower in GRK5 mice compared to wild-type mice. In conclusion, our results suggested that GRK5 is deeply involved in the pathogenesis of inflammatory arthritis, therefore, GRK5 inhibition could be a potential therapeutic target for types of inflammatory arthritis such as RA.
G 蛋白偶联受体激酶 5（GRK5）通过核因子-κB（NF-κB）途径调节炎症反应。本研究探讨了 GRK5 在炎症性关节炎发病机制中的功能作用。免疫组化分析显示，类风湿关节炎（RA）滑膜中滑膜衬里层的 GRK5 阳性细胞比例明显高于健康对照组滑膜。沉默 GRK5 基因可显著抑制脂多糖刺激的人 SW982 滑膜细胞中的基因表达和 NF-κB 激活。同样，人原发性 RA 滑膜细胞中 GRK5 激酶活性的抑制也减弱了炎症因子的基因表达。在胶原抗体诱导性关节炎的小鼠模型中，GRK5 基因敲除（GRK5）小鼠的关节炎评分和血清 IL6 水平明显低于野生型小鼠。组织学分析显示，GRK5 小鼠的滑膜炎和软骨退变程度明显低于野生型小鼠。在激活的鼠巨噬细胞和成纤维样滑膜细胞的体外分析中，与野生型小鼠相比，GRK5 小鼠的炎症因子基因表达和 p65 核易位明显降低。综上所述，我们的结果表明，GRK5 深度参与了炎症性关节炎的发病机制，因此，GRK5 抑制可能成为 RA 等炎症性关节炎的潜在治疗靶点。
Zotero 插件
