小干扰RNA
关节炎
分子生物学
类风湿性关节炎
发病机制
癌症研究
化学
成纤维细胞
医学
免疫学
生物
核糖核酸
生物化学
基因
体外
作者
Michihito Kono,Shinsuke Yasuda,Richard L Stevens,Hideyuki Koide,Takashi Kurita,Yuka Shimizu,Y. Kanetsuka,Kenji Oku,Toshiyuki Bohgaki,Olga Amengual,Tetsuya Horita,Tomohiro Shimizu,Tokifumi Majima,Takao Koike,Tatsuya Atsumi
摘要
Ras guanine nucleotide-releasing protein 4 (RasGRP-4) is a calcium-regulated guanine nucleotide exchange factor and diacylglycerol/phorbol ester receptor not normally expressed in fibroblasts. While RasGRP-4-null mice are resistant to arthritis induced by anti-glucose-6-phosphate isomerase autoantibodies, the relevance of these findings to humans is unknown. We undertook this study to evaluate the importance of RasGRP-4 in the pathogenesis of human and rat arthritis.Synovial tissue from patients with rheumatoid arthritis (RA) and osteoarthritis (OA) were evaluated immunohistochemically for the presence of RasGRP-4 protein. Fibroblast-like synoviocytes (FLS) were isolated from synovial samples, and expression of RasGRP-4 was evaluated by real-time quantitative reverse transcription-polymerase chain reaction analyses. The proliferation potency of FLS was evaluated by exposing the cells to a RasGRP-4-specific small interfering RNA (siRNA). Finally, the ability of RasGRP-4-specific siRNAs to hinder type II collagen-induced arthritis in rats was evaluated to confirm the importance of the signaling protein in the disease.Unexpectedly, RasGRP-4 protein was detected in the synovial hyperplastic lining, where proliferating FLS preferentially reside. FLS isolated from tissues obtained from a subpopulation of RA patients expressed much more RasGRP-4 than did FLS from examined OA patients. Moreover, the level of RasGRP-4 transcript was correlated with the FLS proliferation rate. The ability of cultured FLS to divide was diminished when they were treated with RasGRP-4-specific siRNAs. The intraarticular injection of RasGRP-4-specific siRNAs also dampened experimental arthritis in rats.RasGRP-4 is aberrantly expressed in FLS and helps regulate their growth. This intracellular signaling protein is therefore a candidate target for dampening proliferative synovitis and joint destruction.
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