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Ras Guanine Nucleotide–Releasing Protein 4 Is Aberrantly Expressed in the Fibroblast‐like Synoviocytes of Patients With Rheumatoid Arthritis and Controls Their Proliferation

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
出处
期刊:Arthritis & rheumatology [Wiley]
卷期号:67 (2): 396-407 被引量:17
标识
DOI:10.1002/art.38924
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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