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- Title
Ras Guanine Nucleotide-Releasing Protein 4 Is Aberrantly Expressed in the Fibroblast-like Synoviocytes of Patients With Rheumatoid Arthritis and Controls Their Proliferation.
- Authors
Kono, Michihito; Yasuda, Shinsuke; Stevens, Richard L.; Koide, Hideyuki; Kurita, Takashi; Shimizu, Yuka; Kanetsuka, Yusaku; Oku, Kenji; Bohgaki, Toshiyuki; Amengual, Olga; Horita, Tetsuya; Shimizu, Tomohiro; Majima, Tokifumi; Koike, Takao; Atsumi, Tatsuya
- Abstract
Objective 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. Methods 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. Results 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. Conclusion 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.
- Subjects
JAPAN; SYNOVIAL membranes; ACADEMIC medical centers; IMMUNOHISTOCHEMISTRY; POLYMERASE chain reaction; QUESTIONNAIRES; RESEARCH funding; RHEUMATOID arthritis; REVERSE transcriptase polymerase chain reaction; DESCRIPTIVE statistics; PHYSIOLOGY
- Publication
Arthritis & Rheumatology, 2015, Vol 67, Issue 2, p396
- ISSN
2326-5191
- Publication type
Article
- DOI
10.1002/art.38924