{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T12:34:25Z","timestamp":1788870865643,"version":"build-2803163510"},"reference-count":42,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2015,1,28]],"date-time":"2015-01-28T00:00:00Z","timestamp":1422403200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"NIH","award":["AI059746"],"award-info":[{"award-number":["AI059746"]}]},{"name":"The Japanese Ministry of Education"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2015,2]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Ras guanine nucleotide\u2013releasing protein 4 (RasGRP\u20104) is a calcium\u2010regulated guanine nucleotide exchange factor and diacylglycerol\/phorbol ester receptor not normally expressed in fibroblasts. While RasGRP\u20104\u2013null mice are resistant to arthritis induced by anti\u2013glucose\u20106\u2010phosphate isomerase autoantibodies, the relevance of these findings to humans is unknown. We undertook this study to evaluate the importance of RasGRP\u20104 in the pathogenesis of human and rat arthritis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Synovial tissue from patients with rheumatoid arthritis (RA) and osteoarthritis (OA) were evaluated immunohistochemically for the presence of RasGRP\u20104 protein. Fibroblast\u2010like synoviocytes (FLS) were isolated from synovial samples, and expression of RasGRP\u20104 was evaluated by real\u2010time quantitative reverse transcription\u2013polymerase chain reaction analyses. The proliferation potency of FLS was evaluated by exposing the cells to a RasGRP\u20104\u2013specific small interfering RNA (siRNA). Finally, the ability of RasGRP\u20104\u2013specific siRNAs to hinder type II collagen\u2013induced arthritis in rats was evaluated to confirm the importance of the signaling protein in the disease.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Unexpectedly, RasGRP\u20104 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\u20104 than did FLS from examined OA patients. Moreover, the level of RasGRP\u20104 transcript was correlated with the FLS proliferation rate. The ability of cultured FLS to divide was diminished when they were treated with RasGRP\u20104\u2013specific siRNAs. The intraarticular injection of RasGRP\u20104\u2013specific siRNAs also dampened experimental arthritis in rats.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>RasGRP\u20104 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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/art.38924","type":"journal-article","created":{"date-parts":[[2014,10,20]],"date-time":"2014-10-20T11:06:59Z","timestamp":1413803219000},"page":"396-407","source":"Crossref","is-referenced-by-count":19,"title":["Ras Guanine Nucleotide\u2013Releasing Protein 4 Is Aberrantly Expressed in the Fibroblast\u2010like Synoviocytes of Patients With Rheumatoid Arthritis and Controls Their Proliferation"],"prefix":"10.1002","volume":"67","author":[{"given":"Michihito","family":"Kono","sequence":"first","affiliation":[{"name":"Hokkaido University Graduate School of Medicine Sapporo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinsuke","family":"Yasuda","sequence":"additional","affiliation":[{"name":"Hokkaido University Graduate School of Medicine Sapporo 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