Small GTP-binding protein Rho-mediated signaling promotes proliferation of rheumatoid synovial fibroblasts |
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Authors: | Shingo?Nakayamada Hitoshi?Kurose Kazuyoshi?Saito Akira?Mogami Email author" target="_blank">Yoshiya?TanakaEmail author |
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Institution: | (1) First Department of Internal Medicine, University of Occupational and Environmental Health, School of Medicine, Fukuoka, Japan;(2) Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan;(3) Pharmaceuticals Research Unit, Research &; Development Division, Mitsubishi Pharma Corporation, Yokohama, Japan |
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Abstract: | Rho is a major small GTP-binding protein that is involved in the regulation of various cell functions, including proliferation
and cell migration, through activation of multiple signaling molecules in various types of cells. We studied its roles in
synovial fibroblasts (SFs) in patients with rheumatoid arthritis (RA) and clarified its relevance to RA synovitis, with the
following results. 1)We found that the thrombin receptor was overexpressed on RA synovial fibroblasts (RA SFs) and that thrombin
induced a marked proliferation and progression of the cell cycle to the S phase in these cells. 2)We also found that thrombin
efficiently activated Rho. 3)Rho activation and proliferation and the progression of the cell cycle to the S phase were completely
blocked by p115RGS (an N-terminal regulator of the G-protein signaling domain of p115RhoGEF) and by the C-terminal fragments
of Gα13 (an inhibitor of the interaction of receptors with G13). 4)Thrombin induced the secretion of IL-6 by RA SFs, but this
action was blocked by p115RGS or Gα13. Our findings show that the actions of thrombin on the proliferation of RA SFs, cell-cycle
progression to the S phase, and IL-6 secretion were mainly mediated by the G13 and RhoGEF pathways. These results suggest
that p115RGS and Gα13 could be potent inhibitors of such functions. A rational design of future therapeutic strategies for
RA synovitis could perhaps include the exploitation of the Rho pathway to directly reduce the growth of synovial cells. |
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