Small GTP-binding protein Rho-mediated signaling promotes proliferation of rheumatoid synovial fibroblastsReportar como inadecuado




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Arthritis Research and Therapy

, 7:R476

First Online: 18 February 2005Received: 11 November 2004Revised: 10 January 2005Accepted: 18 January 2005

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. 1We 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. 2We also found that thrombin efficiently activated Rho. 3Rho 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. 4Thrombin 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.

AbbreviationsDMEMDulbecco-s modified Eagle-s medium

ELISAenzyme-linked immunosorbent assay

FACSfluorescence-activated cell sorter

FCSfetal calf serum

Gα12-ctthe carboxy-terminal regions of Gα12

Gα13-ctthe carboxy-terminal regions of Gα13

GAPGTPase-activating protein

GEFguanine nucleotide exchange factor

GFPgreen-fluorescent protein

GSTglutathione S-transferase

ILinterleukin

mAbmonoclonal antibody

OAosteoarthritis

p115RGSregulator of G-protein signaling domain of p115RhoGEF

PBSphosphate-buffered saline

RArheumatoid arthritis

RBDRhotekin-Rho-binding domain

RGSregulator of G-protein signaling

SDstandard deviation

SFsynovial fibroblast

TNFtumor necrosis factor.

Electronic supplementary materialThe online version of this article doi:10.1186-ar1694 contains supplementary material, which is available to authorized users.

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Autor: Shingo Nakayamada - Hitoshi Kurose - Kazuyoshi Saito - Akira Mogami - Yoshiya Tanaka

Fuente: https://link.springer.com/







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