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Originally published In Press as doi:10.1074/jbc.M003188200 on August 21, 2000

J. Biol. Chem., Vol. 275, Issue 45, 35584-35591, November 10, 2000
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Thrombin Is a Potent Inducer of Connective Tissue Growth Factor Production via Proteolytic Activation of Protease-activated Receptor-1*

Rachel C. ChambersDagger , Patricia Leoni, Olivier P. Blanc-Brude, David E. Wembridge, and Geoffrey J. Laurent

From the Centre for Cardiopulmonary Biochemistry and Respiratory Medicine, Royal Free and University College Medical School, UCL, Rayne Institute, 5 University Street, London WC1E 6JJ, United Kingdom

The coagulation protease thrombin plays a critical role in hemostasis and exerts pro-inflammatory and pro-fibrotic effects via proteolytic activation of the major thrombin receptor, protease-activated receptor-1 (PAR-1). Connective tissue growth factor (CTGF) is a novel fibroblast mitogen and also promotes extracellular matrix protein production. It is selectively induced by transforming growth factor beta  (TGF-beta ) and is thought to be the autocrine agent responsible for mediating its pro-fibrotic effects. CTGF is up-regulated during tissue repair and in fibrotic conditions associated with activation of the coagulation cascade. We therefore hypothesized that coagulation proteases promote the production of CTGF by cells at sites of tissue injury. To begin to address this hypothesis, we assessed the effect of coagulation proteases on fibroblast CTGF expression in vitro, and we show that thrombin, at physiological concentrations, up-regulated CTGF mRNA levels 5-fold relative to base line (p < 0.01) in fetal fibroblasts and 7-fold in primary adult fibroblasts (p < 0.01). These effects were cycloheximide-insensitive and were not blocked with a pan-specific TGF-beta -neutralizing antibody. They were further paralleled by a concomitant increase in CTGF protein production and could be mimicked with selective PAR-1 agonists. In addition, fibroblasts derived from PAR-1 knockout mice were unresponsive to thrombin but responded normally to TGF-beta 1. Finally, factor Xa, which is responsible for activating prothrombin during blood coagulation, exerted similar stimulatory effects. We propose that coagulation proteases and PAR-1 may play a role in promoting connective tissue formation during normal tissue repair and the development of fibrosis by up-regulating fibroblast CTGF expression.

* This work was supported by The Wellcome Trust Program Grant 051154, the British Lung Foundation Grant F93/12, and Johnson & Johnson Medical UK.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed: Tel.: 44 020 7679 6978; Fax: 44 020 7679 6973; E-mail: R.Chambers@ucl.ac.uk.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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