Effects and Regulation of Connective Tissue Growth Factor on Hepatic Stellate Cells

Abstract

SUMMARY:Connective tissue growth factor (CTGF) is a 38-kd protein involved in several human fibrotic disorders including atherosclerosis and skin and renal fibrosis. Although it has been shown that human and experimental liver fibrosis is associated with CTGF expression through up-regulation of CTGF mRNA by hepatic stellate cells (HSC), the role of CTGF in the liver has not yet been determined. The aim of the present study was to assess the effects of CTGF on rat primary HSC and its regulation in a well-established model of in vitro liver fibrogenesis. Incubation of primary HSC with recombinant CTGF induced a significant migratory (2.3-fold, 50 ng/ml CTGF) and proliferative effect (1.8-fold, 100 ng/ml CTGF). Type I collagen mRNA expression, as assessed by a real-time RT-PCR procedure, was also increased when cells were incubated in the presence of CTGF (2-fold, 50 ng/ml). Transforming growth factor-␤1 (TGF-␤1) strongly stimulated CTGF mRNA expression, a direct mechanism observed in the absence of any intermediate protein synthesis. Furthermore, spontaneous activation of HSC plated on plastic and stimulation by vascular endothelial growth factor, lipid peroxidation products (HNE, MDA), acetaldehyde, and platelet-derived growth factor (PDGF)-BB significantly up-regulated CTGF mRNA expression in HSC. PDGF-induced CTGF stimulation might be related in part to TGF-␤1 secretion because CTGF mRNA up-regulation observed after PDGF-BB stimulation was abrogated in the presence of neutralizing TGF-␤1 antibody. In conclusion, this study extends the role of CTGF in HSC activation and suggests that CTGF up-regulation might be a central pathway during HSC activation. (Lab Invest 2002, 82:767-773).

Curcumin suppresses the expression of extracellular matrix genes in activated hepatic stellate cells by inhibiting gene expression of connective tissue growth factor

“…Accumulating evidence has suggested that upregulation of CTGF might be a central pathway during HSC activation and hepatic fibrogenesis by mediating many of the profibrotic effects of TGF-␤ (1,41,42,53). CTGF expression in HSCs is significantly enhanced during the process of activation in vitro and in vivo (41,53). HSCs are the major cellular source of CTGF in the liver during liver fibrogenesis (42).…”

“…HSCs are the major cellular source of CTGF in the liver during liver fibrogenesis (42). In response to exogenous CTGF, HSCs demonstrate increased migration, proliferation, adhesion, and expression of type I collagen (6,41). Blockade of CTGF synthesis by antisense oligonucleotides of CTGF resulted in downexpression of type I collagen mRNA in an animal model with experimental liver fibrosis (52).…”

Phenotypic Changes in Hepatic Stellate Cells in Response to Toxic Liver Injury

“…In fibrotic livers, CTGF is predominantly expressed in HSCs and bile duct epithelial cells. In cultured HSCs, CTGF expression is increased in activated HSCs and in HSCs treated with TGF-b [36]. PDGF also stimulates the production of CTGF by HSCs, an effect that is blocked by neutralization of TGF-b [36].…”

“…In cultured HSCs, CTGF expression is increased in activated HSCs and in HSCs treated with TGF-b [36]. PDGF also stimulates the production of CTGF by HSCs, an effect that is blocked by neutralization of TGF-b [36]. Treatment of HSCs with CTGF stimulates collagen production and HSC proliferation and migration [36].…”

“…PDGF also stimulates the production of CTGF by HSCs, an effect that is blocked by neutralization of TGF-b [36]. Treatment of HSCs with CTGF stimulates collagen production and HSC proliferation and migration [36]. In support of a role for CTGF in the development of liver fibrosis, inhibition of CTGF in vivo with an siRNA decreases collagen levels [37].…”