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

• Published in: Laboratory investigation Vol. 82; no. 6; pp. 767 - 773
• Main Authors: Paradis, Valerie, Dargere, Delphine, Bonvoust, Franck, Vidaud, Michel, Segarini, Patricia, Bedossa, Pierre
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.06.2002; Nature Publishing; Nature Publishing Group
• Subjects: Animals; Antibodies, Monoclonal - pharmacology; Biological and medical sciences; Bromodeoxyuridine - metabolism; Cell Division - drug effects; Cell Movement - drug effects; Cell Movement - physiology; Collagen Type I - genetics; Collagen Type I - metabolism; Connective Tissue Growth Factor; DNA Primers - chemistry; Dose-Response Relationship, Drug; Gastroenterology. Liver. Pancreas. Abdomen; Growth Substances - genetics; Growth Substances - metabolism; Growth Substances - pharmacology; Immediate-Early Proteins - genetics; Immediate-Early Proteins - metabolism; Immediate-Early Proteins - pharmacology; Intercellular Signaling Peptides and Proteins; Kupffer Cells - drug effects; Kupffer Cells - metabolism; Kupffer Cells - pathology; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Macrophage Activation - drug effects; Male; Medical sciences; Other diseases. Semiology; Platelet-Derived Growth Factor - pharmacology; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - metabolism; Transforming Growth Factor beta - immunology; Transforming Growth Factor beta - pharmacology; Transforming Growth Factor beta1; Up-Regulation; Spider cell; Human; Cell culture; Biochemical analysis; Pathogenesis; Liver; Hepatic disease; In vitro; Hepatitis; Connective tissue; Chronic; Fibrosis; Digestive diseases; Molecular biology; Growth factor
• ISSN: 0023-6837; 1530-0307
• DOI: 10.1097/01.LAB.0000017365.18894.D3

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-β1 (TGF-β1) 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-β1 secretion because CTGF mRNA up-regulation observed after PDGF-BB stimulation was abrogated in the presence of neutralizing TGF-β1 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.