Connective tissue growth factor: a fibrogenic master switch in fibrotic liver diseases

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Connective tissue growth factor: a fibrogenic master switch in fibrotic liver diseases

Authors: Gressner, Olav A.1; Gressner, Axel M.1

Source: Liver International, Volume 28, Number 8, September 2008 , pp. 1065-1079(15)

Publisher: Blackwell Publishing

Abstract:

Connective tissue growth factor (CTGF=CCN2), one of six members of cysteine-rich, secreted, heparin-binding proteins with a modular structure, is recognized as an important player in fibrogenic pathways as deduced from findings in non-hepatic tissues and emerging results from liver fibrosis. Collectively, the data show strongly increased expression in fibrosing tissues and transforming growth factor (TGF-β)-stimulated expression in hepatocytes, biliary epithelial cells and stellate cells. Functional activity as a mediator of fibre-fibre, fibre-matrix and matrix-matrix interactions, as an enhancer of profibrogenic TGF-β and several secondary effects owing to TGF-β enhancement, and as a down-modulator of the bioactivity of bone morphogenetic protein-7 has been proposed. By changing the activity ratio of TGF-β to its antagonist bone-morphogenetic protein-7, CTGF is proposed as a fibrogenic master switch for epithelial-mesenchymal transition. Consequently, knockdown of CTGF considerably attenuates experimental liver fibrosis. The spill-over of CTGF from the liver into the blood stream proposes this protein as a non-invasive reporter of TGF-β bioactivity in this organ. Indeed, CTGF-levels in sera correlate significantly with fibrogenic activity. The data suggest CTGF as a multifaceted regulatory protein in fibrosis, which offers important translational aspects for diagnosis and follow-up of hepatic fibrogenesis and as a target for therapeutic interventions. In addition, CTGF-promoter polymorphism might be of importance as a prognostic genetic marker to predict the progression of fibrosis.

Keywords: connective tissue growth factor; CTGF; liver fibrosis; pathogenesis; diagnosis; therapy; translational medicine

Document Type: Research article

DOI: 10.1111/j.1478-3231.2008.01826.x

Affiliations: 1: Institute of Clinical Chemistry and Pathobiochemistry, RWTH-University Hospital, Aachen, Germany