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

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.