Connective tissue growth factor: a fibrogenic master switch in fibrotic liver diseases.
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-beta)-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-beta and several secondary effects owing to TGF-beta enhancement, and as a down-modulator of the bioactivity of bone morphogenetic protein-7 has been proposed. By changing the activity ratio of TGF-beta 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-beta 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.
Gressner
Olav A
OA
Institute of Clinical Chemistry and Pathobiochemistry, RWTH-University Hospital, Aachen, Germany.
Gressner
Axel M
AM
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000097:blood / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D008103:Liver Cirrhosis / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism
D015415:Biomarkers; D016212:Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor