Gene regulation of connective tissue growth factor: new targets for antifibrotic therapy?
Connective tissue growth factor (CTGF) has recently received much attention as a possible key determinant of progressive fibrosis and excessive scarring and also of wound repair, neoangiogenesis, bone formation and embryonic development. CTGF is also up regulated in numerous fibrotic diseases, including atherosclerosis and lung-, skin-, pancreas-, liver- and kidney-fibrosis. TGFbeta induces CTGF through different signaling pathways and a specific TGFbeta responsive element in the CTGF promoter. CTGF is thought to act both as a profibrotic marker and as a downstream effector of TGFbeta by mediating at least some of its profibrotic activities. CTGF is an interesting target for future antifibrotic therapies as it is conceivable that inhibition of CTGF might block the profibrotic effects of TGFbeta, without affecting TGFbeta's anti-proliferative and immunosuppressive effects. In addition to TGFbeta, a number of other regulators of CTGF expression have been identified, including vascular endothelial growth factor, tumor necrosis factor alpha, shear stress, cell stretch and static pressure, H(2)O(2), O(2) and NO. In addition to trans-regulatory mechanisms, specific transcription factor binding sites in the CTGF promoter, as well as 3'untranslated region (UTR) regulatory sequences have been identified that are important for basal and induced CTGF expression. Outlining the mechanisms that underlie CTGF gene regulation in normal and fibrotic cells, might help design of future intervention strategies aiming at targeted specific interference with CTGF expression at sites of progressive fibrosis. In addition, alternative therapies targeting CTGF effects are proposed which might lead to a favorable outcome of wound repair and fibrosis.
Blom
Ingrid E
IE
Department of Pathology, H04.312, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
Goldschmeding
Roel
R
Leask
Andrew
A
D000818:Animals; D055513:Connective Tissue Growth Factor; D005355:Fibrosis / Q000517:prevention & control; D005786:Gene Expression Regulation; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics* / Q000502:physiology; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology
C526317:CCN2 protein, human; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D055513:Connective Tissue Growth Factor