J. Cell Commun. Signal. (2009) 3:89–94 DOI 10.1007/s12079-009-0037-7 REVIEW Connective tissue growth factor (CTGF, CCN2) gene regulation: a potent clinical bio-marker of fibroproliferative disease? Andrew Leask & Sunil K. Parapuram & Xu Shi-wen & D. J. Abraham Received: 25 November 2008 / Accepted: 9 January 2009 / Published online: 21 January 2009 # The Author(s) 2009. This article is published with open access at Springerlink.com Abstract The CCN (cyr61, ctgf, nov) family of modular proteins regulate diverse biological affects including cell adhesion, matrix production, tissue remodelling, prolifera- tion and differentiation. Recent targeted gene disruption studies have demonstrated the CCN family to be develop- mentally essential for chondrogenesis, osteogenesis and angiogenesis. CCN2 is induced by agents such as angio- tensin II, endothelin-1, glucocorticoids, HGF, TGFβ, and VEGF, and by hypoxia and biomechanical and shear stress. Dysregulated expression of CCN2 has also been widely documented in many fibroproliferative diseases. This mini- review will focus on CCN2, and the recent progress in understanding CCN2 gene regulation in health and disease. That CCN2 should be considered a novel and informative surrogate clinical bio-marker for fibroproliferative disease is discussed. Keywords CCN2 . CTGF . Fibrosis . Biomarker This article also appears in the newsletter section of the CCN society website: www.ccnsociety.com/. A. Leask (*) : S. K. Parapuram CIHR Group in Skeletal Development and Remodeling, Division of Oral Biology and Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, Dental Sciences Building, London, ON N6A 5C1, Canada e-mail: Andrew.leask@schulich.uwo.ca X. Shi-wen : D. J. Abraham Centre for Rheumatology, Royal Free and University College Medical School, University College London (Royal Free Campus), Rowland Hill Street, London NW3 2PF, UK Introduction The CCN (cyr61, ctgf, nov) family comprises six members (CCN1–6). These proteins act through integrin- and heparan sulfate proteoglycan-mediated adhesive signaling to directly modulate adhesion and indirectly modulate the functional activities of other extracellular ligands such as cytokines, growth factors, morphogens and matrix compo- nents (Leask and Abraham 2006). Of these, connective tissue growth factor (CTGF, CCN2) is perhaps the best studied family member. CCN2 was initially identified as a protein secreted by cultured human endothelial cells (Bradham et al. 1991). In adult mammals, CCN2 exhibits a restricted expression, produced only by hepatic stellate cells (Paradis et al. 1999; Chen et al. 2001) and kidney mesangial cells (Ito et al. 1998; Chen et al. 2002). Although CCN2 is not normally expressed by other mesenchymal cells, it is rapidly induced during the tissue repair process, for example upon injury (Igarashi et al. 1993; Kapoor et al. 2008). The most potent inducer of CCN2 expression thus far identified is TGFβ. The induction of CCN2 by TGFβ is restricted to the mesenchymal cell lineages (e.g. tissue fibroblasts, myofi- broblasts, pericytes) and generally not in epithelial cells (Leask et al. 2001, 2003; Kantarci et al. 2006). However, CCN2 is expressed in response to TGFβ in renal proximal tubule epithelial cells (Phanish et al. 2005). These results indicate that CCN2 gene regulation in response to TGFβ can differ based on the cell type examined. CCN2 is over-expressed in connective tissue pathologies such as in excessive scarring and fibrosis and in stroma surrounding tumors (Blom et al. 2002). Data examining the location of CCN2 expression and the use of genetically modified cells has led to a hypothesis that CCN2 selectively mediates or sustains the specific actions of DO00037; No of Pages