Members of the CCN protein family, including CTGF, are structurally characterized by having four conserved,cysteine-rich domains. These domains are, from N- to C-termini, the insulin-like growth factor binding protein (IGFBP) domain, the von Willebrand type C repeats (vWC) domain, the thrombospondin type 1 repeat (TSR) domain, and a C-terminal domain (CT) with acysteine knot motif. CTGF exerts its functions by binding to various cell surface receptors in a context-dependent manner, includingintegrin receptors,[11][12][13] cell surfaceheparan sulfate proteoglycans (HSPGs),[14]LRPs,[15] and TrkA.[16] In addition, CTGF also binds growth factors and extracellular matrix proteins. The N-terminal half of CTGF interacts withaggrecan,[17] the TSR domain interacts withVEGF[18] and, the CT domain interacts with members of the TGF-β superfamily,fibronectin,perlecan,fibulin-1,slit, andmucins.[5][6]
Knockout mice with the Ctgf gene disrupted die at birth due to respiratory stress as a result of severechondrodysplasia.[19] Ctgf-null mice also show defects in angiogenesis, with impaired interaction between endothelial cells and pericytes and collagen IV deficiency in the endothelial basement membrane.[20] CTGF is also important forpancreatic beta cell development[21] and is critical for normalovarian follicle development andovulation.[22]
CTGF is associated withwound healing and virtually allfibrotic pathology.[9][23] It is thought that CTGF can cooperate withTGF-β to induce sustainedfibrosis[24] and to exacerbate extracellular matrix production in association with other fibrosis-inducing conditions.[23] Overexpression of CTGF in fibroblasts promotes fibrosis in the dermis, kidney, and lung,[25] and deletion of Ctgf in fibroblasts and smooth muscle cells greatly reducesbleomycin-induced skin fibrosis.[26]
In addition to fibrosis, aberrant CTGF expression is also associated with many types of malignancies,diabetic nephropathy[27] andretinopathy, arthritis, and cardiovascular diseases. Several clinical trials are now ongoing that investigate the therapeutic value of targeting CTGF in fibrosis, diabetic nephropathy, andpancreatic cancer.[5]
CTGF (CCN2) has recently been implicated in mood disorders, notably in the postpartum period; these effects may be mediated by its effects on myelination[28]
^Aoyama E, Hattori T, Hoshijima M, Araki D, Nishida T, Kubota S, Takigawa M (June 2009). "N-terminal domains of CCN family 2/connective tissue growth factor bind to aggrecan".Biochem. J.420 (3):413–20.doi:10.1042/BJ20081991.PMID19298220.
^Mori T, Kawara S, Shinozaki M, Hayashi N, Kakinuma T, Igarashi A, Takigawa M, Nakanishi T, Takehara K (October 1999). "Role and interaction of connective tissue growth factor with transforming growth factor-beta in persistent fibrosis: A mouse fibrosis model".J. Cell. Physiol.181 (1):153–9.doi:10.1002/(SICI)1097-4652(199910)181:1<153::AID-JCP16>3.0.CO;2-K.PMID10457363.S2CID21284888.
