CCN2, the connective tissue growth factor

Abstract

The role of extracellular matrix proteins in signaling control and regulation of response to injury, particularly in terms of scarring, is a topic of major importance. Blatant clinical examples of disturbed scarring are keloid production and systemic sclerosis, better known as scleroderma [1, 2]. Both these conditions involve the upregulation of a novel extracellular matrix-secreted protein termed connective tissue growth factor (CTGF). In this issue, Lang et al. implicate CTGF in the pathogenesis of cardiac fibrosis in a model of an infectious heart disease [3]. The investigators relied on a murine model of Coxsackie virus B3 (CVB3) myocarditis. They found that CTGF expression was induced in the course of CVB3 myocarditis. Particularly, fibroblasts expressed the cytokine. CTGF upregulation coincided with transforming growth factor-beta (TGF-β) expression and preceded procollagen type I mRNA expression. The investigators then used siRNAs. When they knocked down CVB3 replication, CTGF expression was diminished. However, suppression of CTGF had no effect on virus replication. Thus, CTGF is now implicated in the scarring after infectious heart disease. That CTGF is involved in cardiac fibrosis occurring with targetorgan damage has been described earlier. The same group has published that the serum and glucocorticoid-inducible kinase (SGK1) is important to cardiac fibrosis occurring in the course of desoxycorticosterone acetate (DOCA salt)induced hypertension and that CTGF is induced as a downstream target of the kinase [4]. We investigated earlier whether CTGF mediates the profibrotic effects of angiotensin II (Ang II) in the heart and kidney and the role of calcineurin-dependent pathways in CTGF gene regulation. We used transgenic rats harboring human renin and angiotensinogen genes. Ang II induced an age-dependent increase in myocardial CTGF expression, which was 3.5-fold greater than in normotensive control rats [5]. CTGF overexpression correlated closely with the Ang II-induced rise in blood pressure. CTGF mRNA and protein were located predominantly in areas with leukocyte infiltration, myocardial, and vascular lesions, and colocalized with TGF-β, collagen I, and collagen III mRNA expressions. Blockade of calcineurin activity with cyclosporine A completely normalized Ang II-induced CTGF overexpression in the heart and kidney, suppressed the inflammatory response, and mitigated Ang II-induced cell proliferation and apoptosis. In contrast, blockade of mTOR (target of rapamycin) pathway with everolimus increased CTGF expression. Apparently, CTGF is an important mediator of fibrosis, and therefore, we need to know about the protein in greater detail. CTGF belongs to the CCN family of matrix signaling modulators [6]. The family is named after three prototypical members, cysteine-rich protein 61 (Cyr61), also termed CCN1; CTGF, termed CCN2; and the nephroblastoma overexpressed protein (Nov), also known as CCN3. The italicized letters show the derivation of the designation “CCN”. However, because their description was almost two decades ago, the CCN family has grown. The molecules comprise up to four modules, an insulin-like growth factor binding protein (IGFBP) domain (module I), a Von Willebrand factor domain (module II), a thrombospondinhomology domain (module III), and a cysteine knot, heparin-binding domain (module IV). A schematic view of CTGF and its modules is shown in Fig. 1a. What do the CCN proteins do? They play key roles in angiogenesis, chondrogenesis, and wound healing. The CCN proteins work by participating in cell proliferation, J Mol Med (2008) 86:1–3 DOI 10.1007/s00109-007-0287-x