Connective tissue growth factor (CCN2, CTGF) and organ fibrosis: lessons from transgenic animals

Abstract

In recent months, four different systems have been reported in the literature in which CCN2 transgenes were individually expressed in podocytes, hepatocytes, cardiomyocytes or respiratory epithelial cells to achieve overexpression in, respectively, the kidney, liver, heart, or lung. These transgenic systems have provided valuable information about the contribution of CCN2 to fibrosis in vivo and have begun to reveal the complexities of the underlying mechanisms involved. On the one hand, studies of these animals have revealed that CCN2 overexpression does not necessarily lead directly to fibrotic pathology but may cause severe non-fibrotic tissue damage due to its other effects on cell function (e.g. heart). On the other hand, overexpression of CCN2 in concert with signaling pathways associated with development (e.g. lung) or fibrosing injuries (e.g. kidney, liver) can lead to the initiation or exacerbation of fibrosis. The significance of these studies is discussed in the context of the requirement for interactions between CCN2 and co-stimulatory factors in the microenvironment for the manifestation of CCN2-dependent fibrosis.

Fig.1

Enhanced thioacetamide-induced hepatic fibrosis in CCN2 transgenic livers. CCN2 FVB/n transgenic mice were produced as described (Tong et al. 2009). Four-week old wild-type (a, b) or homozygous transgenic (c, d) mice (n = 4 per group) were treated three times a week with thioacetamide (200 mg/kg i.p.) for four weeks. Liver sections were stained immunohistochemically for α-smooth muscle actin (a, c; brown staining) or with Sirius Red for collagen deposition (b, d; red staining). Staining is shown at 10×