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

Brigstock DR - J Cell Commun Signal (2009)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Related in: MedlinePlus

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×
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Fig1: 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×

Mentions: The story does not stop there, however. Interesting additional data were reported for the kidney and liver transgenics that provide important clues as to the role of CCN2 in fibrotic pathways. When the kidney transgenic mice were challenged with streptozotocin to induce type I diabetes, they exhibited a more pronounced glomerular pathology than wild-type littermates in as much as they demonstrated mesangial expansion, podocyte loss, and a reduction in the activity of matrix-metalloprotease 2, a matrix-degrading enzyme that is often suppressed in fibrotic conditions. Thus the effect of the CCN2 transgene was to exacerbate some aspects of a fibrotic phenotype in a setting of diabetic nephropathy, although expression of extracellular matrix components such as fibronectin or collagen was unchanged and no fibrosis per se was observed (Yokoi et al. 2008). A somewhat similar but more compelling scenario was observed in our liver transgenic mice after they were subjected to liver injury by carbon tetrachloride administration or ligation of the bile duct (Tong et al. 2009). Both of these interventions are well-characterized methods of inducing hepatic fibrosis yet the transgenic mice fared worse than their wild-type littermates as shown by the presence of more α-smooth muscle actin-positive cells (presumptive activated hepatic stellate cells, a principal pro-fibrogenic cell type in the liver), increased deposition of collagen, and elevated mRNA expression of key fibrotic markers including α-smooth muscle actin, collagen α1(I), and tissue inhibitor of matrix-metalloprotease-1 (the latter of which blocks matrix breakdown and favors collagen accumulation). This phenomenon was highly reproducible as further exemplified by the additional data shown in Fig. 1 which illustrates that the liver transgenic mice treated chronically with the hepatotoxin thioacetamide show a greatly exaggerated fibrotic response in their livers as compared to their wild-type counterparts. We have further shown that homozygous liver transgenic mice exhibit more severe hepatic fibrosis than heterozygous liver transgenic mice in response to carbon tetrachloride (Tong et al. 2009). This finding is important because it suggests that CCN2 transgene dose may also account for some of the phenotypic variability reported between the four transgenic systems, a question that will require clarification through further experimental analysis.Fig.1


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

Brigstock DR - J Cell Commun Signal (2009)

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×
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2821473&req=5

Fig1: 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×
Mentions: The story does not stop there, however. Interesting additional data were reported for the kidney and liver transgenics that provide important clues as to the role of CCN2 in fibrotic pathways. When the kidney transgenic mice were challenged with streptozotocin to induce type I diabetes, they exhibited a more pronounced glomerular pathology than wild-type littermates in as much as they demonstrated mesangial expansion, podocyte loss, and a reduction in the activity of matrix-metalloprotease 2, a matrix-degrading enzyme that is often suppressed in fibrotic conditions. Thus the effect of the CCN2 transgene was to exacerbate some aspects of a fibrotic phenotype in a setting of diabetic nephropathy, although expression of extracellular matrix components such as fibronectin or collagen was unchanged and no fibrosis per se was observed (Yokoi et al. 2008). A somewhat similar but more compelling scenario was observed in our liver transgenic mice after they were subjected to liver injury by carbon tetrachloride administration or ligation of the bile duct (Tong et al. 2009). Both of these interventions are well-characterized methods of inducing hepatic fibrosis yet the transgenic mice fared worse than their wild-type littermates as shown by the presence of more α-smooth muscle actin-positive cells (presumptive activated hepatic stellate cells, a principal pro-fibrogenic cell type in the liver), increased deposition of collagen, and elevated mRNA expression of key fibrotic markers including α-smooth muscle actin, collagen α1(I), and tissue inhibitor of matrix-metalloprotease-1 (the latter of which blocks matrix breakdown and favors collagen accumulation). This phenomenon was highly reproducible as further exemplified by the additional data shown in Fig. 1 which illustrates that the liver transgenic mice treated chronically with the hepatotoxin thioacetamide show a greatly exaggerated fibrotic response in their livers as compared to their wild-type counterparts. We have further shown that homozygous liver transgenic mice exhibit more severe hepatic fibrosis than heterozygous liver transgenic mice in response to carbon tetrachloride (Tong et al. 2009). This finding is important because it suggests that CCN2 transgene dose may also account for some of the phenotypic variability reported between the four transgenic systems, a question that will require clarification through further experimental analysis.Fig.1

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Related in: MedlinePlus