Susceptibility to liver fibrosis in mice expressing a connective tissue growth factor transgene in hepatocytes

Tong, ZhenYue; Chen, Ruju; Alt, Daniel S.; Kemper, Sherri; Perbal, Bernard; Brigstock, David R.

doi:10.1002/hep.23102

Cited by 74 publications

(80 citation statements)

References 34 publications

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“…d HSC maintained in 0.5% FCS showed upregulation of CCN2/CTGF when cells were infected with an adenovirus driving expression of CCN3/NOV. Please note that the stimulation with TGF-β induced CCN2/CTGF expression in HSC e CCN3/NOV overexpression slightly decreased TGF-β-induced collagen type I and α-SMA expression, while remarkably both CCN2 and CCN3 significantly reduced TIMP-1 collagen type I and α-SMA expression, a finding that is in line with a previous report showing that elevated CCN2/ CTGF levels in hepatocytes of transgenic mice in vivo does not cause hepatic injury or fibrosis per se but renders the liver more susceptible to the injurious actions of other fibrotic stimuli (Tong et al 2009). …”

Section: Resultssupporting

confidence: 90%

CCN3/NOV small interfering RNA enhances fibrogenic gene expression in primary hepatic stellate cells and cirrhotic fat storing cell line CFSC

Borkham-Kamphorst

Roeyen

Leur

et al. 2011

J. Cell Commun. Signal.

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Nephroblastoma overexpressed gene encodes a matricellular protein (CCN3/NOV) of the CCN family, comprising CCN1 (CYR61), CCN2 (CTGF), CCN4 (WISP‐1), CCN5 (WISP‐2), and CCN6 (WISP‐3). CCN proteins are involved in the regulation of mitosis, adhesion, apoptosis, extracellular matrix production, growth arrest and migration in multiple cell types. Compared to CCN2/CTGF, known as a profibrotic protein, the biological role of CCN3/NOV in liver fibrosis remains obscure. In this study we showed ccn3/nov mRNA to increase dramatically following hepatic stellate cell activation, reaching peak levels in fully transdifferentiated myofibroblasts. In models of experimental hepatic fibrosis, CCN3/NOV increased significantly at the mRNA and protein levels. CCN3/NOV was found mainly in non‐parenchymal cells along the areas of tissue damage and repair. In the bile‐duct ligation model, CCN3/NOV was localized mainly along portal tracts, while the repeated application of carbon tetrachloride resulted in CCN3/NOV expression mainly in the centrilobular areas. In contrast to CCN2/CTGF, the profibrotic cytokines platelet‐derived growth factor‐B and ‐D as well as transforming growth factor‐β suppressed CCN3/NOV expression. In vitro, CCN3/NOV siRNA attenuated migration in the cirrhotic fat storing cell line CFSC well in line with in vivo findings that various types of cells expressing CCN3/NOV migrate into the area of tissue damage and regeneration. The suppression of CCN3/NOV enhanced expression of profibrotic marker proteins, such as α‐smooth muscle actin, collagen type I, fibronectin, CCN2/CTGF and TIMP‐1 in primary rat hepatic stellate cells and in CFSC. We further found that adenoviral overexpression of CCN2/CTGF suppressed CCN3/NOV expression, while the overexpression of CCN3/NOV as well as the suppression of CCN3/NOV by targeting siRNAs both resulted in enhanced CCN2/CTGF expression. These results indicate the complexity of CCN actions that are far beyond the classic Yin/Yang interplay.

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Section: Resultssupporting

confidence: 90%

CCN3/NOV small interfering RNA enhances fibrogenic gene expression in primary hepatic stellate cells and cirrhotic fat storing cell line CFSC

Borkham-Kamphorst

Roeyen

Leur

et al. 2011

J. Cell Commun. Signal.

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“…Furthermore, transgenic mice expressing CTGF under the control of the albumin gene promoter showed exacerbation of liver fibrosis induced by chronic CCl 4 administration (49), demonstrating that hepatocytederived CTGF plays an important role in liver fibrogenesis. However, Tong et al (49) have also reported that hepatocyte-specific CTGF transgenic mice did not show spontaneous fibrosis in the liver without any fibrotic stimuli. Taken together, these findings support the idea that CTGF produced from hepatocytes may be an important factor for promoting liver fibrosis in the presence of apoptotic stimuli in Mdm2-knockout mice.…”

Section: Discussionmentioning

confidence: 99%

Increases in p53 expression induce CTGF synthesis by mouse and human hepatocytes and result in liver fibrosis in mice

et al. 2011

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The tumor suppressor p53 has been implicated in the pathogenesis of non-cancer-related conditions such as insulin resistance, cardiac failure, and early aging. In addition, accumulation of p53 has been observed in the hepatocytes of individuals with fibrotic liver diseases, but the significance of this is not known. Herein, we have mechanistically linked p53 activation in hepatocytes to liver fibrosis. Hepatocyte-specific deletion in mice of the gene encoding Mdm2, a protein that promotes p53 degradation, led to hepatocyte synthesis of connective tissue growth factor (CTGF; the hepatic fibrogenic master switch), increased hepatocyte apoptosis, and spontaneous liver fibrosis; concurrent removal of p53 completely abolished this phenotype. Compared with wild-type controls, mice with hepatocyte-specific p53 deletion exhibited similar levels of hepatocyte apoptosis but decreased liver fibrosis and hepatic CTGF expression in two models of liver fibrosis. The clinical significance of these data was highlighted by two observations. First, p53 upregulated CTGF in a human hepatocellular carcinoma cell line by repressing miR-17-92. Second, human liver samples showed a correlation between CTGF and p53-regulated gene expression, which were both increased in fibrotic livers. This study reveals that p53 induces CTGF expression and promotes liver fibrosis, suggesting that the p53/CTGF pathway may be a therapeutic target in the treatment of liver fibrosis.

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“…Likewise, increased fibrosis was observed in mice with liver-specific CCN2 overexpression, but only upon tissue injury. This observation suggests that perhaps induced inflammatory mediators could interact with CCN2 to promote increased fibrosis or that the inflammatory microenvironment could change the response of cells to CCN2 (40). This is relevant because CCN2 levels are elevated during disc degeneration, a condition characterized by tissue inflammation (23).…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-inducible Factor (HIF)-1α and CCN2 Form a Regulatory Circuit in Hypoxic Nucleus Pulposus Cells

Tran

Fujita

Huang

et al. 2013

Journal of Biological Chemistry

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Background:The relationship between connective tissue growth factor (CCN2) and hypoxia-inducible factor (HIF)-1 in hypoxic nucleus pulposus is unknown. Results: HIF-1␣ suppresses CCN2 expression, whereas CCN2 represses basal HIF-1␣ levels and transcriptional activity. Conclusion:In nucleus pulposus, HIF-1␣ and CCN2 form a negative regulatory circuit. Significance: Tight control of CCN2 and HIF-1 activities may play a role in disc homeostasis.

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Susceptibility to liver fibrosis in mice expressing a connective tissue growth factor transgene in hepatocytes

Cited by 74 publications

References 34 publications

CCN3/NOV small interfering RNA enhances fibrogenic gene expression in primary hepatic stellate cells and cirrhotic fat storing cell line CFSC

CCN3/NOV small interfering RNA enhances fibrogenic gene expression in primary hepatic stellate cells and cirrhotic fat storing cell line CFSC

Increases in p53 expression induce CTGF synthesis by mouse and human hepatocytes and result in liver fibrosis in mice

Hypoxia-inducible Factor (HIF)-1α and CCN2 Form a Regulatory Circuit in Hypoxic Nucleus Pulposus Cells

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