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Modern pathogenetic concepts of liver fibrosis suggest stellate cells and TGF-beta as major players and therapeutic targets.

ABSTRACT: Hepatic fibrosis is a scarring process that is associated with an increased and altered deposition of extracellular matrix in liver. At the cellular and molecular level, this progressive process is mainly characterized by cellular activation of hepatic stellate cells and aberrant activity of transforming growth factor-beta1 and its downstream cellular mediators. Although the cellular responses to this cytokine are complex, the signalling pathways of this pivotal cytokine during the fibrogenic response and its connection to other signal cascades are now understood in some detail. Based on the current advances in understanding the pleiotropic reactions during fibrogenesis, various inhibitors of transforming growth factor-beta were developed and are now being investigated as potential drug candidates in experimental models of hepatic injury. Although it is too early to favour one of these antagonists for the treatment of hepatic fibrogenesis in human, the experimental results obtained yet provide stimulatory impulses for the development of an effective treatment of choice in the not too distant future. The present review summarises the actual knowledge on the pathogenesis of hepatic fibrogenesis, the role of transforming growth factor-beta and its signalling pathways in promoting the fibrogenic response, and the therapeutic modalities that are presently in the spotlight of many investigations and are already on the way to take the plunge into clinical studies.

SUBMITTER: Gressner AM

PROVIDER: S-EPMC3933103 | biostudies-other | 2006 Jan-Mar

REPOSITORIES: biostudies-other

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Modern pathogenetic concepts of liver fibrosis suggest stellate cells and TGF-beta as major players and therapeutic targets.

Gressner A M AM Weiskirchen R R

Journal of cellular and molecular medicine 20060101 1

Hepatic fibrosis is a scarring process that is associated with an increased and altered deposition of extracellular matrix in liver. At the cellular and molecular level, this progressive process is mainly characterized by cellular activation of hepatic stellate cells and aberrant activity of transforming growth factor-beta1 and its downstream cellular mediators. Although the cellular responses to this cytokine are complex, the signalling pathways of this pivotal cytokine during the fibrogenic re ...[more]

PMID: 16563223

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Project description:BACKGROUND:Hepatic fibrosis is caused by chronic liver injury and may progress toward liver cirrhosis, and even hepatocellular carcinoma. However, current treatment is not satisfactory. Therefore, there is a mandate to find novel therapeutic targets to improve therapy, and biomarkers to monitor therapeutic response. METHODS:Liver fibrosis was induced by carbon tetrachloride (CCl4) or thioacetamide (TAA) in wild type (WT) or CTHRC1-/- mice, followed by immunofluorescence and immunohistochemical analyses. CTHRC1 monoclonal antibody (mAb) was used to abrogate the effect of CTHRC1 in vitro and in vivo. RESULTS:Here, we reported that collagen triple helix repeat containing 1 (CTHRC1), a secreted protein derived from hepatic stellate cells (HSCs), was significantly up-regulated in fibrotic liver tissues. CTHRC1 promoted HSCs transformation from a quiescent to an activated state, and enhanced migratory or contractile capacities of HSCs by activating TGF-? signaling. Meanwhile, CTHRC1 competitively bound to Wnt noncononical receptor and promoted the contractility but not activation of HSCs. CCl4 or TAA-induced liver fibrosis was attenuated in CTHRC-/- mice compared with littermate control, while a monoclonal antibody of CTHRC1 suppressed liver fibrosis in WT mice treated with CCl4 or TAA. INTERPRETATION:We demonstrated that CTHRC1 is a new regulator of liver fibrosis by modulating TGF-? signaling. Targeting CTHRC1 could be a promising therapeutic approach, which can suppress TGF-? signaling and avoid the side effects caused by directly targeting TGF-?. CTHRC1 could also be a potential biomarker for monitoring response to anti-fibrotic therapy. FUND: This study was supported by the National Natural Science Foundation of China (ID 81672358, 81871923, 81872242, 81802890), the Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support (ID 20181708), the Natural Science Foundation of Shanghai (ID 17ZR1428300, 18ZR1436900), and Shanghai Municipal Health Bureau (ID 2018BR32). The funders did not play a role in manuscript design, data collection, data analysis, interpretation nor writing of the manuscript.

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Modern pathogenetic concepts of liver fibrosis suggest stellate cells and TGF-beta as major players and therapeutic targets.

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Modern pathogenetic concepts of liver fibrosis suggest stellate cells and TGF-beta as major players and therapeutic targets.

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