| First Author | Li J | Year | 2019 |
| Journal | EBioMedicine | Volume | 40 |
| Pages | 43-55 | PubMed ID | 30639416 |
| Mgi Jnum | J:336041 | Mgi Id | MGI:7485913 |
| Doi | 10.1016/j.ebiom.2019.01.009 | Citation | Li J, et al. (2019) Autocrine CTHRC1 activates hepatic stellate cells and promotes liver fibrosis by activating TGF-beta signaling. EBioMedicine 40:43-55 |
| abstractText | 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 (CCl(4)) 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-beta signaling. Meanwhile, CTHRC1 competitively bound to Wnt noncononical receptor and promoted the contractility but not activation of HSCs. CCl(4) 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 CCl(4) or TAA. INTERPRETATION: We demonstrated that CTHRC1 is a new regulator of liver fibrosis by modulating TGF-beta signaling. Targeting CTHRC1 could be a promising therapeutic approach, which can suppress TGF-beta signaling and avoid the side effects caused by directly targeting TGF-beta. 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. |
