論文 - 詳細
| RRC ID | 75739 |
|---|---|
| 著者 | Li J, Wang Y, Ma M, Jiang S, Zhang X, Zhang Y, Yang X, Xu C, Tian G, Li Q, Wang Y, Zhu L, Nie H, Feng M, Xia Q, Gu J, Xu Q, Zhang Z. |
| タイトル | Autocrine CTHRC1 activates hepatic stellate cells and promotes liver fibrosis by activating TGF-β signaling. |
| ジャーナル | EBioMedicine |
| Abstract |
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-β 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-β signaling. Targeting CTHRC1 could be a promising therapeutic approach, which can suppress TGF-β signaling and avoid the side effects caused by directly targeting TGF-β. 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. |
| 巻・号 | 40 |
| ページ | 43-55 |
| 公開日 | 2019-2-1 |
| DOI | 10.1016/j.ebiom.2019.01.009 |
| PII | S2352-3964(19)30009-X |
| PMID | 30639416 |
| PMC | PMC6412555 |
| MeSH | Animals Autocrine Communication* Cell Line Cell Movement Cells, Cultured Collagen / chemistry Collagen / metabolism Extracellular Matrix Proteins / chemistry Extracellular Matrix Proteins / metabolism* Hepatic Stellate Cells / metabolism* Humans Liver Cirrhosis / etiology* Liver Cirrhosis / metabolism* Liver Cirrhosis / pathology Male Mice Mice, Knockout Models, Biological Rats Signal Transduction* Transforming Growth Factor beta / metabolism* Wnt Signaling Pathway |
| IF | 5.736 |
| リソース情報 | |
| 実験動物マウス | RBRC03519 |