BMP-2 Restoration Rescues Liver Fibrosis Injuries by Attenuating TGF-β1 Signaling

• Main Authors: Yueh-hua Chung, 鍾悅華
• Other Authors: Ming-Hong Tai
• Format: Others
• Language: en_US
• Published: 2018
• Online Access: http://ndltd.ncl.edu.tw/handle/g8hyaf

博士 === 國立中山大學 === 生物醫學研究所 === 106 === Objective: Transforming growth factor-β (TGF-β) plays a central role in hepatic fibrogenesis. This study investigated the function and mechanism of bone morphogenetic protein-2 (BMP-2) in regulation of hepatic fibrogenesis. Methods: BMP-2 expression in fibrotic liver was measured in human tissue microarray and mouse models of liver fibrosis induced by bile duct ligation (BDL) surgery or carbon tetrachloride (CCl4) administration. Adenovirus-mediated BMP-2 gene delivery was used to test the prophylactic effect on liver fibrosis. Primary hepatic stellate cells (HSC) and cell lines, HSC-T6 cells and Clone 9, were used to study the interplay between BMP-2 and TGF-β1. Results: Hepatic BMP-2 expression was significantly decreased in either human fibrotic tissues or mice fibrosis models, with a negative correlation with hepatic TGF-β1 contents. BMP-2 gene delivery alleviated the elevations of serum hepatic enzymes, HSC activation markers, and liver fibrosis in both models. Mechanistically, exogenous TGF-β1 dose-dependently reduced BMP-2 expression, whereas BMP-2 significantly suppressed expression of TGF-β and its cognate type I and II receptor peptides, as well as the induced Smad3 phosphorylation levels in primary mouse HSCs. Aside from its suppressive effects on cell proliferation and migration, BMP-2 treatment prominently attenuated the TGF-β1-stimulated α-smooth muscle actin and fibronectin expression, and reversed the TGF-β1-modulated epithelial-to-mesenchymal transition marker expression in mouse HSCs. Conclusions: The mutual regulation between BMP-2 and TGF-β1 signaling axes may constitute the anti-fibrogenic mechanism of BMP-2 in the pathogenesis of liver fibrosis. BMP-2 may potentially serve as a novel therapeutic target for treatment of liver fibrosis.