BMP-2 restoration aids in recovery from liver fibrosis by attenuating TGF-β1 signaling

Yueh Hua Chung, Ying Hsien Huang, Tien Huei Chu, Chun Lin Chen, Pey Ru Lin, Shih Chung Huang, Deng Chyang Wu, Chao Cheng Huang, Tsung Hui Hu, Ying Hsien Kao, Ming Hong Tai*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

26 Scopus citations

Abstract

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. BMP-2 expression in fibrotic liver was measured in human tissue microarray and mouse models of liver fibrosis induced by bile duct ligation surgery or carbon tetrachloride administration. Adenovirus-mediated BMP-2 gene delivery was used to test the prophylactic effect on liver fibrosis. Primary hepatic stellate cells (HSC), HSC-T6 and clone-9 cell lines were used to study the interplay between BMP-2 and TGF-β1. Hepatic BMP-2 was localized in parenchymal hepatocytes and activated HSCs and significantly decreased in human and mouse fibrotic livers, showing an opposite pattern of hepatic TGF-β1 contents. BMP-2 gene delivery alleviated the elevations of serum hepatic enzymes, cholangiocyte marker CK19, 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-SMA and fibronectin expression, and reversed the TGF-β1-modulated epithelial-to-mesenchymal transition marker expression in mouse HSCs. 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.

Original languageEnglish
Pages (from-to)999-1013
Number of pages15
JournalLaboratory Investigation
Volume98
Issue number8
DOIs
StatePublished - 01 08 2018
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2018, United States & Canadian Academy of Pathology.

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