Adenovirus-mediated expression of BMP-7 suppresses the development of liver fibrosis in rats

Kohji Kinoshita ¹, Yuji Iimuro ¹, Kohji Otogawa ², Shizuya Saika ³, Yutaka Inagaki ⁴, Yuji Nakajima ², Norifumi Kawada ², Jiro Fujimoto ¹, Scott Friedman ⁵ and Kazuo Ikeda ^2*

¹ Hyogo College of Medicine, Japan
² Graduate School of Medicine, Osaka City University, Japan
³ Wakayama Medical University, Japan
⁴ Tokai University School of Medicine, Japan
⁵ Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, United States

^* To whom correspondence should be addressed. E-mail: ikeda{at}med.osaka-cu.ac.jp.

Accepted 13 October 2006

Abstract

Background: Liver cirrhosis, which is caused by the undesirable accumulation of extracellular matrix materials (ECM), is a serious clinical problem that can progress to severe hepatic failure. Transforming growth factor- (TGF-) plays a pivotal role in ECM production during the process. Bone morphogenetic protein (BMP)-7, a member of the TGF- superfamily, can antagonize the fibrogenic activity of TGF-.

Aim: In this study, we tested whether adenovirus- mediated overexpression of BMP-7 (Ad-BMP-7) antagonized the effect of TGF- in vitro and in vivo.

Methods and Results: In primary-cultured rat stellate cells and the LX-2 human stellate cell line, induction of BMP-7 by Ad-BMP-7 infection decreased the expression of collagen 1A2 mRNA and smooth muscle & [alpha]-actin in the presence or absence of TGF-, via Smad1/5/8 phosphorylation. BMP-7 triggered the mRNA expression of inhibitors of differentiation 2 (Id2) in LX-2. Although endogenous expression of BMP-7 was hardly detectable, Smad1 and Id2 overexpression increased BMP-7 expression in LX-2. A liver fibrosis model was induced by the repetitive intraperitoneal injection of thioacetamide (200 mg/kg body weight) twice per week for up to 7 weeks. In rats that were received Ad-BMP-7 via tail vein, hydroxyproline content and the areas stained by Sirius red dye in the liver were significantly reduced compared to the controls. Furthermore, Ad-Id2 reduced fibrosis as well.

Conclusion: These data demonstrate that BMP-7, Smad1/5/8 and Ids interact reciprocally and antagonize hepatic fibrogenesis.

Keywords: BMP-7, Id2, TGF- , hepatic stellate cells, liver fibrosis

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