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

Kohji Kinoshita, Yuji Iimuro, Kohji Otogawa, Shizuya Saika, Yutaka Inagaki, Yuji Nakajima, Norifumi Kawada, Jiro Fujimoto, Scott L. Friedman, Kazuo Ikeda

Research output: Contribution to journalArticlepeer-review

129 Scopus citations


Background: Liver cirrhosis, which is caused by the accumulation of extracellular matrix materials, is a serious clinical problem that can progress to hepatic failure. Transforming growth factor-β (TGFβ) plays a pivotal role in extracellular matrix production, but bone morphogenetic protein (BMP)-7, a member of the TGFβ superfamily, can antagonise the fibrogenic activity of TGFβ. Aim: In this study, we examined whether adenovirus-mediated overexpression of BMP-7 (Ad-BMP-7) antagonised the effect of TGFβ 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 α-actin in the presence or absence of TGFβ, via Smad 1/5/8 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 administered Ad-BMP-7 via the tail vein, hydroxyproline content and the areas stained by Sirius red dye in the liver were significantly reduced compared to controls. Ad-ld2 also reduced fibrosis. Conclusion: These data demonstrate that BMP-7, Smad 1/5/8 and Ids interact to antagonise hepatic fibrogenesis.

Original languageEnglish
Pages (from-to)706-714
Number of pages9
Issue number5
StatePublished - May 2007


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