LIVER FIBROSIS

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

Kohji Kinoshita¹, Yuji Iimuro¹, Kohji Otogawa², Shizuya Saika³, Yutaka Inagaki⁴, Yuji Nakajima⁵, Norifumi Kawada², Jiro Fujimoto¹, Scott L Friedman⁶, Kazuo Ikeda⁶

¹ First Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan
² Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan
³ Department of Ophthalmology, Wakayama Medical University, Wakayama, Japan
⁴ Liver Fibrosis Research Unit, Department of Community Health, Tokai University School of Medicine, Isehara, Japan
⁵ Department of Anatomy, Graduate School of Medicine, Osaka City University, Osaka, Japan
⁶ Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, New York, USA

Correspondence to:
Dr Kazuo Ikeda
Department of Anatomy, Graduate School of Medicine, Osaka City University, 1-4-3, Asahimachi, Abeno, Osaka 545-8585, Japan;ikeda{at}med.osaka-cu.ac.jp

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-ß (TGFß) plays a pivotal role in extracellular matrix production, but bone morphogenetic protein (BMP)-7, a member of the TGFß superfamily, can antagonise the fibrogenic activity of TGFß.

Aim: In this study, we examined whether adenovirus-mediated overexpression of BMP-7 (Ad-BMP-7) antagonised the effect of TGFß 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 -actin in the presence or absence of TGFß, 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-Id2 also reduced fibrosis.

Conclusion: These data demonstrate that BMP-7, Smad 1/5/8 and Ids interact to antagonise hepatic fibrogenesis.

Abbreviations: SMA, smooth muscle -actin; bHLH, basic helix-loop-helix; BMP-7, bone morphogenetic protein-7; COL1A2, type I 2 collagen; DMEM, Dulbecco’s modified Eagle’s medium; FCS, fetal calf serum; GFP, green fluorescent protein; HSC, hepatic stellate cells; Id2, inhibitors of differentiation 2; MOI, multiplicity of infection; PFU, plaque forming units; TAA, thioacetamide; TGFß, transforming growth factor-ß

Keywords: BMP-7; hepatic stellate cells; Id2; liver fibrosis; TGFß

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