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Adenovirus-mediated expression of BMP-7 suppresses the development of liver fibrosis in rats
  1. Kohji Kinoshita1,
  2. Yuji Iimuro1,
  3. Kohji Otogawa2,
  4. Shizuya Saika3,
  5. Yutaka Inagaki4,
  6. Yuji Nakajima5,
  7. Norifumi Kawada2,
  8. Jiro Fujimoto1,
  9. Scott L Friedman6,
  10. Kazuo Ikeda6
  1. 1First Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan
  2. 2Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan
  3. 3Department of Ophthalmology, Wakayama Medical University, Wakayama, Japan
  4. 4Liver Fibrosis Research Unit, Department of Community Health, Tokai University School of Medicine, Isehara, Japan
  5. 5Department of Anatomy, Graduate School of Medicine, Osaka City University, Osaka, Japan
  6. 6Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, New York, USA
  1. 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

Abstract

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-Id2 also reduced fibrosis.

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

  • αSMA, smooth muscle α-actin
  • bHLH, basic helix-loop-helix
  • BMP-7, bone morphogenetic protein-7
  • COL1A2, type I α2 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
  • TGFβ, transforming growth factor-β
  • BMP-7
  • hepatic stellate cells
  • Id2
  • liver fibrosis
  • TGFβ
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Footnotes

  • Published Online First 24 November 2006

  • Competing interests: None declared.

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