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-β (TGF-β) plays a pivotal role in ECM production during the process. Bone morphogenetic protein (BMP)-7, a member of the TGF-β superfamily, can antagonize the fibrogenic activity of TGF-β.
Aim: In this study, we tested whether adenovirus- mediated overexpression of BMP-7 (Ad-BMP-7) antagonized the effect of TGF-β 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-β, 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.
- TGF- β
- hepatic stellate cells
- liver fibrosis
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