Adenovirus-mediated expression of BMP-7 suppresses the development of liver fibrosis in rats
Adenovirus-mediated expression of BMP-7 suppresses the development of liver fibrosis in rats
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DOI：
10.1136/gut.2006.092460
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发表时间：
2007-05-01
期刊：
影响因子：
24.5
通讯作者：
Ikeda, Kazuo
中科院分区：
文献类型：
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作者：
Kinoshita, Kohji;Iimuro, Yuji;Ikeda, Kazuo
背景：由细胞外基质积聚引起的肝硬变是一种严重的临床问题，可发展为肝功能衰竭。转化生长因子-β在细胞外基质的产生中起关键作用，而转化生长因子-β超家族成员骨形态发生蛋白-7(BMP-7)可拮抗转化生长因子-β的促纤维化作用。目的：观察腺病毒介导的骨形态发生蛋白-7(Ad-BMP-7)过表达在体内外能否拮抗转化生长因子-β的作用。Ad-BMP-7感染诱导的BMP-7通过Smad1/5/8磷酸化，在TGFb存在或不存在的情况下，降低胶原1A2 mRNA和平滑肌α-肌动蛋白的表达。BMP-7可诱导LX-2细胞分化抑制因子2(LD2)的mRNA表达。虽然内源性BMP-7的表达很少，但Smad1和LD2的过表达增加了LX-2中BMP-7的表达。以硫代乙酰胺(200 mg/kg体重)每周2次重复注射复制大鼠肝纤维化模型，共7周。与对照组相比，尾静脉注射Ad-BMP-7的大鼠肝脏羟脯氨酸含量和天狼星红染色面积显著减少。结论：BMP-7、Smad1/5/8和Ids相互作用具有抗肝纤维化的作用。
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-beta (TGF beta) plays a pivotal role in extracellular matrix production, but bone morphogenetic protein (BMP)-7, a member of the TGF beta superfamily, can antagonise the fibrogenic activity of TGFb.Aim: In this study, we examined whether adenovirus-mediated overexpression of BMP-7 (Ad-BMP-7) antagonised the effect of TGF beta 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 TGFb, via Smad 1/5/8 phosphorylation. BMP-7 triggered the mRNA expression of inhibitors of differentiation 2 (ld2) in LX-2. Although endogenous expression of BMP-7 was hardly detectable, Smad1 and ld2 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.