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首页> 外文期刊>American Journal of Physiology >BMP-7 opposes TGF-beta1-mediated collagen induction in mouse pulmonary myofibroblasts through Id2.
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BMP-7 opposes TGF-beta1-mediated collagen induction in mouse pulmonary myofibroblasts through Id2.

机译：BMP-7反对通过Id2在小鼠肺成纤维细胞中TGF-β1介导的胶原蛋白诱导。

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摘要

Mesenchymal cells, primarily fibroblasts and myofibroblasts, are the principal matrix-producing cells during pulmonary fibrogenesis. Transforming growth factor (TGF)-beta signaling plays an important role in stimulating the expression of type I collagen of these cells. Bone morphogenetic protein (BMP)-7, a member of the TGF-beta superfamily, has been reported to oppose the fibrogenic activity of TGF-beta1. Here, we have addressed the effects of BMP-7 on the fibrogenic activity of pulmonary myofibroblasts. We first established cell lines from the lungs of transgenic mice harboring the COL1A2 upstream sequence fused to luciferase. They displayed a spindle shape and expressed vimentin and alpha-smooth muscle actin, but not E-cadherin. COL1A2 promoter activity was dose dependently induced by TGF-beta1, which was further augmented by adenoviral overexpression of Smad3, but was downregulated by Smad7. Under the identical condition, adenoviral overexpression of BMP-7 attenuated the TGF-beta1-dependent COL1A2 promoter activity. By immunocytochemistry, the ectopic expression of BMP-7 led to the nuclear localization of phospho-Smad1/5/8 and suppressed that of Smad3. BMP-7 suppressed the expression of mRNAs for COL1A2 and tissue inhibitor of metalloproteinase-2 while increasing those of inhibitors of differentiation (Id) 2 and 3. Ectopic expression of Id2 and Id3 was found to decrease the COL1A2 promoter activity. Finally, BMP-7 and Id2 decreased TGF-beta1-dependent collagen protein secretion. In conclusion, these data demonstrate that BMP-7 antagonizes the TGF-beta1-dependent fibrogenic activity of mouse pulmonary myofibroblastic cells by inducing Id2 and Id3.
机译：间充质细胞，主要是成纤维细胞和成肌纤维细胞，是肺纤维化过程中主要的基质产生细胞。转化生长因子（TGF）-β信号转导在刺激这些细胞的I型胶原蛋白表达中起重要作用。据报道，骨形态发生蛋白（BMP）-7是TGF-β超家族的成员，它与TGF-β1的纤维化活性相反。在这里，我们已经解决了BMP-7对肺成纤维细胞成纤维活性的影响。我们首先从具有COL1A2上游序列的荧光素酶融合的转基因小鼠的肺中建立细胞系。他们表现出纺锤形，表达波形蛋白和α-平滑肌肌动蛋白，但不表达E-钙粘蛋白。 TGF-beta1剂量依赖性地诱导了COL1A2启动子的活性，Smad3的腺病毒过表达进一步增强了TGF-beta1的活性，但Smad7却下调了该活性。在相同的条件下，BMP-7的腺病毒过度表达减弱了TGF-beta1依赖性COL1A2启动子的活性。通过免疫细胞化学，BMP-7的异位表达导致磷酸化Smad1 / 5/8的核定位并抑制了Smad3的核定位。 BMP-7抑制了COL1A2和金属蛋白酶2的组织抑制剂的mRNA表达，同时增加了分化抑制剂（Id）2和3的mRNA表达。发现Id2和Id3的异位表达降低了COL1A2启动子活性。最后，BMP-7和Id2减少了TGF-beta1依赖性胶原蛋白的分泌。总之，这些数据证明BMP-7通过诱导Id2和Id3拮抗小鼠肺成肌纤维细胞的TGF-β1依赖性成纤维活性。

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