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Identification of bone morphogenetic protein 9 (BMP9) as a novel profibrotic factor in vitro

机译:骨形态发生蛋白9(BMP9)的体外鉴定为新型纤溶因子

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Upregulated synthesis of extracellular matrix (ECM) proteins by myofibroblasts is a common phenomenon in the development of fibrosis. Although the role of TGF-beta in fibrosis development has been extensively studied, the involvement of other members of this superfamily of cytokines, the bone morphogenetic proteins (BMPs) in organ fibrosis has given contradictory results. BMP9 is the main ligand for activin receptor-like kinase-1 (ALK1) TGF-beta 1 type I receptor and its effect on fibrosis development is unknown. Our purpose was to study the effect of BMP9 in ECM protein synthesis in fibroblasts, as well as the involved receptors and signaling pathways. In cultured mice fibroblasts, BMP9 induces an increase in collagen, fibronectin and connective tissue growth factor expression, associated with Smad1/5/8, Smad2/3 and Erk1/2 activation. ALK5 inhibition with SB431542 or ALK1/2/3/6 with dorsomorphin-1, inhibition of Smad3 activation with SIS3, and inhibition of the MAPK/Erk1/2 with U0126, demonstrates the involvement of these pathways in BMP9-induced ECM synthesis in MEFs. Whereas BMP9 induced Smad1/5/8 phosphorylation through ALK1, it also induces Smad2/3 phosphorylation through ALK5 but only in the presence of ALK1.
机译:肌成纤维细胞上调细胞外基质(ECM)蛋白的合成是纤维化发展中的常见现象。尽管已经对TGF-β在纤维化发展中的作用进行了广泛的研究,但该细胞因子超家族的其他成员,骨形态发生蛋白(BMP)在器官纤维化中的参与却产生了矛盾的结果。 BMP9是激活素受体样激酶1(ALK1)TGF-beta 1 I型受体的主要配体,其对纤维化发展的作用尚不清楚。我们的目的是研究BMP9在成纤维细胞ECM蛋白合成中的作用以及涉及的受体和信号传导途径。在培养的小鼠成纤维细胞中,BMP9诱导胶原蛋白,纤连蛋白和结缔组织生长因子表达的增加,与Smad1 / 5/8,Smad2 / 3和Erk1 / 2激活相关。用SB431542或ALK1 / 2/3/6用dorsomorphin-1抑制ALK5,用SIS3抑制Smad3激活,用U0126抑制MAPK / Erk1 / 2,证明这些途径参与了MEF中BMP9诱导的ECM合成。 。 BMP9通过ALK1诱导Smad1 / 5/8磷酸化,但它也通过ALK5诱导Smad2 / 3磷酸化,但仅在ALK1存在的情况下。

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