Hey1 Basic Helix-Loop-Helix Protein Plays an Important Role in Mediating BMP9-induced Osteogenic Differentiation of Mesenchymal Progenitor Cells
Hey1 Basic Helix-Loop-Helix Protein Plays an Important Role in Mediating BMP9-induced Osteogenic Differentiation of Mesenchymal Progenitor Cells
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Hey1 碱性螺旋-环-螺旋蛋白在介导 BMP9 诱导的间充质祖细胞成骨分化中发挥重要作用
DOI：
10.1074/jbc.m806389200
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发表时间：
2009-01-02
影响因子：
4.8
通讯作者：
He, Tong-Chuan
中科院分区：
文献类型：
--
作者：
Sharff, Katie A.;Song, Wen-Xin;He, Tong-Chuan
多能间充质干细胞（MSC）是骨髓基质祖细胞，可分化为成骨、软骨、脂肪和肌细胞谱系。我们以前证明，骨形态发生蛋白（BMP）9是一个最有效的，但最少的特点是骨形态发生蛋白，能够诱导骨髓间充质干细胞在体外和体内的成骨分化。在这里，我们进行了基因表达谱分析，并确定了分裂相关阻遏蛋白碱性螺旋-环-螺旋家族的毛状/增强子Hey 1是BMP 9刺激的MSC中最显著上调的早期靶标之一。我们证明，Hey 1的表达上调在BMP 9诱导的成骨分化的早期阶段。染色质免疫沉淀分析表明Hey 1可能是BMP 9诱导的Smad信号通路的直接靶点。在体外和体内，沉默Hey 1表达减少了BMP 9诱导的成骨分化，并导致软骨分化。同样，组成性Hey 1表达增强BMP 9介导的骨基质矿化。Hey 1和Runx 2在BMP 9诱导的成骨分化中协同作用，并且在Hey 1不存在的情况下Runx 2表达显著降低，表明Runx 2可能在Hey 1下游起作用。因此，外源性Runx 2表达挽救了Hey 1敲低引起的成骨分化缺陷。因此，我们的研究结果表明，Hey 1，通过其与Runx 2的相互作用，可能在调节BMP 9诱导的骨髓间充质干细胞成骨细胞谱系分化中发挥重要作用。
Pluripotent mesenchymal stem cells (MSCs) are bone marrow stromal progenitor cells that can differentiate into osteogenic, chondrogenic, adipogenic, and myogenic lineages. We previously demonstrated that bone morphogenetic protein (BMP) 9 is one of the most potent and yet least characterized BMPs that are able to induce osteogenic differentiation of MSCs both in vitro and in vivo. Here, we conducted gene expression-profiling analysis and identified that Hey1 of the hairy/Enhancer of split-related repressor protein basic helix-loop-helix family was among the most significantly up-regulated early targets in BMP9-stimulated MSCs. We demonstrated that Hey1 expression was up-regulated at the immediate early stage of BMP9-induced osteogenic differentiation. Chromatin immunoprecipitation analysis indicated that Hey1 may be a direct target of the BMP9-induced Smad signaling pathway. Silencing Hey1 expression diminished BMP9-induced osteogenic differentiation both in vitro and in vivo and led to chondrogenic differentiation. Likewise, constitutive Hey1 expression augmented BMP9-mediated bone matrix mineralization. Hey1 and Runx2 were shown to act synergistically in BMP9-induced osteogenic differentiation, and Runx2 expression significantly decreased in the absence of Hey1, suggesting that Runx2 may function downstream of Hey1. Accordingly, the defective osteogenic differentiation caused by Hey1 knockdown was rescued by exogenous Runx2 expression. Thus, our findings suggest that Hey1, through its interplay with Runx2, may play an important role in regulating BMP9-induced osteoblast lineage differentiation of MSCs.