TGFβ/BMP Type I Receptors ALK1 and ALK2 Are Essential for BMP9-induced Osteogenic Signaling in Mesenchymal Stem Cells
TGFβ/BMP Type I Receptors ALK1 and ALK2 Are Essential for BMP9-induced Osteogenic Signaling in Mesenchymal Stem Cells
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DOI：
10.1074/jbc.m110.130518
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发表时间：
2010-09-17
影响因子：
4.8
通讯作者：
He, Tong-Chuan
中科院分区：
文献类型：
--
作者：
Luo, Jinyong;Tang, Min;He, Tong-Chuan
间充质干细胞（MSCs）是骨髓间质细胞，可以分化成多个谱系。我们之前已经证明BMP9是诱导MSCs成骨分化最有效的bmp之一。BMP9是研究最少的bmp之一。尽管最近有报道称ALK1、ALK5和/或内啡肽是内皮细胞中潜在的BMP9 I型受体，但对于BMP9诱导的MSCs成骨分化中I型受体的参与知之甚少。在这里，我们全面分析了7种I型受体在bmp9诱导的MSCs成骨信号传导中的功能作用。我们发现这7种I型受体中的大多数都在间充质干细胞中表达。然而，使用7种I型受体的显性阴性突变体，我们证明只有ALK1和ALK2突变体有效地抑制bmp9诱导的体外成骨分化和MSC植入试验中的异位骨化。蛋白质片段互补实验表明，ALK1和ALK2直接与BMP9相互作用。同样，在体外和体内，RNAi沉默ALK1和ALK2的表达可抑制bmp9诱导的BMPR-Smad活性和MSCs的成骨分化。因此，我们的研究结果强烈提示ALK1和ALK2可能在介导bmp9诱导的成骨分化中发挥重要作用。这些发现将进一步帮助我们理解BMP9调控间充质干细胞成骨分化的分子机制。
Mesenchymal stem cells (MSCs) are bone marrow stromal cells that can differentiate into multiple lineages. We previously demonstrated that BMP9 is one of the most potent BMPs to induce osteogenic differentiation of MSCs. BMP9 is one of the least studied BMPs. Whereas ALK1, ALK5, and/or endoglin have recently been reported as potential BMP9 type I receptors in endothelial cells, little is known about type I receptor involvement in BMP9-induced osteogenic differentiation in MSCs. Here, we conduct a comprehensive analysis of the functional role of seven type I receptors in BMP9-induced osteogenic signaling in MSCs. We have found that most of the seven type I receptors are expressed in MSCs. However, using dominant-negative mutants for the seven type I receptors, we demonstrate that only ALK1 and ALK2 mutants effectively inhibit BMP9-induced osteogenic differentiation in vitro and ectopic ossification in MSC implantation assays. Protein fragment complementation assays demonstrate that ALK1 and ALK2 directly interact with BMP9. Likewise, RNAi silencing of ALK1 and ALK2 expression inhibits BMP9-induced BMPR-Smad activity and osteogenic differentiation in MSCs both in vitro and in vivo. Therefore, our results strongly suggest that ALK1 and ALK2 may play an important role in mediating BMP9-induced osteogenic differentiation. These findings should further aid us in understanding the molecular mechanism through which BMP9 regulates osteogenic differentiation of MSCs.