BMP9-regulated angiogenic signaling plays an important role in the osteogenic differentiation of mesenchymal progenitor cells
BMP9-regulated angiogenic signaling plays an important role in the osteogenic differentiation of mesenchymal progenitor cells
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BMP9调节的血管生成信号在间充质祖细胞的成骨分化中发挥重要作用
DOI：
10.1242/jcs.114231
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发表时间：
2013-01-15
影响因子：
4
通讯作者：
Huang, Wei
中科院分区：
文献类型：
--
作者：
Hu, Ning;Jiang, Dianming;Huang, Wei
间充质基质祖细胞（MSC）是可以从许多组织中分离的多能祖细胞。骨髓间充质干细胞在适当的刺激下可以向成骨细胞分化。骨形态发生蛋白9（BMP 9）是最具成骨活性的骨形态发生蛋白之一。作为研究最少的BMPs之一，BMP 9已被证明可以调节内皮细胞中的血管生成。然而，目前尚不清楚BMP 9调节的血管生成信号是否在BMP 9启动的MSC成骨途径中发挥任何重要作用。在此，我们研究了低氧诱导因子1（HIF 1）介导的血管生成信号在BMP 9调控的MSCs成骨分化中的功能作用。我们发现BMP 9通过Smad 1/5/8信号通路诱导骨髓间充质干细胞表达HIF 1。HIF 1的外源性表达增强BMP 9诱导的MSCs在体外和体内的成骨分化。siRNA介导的HIF 1或HIF 1抑制剂CAY 10585沉默极大地减弱了骨髓间充质干细胞中BMP 9诱导的成骨信号传导。由钴诱导的缺氧调节的HIF 1表达也概括了HIF 1和BMP 9在成骨分化中的协同作用。从机制上讲，HIF 1通过诱导MSC中的血管生成信号和成骨信号来发挥其与BMP 9的协同作用。因此，我们的研究结果不仅扩大了我们对BMP 9调节成骨细胞谱系特异性分化背后的分子基础的理解，而且还提供了一个机会，利用BMP 9诱导的再生医学中成骨和血管生成信号通路之间的协同作用。
Summary Mesenchymal stromal progenitor cells (MSCs) are multipotent progenitors that can be isolated from numerous tissues. MSCs can undergo osteogenic differentiation under proper stimuli. We have recently demonstrated that bone morphogenetic protein 9 (BMP9) is one of the most osteogenic BMPs. As one of the least studied BMPs, BMP9 has been shown to regulate angiogenesis in endothelial cells. However, it is unclear whether BMP9-regulated angiogenic signaling plays any important role in the BMP9-initiated osteogenic pathway in MSCs. Here, we investigate the functional role of hypoxia-inducible factor 1&agr; (HIF1&agr;)-mediated angiogenic signaling in BMP9-regulated osteogenic differentiation of MSCs. We find that BMP9 induces HIF1&agr; expression in MSCs through Smad1/5/8 signaling. Exogenous expression of HIF1&agr; potentiates BMP9-induced osteogenic differentiation of MSCs both in vitro and in vivo. siRNA-mediated silencing of HIF1&agr; or HIF1&agr; inhibitor CAY10585 profoundly blunts BMP9-induced osteogenic signaling in MSCs. HIF1&agr; expression regulated by cobalt-induced hypoxia also recapitulates the synergistic effect between HIF1&agr; and BMP9 in osteogenic differentiation. Mechanistically, HIF1&agr; is shown to exert its synergistic effect with BMP9 by inducing both angiogenic signaling and osteogenic signaling in MSCs. Thus, our findings should not only expand our understanding of the molecular basis behind BMP9-regulated osteoblastic lineage-specific differentiation, but also provide an opportunity to harness the BMP9-induced synergy between osteogenic and angiogenic signaling pathways in regenerative medicine.