BMP-2/4 and BMP-6/7 differentially utilize cell surface receptors to induce osteoblastic differentiation of human bone marrow-derived mesenchymal stem cells
BMP-2/4 and BMP-6/7 differentially utilize cell surface receptors to induce osteoblastic differentiation of human bone marrow-derived mesenchymal stem cells
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DOI：
10.1074/jbc.m800850200
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发表时间：
2008-07-25
影响因子：
4.8
通讯作者：
Alaoui-Ismaili, Moulay Hicham
中科院分区：
文献类型：
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作者：
Lavery, Karen;Swain, Pamela;Alaoui-Ismaili, Moulay Hicham
骨形态发生蛋白（BMP）是生长因子的转化生长因子-β超家族的成员，并且在临床上用于诱导新骨形成。本研究的目的是评估受体利用BMP-2，BMP-4，BMP-6和BMP-7在原代人间充质干细胞（hMSC），一种生理相关的细胞类型，可能介导的BMP的体内效应。RNA干扰介导的基因敲低揭示了hMSC中骨诱导性BMP活性是通过I型受体ACVR 1A和BMPR 1A以及II型受体ACVR 2A和BMPR 2引起的。BMPR 1B和ACVR 2B以低水平表达，并且未发现在本研究中评价的任何BMP的信号传导中起显著作用。II型受体利用率在BMP-2/4和BMP-6/7之间显著不同。相对于BMP-6/7，观察到BMP-2/4对BMPR 2的更大依赖性，而ACVR 2A对BMP-6/7的信号传导比BMP-2/4更关键。I型受体也观察到显著差异。虽然BMP-2/4主要使用BMPR 1A进行信号传导，但ACVR 1A是BMP-6/7的优选I型受体。BMP-2/4和BMP-6/7的信号传导均由ACVR 1A或BMPR 1A的同二聚体介导。部分BMP-2/4信号传导也需要同时表达BMPR 1A和ACVR 1A，表明BMP-2/4信号传导部分通过ACVR 1A/BMPR 1A异二聚体。ACVR 1A和BMPR 1A形成同源二聚体和异源二聚体的能力通过生物发光共振能量转移分析证实。这些结果表明BMP-2/4和BMP-6/7诱导原代hMSC成骨细胞分化的不同机制。
Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-beta superfamily of growth factors and are used clinically to induce new bone formation. The purpose of this study was to evaluate receptor utilization by BMP-2, BMP-4, BMP-6, and BMP-7 in primary human mesenchymal stem cells (hMSC), a physiologically relevant cell type that probably mediates the in vivo effects of BMPs. RNA interference-mediated gene knockdown revealed that osteoinductive BMP activities in hMSC are elicited through the type I receptors ACVR1A and BMPR1A and the type II receptors ACVR2A and BMPR2. BMPR1B and ACVR2B were expressed at low levels and were not found to play a significant role in signaling by any of the BMPs evaluated in this study. Type II receptor utilization differed significantly between BMP-2/4 and BMP-6/7. A greater reliance on BMPR2 was observed for BMP-2/4 relative to BMP-6/7, whereas ACVR2A was more critical to signaling by BMP-6/7 than BMP-2/4. Significant differences were also observed for the type I receptors. Although BMP-2/4 used predominantly BMPR1A for signaling, ACVR1A was the preferred type I receptor for BMP-6/7. Signaling by both BMP-2/4 and BMP-6/7 was mediated by homodimers of ACVR1A or BMPR1A. A portion of BMP-2/4 signaling also required concurrent BMPR1A and ACVR1A expression, suggesting that BMP-2/4 signal in part through ACVR1A/BMPR1A heterodimers. The capacity of ACVR1A and BMPR1A to form homodimers and heterodimers was confirmed by bioluminescence resonance energy transfer analyses. These results suggest different mechanisms for BMP-2/4- and BMP-6/7-induced osteoblastic differentiation in primary hMSC.