Different effects of BMP-2 on marrow stromal cells from human and rat bone
Different effects of BMP-2 on marrow stromal cells from human and rat bone
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DOI：
10.1159/000075032
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发表时间：
2004-01-01
影响因子：
2.7
通讯作者：
Leboy, PS
中科院分区：
文献类型：
--
作者：
Osyczka, AM;Diefenderfer, DL;Leboy, PS
骨形态发生蛋白（BMPs）能促进骨祖细胞的分化，也能诱导大鼠和小鼠骨髓基质细胞（MSC）成骨。然而，与动物模型的结果相比，BMP在诱导人MSC进行成骨方面相对低效，并且在人体临床试验中促进骨形成的效果要差得多。先前的研究表明，虽然人MSC对地塞米松的成骨细胞标志物碱性磷酸酶水平升高作出反应，但大多数人MSC分离物对BMP-2、BMP-4或BMP-7的碱性磷酸酶诱导反应失败。已知由BMP诱导的几个其他基因被适当地调节;因此，人MSC能够进行一些BMP激活的信号传导。BMP受体ALK-3和ALK-6的分析表明，尽管ALK-6 mRNA在人MSC中不表达，但过表达组成型活性ALK-6受体不会诱导碱性磷酸酶升高。实时荧光定量RT-PCR检测BMP 2和地塞米松作用6天后MSC中成骨细胞相关转录因子的表达。Msx-2是一种抑制骨祖细胞分化的转录因子，在BMP-2处理的人MSC中显示出10倍的升高，但在BMP-2处理的大鼠MSC中没有。然而，在人类和大鼠MSC中Msx-2的过表达并没有改变碱性磷酸酶水平，这表明BMP刺激的碱性磷酸酶的缺乏不是由BMP-2诱导的Msx-2增加引起的。虽然Runx 2亚型已涉及成骨细胞分化的控制，这种转录因子的水平不受BMP处理。据报道，FKHR转录因子在小鼠细胞中调节碱性磷酸酶转录，其表达在BMP-2的作用下显示出适度的增加，但在地塞米松处理的细胞中增加得多。我们认为BMP对骨/肝/肾碱性磷酸酶基因的调节是间接的，需要表达在啮齿动物和人MSC中表现不同的新转录因子。版权所有（C）2004 S. Karger AG，巴塞尔。
Bone morphogenetic proteins (BMPs) promote the differentiation of osteoprogenitor cells, and also induce osteogenesis in bone marrow stromal cells ( MSC) from rats and mice. However, compared to results with animal models, BMPs are relatively inefficient in inducing human MSC to undergo osteogenesis, and are much less effective in promoting bone formation in human clinical trials. Previous studies indicated that, while human MSC respond to dexamethasone with elevated levels of the osteoblast marker alkaline phosphatase, most isolates of human MSC fail to show alkaline phosphatase induction in response to BMP-2, BMP-4, or BMP-7. Several other genes known to be induced by BMPs are appropriately regulated; thus, human MSC are capable of some BMP-activated signaling. Analysis of the BMP receptors ALK-3 and ALK-6 indicated that, although ALK-6 mRNA was not expressed in human MSC, overexpressing a constitutively active ALK-6 receptor did not induce elevated alkaline phosphatase. Real-time RT-PCR was used to investigate expression of several osteoblast-related transcription factors in MSC after 6 days' exposure to BMP2 or dexamethasone. Msx-2, a transcription factor that has been reported to inhibit differentiation of osteoprogenitor cells, showed 10-fold elevation in BMP-2-treated human MSC, but not in BMP-2-treated rat MSC. Overexpression of Msx-2 in human and rat MSC, however, did not alter alkaline phosphatase levels, which suggests that absence of BMP-stimulated alkaline phosphatase was not caused by the BMP-2-induced increase in Msx-2. Although Runx2 isoforms have been implicated in control of osteoblast differentiation, levels of this transcription factor were unaffected by BMP treatment. Expression of the FKHR transcription factor, which has been reported to regulate alkaline phosphatase transcription in mouse cells, showed a modest increase in response to BMP-2, but a much greater increase in dexamethasone-treated cells. We propose that BMP regulation of the bone/liver/kidney alkaline phosphatase gene is indirect, requiring expression of new transcription factor(s) that behave differently in rodent and human MSC. Copyright (C) 2004 S. Karger AG, Basel.