BMP-2 and insulin-like growth factor-I mediate osterix (Osx) expression in human mesenchymal stem cells via the MAPK and protein kinase D signaling pathways
BMP-2 and insulin-like growth factor-I mediate osterix (Osx) expression in human mesenchymal stem cells via the MAPK and protein kinase D signaling pathways
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DOI：
10.1074/jbc.m503845200
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发表时间：
2005-09-09
影响因子：
4.8
通讯作者：
Campbell, PG
中科院分区：
文献类型：
--
作者：
Celil, AB;Campbell, PG
遗传学研究将转录因子Osterix （Osx）置于Runx2的下游，但关于成骨细胞分化过程中Osx的调控信息有限。骨形态发生蛋白-2 （BMP-2）和胰岛素样生长因子- i （IGF-I）对Osx表达的重要作用，以及p38对BMP-2介导作用的要求，我们小组之前报道过。在本研究中，我们继续研究BMP-2和IGF-1在成骨细胞谱系进展过程中调控Osx表达的分子机制。igf - i介导的Osx表达需要所有三种MAPK成分（Erk、p38和JNK），而BMP-2则需要p38和JNK信号。作为生长因子信号的常见介质，我们还研究了蛋白激酶C/D （PKC/D）信号的参与。在PKD抑制剂的作用下，BMP-2和igf - i介导的Osx表达被阻断。传统PKCs的选择性抑制剂对bmp -2介导的Osx表达没有影响。BMP-2和igf - 1诱导PKD选择性磷酸化，PKD是矿化所必需的。PKC/D和MAPK信号也介导Runx2的活性。因此，为了证明Runx2在Osx调控中的意义，我们使用Runx2的显性阴性结构和Runx2降解的泛素化介质来阻断Runx2的活性。我们发现，阻断Runx2活性可以抑制bmp -2介导的Osx诱导。这些研究表明，多种信号通路介导Osx，这是成骨细胞分化和骨形成的关键基因。除Runx2外，在成骨细胞谱系进展过程中，可能还需要其他信号成分来调节Osx。
Genetic studies place the transcription factor Osterix (Osx) downstream of Runx2, but limited information is available about Osx regulation during osteoblastic differentiation. An important role for bone morphogenetic protein-2 (BMP-2) and insulin-like growth factor-I (IGF-I) on Osx expression and the requirement for p38 for the BMP-2-mediated effect was reported previously by our group. In this study, we continued to investigate the molecular mechanisms by which BMP-2 and IGF-1 regulate Osx expression during osteoblast lineage progression. IGF-I-mediated Osx expression required all three MAPK components (Erk, p38, and JNK), whereas BMP-2 required p38 and JNK signaling. As a common mediator of growth factor signaling, we also investigated the involvement of protein kinase C/D (PKC/D) signaling. BMP-2- and IGF-I-mediated Osx expression was blocked in response to a PKD inhibitor. A selective inhibitor of conventional PKCs had no effect on the BMP-2-mediated Osx expression. BMP-2 and IGF-I induced a selective phosphorylation of PKD, and PKD was required for mineralization. PKC/D and MAPK signaling also mediate Runx2 activity. Therefore, to document the implication for Runx2 in Osx regulation, we blocked Runx2 activity using a dominant negative Runx2 construct and an ubiquitination mediator for Runx2 degradation. We showed that blocking Runx2 activity inhibited the BMP-2-mediated induction of Osx. These studies implicated that multiple signaling pathways mediate Osx, a critical gene for osteoblast differentiation and bone formation. In addition to Runx2, other signaling components may be necessary to regulate Osx during osteoblast lineage progression.