Hepatocyte Growth Factor and p38 Promote Osteogenic Differentiation of Human Mesenchymal Stem Cells
Hepatocyte Growth Factor and p38 Promote Osteogenic Differentiation of Human Mesenchymal Stem Cells
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DOI：
10.1210/me.2013-1286
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发表时间：
2014-05-01
影响因子：
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通讯作者：
Howard, Guy A.
中科院分区：
文献类型：
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作者：
Aenlle, Kristina K.;Curtis, Kevin M.;Howard, Guy A.
肝细胞生长因子(HGF)是一种旁分泌因子，参与器官发生、组织修复和伤口愈合。我们在这里报道，HGF通过转录人间充质干细胞中的关键成骨标志物，包括骨钙素、Osterix和骨保护素来促进成骨分化，是建立成骨细胞矿化的必要成分。用c-Met抑制剂(HGF受体)PHA665752或HGF中和抗体阻断内源性HGF可减少矿化，PHA665752显著降低碱性磷酸酶的活性。此外，我们报道了HGF促进成骨分化涉及p38的快速磷酸化及其亚型p38α和p38β的不同调节。Western印迹分析显示p38α和p38β蛋白水平显著升高，逆转录定量聚合酶链式反应显示HGF使p38α和p38β蛋白的转录水平均升高。使用小干扰RNA减少p38α和p38β的转录，我们发现p38α和p38β在HGF诱导的关键成骨标记表达中的不同作用。综上所述，我们的数据证明了p38信号在HGF调节成骨分化中的重要性。
Hepatocyte growth factor (HGF) is a paracrine factor involved in organogenesis, tissue repair, and wound healing. We report here that HGF promotes osteogenic differentiation through the transcription of key osteogenic markers, including osteocalcin, osterix, and osteoprotegerin in human mesenchymal stem cells and is a necessary component for the establishment of osteoblast mineralization. Blocking endogenous HGF using PHA665752, a c-Met inhibitor (the HGF receptor), or an HGF-neutralizing antibody attenuates mineralization, and PHA665752 markedly reduced alkaline phosphatase activity. Moreover, we report that HGF promotion of osteogenic differentiation involves the rapid phosphorylation of p38 and differential regulation of its isoforms, p38 alpha and p38 beta. Western blot analysis revealed a significantly increased level of p38 alpha and p38 beta protein, and reverse transcription quantitative PCR revealed that HGF increased the transcriptional level of both p38 alpha and p38 beta. Using small interfering RNA to reduce the transcription of p38 alpha and p38 beta, we saw differential roles for p38 alpha and p38 beta on the HGF-induced expression of key osteogenic markers. In summary, our data demonstrate the importance of p38 signaling in HGF regulation of osteogenic differentiation.