Heparin-binding EGF-like growth factor and miR-1192 exert opposite effect on Runx2-induced osteogenic differentiation.
Heparin-binding EGF-like growth factor and miR-1192 exert opposite effect on Runx2-induced osteogenic differentiation.
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肝素结合 EGF 样生长因子和 miR-1192 对 Runx2 诱导的成骨分化发挥相反作用
DOI：
10.1038/cddis.2013.363
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发表时间：
2013-10-17
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
成骨细胞分化是骨形成过程中的关键事件。矮小相关转录因子-2(Runx2)是成骨细胞分化和骨形成所必需的。然而，Runx2调控成骨分化的潜在机制仍不清楚。在这里，我们利用表达Runx2的C2C12/Runx2 Dox亚系探索了相应的机制。我们发现Runx2诱导的C2C12细胞成骨分化导致表皮生长因子(EGF)家族成员之一的肝素结合EGF样生长因子(HB-EGF)的表达持续下降。强制表达HB-EGF或用HB-EGF处理能够降低碱性磷酸酶(ALP)的表达，ALP是成骨细胞早期分化的明确标志。HB-EGF介导的ALP抑制依赖于EGFR及其下游的细胞外信号调节激酶、c-jun氨基末端激酶、丝裂原活化蛋白激酶通路以及磷脂酰肌醇3-激酶/Akt通路的激活。Runx2特异性地与Hegf启动子结合，提示Hegf转录直接受到Runx2的抑制。Runx2可上调miR-1192，从而促进Runx2诱导的成骨分化。此外，miR-1192通过翻译抑制直接靶向Hegf，提示miR-1192通过下调HB-EGF来增强Runx2诱导的成骨分化。综上所述，我们的结果提示，Runx2通过转录和转录后机制下调HB-EGF，抑制HB-EGF-EGFR信号通路，从而诱导C2C12细胞成骨分化。
Osteoblast differentiation is a pivotal event in bone formation. Runt-related transcription factor-2 (Runx2) is an essential factor required for osteoblast differentiation and bone formation. However, the underlying mechanism of Runx2-regulated osteogenic differentiation is still unclear. Here, we explored the corresponding mechanism using the C2C12/Runx2 Dox subline, which expresses Runx2 in response to doxycycline (Dox). We found that Runx2-induced osteogenic differentiation of C2C12 cells results in a sustained decrease in the expression of heparin-binding EGF-like growth factor (HB-EGF), a member of the epidermal growth factor (EGF) family. Forced expression of HB-EGF or treatment with HB-EGF is capable of reducing the expression of alkaline phosphatase (ALP), a defined marker of early osteoblast differentiation. HB-EGF-mediated inhibition of ALP depends upon activation of the EGFR and the downstream extracellular signal-regulated kinase, c-Jun N-terminal kinase mitogen-activated protein kinase pathways as well as phosphatidylinositol 3-kinase/Akt pathway. Runx2 specifically binds to the Hbegf promoter, suggesting that Hbegf transcription is directly inhibited by Runx2. Runx2 can upregulate miR-1192, which enhances Runx2-induced osteogenic differentiation. Moreover, miR-1192 directly targets Hbegf through translational inhibition, suggesting enhancement of Runx2-induced osteogenic differentiation by miR-1192 through the downregulation of HB-EGF. Taken together, our results suggest that Runx2 induces osteogenic differentiation of C2C12 cells by inactivating HB-EGF-EGFR signaling through the downregulation of HB-EGF via both transcriptional and post-transcriptional mechanisms.
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