TCF3, a novel positive regulator of osteogenesis, plays a crucial role in miR-17 modulating the diverse effect of canonical Wnt signaling in different microenvironments.
TCF3, a novel positive regulator of osteogenesis, plays a crucial role in miR-17 modulating the diverse effect of canonical Wnt signaling in different microenvironments.
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TCF3 是一种新型的成骨正调节因子，在 miR-17 调节不同微环境中经典 Wnt 信号传导的多种作用中发挥着至关重要的作用。
DOI：
10.1038/cddis.2013.65
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发表时间：
2013-03-14
影响因子：
9
通讯作者：
中科院分区：
文献类型：
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作者：
Wnt信号通路是一条高度保守的信号通路，在胚胎发育到骨形成过程中发挥着重要作用。Wnt信号通路对成骨的影响依赖于其细胞环境和靶基因的表达。然而，其分子机制仍不清楚。在此基础上，我们观察了经典Wnt信号在不同培养环境下对牙周膜干细胞（PDLSCs）成骨分化的影响。此外，我们发现miR-17的表达水平也随着培养环境的改变而变化。因此，我们推测miR-17和经典Wnt信号可能存在潜在的相互作用，特别是在不同微环境中的内在调控关系。在本研究中，我们观察到经典Wnt信号在完全培养液中促进PDLSCs的成骨，而在成骨分化培养基中抑制PDLSCs的成骨。有趣的是，内源性miR-17表达水平的改变可以部分逆转经典Wnt信号传导的不同作用。此外，miR-17的作用与其靶基因TCF 3（transcription factor 3）有关，TCF 3是经典Wnt通路的关键转录因子。TCF 3的过表达减弱了miR-17对调节经典Wnt信号传导的作用。最后，我们阐明了TCF 3在体外和体内均增强骨生成。总之，miR-17的表达水平不同是导致经典Wnt信号通路作用不同的主要原因，而TCF 3是miR-17-经典Wnt信号通路调控环的关键节点。这种对microRNA在不同微环境中调节信号通路的理解可能为微调骨相关疾病的成骨过程铺平道路。
Wnt signaling pathways are a highly conserved pathway, which plays an important role from the embryonic development to bone formation. The effect of Wnt pathway on osteogenesis relies on their cellular environment and the expression of target genes. However, the molecular mechanism of that remains unclear. On the basis of the preliminary results, we observed the contrary effect of canonical Wnt signaling on osteogenic differentiation of periodontal ligament stem cells (PDLSCs) in the different culture environment. Furthermore, we found that the expression level of miR-17 was also varied with the change in the culture environment. Therefore, we hypothesized that miR-17 and canonical Wnt signaling may have potential interactions, particularly the inner regulation relationship in different microenvironments. In this paper, we observed that canonical Wnt signaling promoted osteogenesis of PDLSCs in the fully culture medium, while inhibited it in the osteogenic differentiation medium. Interestingly, alteration in the expression level of endogenous miR-17 could partially reverse the different effect of canonical Wnt signaling. Furthermore, the role of miR-17 was because of its target gene TCF3 (transcription factor 3), a key transcription factor of canonical Wnt pathway. Overexpression of TCF3 attenuated the effect of miR-17 on modulating canonical Wnt signaling. Finally, we elucidated that TCF3 enhanced osteogenesis both in vitro and in vivo. In brief, the different level of miR-17 was the main cause of the different effect of canonical Wnt signaling, and TCF3 was the crucial node of miR-17–canonial Wnt signaling regulation loop. This understanding of microRNAs regulating signaling pathways in different microenvironments may pave the way for fine-tuning the process of osteogenesis in bone-related disorders.
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影响因子：
4.6
作者：
Andoniadou, Cynthia L.;Signore, Massimo;Martinez-Barbera, Juan Pedro
通讯作者：
Martinez-Barbera, Juan Pedro
影响因子：
20.3
作者：
Li, Yanmei;Vecchiarelli-Federico, Laura M.;Ben-David, Yaacov
通讯作者：
Ben-David, Yaacov
影响因子：
7.6
作者：
Huang GT;Gronthos S;Shi S
通讯作者：
Shi S
DOI：
10.1083/jcb.200102074
发表时间：
2001-09-03
期刊：
The Journal of cell biology
影响因子：
--
作者：
Lee E;Salic A;Kirschner MW
通讯作者：
Kirschner MW
DOI：
10.1073/pnas.0804438105
发表时间：
2008-09-16
影响因子：
11.1
作者：
Li, Zhaoyong;Hassan, Mohammad Q.;Stein, Gary S.
通讯作者：
Stein, Gary S.