Non-canonical Wnt signaling and N-cadherin related beta-catenin signaling play a role in mechanically induced osteogenic cell fate.
Non-canonical Wnt signaling and N-cadherin related beta-catenin signaling play a role in mechanically induced osteogenic cell fate.
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DOI：
10.1371/journal.pone.0005388
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发表时间：
2009
期刊：
影响因子：
3.7
通讯作者：
Jacobs CR
中科院分区：
文献类型：
--
作者：
Arnsdorf EJ;Tummala P;Jacobs CR
了解机械微环境如何影响细胞命运，以及更重要的是，通过什么分子机制，不仅将增进对间充质干细胞生物学的了解，也将增进再生医学领域的知识。机械刺激，特别是负载诱导的振荡流体流动，在促进骨骼健康发育、动态平衡和形态方面发挥着至关重要的作用。最近的研究表明，这种负荷诱导的液体流动可能通过上调多个成骨基因来调节成骨分化；然而，涉及将物理信号转导到改变细胞命运的分子机制尚未确定。通过免疫染色、免疫印迹分析和荧光素酶检测，我们证明了振荡流体流调节β-连环蛋白的核转位和基因转录。此外，实时RT-PCR分析表明，Flow诱导Wnt5a和Ror2上调，这两项都是在Flow暴露时激活小GTP酶RhoA所必需的。此外，虽然β-连环蛋白的磷酸化不受FLOW的影响，但它与N-钙粘连蛋白的结合是改变的，这表明Flow诱导的β-连环蛋白信号是由粘着连接信号启动的。我们认为，骨的机械微环境有可能通过启动多个关键的分子通路来调节成骨分化，这些分子通路对于这种谱系承诺是必不可少的。具体地说，涉及Ror2和RhoA的非规范Wnt5a信号以及N-钙粘素介导的β-连环蛋白信号是机械诱导成骨分化所必需的。
Understanding how the mechanical microenvironment influences cell fate, and more importantly, by what molecular mechanisms, will enhance not only the knowledge of mesenchymal stem cell biology but also the field of regenerative medicine. Mechanical stimuli, specifically loading induced oscillatory fluid flow, plays a vital role in promoting healthy bone development, homeostasis and morphology. Recent studies suggest that such loading induced fluid flow has the potential to regulate osteogenic differentiation via the upregulation of multiple osteogenic genes; however, the molecular mechanisms involved in the transduction of a physical signal into altered cell fate have yet to be determined. Using immuno-staining, western blot analysis and luciferase assays, we demonstrate the oscillatory fluid flow regulates β-catenin nuclear translocation and gene transcription. Additionally, real time RT-PCR analysis suggests that flow induces Wnt5a and Ror2 upregulation, both of which are essential for activating the small GTPase, RhoA, upon flow exposure. Furthermore, although β-catenin phosphorylation is not altered by flow, its association with N-cadherin is, indicating that flow-induced β-catenin signaling is initiated by adherens junction signaling. We propose that the mechanical microenvironment of bone has the potential to regulate osteogenic differentiation by initiating multiple key molecular pathways that are essential for such lineage commitment. Specifically, non-canonical Wnt5a signaling involving Ror2 and RhoA as well as N-cadherin mediated β-catenin signaling are necessary for mechanically induced osteogenic differentiation.
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DOI：
10.1083/jcb.200203064
发表时间：
2002-08-05
期刊：
The Journal of cell biology
影响因子：
--
作者：
Hanai J;Gloy J;Karumanchi SA;Kale S;Tang J;Hu G;Chan B;Ramchandran R;Jha V;Sukhatme VP;Sokol S
通讯作者：
Sokol S
影响因子：
64.5
作者：
Gong, YQ;Slee, RB;Warman, ML
通讯作者：
Warman, ML
影响因子：
4
作者：
Baksh, Dolores;Boland, Genevieve M.;Tuan, Rocky S.
通讯作者：
Tuan, Rocky S.
影响因子：
8.2
作者：
Bodine, Peter V. N.;Komm, Barry S.
通讯作者：
Komm, Barry S.
影响因子：
5.3
作者：
Hay, Eric;Laplantine, Emmanuel;Marie, Pierre J.
通讯作者：
Marie, Pierre J.