Mechanical induction of PGE2 in osteocytes blocks glucocorticoid-induced apoptosis through both the β-catenin and PKA pathways.
Mechanical induction of PGE2 in osteocytes blocks glucocorticoid-induced apoptosis through both the β-catenin and PKA pathways.
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DOI：
10.1002/jbmr.168
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发表时间：
2010-12
影响因子：
6.2
通讯作者：
Bonewald, Lynda F.
中科院分区：
文献类型：
--
作者：
Kitase, Yukiko;Barragan, Leonardo;Qing, Hai;Kondoh, Shino;Jiang, Jean X.;Johnson, Mark L.;Bonewald, Lynda F.
已知糖皮质激素可诱导骨细胞凋亡，而机械负荷已被证明可维持骨细胞活力。在这里，我们表明，流体流动剪切应力的形式的机械负荷块地塞米松诱导的骨细胞样细胞（MLO-Y 4）的凋亡。前列腺素E2（PGE 2），骨细胞产生的快速诱导的信号分子，被证明是对地塞米松诱导的细胞凋亡的保护，而吲哚美辛逆转剪切应力的抗凋亡作用。剪切应力的这种保护作用是通过EP 2和EP 4受体介导的，导致cAMP/蛋白激酶A信号通路的激活。磷脂酰肌醇3-激酶（糖原合成激酶3的抑制剂）的激活也发生了，导致β-连环蛋白（Wnt信号通路的重要信号转导子）的核转位。切应力和前列腺素均增加糖原合成激酶3 α/β的磷酸化。氯化锂，Wnt通路的激活剂，也对糖皮质激素诱导的细胞凋亡有保护作用。尽管已知机械负荷增加环氧合酶-2和EP 2受体表达和前列腺素产生，但地塞米松显示抑制前列腺素途径的这些组分的表达并减少β-连环蛋白表达。β-连环蛋白siRNA敲低实验消除了PGE 2的保护作用，证实了β-连环蛋白在介导针对地塞米松诱导的细胞死亡的保护中的核心作用。我们的数据支持PGE 2通过cAMP/PKA和β-catenin信号通路在流体流动剪切应力保护骨细胞凋亡中发挥核心作用。© 2010美国骨与矿物质研究学会。
Glucocorticoids are known to induce osteocyte apoptosis, whereas mechanical loading has been shown to sustain osteocyte viability. Here we show that mechanical loading in the form of fluid-flow shear stress blocks dexamethasone-induced apoptosis of osteocyte-like cells (MLO-Y4). Prostaglandin E2 (PGE2), a rapidly induced signaling molecule produced by osteocytes, was shown to be protective against dexamethasone-induced apoptosis, whereas indomethacin reversed the antiapoptotic effects of shear stress. This protective effect of shear stress was mediated through EP2 and EP4 receptors, leading to activation of the cAMP/protein kinase A signaling pathway. Activation of phosphatidylinositol 3-kinase, an inhibitor of glycogen synthesis kinase 3, also occurred, leading to the nuclear translocation of β-catenin, an important signal transducer of the Wnt signaling pathway. Both shear stress and prostaglandin increased the phosphorylation of glycogen synthesis kinase 3 α/β. Lithium chloride, an activator of the Wnt pathway, also was protective against glucocorticoid-induced apoptosis. Whereas it is known that mechanical loading increases cyclooxygenase-2 and EP2 receptor expression and prostaglandin production, dexamethasone was shown to inhibit expression of these components of the prostaglandin pathway and to reduce β-catenin protein expression. β-catenin siRNA knockdown experiments abrogated the protective effects of PGE2, confirming the central role of β-catenin in mediating the protection against dexamethasone-induced cell death. Our data support a central role for PGE2 acting through the cAMP/PKA and β-catenin signaling pathways in the protection of osteocyte apoptosis by fluid-flow shear stress. © 2010 American Society for Bone and Mineral Research.
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影响因子：
4.8
作者：
Jensen, Jorgen;Brennesvik, Erlend O.;Shepherd, Peter R.
通讯作者：
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影响因子：
3.3
作者：
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DOI：
10.1016/j.bbrc.2004.06.056
发表时间：
2004-08-06
影响因子：
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作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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