期刊
JOURNAL OF BONE AND MINERAL RESEARCH
卷 25, 期 12, 页码 2381-2392出版社
WILEY-BLACKWELL
DOI: 10.1002/jbmr.168
关键词
OSTEOCYTES; MLO-Y4 CELLS APOPTOSIS; PGE(2); WNT SIGNALING
资金
- NIH/NIAMS [PO1 AR046798, RO1 AR053949]
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 E-2 (PGE(2)), 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 beta-catenin, an important signal transducer of the Wnt signaling pathway Both shear stress and prostaglandin increased the phosphorylation of glycogen synthesis kinase 3 alpha/beta 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 beta-catenin protein expression beta-catenin siRNA knockdown experiments abrogated the protective effects of PGE(2), confirming the central role of beta-catenin in mediating the protection against dexamethasone-induced cell death Our data support a central role for PGE(2) acting through the cAMP/PKA and beta-catenin signaling pathways in the protection of osteocyte apoptosis by fluid-flow shear stress (C) 2010 American Society for Bone and Mineral Research
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