• Yukiko Kitase, Leonardo Barragan, Hai Qing, Shino Kondoh, Jean X Jiang, Mark L Johnson, and Lynda F Bonewald.
• Department of Oral Biology, School of Dentistry, University of Missouri at Kansas City, Kansas City, MO, USA.
• J. Bone Miner. Res. 2010 Dec 1; 25 (12): 2657-68.

AbstractGlucocorticoids 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 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 PGE(2), confirming the central role of β-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 β-catenin signaling pathways in the protection of osteocyte apoptosis by fluid-flow shear stress.Copyright © 2010 American Society for Bone and Mineral Research.

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