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Mechanical Induction of PGE2 in Osteocytes Blocks Glucocorticoid-Induced Apoptosis Through Both the β-Catenin and PKA Pathways
Authors
Aguirre
Ajubi
+57 more
Aoudjit
Babij
Bakker
Bonewald
Bonewald
Burger
Castellone
Cherian
Cherian
Dalle Carbonare
Delfino
Dempster
Dodd
Dovio
Dunstan
Fujino
Gross
Hillsley
Hull
Jensen
Johnson
Kamel
Kato
Klein-Nulend
Knothe Tate
Kogianni
Lane
Leclerc
Lee
Li
Lin
Lin
Machwate
Manolagas
Manolagas
Miwa
Noble
Plotkin
Plotkin
Regan
Sawakami
Shao
Sugimoto
Tatsumi
Taylor
Vassiliou
Verborgt
Vezeridis
Wang
Wang
Wang
Weinbaum
Weinreb
Weinstein
Xia
Xie
Zhang
Publication date
Publisher
Wiley Subscription Services, Inc., A Wiley Company
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on
PubMed
Abstract
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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info:doi/10.1002%2Fjbmr.168
Last time updated on 04/12/2019