title: Mechanical induction of PGE2 in osteocytes blocks glucocorticoid-induced apoptosis through both the β-catenin and PKA pathways.
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 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.
authors.affiliation: Department of Oral Biology, School of Dentistry, University of Missouri at Kansas City, Kansas City, MO, USA.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Kitase
authors.forename: Leonardo
authors.initials: L
authors.lastname: Barragan
authors.forename: Hai
authors.initials: H
authors.lastname: Qing
authors.forename: Shino
authors.initials: S
authors.lastname: Kondoh
authors.forename: Jean X
authors.initials: JX
authors.lastname: Jiang
authors.forename: Mark L
authors.initials: ML
authors.lastname: Johnson
authors.forename: Lynda F
authors.initials: LF
authors.lastname: Bonewald
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism*; D005938:Glucocorticoids / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007213:Indomethacin / Q000494:pharmacology; D018021:Lithium Chloride / Q000494:pharmacology; D051379:Mice; D008954:Models, Biological; D010011:Osteocytes / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D058539:Phosphatidylinositol 3-Kinase; D020011:Protective Agents / Q000494:pharmacology; D055550:Protein Stability / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000378:metabolism; D012212:Rheology / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013314:Stress, Mechanical; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D017077:Culture Media, Conditioned; D005938:Glucocorticoids; D020011:Protective Agents; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D051176:beta Catenin; D003907:Dexamethasone; D058539:Phosphatidylinositol 3-Kinase; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D017868:Cyclic AMP-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride; D015232:Dinoprostone; D007213:Indomethacin