Mechanical induction of PGE2 in osteocytes blocks glucocorticoid-induced apoptosis through both the β-catenin and PKA pathways
Open Access
- 23 November 2010
- journal article
- research article
- Published by Oxford University Press (OUP) in Journal of Bone and Mineral Research
- Vol. 25 (12), 2657-2668
- https://doi.org/10.1002/jbmr.168
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.Keywords
This publication has 58 references indexed in Scilit:
- Prostaglandin Promotion of Osteocyte Gap Junction Function through Transcriptional Regulation of Connexin 43 by Glycogen Synthase Kinase 3/β-Catenin SignalingMolecular and Cellular Biology, 2010
- Osteocytes, mechanosensing and Wnt signalingBone, 2008
- Wnt/β-Catenin Signaling Modulates Survival of High Glucose–Stressed Mesangial CellsJournal of the American Society of Nephrology, 2006
- Osteocytes subjected to pulsating fluid flow regulate osteoblast proliferation and differentiationBiochemical and Biophysical Research Communications, 2006
- Prostaglandin E2 (PGE2) increases the number of rat bone marrow osteogenic stromal cells (BMSC) via binding the EP4 receptor, activating sphingosine kinase and inhibiting caspase activityProstaglandins, Leukotrienes & Essential Fatty Acids, 2006
- Prostaglandin E2promotes cell survival of glomerular epithelial cells via the EP4 receptorAmerican Journal of Physiology-Renal Physiology, 2006
- Prostaglandin E2 Stimulates the β-Catenin/T Cell Factor-dependent Transcription in Colon CancerOnline Journal of Public Health Informatics, 2005
- Establishment of an Osteocyte-like Cell Line, MLO-Y4Journal of Bone and Mineral Research, 1997
- Pulsating Fluid Flow Increases Prostaglandin Production by Cultured Chicken Osteocytes—A Cytoskeleton-Dependent ProcessBiochemical and Biophysical Research Communications, 1996
- Review: Bone tissue engineering: The role of interstitial fluid flowBiotechnology & Bioengineering, 1994