title: Signal transduction pathways involved in fluid flow-induced PGE2 production by cultured osteocytes.
abstract: To maintain its structural competence, the skeleton adapts to changes in its mechanical environment. Osteocytes are generally considered the bone mechanosensory cells that translate mechanical signals into biochemical, bone metabolism-regulating stimuli necessary for the adaptive process. Prostaglandins are an important part of this mechanobiochemical signaling. We investigated the signal transduction pathways in osteocytes through which mechanical stress generates an acute release of prostaglandin E2 (PGE2). Isolated chicken osteocytes were subjected to 10 min of pulsating fluid flow (PFF; 0.7 +/- 0.03 Pa at 5 Hz), and PGE2 release was measured. Blockers of Ca2+ entry into the cell or Ca2+ release from internal stores markedly inhibited the PFF-induced PGE2 release, as did disruption of the actin cytoskeleton by cytochalasin B. Specific inhibitors of Ca2+-activated phospholipase C, protein kinase C, and phospholipase A2 also decreased PFF-induced PGE2 release. These results are consistent with the hypothesis that PFF raises intracellular Ca2+ by an enhanced entry through mechanosensitive ion channels in combination with Ca2+- and inositol trisphosphate (the product of phospholipase C)-induced Ca2+ release from intracellular stores. Ca2+ and protein kinase C then stimulate phospholipase A2 activity, arachidonic acid production, and ultimately PGE2 release.
authors.affiliation: Department of Oral Cell Biology, ACTA-Vrije Universiteit, 1081 BT Amsterdam, The Netherlands.
authors.forename: N E
authors.initials: NE
authors.lastname: Ajubi
authors.forename: J
authors.initials: J
authors.lastname: Klein-Nulend
authors.forename: M J
authors.initials: MJ
authors.lastname: Alblas
authors.forename: E H
authors.initials: EH
authors.lastname: Burger
authors.forename: P J
authors.initials: PJ
authors.lastname: Nijweide
mesh_terms: D000199:Actins / Q000502:physiology; D000818:Animals; D016718:Arachidonic Acid / Q000096:biosynthesis; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002469:Cell Separation; D002478:Cells, Cultured; D002642:Chick Embryo / Q000166:cytology / Q000378:metabolism; D003571:Cytochalasin B / Q000494:pharmacology; D003599:Cytoskeleton / Q000187:drug effects; D015232:Dinoprostone / Q000096:biosynthesis*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D010011:Osteocytes / Q000187:drug effects / Q000378:metabolism*; D010741:Phospholipases A / Q000037:antagonists & inhibitors; D054467:Phospholipases A2; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000502:physiology*; D012886:Skull / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D013314:Stress, Mechanical; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors
chemical_list: D000199:Actins; D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D016718:Arachidonic Acid; D003571:Cytochalasin B; D011493:Protein Kinase C; D010741:Phospholipases A; D054467:Phospholipases A2; D010738:Type C Phospholipases; D015232:Dinoprostone