title: Human bone cell hyperpolarization response to cyclical mechanical strain is mediated by an interleukin-1beta autocrine/paracrine loop.
abstract: Mechanical stimuli imparted by stretch, pressure, tension, fluid flow, and shear stress result in a variety of biochemical responses important in bone (re)modeling. The molecules involved in the recognition and transduction of mechanical stimuli that lead to modulation of bone cell function are not yet fully characterized. Cyclical pressure-induced strain (PIS) induces a rapid change in membrane potential of human bone cells (HBC) because of opening of membrane ion channels. This response is mediated via integrins and requires tyrosine kinase activity and an intact actin cytoskeleton. We have used this electrophysiological response to further study the signaling events occurring early after mechanical stimulation of HBC. Stimulation of HBC at 0.33 Hz PIS, but not 0.104 Hz PIS, results in the production of a transferable factor that induces membrane hyperpolarization of unstimulated HBC. The production of this factor is inhibited by antibodies to beta1-integrin. Interleukin-1beta (IL-1beta and prostaglandin E2 (PGE2) were identified as candidate molecules for the transferable factor as both were shown to induce HBC hyperpolarization by opening of small conductance calcium-activated potassium channels, the means by which 0.33 Hz PIS causes HBC hyperpolarization. Antibodies to IL-1beta, but not other cytokines studied, inhibit the hyperpolarization response of HBC to 0.33 Hz PIS. Comparison of the signaling pathways required for 0.33 Hz PIS and IL-1beta-induced membrane hyperpolarization shows that both involve the phospholipase C/inositol triphosphate pathway, protein kinase C (PKC), and prostaglandin synthesis. Unlike 0.33 Hz PIS-induced membrane hyperpolarization, IL-1beta-induced hyperpolarization does not require tyrosine kinase activity or an intact actin cytoskeleton. These studies suggest that 0.33 Hz PIS of HBC induces a rapid, integrin-mediated, release of IL-1beta with a subsequent autocrine/paracrine loop resulting in membrane hyperpolarization. IL-1beta production in response to mechanical stimuli is potentially of importance in regulation of bone (re)modeling.
authors.affiliation: Department of Pathology, Edinburgh University Medical School, United Kingdom.
authors.forename: D M
authors.initials: DM
authors.lastname: Salter
authors.forename: W H
authors.initials: WH
authors.lastname: Wallace
authors.forename: J E
authors.initials: JE
authors.lastname: Robb
authors.forename: H
authors.initials: H
authors.lastname: Caldwell
authors.forename: M O
authors.initials: MO
authors.lastname: Wright
mesh_terms: D000906:Antibodies / Q000494:pharmacology; D016718:Arachidonic Acid / Q000037:antagonists & inhibitors; D019898:Autocrine Communication / Q000187:drug effects; D001842:Bone and Bones / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D002648:Child; D017077:Culture Media, Conditioned; D003599:Cytoskeleton / Q000187:drug effects; D015232:Dinoprostone / Q000494:pharmacology; D004558:Electric Stimulation; D005682:Gadolinium / Q000494:pharmacology; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D015850:Interleukin-6 / Q000502:physiology; D007473:Ion Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D019899:Paracrine Communication / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013314:Stress, Mechanical; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000502:physiology; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000093242:Interleukin-6 Inhibitors
chemical_list: D000906:Antibodies; D016718:Arachidonic Acid; D017077:Culture Media, Conditioned; D015232:Dinoprostone; D005682:Gadolinium; D019012:Integrin beta1; D007375:Interleukin-1; D015850:Interleukin-6; D007473:Ion Channels; D011493:Protein Kinase C; D011505:Protein-Tyrosine Kinases; D016212:Transforming Growth Factor beta; D010738:Type C Phospholipases; D000093242:Interleukin-6 Inhibitors