Bone resorption in organ culture: inhibition by the divalent cation ionophores A23187 and X-537A.
The ionophores A23187 and X-537A were used as probes to investigate the possible role of calcium uptake by bone as a mediator for the stimulation of bone resorption induced by parathyroid hormone (PTH) and other agents in cultured mouse calvaria. The ionophores alone at concentrations from 1 nM to 20 muM did not stimulate bone resorption, nor did they potentiate bone resorption stimulated by submaximal concentrations of PTH after either brief (15-60 min) or extended (1-3 day) exposure to the ionophores. Unexpectedly, we found that the ionophores inhibit in a dose-dependent manner bone resorption stimulated by PTH and a wide variety of other compounds (prostaglandin E2, 1alpha-hydroxycholecalciferol, 3-isobutyl-1-methyl-xanthine, and phorbol myristate acetate). This inhibition was not due to irreversible damage to the bones by the ionophores, because the inhibition was reversible even after 24 h of treatment. Inhibition of bone resorption by the ionophores was observed in media of both high and low calcium concentration, indicating that the inhibition was not due to a critical extracellular calcium concentration. Inhibition by the ionophores differs qualitatively in several ways from that produced by calcitonin, a natural inhibitor of bone resorption. Furthermore, A23187 at 1.0 mug/ml had no effect on the accumulation of cyclic AMP in the medium of either control, PTH- or calcitonin treated calvaria. We conclude that the ionophores A23187 or X537A do not stimulate bone resorption nor potentiate the effects of stimulators of bone resorption; instead they are inhibitors of bone resorption stimulated by a wide variety of compounds.
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001862:Bone Resorption / Q000187:drug effects*; D001842:Bone and Bones / Q000032:analysis; D000001:Calcimycin / Q000494:pharmacology*; D002116:Calcitonin / Q000502:physiology; D002118:Calcium / Q000502:physiology; D000242:Cyclic AMP / Q000032:analysis; D007832:Lasalocid / Q000494:pharmacology*; D051379:Mice; D009924:Organ Culture Techniques; D010281:Parathyroid Hormone / Q000494:pharmacology; D013997:Time Factors
D000900:Anti-Bacterial Agents; D010281:Parathyroid Hormone; D000001:Calcimycin; D002116:Calcitonin; D000242:Cyclic AMP; D002118:Calcium; D007832:Lasalocid