Inhibition by the Divalent Cation Ionophores

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 ,uM 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, la-hydroxycholecalciferol, 3-isobutyll-methylxanthine, 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 ,ug/ml had no effect on the accumulation of cyclic AMP in the medium of either control, PTHor calcitonintreated calvaria. We conclude that the ionophores A23187 or X-537A do not stimulate bone resorption This investigation was presented in part at the 57th annual meeting ofThe Endocrine Society, New York, 19 June, 1975. Dr. Ivey is the recipient of a research fellowship from The Arthritis Foundation. Dr. Wright is the recipient of a research fellowship from The Medical Foundation, Inc., Boston, Massachusetts. Receivedfor publication 17 November 1975 and in revised form 20 August 1976. nor potentiate the effects of stimulators of bone resorption; instead they are inhibitors of bone resorption stimulated by a wide variety of compounds.