Inhibition of Bone Resorption in Tissue Culture by Membrane-Stabilizing Drugs*

Abstract

We have investigated the ability of membranestabilizing drugs to alter bone resorption in tissue culture. Parathyroid hormone (PTH)-stimulated demineralization, as measured by release of previously incorporated 45Ca from fetal rat radii and ulnae, was abolished by simultaneous treatment with DL-, D-, and L-propranolol (10-5–10-4 M). PTH decreased skeletal dry weight and 40Ca content, and these effects were inhibited by DL-propranolol. After an initial treatment with PTH for 24 h, added DL-propranolol had no effect on hormone-scimulated release of 45Ca at 6 h but diminished the effect of PTH progressively at 24 and 48 h. Pretreatment of bones for 24 h with DLpropranolol did not alter their resorptive response to subsequent PTH treatment. PTH-stimulated 45Ca release was also reduced by lidocaine, tetracaine, and quinidine (10-4 M). Quinidine pretreatment for 24 h did not affect the response to subsequent PTH treatment. Neither practolol nor the quaternary lidocaine derivative QX-222 altered PTH-stimulated resorption. Demineralization was also increased by osteoclast-activating factor, prostaglandin E2, N,O′-dibutyryl cAMP, and 1,25-dihydroxycholecalciferol. The resorptive response to these agents was decreased by maximal concentrations of DL-, D-, and Lpropranolol. DL-Propranolol did not alter the incorporation of [3H]uridine into RNA or [3H]thymidine into DNA by cultured bones. All of the agents found to inhibit resorption block membraneassociated events such as depolarization and calcium entry. Our results suggest that these events may be involved in the control of bone turnover as stimulated by a variety of agents.