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Am J Physiol Renal Physiol 271: F1139-F1146, 1996;
0363-6127/96 $5.00
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AJP - Renal Physiology, Vol 271, Issue 6 1139-F1146, Copyright © 1996 by American Physiological Society

ARTICLES

Parathyroid hormone-induced calcium efflux from cultured bone is mediated by protein kinase C translocation

S. M. Sprague, M. M. Popovtzer, M. Dranitzki-Elhalel and H. Wald
Section of Nephrology and Hypertension, Hadassah University Hospital, Hebrew University, Jerusalem, Israel.

Activation of adenylate cyclase is believed to be the major intracellular mediator of bone resorption induced by parathyroid hormone (PTH), prostaglandins, and various bone resorbing cytokines. Studies have demonstrated a dissociation between PTH-induced bone resorption and adenosine 3',5'-cyclic monophosphate (cAMP) formation, as well as suggested a role of protein kinase C (PKC) in mediating in part the actions of PTH. We therefore investigated the relative contribution of the adenylate cyclase or PKC signal transduction pathways in mediating the PTH-induced net calcium release from cultured neonatal calvariae, an in vitro model of bone resorption. PTH (10(-11) to 10(-7) M) caused a dose-dependent increase in calcium efflux from cultured bone and activated both cAMP and PKC. To determine the role of each of these second messengers in mediating PTH-induced calcium release from bone, calvariae were preincubated with either the adenylate cyclase inhibitor SQ-22536 (10(-5) to 10(-4) M) or the PKC inhibitor staurosporine (10(-7) M) before coincubation with PTH. Compared with control, PTH caused a significant calcium efflux, whereas preincubation with SQ-22536 had no effect on basal calcium efflux and partially inhibited the calcium efflux caused by PTH. In contrast preincubation with staurosporine completely obliterated the PTH-induced calcium efflux. PTH is a potent stimulator of calcium release and activates both the cAMP and PKC signal transduction pathways in cultured bone. Inhibition of PTH-stimulated PKC activity completely abolished the PTH-induced calcium efflux from calvariae, whereas PTH-induced calcium efflux persisted despite adenylate cyclase inhibition. Thus the bone resorbing effect of PTH appears to be dependent predominantly on activation of PKC.




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