Inhibition by ouabain of parathyroid hormone-stimulated bone resorption
Krieger, N.S.; Tashjian, A.H.
Journal of Pharmacology and Experimental Therapeutics 217(3): 586-591
1981
ISSN/ISBN: 0022-3565 PMID: 6262491 Document Number: 175199
Parathyroid hormone (PTH) stimulates bone resorption in organ culture and is believed to act via plasma membrane receptors. Agents that alter ion transfer across membranes, such as ionophores, have been shown to inhibit PTH-stimulated Ca release from bone. A role for Na ion transport in the process of bone resorption was recently postulated. Inhibition of stimulated bone resorption by the cardiac glycoside, ouabain is reported. Ouabain caused a dose-dependent inhibition of Ca release from neonatal mouse calvaria stimulated to resorb by 0.1 U/ml of PTH which was maximal at 0.3 mM. Ouabain was active whether added concurrently with PTH or after stimulated resorption had begun; inhibition was significant within 6 h. Inhibition was also observed if calvaria were preincubated with ouabain before treatment with PTH alone. After prolonged (> 24 h) treatment, the inhibitory effect of ouabain was not readily reversible. Resorption stimulated by prostaglandin E2, 1,25-dihydroxyvitamin D3 or epidermal growth factor was also inhibited, indicating that the action was not specific for the PTH receptor. Ouabain did not prevent the enhancement of cAMP production induced by PTH. The action of ouabain appeared to be due to inhibition of Na,K-ATPase in bone. Maximal inhibition of 86Rb uptake by calvaria occurred at the same concentration of ouabain that maximally inhibited stimulated bone resorption. In addition, high K+ prevented the inhibition of resorption produced by ouabain. PTH-stimulated release of Ca from bone evidently requires a Na/Ca exchange mechanism. Ouabain inhibition of the Na,K-ATPase would cause an increase in intracellular Na concentration which would decrease the transmembrane Na gradient, thereby creating conditions unfavorable for subsequent Ca efflux coupled to Na influx.