Alpha-difluoromethylornithine inhibits bone resorption in vitro without decreasing beta-glucuronidase release.
Our previous studies suggested that the ornithine decarboxylase inhibitor alpha-difluoromethylornithine (DFMO) inhibits bone resorption by mechanisms that are independent of polyamine depletion. To determine whether DFMO prevents calcitriol-stimulated bone resorption by acting at a step before or after osteoclast activation, we compared the effects of DFMO on release of calcium and beta-glucuronidase from cultured neonatal mouse calvaria. DFMO, at concentrations of 7.5-20 mM, inhibited release of calcium from calcitriol-stimulated calvaria but failed to inhibit the calcitriol-stimulated increase in beta-glucuronidase secretion. In contrast, ornithine, putrescine, spermidine, and spermine, at concentrations with effects on resorption comparable to those of DFMO, inhibited the effects of calcitriol on both calcium and beta-glucuronidase release. NaF (0.2 mM), like DFMO, inhibited calcitriol-stimulated calcium release without affecting medium beta-glucuronidase activity, whereas elevated phosphate (3 mM) inhibited both activities. The results suggest that DFMO, over the concentration range studied, inhibits calcium release by making the matrix resistant to resorption rather than by acting at a cellular locus.
Stern
P H
PH
Department of Pharmacology, Northwestern University, Chicago, Illinois 60611.
Lucas
R C
RC
Seidenfeld
J
J
D000818:Animals; D001862:Bone Resorption / Q000188:drug therapy* / Q000201:enzymology; D001842:Bone and Bones / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002117:Calcitriol / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism / Q000502:physiology; D002478:Cells, Cultured; D000518:Eflornithine / Q000494:pharmacology*; D005260:Female; D005966:Glucuronidase / Q000378:metabolism*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009952:Ornithine / Q000494:pharmacology; D010710:Phosphates / Q000494:pharmacology; D011073:Polyamines / Q000494:pharmacology; D012969:Sodium Fluoride / Q000494:pharmacology
D010710:Phosphates; D011073:Polyamines; D012969:Sodium Fluoride; D009952:Ornithine; D005966:Glucuronidase; D002117:Calcitriol; D002118:Calcium; D000518:Eflornithine