The cyclic-AMP antagonist adenosine-3',5'-cyclic monophosphosphorothioate, RP-isomer inhibits parathyroid hormone induced bone resorption, in vitro.
Stimulation of osteoclastic bone resorption is mediated via the osteoblasts. In order to investigate the second messenger events that cause the osteoblasts to initiate bone resorption we have evaluated the effect of the cyclic AMP antagonist adenosine-3'5'-cyclic monophosphosphorothioate, Rp-isomer (Rp-cAMPS) on bone resorption in vitro, by measuring the release of prelabelled 45Ca from cultured neonatal mouse calvarial bones. Forskolin (FSK, at and above 10 nM), an agent that enhances cyclic AMP-formation, stimulated bone resorption in 96 h cultures. Addition of Rp-cAMPS to the incubation media dose-dependently inhibited bone resorption induced by FSK (0.5 microM), with total inhibition obtained at 30 microM Rp-cAMPS. Bone resorption stimulated by parathyroid hormone (PTH, 0.1-10 nM, 72 h) was also inhibited by Rp-cAMPS (30 microM), while bone resorption induced by 1.25(OH)2D3 (1-10 nM, 72 h) was unaffected by Rp-cAMPS. These data demonstrate that PTH and 1,25(OH)2D3 cause bone resorption via different mechanisms and that cyclic AMP is the major second messenger in PTH-induced bone resorption.
Department of Internal Medicine, University Hospital, Uppsala, Sweden.
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Ljunggren
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Ljunghall
D000818:Animals; D000831:Animals, Newborn; D001862:Bone Resorption; D001842:Bone and Bones / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D002117:Calcitriol / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007536:Isomerism; D007700:Kinetics; D051379:Mice; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors; D011506:Proteins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D013873:Thionucleotides / Q000494:pharmacology*
D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments; D047428:Protein Kinase Inhibitors; D011506:Proteins; D013873:Thionucleotides; C054296:parathyroid hormone-related protein (1-34); D005576:Colforsin; C016957:adenosine-3',5'-cyclic phosphorothioate; D000242:Cyclic AMP; D002117:Calcitriol; D002118:Calcium