Effects of phorbol esters and pertussis toxin on calcitonin-stimulated accumulation of cyclic AMP in neonatal mouse calvarial bones.
Calcitonin (CT) is a well-known inhibitor of osteoclastic bone resorption both in vivo and in vitro. The effect is mediated by activation of adenylate cyclase and subsequent increased levels of cyclic AMP (cAMP). We report here that CT-induced (30 nmol/liter) accumulation of cAMP in cultured neonatal mouse calvaria is enhanced two-fold by 12-O-tetradecanoylphorbol-13-acetate (TPA; 100 nmol/liter) and phorbol 12,13-dibutyrate (PDBU; 100 nmol/liter), two protein kinase C (PKC)-activating phorbol esters, whereas phorbol 13-monoacetate (phorb-13; 100 nmol/liter), a related compound that does not activate PKC, has no effect. The ability of TPA and PDBU to enhance CT-stimulated cAMP accumulation was obtained also in the presence of indomethacin (1 mumol/liter). Kinetic studies revealed that TPA enhanced the cAMP response to CT at all the time points at which CT had a significant effect per se and that TPA did not alter the time-course of the cAMP response to CT. Treatment with pertussis toxin (100 ng/ml) enhanced cAMP response to parathyroid hormone (10 nmol/liter) and prostaglandin E2, but not to CT. From these data it is concluded that PKC, but not pertussis toxin-sensitive guanyl nucleotide-binding proteins (G-proteins), can interact with and modify the signal transducing system for CT in osteoclasts.
Ransjö
M
M
Department of Orthodontics, University of Umeå, Sweden.
Lerner
U H
UH
D037361:Adenylate Cyclase Toxin; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001862:Bone Resorption; D002116:Calcitonin / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism*; D015232:Dinoprostone / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism; D007213:Indomethacin / Q000494:pharmacology; D051379:Mice; D010010:Osteoclasts / Q000187:drug effects* / Q000378:metabolism; D010281:Parathyroid Hormone / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D037342:Pertussis Toxin; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D010703:Phorbol Esters / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology*
D037361:Adenylate Cyclase Toxin; D010281:Parathyroid Hormone; D010446:Peptide Fragments; D010703:Phorbol Esters; D010566:Virulence Factors, Bordetella; C025076:parathyroid hormone (1-34), bovine; C050164:phorbol 13-monoacetate; D015240:Phorbol 12,13-Dibutyrate; D002116:Calcitonin; D000242:Cyclic AMP; D037342:Pertussis Toxin; D011493:Protein Kinase C; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate; D007213:Indomethacin