Delayed stimulation of bone resorption in vitro by phosphodiesterase inhibitors requires the presence of adenylate cyclase stimulation.
The effect on cyclic AMP levels and bone resorption by two methylxanthine cyclic AMP phosphodiesterase (PDE) inhibitors, isobutyl-methylxanthine (IBMX) and theophylline, and two non-xanthine PDE inhibitors, Ro 20-1724 and rolipram, was studied in cultured mouse calvarial bones. Cyclic AMP accumulation in calvarial bones increased when Ro 20-1724 (0.1 mmol/l) or rolipram (30 mumol/l) was present in culture medium in 2 h incubations, and when IBMX (0.3 mmol/l) or theophylline (3 mmol/l) was present in 4 h incubations. The cyclic AMP response to PDE-inhibitors could be completely abolished by the cyclooxygenase-inhibitor indomethacin (1 mumol/l). In 120 h cultures, IBMX, theophylline, Ro 20-1724 and rolipram stimulated the release of 45Ca from calvarial bones prelabelled in vivo with 45Ca. This stimulatory effect could not be seen when the endogenous production of prostaglandins was reduced by adding indomethacin (1 mumol/l), hydrocortisone (1 mumol/l) or meclofenamic acid (1 mumol/l) to culture medium. These concentrations of indomethacin, hydrocortisone and meclofenamic acid did not reduce PTH- (10 nmol/l) or choleratoxin-stimulated (0.1 micrograms/ml) 45Ca release from mouse calvarial bones cultured for 120 h. The stimulation of 45Ca release in long-term cultures by the PDE inhibitors could be demonstrated in the presence of indomethacin, provided adenylate cyclase was stimulated by forskolin (1-10 nmol/l). The stimulatory effect of 1 alpha (OH)D3 on 45Ca release could not be potentiated by the PDE-inhibitor rolipram. These results suggest that basal adenylate cyclase activity in cultured murine calvaria is very low and that therefore PDE inhibitors are inactive unless a stimulator of adenylate cyclase is present. The adenylate cyclase stimulator may be an endogenous autacoid such as a prostaglandin.
Ransjö
M
M
Department of Oral Pathology, University of Umeå, Sweden.
Fredholm
B B
BB
Lerner
U H
UH
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D001862:Bone Resorption / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002772:Cholera Toxin / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis; D006854:Hydrocortisone / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D008469:Meclofenamic Acid / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000494:pharmacology; D020889:Rolipram; D012886:Skull / Q000166:cytology / Q000378:metabolism; D013806:Theophylline / Q000494:pharmacology
D010726:Phosphodiesterase Inhibitors; D011760:Pyrrolidinones; D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone; D008469:Meclofenamic Acid; D002772:Cholera Toxin; D013806:Theophylline; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D020889:Rolipram; D002118:Calcium; D015056:1-Methyl-3-isobutylxanthine; D006854:Hydrocortisone; D007213:Indomethacin