Prostaglandin-related bone resorption in cultured neonatal mouse calvaria: evaluation of biopotency of nonsteroidal anti-inflammatory drugs.
The objective of this study was the development of an assay based on suppression of endogenous prostaglandin synthesis in cultured neonatal mouse calvaria for evaluation of the biopotency of nonsteroidal anti-inflammatory drugs in bone. In preliminary trials, osteolytic activity due to spontaneous prostaglandin production over a 72 h culture period was found highly variable, and could not be stabilized by addition of the common precursor arachidonic acid to the culture medium. Eventually, continuous exposure of mouse calvaria to moderate concentrations of thrombin (greater than or equal to 14 U/ml medium) proved to be satisfactory to achieve stable rates of bone resorption through continuous stimulation of prostaglandin synthesis from endogenous sources. Notably, the extent of net calcium release into the medium was highly reproducible in different experiments. As an example for possible applications of the bioassay, the ability of acemetacin to interfere with prostaglandin synthesis in bone, which had not been assessed before, was evaluated in a comparative assay with indomethacin and acetylsalicylic acid. While 1 X 10(-8) M acemetacin appeared to augment thrombin-induced bone resorption, as did 5 X 10(-6) M acetylsalicylic acid, a dose-dependent inhibition of calcium release was observed between 10(-7)-10(-5) M acemetacin. In this respect, the biopotency of indomethacin was 50 times higher than that of acemetacin and exceeded that of acetylsalicylic acid by a factor of more than 2000. These data could be useful for the appraisal of multiple effects of the investigated drugs on prostaglandin-related bone turnover.
D000818:Animals; D000831:Animals, Newborn; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000494:pharmacology; D001241:Aspirin / Q000494:pharmacology; D001862:Bone Resorption / Q000187:drug effects*; D002478:Cells, Cultured; D007213:Indomethacin / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D010281:Parathyroid Hormone / Q000494:pharmacology; D011453:Prostaglandins / Q000096:biosynthesis / Q000502:physiology*; D013917:Thrombin / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; D001095:Arachidonic Acids; D010281:Parathyroid Hormone; D011453:Prostaglandins; D016718:Arachidonic Acid; C026784:acemetacin; D013917:Thrombin; D001241:Aspirin; D007213:Indomethacin