title: Stimulation of prostaglandin production in bone by phorbol diesters and melittin.
abstract: The production of prostaglandin E2 (PGE2) and bone resorption were studied in neonatal mouse calvaria in organ culture. Two tumor promoters 12-O-tetradecanoyl-phorbol-13-acetate (TPA) and phorbol-12, 13-di-decanoate, but not the non-tumor promoters 4alpha-phorbol-12,13-didecanoate and phorbol, stimulated both PGE2 synthesis in bone and bone resorption. The effect of TPA was maximum at about 25 ng/ml, and half-maximum stimulation occurred at about 8 ng/ml TPA. The effects of TPA on the production of PGE2 and bone resorption were inhibited completely by indomethacin (5.6 X 10(-8) to 5.6 X 10(-7) M). The been venom toxin, melittin, was also a potent stimulator of prostaglandin synthesis in bone and bone resorption. The effect of melittin was maximum at about 25 ng/ml, and the dose-response curve was biphasic. The effects of melittin on the production of PGE2 and bone resorption were also inhbited by indomethacin. Indomethacin did not inhibit the bone resorption-stimulating activity of exogenously added PGE2. We conclude that phorbol diesters, which have irritant and tumor-promoting activity in mouse skin, and the polypeptide melittin can act directly on bone to stimulate resorption by a mechanism involving the local production of PGE2 or possible other indomethacin-inhibited metabolites odonic acid.
mesh_terms: D000818:Animals; D001514:Bee Venoms / Q000494:pharmacology*; D001862:Bone Resorption / Q000187:drug effects; D001842:Bone and Bones / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007213:Indomethacin / Q000494:pharmacology; D008555:Melitten / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051379:Mice; D009924:Organ Culture Techniques; D010703:Phorbol Esters / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D010704:Phorbols / Q000494:pharmacology*; D011453:Prostaglandins / Q000032:analysis; D011458:Prostaglandins E / Q000096:biosynthesis*
chemical_list: D001514:Bee Venoms; D010703:Phorbol Esters; D010704:Phorbols; D011453:Prostaglandins; D011458:Prostaglandins E; D008555:Melitten; D002118:Calcium; D007213:Indomethacin