Stimulation of prostaglandin production in bone by phorbol diesters and melittin

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.