Stimulation of prostaglandin production in bone by phorbol diesters and melittin

Abstract

The production of prostaglandin E 2 (PGE 2) 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 4α-phorbol-12,13-didecanoate and phorbol, stimulated both PGE 2 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 PGE 2 and bone resorption were inhibited completely by indomethacin (5.6 × 10 −8 to 5.6 × 10 −7 M). The bee 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 PGE 2 and bone resorption were also inhibited by indomethacin. Indomethacin did not inhibit the bone resorption-stimulating activity of exogenously added PGE 2. 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 PGE 2 or possibly other indomethacin-inhibited metabolites of arachidonic acid.