AUTOREGULATION OF PROSTAGLANDIN-E(2)-INDUCED CA2+ INFLUX IN OSTEOBLAST-LIKE CELLS - INHIBITION BY SELF-INDUCED ACTIVATION OF PROTEIN-KINASE-C

In cloned osteoblast-like MC3T3-E1 cells, prostaglandin E2 (PGE2) stimulated Ca-45(2+) influx even in the presence of nifedipine, a Ca2+ antagonist that inhibits voltage-dependent Ca2+ channel, in a dose-dependent manner, attaining a maximum at 0.5-mu-M. Dose of PGE2 above 0.5-mu-M caused less than maximal stimulation. While PGE2 StiMulated the formation of inositol trisphosphate dose dependently in the range between 1 nM and 10-mu-M. 12-O-Tetradecanoylphorbol-13-acetate (TPA), a protein kinase C (PKC)-activating phorbol ester, which by itself had little effect on Ca-45(2+) influx, significantly suppressed the Ca-45(2+) influx induced by PGE2 in a dose-dependent manner between 1 nM and 1-mu-M. 4-alpha-Phorbol 12,13-didecanoate, a phorbol ester which is inactive for PKC, showed little effect in this capacity. Staurosporine, a PKC inhibitor, enhanced the PGE2-induced Ca-45(2+) influx. On the other hand, dibutyryl cAMP had little effect on the Ca-45(2+) influx induced by PGE2. Our data suggest that PGE, regulates Ca2+ influx through self-induced activation of PKC. These results indicate that there is an autoregulatory mechanism in signal transduction by PGE2, and PGE2 modulates osteoblast functions through the interaction between Ca2+ influx and phosphoinositide hydrolysis in osteoblast-like cells.