CORTISOL MODULATES THE ACTIONS OF INTERLEUKIN-1-ALPHA ON BONE-FORMATION, RESORPTION, AND PROSTAGLANDIN PRODUCTION IN CULTURED MOUSE PARIETAL BONES

Previous studies have shown that both interleukin-1 (IL-1) and glucocorticoids inhibit collagen synthesis in bone organ and cell cultures. In this study we examined their interactions in cultured neonatal mouse parietal bones. IL-1-alpha stimulated [H-3]thymidine incorporation. Cortisol decreased thymidine incorporation, but did not block the effect of IL-1. Both cortisol and IL-1-alpha decreased the incorporation of [H-3]proline into collagenase-digestible protein (CDP) and reduced alpha-1(I)procollagen mRNA levels at 72 h. Noncollagen protein (NCP) labeling was increased by IL-1 and decreased by cortisol. In the presence of cortisol, IL-1-alpha (6 pM) increased CDP as well as NCP labeling. The increase in CDP labeling was paralleled by an increase in alpha-1(I)procollagen mRNA, suggesting a pretranslational site for the cortisol-IL-1-alpha interaction. In the same bones, cortisol consistently blocked IL-1-alpha-stimulated Ca-45 release and prostaglandin E2 (PGE2) production. The ability of IL-1-alpha to increase CDP in the presence of cortisol was the same in the presence or absence of indomethacin, an inhibitor of PGE2 synthesis, or aphidicholin (30-mu-M), an inhibitor of DNA synthesis, indicating that the reversal was neither PG mediated nor dependent on cell proliferation. In conclusion, our results demonstrate that IL-1 inhibits collagen, but not NCP or DNA, synthesis and that cortisol inhibits IL-1-alpha-induced bone resorption and PGE2 production and reverses its inhibitory effect on collagen synthesis in cultured neonatal mouse calvariae.