TUMOR-NECROSIS-FACTOR-ALPHA INHIBITS THE STIMULATORY EFFECT OF THE PARATHYROID HORMONE-RELATED PROTEIN ON CYCLIC-AMP FORMATION IN OSTEOBLAST-LIKE CELLS VIA PROTEIN KINASE-C+

Tumor necrosis factor α (TNF α) and parathyroid hormone-related protein (PTHrP) are both factors that have been implicated in the mechanism of hypercalcemia of malignancy. In this study we investigated the effect of TNF α on the PTHrP-stimulated accumulation of intracellular cyclic AMP in osteoblast-like cells. In the clonal cell line Saos-2 and in primary cell cultures from fetal rat calvaria, PTHrP-stimulated accumulation of cAMP was time- and dose-dependently inhibited by exposure to TNF α. Significant inhibition occurred at concentrations as low as 2 × 10-12 M and was maximal at 1 × 10-9 M. Inhibition was observed after 6 h and was maximal after 18 h. Inhibition by TNF α was probably mediated by protein kinase C, since the phorbol ester PMA mimicked the effect of TNF α, and the protein kinase C inhibitor H-7 completely abolished the effect of TNF α. In conclusion, these observations suggest a possible mechanism by which TNF α may modulate the effect of PTHrP on osteoblast function in the syndrome of humoral hypercalcemia of malignancy. © 1992 Academic Press, Inc.