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 alpha (TNF alpha) 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 alpha 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 alpha. Significant inhibition occurred at concentrations as low as 2 x 10(-12) M and was maximal at 1 x 10(-9) M. Inhibition was observed after 6 h and was maximal after 18 h. Inhibition by TNF alpha was probably mediated by protein kinase C, since the phorbol ester PMA mimicked the effect of TNF alpha, and the protein kinase C inhibitor H-7 completely abolished the effect of TNF alpha. In conclusion, these observations suggest a possible mechanism by which TNF alpha may modulate the effect of PTHrP on osteoblast function in the syndrome of humoral hypercalcemia of malignancy.