Parathyroid hormone-related protein stimulates prostaglandin E2 release from human osteoblast-like cells: modulating...

Parathyroid hormone-related protein (PTHrP) is a potent bone-resorbing protein that frequently mediates the humoral hypercalcemia of malignancy syndrome. Since prostaglandins may mediate the bone-resorptive action of certain hormones, we examined the effect of PTHrP on prostaglandin E2 (PGE2) secretion by human osteoblast-like cells. There was low-level basal secretion of PGE2 by Saos-2 cells (8.1 +/- 0.6 pg/ml). Using four different preparations of PTHrP, it was observed that with increasing peptide length, from 36 to 141 amino acids, a significant increase in efficacy for PGE2 release was seen in these cells. All forms of PTHrP were agonists for PGE2 release, with effects seen at concentrations as low as 10(-12) M in 48 h conditioned media. The amino terminus of the molecule appeared critical for this effect since the truncated derivative PTHrP-(7-34) did not induce significant PGE2 secretion. However, the influence of peptide length could not be explained by differential activation of adenylate cyclase since [Tyr36]PTHrP-(1-36)amide was equipotent to the longest peptide preparation, PTHrP-(1-141), in stimulating cyclic AMP accumulation in the Saos-2 cells. In contrast, PTHrP-(1-141) was significantly more effective than [Tyr35]PTHrP-(1-36)-amide in inducing a rise in cytosolic calcium. Further, this effect was noted at concentrations lower than those that caused significant cyclic AMP accumulation in the Saos-2 cells. PTHrP-(1-141) induced the release of PGE2 from primary human bone cell cultures to levels entirely comparable to those seen in the Saos-2 cells. PTHrP-(1-141) also induced PGE2 release by cultured fetal rat long bones at 72 h. We conclude that the carboxy-terminal region of PTHrP has important effects on cellular signal transduction pathways and on the release of a potent bone-active cytokine, PGE2.