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 [Tyr26]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.
ASJC Scopus subject areas
- Endocrinology, Diabetes and Metabolism
- Orthopedics and Sports Medicine