Parathyroid hormone-related protein stimulates prostaglandin E2 release from human osteoblast-like cells: modulating effect of peptide length.
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.
Mitnick
M
M
Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut.
Isales
C
C
Paliwal
I
I
Insogna
K
K
D000262:Adenylyl Cyclases / Q000378:metabolism; D001862:Bone Resorption; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism*; D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011506:Proteins / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*
C470121:PTHLH protein, human; D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments; D011506:Proteins; C065306:parathyroid hormone-related protein (1-36), TyrNH2(36)-; C065305:parathyroid hormone-related protein (1-74); C066079:parathyroid hormone-related protein (1-108); D000242:Cyclic AMP; D011451:Prostaglandin-Endoperoxide Synthases; D000262:Adenylyl Cyclases; D015232:Dinoprostone; D002118:Calcium; D007213:Indomethacin