Synthetic carboxyl-terminal fragments of parathyroid hormone (PTH) decrease ionized calcium concentration in rats by acting on a receptor different from the PTH/PTH-related peptide receptor

Even if the carboxyl-terminal (C-) fragments/intact (I-) PTH ratio is tightly regulated by the ionized calcium (Ca2+) concentration in humans and animals, in health and in disease, the physiological roles of C-PTH fragments and of the C-PTH receptor remain elusive. To explore these issues, we studied the influence of synthetic C-PTH peptides of various lengths on Ca2+ concentration and on the calcemic response to human (h) PTH-(1-34) and hPTH-( 1-84) in anesthetized thyroparathyroidectomized (TPTX) rats. We also looked at the capacity of these PTH preparations to react with the PTH/PTHrP receptor and with a receptor for the carboxyl (C)-terminal portion of PTH (C-PTH receptor) in rat osteosarcoma cells, ROS 17/2.8. The Ca2+ concentration was reduced by 0.19 +/- 0.03 mmol/liter over 2 h in all TPTX groups. Infusion of solvent over 2 more h had no further effect on the Ca2+ concentration (-0.01 +/- 0.01 mmol/liter), whereas infusion of hPTH-(7-84) or a fragment mixture [10% hPTH-(7-84) and 45% each of hPTH-(39 - 84) and hPTH-(53- 84)] 10 nmol/h further decreased the Ca2+ concentration by 0.18 +/- 0.02 (P ( 0.001) and 0.07 +/- 0.04 mmol/liter (P < 0.001), respectively. Infusion of hPTH (1-84) or hPTH-(1-34) (1 nmol/h) increased the Ca2+ concentration by 0.16 0.03 (P < 0.001) and 0.19 0.03 mmol/liter (P ( 0.001), respectively. Adding hPTH-(7-84) (10 nmol/h) to these preparations prevented the calcemic response and maintained Ca2+ concentrations equal to or below levels observed in TPTX animals infused with solvent alone. Adding the fragment mixture (10 nmol/h) to hPTH(1-84) did not prevent a normal calcemic response, but partially blocked the response to hPTH-(1-34), and more than 3 nmol/h hPTH(7- 84) prevented it. Both hPTH-(1- 84) and hPTH-(1-34) stimulated cAMP production in ROS 17/2.8 clonal cells, whereas hPTH-(7-84) was ineffective in this respect. Both hPTH-(1-84) and hPTH-(1-34) displaced I-125-[Nle(8.18),Tyr(34)]hPTH-(1-34) amide from the PTHI PTHrP receptor, whereas hPTH-(7-84) had no such influence. Both hPTH-( 1- 84) and hPTH-( 7- 84) displaced I-125- [Tyr34]hPTH-(19 -84) from the C-PTH receptor, the former preparation being more potent on a molar basis, whereas hPTH-(1-34) had no effect. These results suggest that C-PTH fragments, particularly hPTH-(7-84), can influence the Ca2+ concentration negatively in vivo and limit in such a way the calcemic responses to hPTH-(1-84) and hPTH-(1-34) by interacting with a receptor different from the PTH/PTHrP receptor, possibly a C-PTH receptor.