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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

Centre de Recherche, Centre Hospitalier de l’Université de Montréal, Hôpital Saint-Luc, et Départements de Médecine et Biochimie (R.L.), Université de Montréal, Montréal, Québec, Canada H2X 1P1

Address all correspondence and requests for reprints to: Pierre D’Amour, M.D., Centre de Recherche, Centre Hospitalier de l’Université de Montréal, Hôpital Saint-Luc, 264 René Lévesque boulevard East, Montréal, Québec, Canada H2X 1P1. E-mail: rechcalcium{at}ssss.gouv.qc.ca

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 ¹²⁵I-[Nle^8,18,Tyr³⁴]hPTH-(1–34) amide from the PTH/PTHrP receptor, whereas hPTH-(7–84) had no such influence. Both hPTH-(1–84) and hPTH-(7–84) displaced ¹²⁵I-[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.