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

Abstract

Even if the carboxyl-terminal (C-) fragments/intact (I-) PTH ratio is tightly regulated by the ionized calcium (Ca(2+)) 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 Ca(2+) 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 Ca(2+) 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 Ca(2+) 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 Ca(2+) 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 Ca(2+) 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 Ca(2+) 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 (125)I-[Nle(8,18),Tyr(34)]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 (125)I-[Tyr(34)]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 Ca(2+) 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.

Parathyroid hormone and its fragments in children with chronic renal failure

“…Explanations for the necessity of supra-physiological PTH levels have been based upon the concept of 'skeletal resistance to PTH', the mechanism for which is unclear [9]. However, it has recently been recognized that current immunoradiometric ('intact' IRMA) PTH assays exhibit cross-reactivity between 1-84 PTH and long carboxyl-terminal PTH (C-PTH) fragments (likely to be 7-84 PTH [10]), resulting in an overestimation of the actual PTH levels [11,12]. Furthermore, it has been shown that 7-84 PTH has an inhibitory effect upon the biological actions of 1-84 PTH, mediated at a separate C-terminal receptor [13,14,15].…”

Intraoperative calcium monitoring is insufficient to predict the surgical success of parathyroidectomy for primary hyperparathyroidism

“…For example, PTH(7-84; C-PTH) further decreases serum calcium within 2 h in parathyroidectomized rats and antagonizes iPTH(1-84) induced calcium increase. 22 Furthermore, PTH(28-48) and PTH(53-84) antagonized iPTH(1-34)-induced calcium release in chick bone organ culture systems. 23 Therefore, it could be hypothesized that preoperative calcium levels and short-term changes in serum calcium concentrations are the results of an individual C-PTH/ iPTH ratio in patients.…”

New PTH assays and renal osteodystrophy

“…The synthesis and secretion of these fragments by the parathyroid glands are likely to be regulated by calcium and, possibly, other agents such as 1,25(OH) 2 D and phosphate. Such findings suggest that amino-terminally truncated fragments of the PTH(1-84) molecule may contribute to the skeletal PTH resistance that occurs in patients with renal failure [26,34].…”

“…Furthermore, PTH(7-84) inhibits the formation of TRAP-positive bone resorbing cells in vitro [32] and inhibits bone formation in vivo [33]. In addition, Nguyen-Yamamoto et al [34] demonstrated that PTH (7-84), with or without a mixture of other carboxyl-terminal PTH-fragments, inhibited the calcemic effect of PTH in vivo, indicating that these actions are not mediated through the PTH/PTHrP receptor, but instead via a receptor that interacts only with carboxyl-terminal portions of PTH. Thus, there is a growing body of evidence that at least some of the different carboxyl-terminal PTH fragments are biologically active.…”