Immunological evidences for post-translational control of the parathyroid function by ionized calcium in dogs

Cloutier, Marianne; Rousseau, Louise; Gascon-Barré, Marielle; D'Amour, P

doi:10.1016/s0169-6009(08)80068-2

Cited by 12 publications

(7 citation statements)

References 26 publications

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“…This difference of the coefficient would be due to N‐PTH overproduction or some PTH fractions, such as 7–84 PTH fragment. During hypercalcemia, the proportional decrease in carboxyl terminal fragments is less than that of 1–84 PTH (22–24). In hemodialysis patients, the percent of non‐1–84 PTH was shown to directly correlate with the predialysis serum calcium concentration, with an increase in the serum calcium concentration associated with a reduction in the ratio of 1–84 PTH/non‐1–84 PTH (7,8).…”

Section: Discussionmentioning

confidence: 98%

Comparison between Whole and Intact Parathyroid Hormone Assays

et al. 2011

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The standard measurement of parathyroid hormone (PTH) is the intact PTH (iPTH) assay, which is used for approximately 90% of Japanese dialysis patients. The iPTH assay reacts not only with 1-84 PTH, but also with large truncated fragments of non-1-84 PTH, including 7-84 PTH. On the other hand, the whole PTH assay is specific for 1-84 PTH. The aim of the current study was to define the validity of both whole and intact PTH assays. A total of 738 hemodialysis patients were enrolled from twelve dialysis services. The serum PTH level was evaluated by both intact and whole PTH assays simultaneously. Non-1-84 PTH was determined by subtracting the whole PTH value from that of the intact PTH assay. The median level of whole PTH was 121 pg/mL, and that of iPTH was 210 pg/mL. The whole PTH assay had a very high correlation with the iPTH assay (r = 0.870, P < 0.001). For 43 out of 738 patients (5.8%) the value for intact PTH-whole PTH was <0. Both assays significantly correlated with non-1-84 PTH (P < 0.001), while the iPTH assay, particularly, had a very high correlation with non-1-84 PTH (r = 0.791). As a whole, 18% of the total population was misclassified into a different Japanese guideline category. Stratified by Japanese guideline classifications, 28% of patients within an iPTH target range were misclassified. Using Bland-Altman plot analysis, as the serum PTH level increased, there was a large difference between two assays. Both PTH assays correlate strongly, although the whole PTH assay may be more useful for precise evaluation of PTH function than the iPTH assay.

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Section: Discussionmentioning

confidence: 98%

Comparison between Whole and Intact Parathyroid Hormone Assays

et al. 2011

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“…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- , and more than 3 nmol/h hPTH-(7-84) prevented it. First, their concentration, relative to that of intact (I-) PTH, estimated though the C-PTH/I-PTH ratio, is regulated by the Ca 2ϩ concentration in healthy individuals (1)(2)(3) and patients with parathyroid diseases (4 -10). Both hPTH-(1-84) and hPTH- 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.…”

mentioning

confidence: 99%

“…Both hPTH-(1-84) and hPTH-(1-34) stimulated cAMP production in ROS 17/2.8 clonal cells, whereas hPTH- was ineffective in this respect. Acutely, hypercalcemia suppresses I-PTH more efficiently than C-PTH and elevates the C-PTH/I-PTH ratio, whereas hypocalcemia increases I-PTH more efficiently than C-PTH and decreases the C-PTH/I-PTH ratio (1)(2)(3). 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.…”

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confidence: 99%

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

et al. 2001

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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.

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confidence: 99%

“…Ca 2+ concentration also influences PTH secretion qualitatively (2,3,11,12). While suppressing PTH concentration, hypercalcemia favors C-PTH fragment secretion over that of PTH(1 -84) (11), C-PTH fragments now accounting for 90% of circulating PTH immunoheterogeneity, and PTH(1 -84) only 10%, causing a high C-PTH/PTH(1-84) ratio in the circulation (2,3,12). Hypocalcemia stimulates the secretion of PTH(1 -84) more than that of C-PTH fragments (11), PTH(1 -84) now accounting for 30% of circulating PTH immunoheterogeneity, and C-PTH fragments 70%, causing a low C-PTH/PTH(1 -84) ratio in the circulation (2,3,12).…”

mentioning

confidence: 99%

Effects of acute and chronic hypercalcemia on parathyroid function and circulating parathyroid hormone molecular forms

D'Amour¹

2002

European Journal of Endocrinology

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Bas et al.(1), in this issue, have demonstrated that acute hypercalcemic clamp over 2 h in rabbits reduces the subsequent intact (I) parathyroid hormone (PTH) response to hypocalcemia by 50%, while chronic hypercalcemia, secondary to experimental renal failure in the same animal model, fails to reduce the I-PTH response to hypocalcemia. These results raise questions about the acute and chronic influence of calcium concentration on parathyroid function and on circulating PTH molecular forms. To understand and appropriately discuss these differences, it is necessary to review various aspects of PTH physiology.Circulating PTH is immunoheterogenous. Under normocalcemic conditions, it is composed of 20% PTH(1 -84), the biologically active form of the hormone on the PTH/PTHrP receptor, and of 80% carboxylterminal (C) fragments, considered until recently to be biologically inactive (2, 3). The main circulating C-PTH fragments observed during the peripheral metabolism of 125 I-bovine (b) PTH(1 -84) in rats start at positions 34, 37 and 39 (4) of the bPTH structure. Porcine (p) parathyroid cells have been demonstrated to secrete pPTH fragments starting at positions 34 and 37 (5). Studies in humans have also outlined the existence of smaller C-PTH fragments (6) and, more recently, of larger C-PTH fragments with a partially preserved aminoterminal structure (7), called non-(1 -84)PTH. These non-(1 -84)PTH molecular form or forms have been described in humans during the analysis of normal and abnormal serum HPLC profiles using Nichol's I-PTH assay (7), the same assay as that employed by Bas et al.(1) in their study. Most I-PTH assays have since been demonstrated to also react with non-(1 -84)PTH (8). Non-(1 -84)PTH accounts for 10% of C-PTH fragments and for 20% of I-PTH immunoreactivity in normal individuals. It is of particular interest because, on theoretical grounds, it could react with the PTH/PTHrP receptor and interfere with the biological effects of PTH(1 -84).Hypercalcemia acutely suppresses PTH secretion to a non-suppressible and detectable PTH concentration (9) while hypocalcemia stimulates PTH secretion to a maximum (9), both stimuli contributing to the sigmoidal relationship between Ca 2+ and PTH concentrations (10). Ca 2+ concentration also influences PTH secretion qualitatively (2, 3, 11, 12). While suppressing PTH concentration, hypercalcemia favors C-PTH fragment secretion over that of PTH(1 -84) (11), C-PTH fragments now accounting for 90% of circulating PTH immunoheterogeneity, and PTH(1 -84) only 10%, causing a high C-PTH/PTH(1-84) ratio in the circulation (2, 3, 12). Hypocalcemia stimulates the secretion of PTH(1 -84) more than that of C-PTH fragments (11), PTH(1 -84) now accounting for 30% of circulating PTH immunoheterogeneity, and C-PTH fragments 70%, causing a low C-PTH/PTH(1 -84) ratio in the circulation (2,3,12). This acute control of PTH secretion and of circulating PTH molecular forms is post-translational (13 -15). PTH synthesis always proceeds maximally in the parathyroid glands, and the amoun...

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Immunological evidences for post-translational control of the parathyroid function by ionized calcium in dogs

Cited by 12 publications

References 26 publications

Comparison between Whole and Intact Parathyroid Hormone Assays

Comparison between Whole and Intact Parathyroid Hormone Assays

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

Effects of acute and chronic hypercalcemia on parathyroid function and circulating parathyroid hormone molecular forms

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