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PubMed1992

Structural changes in condylar cartilage following prolonged exposure to the human parathyroid hormone fragment (hPTH) 1-34 in vitro.

This investigation presents the structural changes in condylar cartilage incubated in the presence of human parathyroid hormone (1-34) in an organ culture system for 6 to 12 days. Control cultures maintained their cartilaginous characteristics whereas human parathyroid hormone (1-34)-treated cultures revealed the following modifications: (1) The chondroprogenitor cell zone at the apical region of the explant underwent a substantial enlargement. The cells changed from a mesenchyme-like morphology into polygonal, glycogen-rich cells that were tightly attached to each other by a fibrillar intercellular matrix, but even by 12 days the apical region was comprised of healthy cells. (2) The mineralizing zone in the hypertrophic cartilage revealed a change in its cellular population. Hypertrophic chondrocytes were replaced by cells with amoeboid extensions and large numbers of secretory granules or vesicles. Based upon the above findings it appears that the chondroprogenitor cells that are initially stimulated to proliferate, are being suppressed from subsequent differentiation into chondroblasts; and that hypertrophic chondrocytes apparently undergo a dedifferentiation process followed by development into an as yet unknown cell population.

Animals↗
PubMed1980

Vitamin D and parathyroid hormone degradation by the kidney.

Parathyroid function is controlled by the regulation of hormone secretion as well as degradation, through the action of calcium and vitamin D derivatives. In order to clarify the relationship between vitamin D metabolism and parathyroid degradation system, parathyroid hormone (PTH)-degrading activities of the kidney were measured in vitamin D repleted and depleted rats given various derivatives of vitamin D. Kidney calcium content rose markedly in animals given 10 microgram/kg 1 alpha(OH) vitamin D3 and 1,000 microgram/kg dihydrotachysterol and PTH-degrading activity rose only in these animals, indicating a parallelism between kidney calcium content and PTH-degrading activity of the kidney tissue. These vitamin D derivatives also increased the PTH-degrading activity of kidney tissue when they were added in vitro.

Animals↗
PubMed1996

Parathyroid hormone secretion in chronic renal failure.

The aim of study was to introduce and evaluate a method for quantifying the parathyroid hormone (PTH) secretion during hemodialysis in secondary hyperparathyroidism due to end-stage renal failure. We developed a method suitable for inducing sequential hypocalcemia and hypercalcemia during hemodialysis. During the development of the method we found significantly different results of blood ionized calcium and serum PTH concentration when obtained from the arterial blood line on the dialysis unit or from peripheral venous blood. However, when corrected for the calculated recirculation of 3 to 25%, the result obtained from arterial blood was comparable to the result from venous blood. Furthermore, the results obtained from venous blood were comparable to the results of sequential citrate and calcium clamping performed on a non-dialysis day. From our data of venous blood during hemodialysis, blood PTH/ionized calcium curves were constructed, and a mean calcium set-point of 1.16 mmol/liter was estimated compared to the normal mean of about 1.13 mmol/liter. In conclusion, we demonstrate that it is important to use a standardized method to evaluate parathyroid hormone dynamics in chronic renal failure. By the use of a standardized method we show that the calcium set-point is normal or slightly elevated, indicating normal parathyroid reactivity to calcium in chronic renal failure.

Adult↗
PubMed1988

The value to the surgeon of parathyroid hormone assays in primary hyperparathyroidism.

The role of various parathyroid hormone (PTH) radio-immunoassays in the diagnosis of primary hyperparathyroidism (PHP) is controversial. A series of 204 patients with surgically proven PHP was studied. Serum total calcium, serum ionized calcium, amino (N)-terminal PTH and carboxyl(C)-terminal PTH were assessed in relation to the volume and weight of adenomatous or hyperplastic parathyroid tissue excised at operation. N-terminal PTH was elevated above the normal laboratory range in only 24% of patients and correlated relatively poorly with the volume of abnormal parathyroid tissue (r = 0.20, P = 0.05). C-terminal PTH was elevated above the normal range in 91% of patients and had a strong correlation with the volume of abnormal parathyroid tissue (r = 0.63, P less than 0.001). The correlation coefficients between C-terminal PTH and serum total calcium and serum ionized calcium were both 0.63 (P less than 0.001). In contrast, there was no correlation between N-terminal PTH and serum total calcium (r = -0.02), serum ionized calcium (r = -0.04) or C-terminal PTH (r = 0.09). A combination of hypercalcaemia and elevated C-terminal PTH can be regarded as strong diagnostic evidence of PHP. Furthermore, the level of C-terminal PTH can assist the surgeon by approximately predicting the amount of adenomatous or hyperplastic parathyroid tissue that may be expected at surgical exploration.

Adolescent↗
PubMed2000

[Parathyroidectomy by elective route with perioperative measurement of parathyroid hormone. Report of 80 cases].

STUDY AIM: The aim of this study was to report a series of 80 patients treated by unilateral neck exploration for a sporadic primary hyperparathyroidism. PATIENTS AND METHOD: Between April 1992 and November 1998, 80 patients (65 women and 15 men, mean age: 63.5 years) with a single gland enlargement localized by ultrasonography, were operated on through a short unilateral neck incision, under general anesthesia in 72 cases and local in eight cases. The enlarged gland was removed with intraoperative pathological examination and intraoperative monitoring of parathyroid hormone. RESULTS: Mean duration of surgery was 25 minutes. There was no postoperative mortality or morbidity. Mean duration of hospital stay was two days. The enlarged gland was an adenoma in 75 cases and an hyperplasia in five. Adequate intraoperative parathyroid hormone decrease was observed. Postoperative calcemia was normal in 78 patients (97.5%). Among 76 surviving patients, with a 31-month follow-up, there was only a suspicion of persistent hyperparathyroidism in two patients. CONCLUSIONS: Minimal invasive approach by unilateral neck exploration may be performed with safety and efficiency in patients with a single gland enlargement under intraoperative monitoring of parathyroid hormone.

Adult↗
PubMed2000

The hypomagnesaemic action of FK506: urinary excretion of magnesium and calcium and the role of parathyroid hormone.

A side-effect of the immunosuppressive drug FK506 (Prograf; tacrolimus) is hypomagnesaemia. We have investigated the effects of short-term (7-day) treatment of rats with FK506, using a protocol designed to indicate whether there are modifications in the renal tubular handling of magnesium and other electrolytes, or in the tissue deposition of magnesium, which may account for the hypomagnesaemia. We have also investigated whether parathyroid hormone has a role in the observed hypomagnesaemia. Two studies have been performed; in the first we administered FK506 (0.5 mg x kg(-1) body weight x day(-1)) or vehicle by intraperitoneal injection for 7 days, and then housed the rats in metabolic cages for the 24 h collection of urine. At the end of the metabolic cage period, the animals were anaesthetized, and blood and tissue samples were taken for analysis. In the second set of experiments the dosage regime was identical, but at the end of the treatment period the animals were anaesthetized for implantation of arterial and venous cannulae, and then received a saline (plus inulin) infusion for 6 h, during which time blood and urine samples were collected. The dose of FK506 employed did not decrease the glomerular filtration rate. FK506 elicited hypomagnesaemia in both sets of experiments, accompanied by inappropriately high fractional excretion of magnesium. There was also evidence of disruption of the normal renal reabsorption of calcium, but this did not result in hypocalcaemia. Plasma parathyroid hormone activity was not significantly different between the two groups, and there was no evidence of altered tissue content of magnesium in kidney, liver, heart, skeletal muscle or bone. The study confirms that hypomagnesaemia is a significant side-effect of FK506, even at a relatively low dose which did not decrease the glomerular filtration rate. The effect is not due to a decrease in parathyroid hormone release, or to translocation of magnesium from plasma to tissues, but does reflect decreased renal tubular magnesium (and calcium) reabsorption.

Animals↗
PubMed1991

Radioimmunoassay of parathyroid hormone in cats.

A radioimmunoassay for measurement of midmolecule parathyroid hormone (PTH) concentration in serum from dogs was validated for use on serum from cats. The assay detected an increase in serum concentration of PTH after IV infusion of Na2 EDTA in healthy cats. Infusion of calcium chloride caused a decrease in measured PTH. Accuracy of the assay was demonstrated by quantitative recovery of a feline parathyroid gland extract added to pooled feline sera. Mean interassay and intra-assay coefficients of variation were 0.13 and 0.07, respectively. Sensitivity of the assay was 0.1 ng of PTH/ml. The median PTH concentration measured in 40 adult cats was 3.5 ng/ml, with a range of 1.16 to 11.0 ng/ml.

Animals↗
PubMed1989

[Comparison of hypotensive effects of acutely administered human parathyroid hormone (1-34) in normal young and elderly subjects].

The effects of acute administration of human parathyroid hormone (1-34) [PTH(1-34)] on the blood pressure of 15 young (mean age +/- SD, 20.9 +/- 1.7 years; 7 males and 8 females) and 11 elderly (78.1 +/- 5.9 years; 4 males and 7 females) normal subjects were compared. The elderly subjects have a slightly, but significantly higher mean basal systolic blood pressure (132.4 +/- 17.7 mmHg) than the young subjects (118.7 +/- 11.4 mmHg), but the basal diastolic and mean blood pressures of the two groups were similar. Intravenous bolus infusion of PTH(1-34) at a dose of 100 U induced transient, but marked hypotension in all subjects. The mean maximal decrease in systolic blood pressure (-delta SBP was significantly more (p less than 0.01) in the elderly subjects (42.5 +/- 13.9 mmHg) than in the young subjects (8.0 +/- 8.9 mmHg), but the maximal decrease in diastolic blood pressure (-delta DBP) was similar in the elderly (25.6 +/- 13.9 mmHg) and young (27.3 +/- 10.9 mmHg) subjects. The maximal decrease in the mean blood pressure (-delta MBP) was also significantly higher (p less than 0.01) in the elderly subjects (31.9 +/- 8.7 mmHg) than in young ones (20.6 +/- 7.6 mmHg). The corrected serum level of calcium (scCa) was significantly (p less than 0.01) lower in the elderly subjects (9.6 +/- 0.2 mg/dl) than in the young ones (10.0 +/- 0.3 mg/dl), and the serum level of C-terminal parathyroid hormone (C-PTH) was significantly higher in the elderly subjects (270 +/- 80 pg/ml) than in the young ones (150 +/- 80 pg/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Rat collagenase. Cloning, amino acid sequence comparison, and parathyroid hormone regulation in osteoblastic cells.

We have isolated clones for rat collagenase from a rat osteoblastic cell cDNA library. These clones have been sequenced and the amino acids deduced. The calculated molecular weight is 51,352 for the proenzyme and 42,229 for the active enzyme. The deduced amino acid sequence was compared to those previously reported for: 1) human collagenase, 2) rat transin 1 (stromelysin), 3) human stromelysin, and 4) rabbit collagenase. The number of amino acids conserved was 47, 47, 50, and 47%, respectively. We also compared the collagenase mRNA and protein in different rat cells (osteoblast, uterine smooth muscle, synovial fibroblast) and determined that in rat uterine cells the message is slightly larger, although collagenase protein in all three cell types was identical in size. Parathyroid hormone dramatically induces the 2.9-kilobase collagenase mRNA in the rat osteoblastic cells, UMR 106-01. Nuclear run-on studies in UMR 106-01 cells demonstrated a 4-8-fold induction in the rate of synthesis of collagenase mRNA at 2 and 4 after parathyroid hormone treatment, with steady state levels of mRNA increased 100-fold at 4 h. Thus, parathyroid hormone regulation of the collagenase gene in UMR 106-01 cells is in part transcriptional.

Amino Acid Sequence↗
PubMed2001

Internalization determinants of the parathyroid hormone receptor differentially regulate beta-arrestin/receptor association.

beta-Arrestins have been implicated in regulating internalization of the parathyroid hormone receptor (PTHR), but the structural features in the receptor required for this effect are unknown. In the present study performed in HEK-293 cells, we demonstrated that different topological domains of PTHR are implicated in agonist-dependent receptor internalization; truncation of the cytoplasmic tail (PTHR-TR), selective mutations of the cytoplasmic tail to remove the sites of parathyroid hormone (PTH)-stimulated phosphorylation (PTHR-PD), and mutations in the third transmembrane helix (N289A) or in the third cytoplasmic loop (K382A) resulted in a 30-60% reduction in (125)I-PTH-related protein internalization. To better define the role of these internalization determinants, we have tested the ability of these mutant PTHRs to associate with beta-arrestins by using three different methodological approaches: 1) ability of overexpression of beta-arrestins to restore the internalization of (125)I-PTH-related protein for the mutant PTHRs; 2) visualization of PTH-mediated trafficking of beta-arrestin1 and -2 fused to the green fluorescent protein with receptors by confocal microscopy; 3) quantification of beta-arrestin1-green fluorescent protein translocation by Western blot. Our data reveal that the receptor' cytoplasmic tail contains determinants of beta-arrestin interaction that are distinct from the phosphorylation sites and are sufficient for transient association of beta-arrestin2, but stable association requires receptor phosphorylation. Determinants in the receptor's core (Asn-289 and Lys-382) appear to regulate internalization of the receptor/beta-arrestin complex toward early endocytic endosomes during the initial step of endocytosis.

Arrestins↗
PubMed1984

Maternal-fetal relationships in the parathyroidectomized rat. Intestinal calcium transport, serum calcium, immunoreactive parathyroid hormone and calcitonin.

We studied the role of the parathyroids in the adaptation of intestinal Ca transport that occurs during pregnancy, and whether maternal hypoparathyroidism causes fetal hyperparathyroidism. Serum Ca of pregnant parathyroidectomized (PTX) rats was significantly greater than nonpregnant, PTX animals. Intestinal active Ca transport was increased 2.1- and 2.2-fold by pregnancy in intact and PTX rats, respectively. Serum levels of immunoreactive parathyroid hormone (PTH) were nondetectable in PTX-pregnant rats. Fetuses from PTX rats appeared grossly normal. The serum PTH was not different in fetuses from PTX compared to fetuses from intact mothers and serum Ca, Mg, and P were normal. Thus, alleviation of maternal hypocalcemia during pregnancy in PTX rats may be due to an adaptive increase in intestinal Ca transport, which does not require the parathyroids. Fetuses from PTX mothers were euparathyroid and were protected from Ca deficiency during pregnancy.

Animals↗
PubMed1994

Effects of infusion of parathyroid hormone and primary hyperparathyroidism on formation and breakdown of type I collagen.

The influence of chronic and acute exposure to parathyroid hormone (PTH) on formation and breakdown of type I collagen, using two recently developed radioimmunoassays for serum PICP (the carboxyterminal propeptide of type I procollagen) and serum ICTP (the carboxyterminal telopeptide of type I collagen), have been evaluated. Fasting morning values were obtained from 18 women with primary hyperparathyroidism (HPT) and an equal number of age-matched, healthy controls. A 24-hour infusion of synthetic human parathyroid hormone (PTH 1-38) was performed in 14 healthy females. The patients with HPT had higher values for serum ICTP than the controls (6.0 +/- 3.0 and 4.1 +/- 2.1 micrograms/liter; P < 0.05), whereas the serum PICP concentrations were not different (170 +/- 72 and 151 +/- 65 micrograms/liter; n.s.). During infusion of PTH in healthy subjects, there was an increase of the serum ICTP concentrations (from 3.6 +/- 1.3 to 4.4 +/- 1.8 micrograms/liter; P < 0.001) whereas those of serum PICP decreased (from 185 +/- 78 to 118 +/- 42 micrograms/liter; P < or = 0.0001). The increase of serum ICTP during infusion of PTH was positively related to the increase of serum calcium and other indices of bone resorption, i.e., fasting urinary excretions of hydroxyproline and calcium. The decrease of serum PICP was also related to the changes of serum ICTP and hydroxyproline in urine, serum calcium, and alkaline phosphatase but not to osteocalcin, an established marker of osteoblastic activity. The findings support the fact that serum ICTP is a valuable method for evaluating bone resorption and is also easy to perform.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Efficient secretion of human parathyroid hormone by Saccharomyces cerevisiae.

A cDNA encoding mature human parathyroid hormone (hPTH) was expressed in Saccharomyces cerevisiae, after fusion to the prepro region of yeast mating factor alpha (MF alpha). Radioimmunoassay showed high levels of hPTH immunoreactive material in the growth medium (up to 10 micrograms/ml). More than 95% of the immunoreactive material was found extracellularly as multiple forms of hormone peptides. Three internal cleavage sites were identified in the hPTH molecule. The major cleavage site, after a pair of basic amino acids (aa) (Arg25Lys26 decreases Lys27), resembles that recognized by the KEX2 gene product on which the MF alpha expression-secretion system depends. The use of a protease-deficient yeast strain and the addition of high concentrations of aa to the growth medium, however, not only changed the peptide pattern, but also resulted in a significant increase in the yield of intact hPTH (1-84) (more than 20% of the total amount of immunoreactive material). The secreted hPTH (1-84) migrates like a hPTH standard in two different gel-electrophoretic systems, co-elutes with standard hPTH on reverse-phase high-performance liquid chromatography, reacts with two hPTH antibodies raised against different parts of the peptide, has a correct N-terminal aa sequence, and has full biological activity in a hormone-sensitive osteoblast adenylate cyclase assay.

Adenylyl Cyclases↗
PubMed1976

Changes in blood flow to bones during the hypocalcemic and hypercalcemic phases of the response to parathyroid hormone.

Labeled microspheres were used to measure blood flow to the leg bones of the laying hen at 0, 3, and 30 min after iv injection of parathyroid hormone (PTH) (Wilson) or the synthetic 1 to 34 fragment of bovine parathyroid hormone (PTH 1-34). At 3 min, which corresponds to the hypocalcemic phase of the PTH response, blood flow to the combined femur, tibia, and metatarus was significantly reduced by PTH (Wilson) relative to 0 time and to carrier-injected controls. At 30 min, i.e., the time of maximum hypercalcemia in the hen, blood flow to these bones was significantly increased relative to 0 time. The results obtained with PTH 1-34 were similar, except that the decrease at 3 min was only significant in comparison with the controls injected with inactivated hormone. Femoral blood flow and the venous minus arterial calcium gradients across the femur were positively correlated, irrespective of sampling time (0 or 30 min) or type of injection (PTH [Wilson] or carrier). Taken together, these results suggest that there is a relationship between calcium mobilization from bone and the rate of osseous blood flow. Other organs which showed significant changes in blood flow after PTH (Wilson) were the adrenals, thyroids, and shell gland; the cerebellum, parathyroids, heart, spleen, liver, pancreas, duodenum, magnum, isthmus, and kidneys were not affected.

Adrenal Glands↗
PubMed1971

Synthesis of a biologically active N-terminal tetratriacontapeptide of parathyroid hormone.

Determination of the amino acid sequence of bovine parathyroid hormone has led to the synthesis of a tetratriacontapeptide corresponding to the amino-terminal 1-34 residues of the native molecule. The specific biological effects of this synthetic peptide on bone and kidney are qualitatively identical to those of the native hormone in classical bioassays in vivo and in several systems in vitro. Potency of the synthetic peptide equals or exceeds that of a biologically active fragment of comparable size isolated from the native hormone; the synthetic and natural peptides show complete immunological cross-reactivity. Thus, essential requirements for the physiological actions of the peptide on both skeletal and renal tissue are contained within the 34 amino-terminal amino acids. The potency of the synthetic peptide, relative to that of the native (84-amino acid) polypeptide, is greater in vitro than in vivo; this suggests that the carboxyl terminal two-thirds of the native hormone may protect the circulating polypeptide from rapid metabolic degradation.

Adenylyl Cyclases↗
PubMed2001

Use of intraoperative parathyroid hormone measurement does not improve success of bilateral neck exploration for hyperparathyroidism.

HYPOTHESIS: Use of intraoperative measurement of intact parathyroid hormone (iPTH) to confirm complete excision of hyperfunctioning parathyroid tissue does not improve overall operative success rates. DESIGN: Case series of patients undergoing parathyroidectomy with or without intraoperative iPTH measurement. SETTING: University teaching hospital. PATIENTS AND INTERVENTIONS: Fifty patients undergoing parathyroidectomy before our institution of intraoperative iPTH sampling in March 1999 (group 1) were compared with 50 patients undergoing parathyroidectomy after this technique was adopted (group 2). Overall, 100 patients underwent operation between December 1996 and May 2000. Serum calcium and iPTH levels were measured at 1- and 3-month intervals. Intraoperative frozen sections and operative times were also analyzed. RESULTS: Mean preoperative calcium levels were 2.85 and 2.82 mmol/L (11.4 and 11.3 mg/dL) in groups 1 and 2, respectively. One-month postoperative calcium values were identical in both groups at 2.35 mmol/L (9.4 mg/dL) (group 1 SD = 0.18 [0.74], group 2 SD = 0.20 [0.82]). At 1 month, all but 1 patient in group 1 had normalized calcium values (2% failure rate), while 3 patients in group 2 (6%) remained hypercalcemic. All 3 patients in group 2 had intraoperative iPTH levels that returned to normal. There was a significant difference in the number of intraoperative frozen sections between groups, with a mean (SD) of 3.4 (1.7) in group 1 and 2.0 (1.6) in group 2 (P<.01). There was no significant difference in operative times between groups. CONCLUSIONS: Use of intraoperative iPTH sampling did not significantly affect the overall success of parathyroidectomy, as determined by postoperative normocalcemia. There was, however, a significant decrease in the number of frozen sections sent at operation.

Adenoma↗
PubMed1999

Daily follow-up of serum parathyroid hormone and calcium after surgery for primary hyperparathyroidism.

OBJECTIVE: To describe the course of parathyroid hormone (PTH) and serum calcium after surgery for primary hyperparathyroidism and to evaluate the usefulness of daily measurement of these parameters. DESIGN: Prospective clinical study. SETTING: University hospital K. U. Leuven. METHOD: Daily monitoring of PTH and serum calcium (preoperatively, the first to the 5th postoperative day, and around the 10th day) in 30 patients where a parathyroid adenoma was removed and in 1 patient with a negative neck exploration. RESULTS: In the adenoma cases, PTH and serum calcium showed a sharp drop of PTH to a very low level already on the first postoperative day, whereafter a rapid recovery of the PTH was seen. Serum calcium decreased more slowly: on average, the lowest calcium level was measured on the third day, when a majority of the patients were temporarily hypocalcemic; after 2 weeks, only four patients remained slightly hypocalcemic and no one showed recurrence of the hypercalcemia. In contrast, after unsuccessful surgery (biopsy of four normal glands), the PTH decrease on the first day was far less pronounced and the hypercalcemia disappeared only for a short time. CONCLUSIONS: After removal of a parathyroid adenoma, an abrupt fall of PTH precedes the decrease of serum calcium. The first day's PTH level is a reliable indicator of the success of the intervention, and it should be a major point in the postoperative biochemical follow-up. Repeated measurements of serum calcium are useful, but the daily dosage of PTH might be omitted for economic reasons.

Adenoma↗