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PubMed1988

Effects of the parathyroid hormone antagonist [Tyr34]bPTH-(7-34)amide on avian renal phosphate transport.

The in vivo parathyroid hormone antagonist, [Tyr34]bPTH-(7-34)amide, was tested for its ability to block endogenous parathyroid hormone (PTH) activity in parathyroid-intact European starlings. The inhibitor was infused at two dose levels, 0.005 and 0.05 mg/hr. A third group received a vehicle/control infusion. High-dose infusion led to rapid and significant decreases in plasma calcium and in both absolute and relative phosphate (Pi) excretion. Low-dose infusion significantly reduced plasma calcium, but had no effect on Pi excretion. Plasma Pi tended to increase with time in all three groups. Removal of the antagonist after 140 min of high-dose infusion led to a rapid recovery of relative Pi excretion, and a subsequent overshoot to more than twice the original control level. To further test the ability of the antagonist to block endogenous PTH activity, an EGTA challenge was used to induce hypocalcemia and subsequent elevation of circulating PTH levels. In vehicle-infused birds, EGTA challenge led to a doubling of relative Pi excretion, but in birds receiving the high-dose infusion, no effect of EGTA was observed. These results demonstrate that [Tyr34]bPTH-(7-34)amide can completely block endogenous PTH activity in birds at the receptor level, including the hormone response of the renal Pi secretory transport mechanism.

Animals↗
PubMed1978

Search for the uremic toxin. Decreased motor-nerve conduction velocity and elevated parathyroid hormone in uremia.

In a retrospective analysis to determine whether secondary hyperparathyroidism in uremia has a role in uremic peripheral neuropathy, we simultaneously measured motor-nerve conduction velocity and serum parathormone level in 42 uremic patients. We compared age-matched groups of nondiabetic uremic patients, divided into three groups according to serum parathyroid hormone, for degree of impairment of motor-nerve conduction velocity, and 12 diabetic patients with uremia. The group with highest levels had a significantly (P less than 0.01) lower conduction velocity (25.3 +/- 4.9 m per second) than the group with normal or slightly elevated parathyroid hormone, who had only mild depression of nerve conduction (45.1 +/- 1.3 m per second). Mean serum calcium and creatinine were not significantly different between groups. Nerve conduction velocity was similarly depressed in 17 patients on additional dialysis studied prospectively and divided into groups according to parathyroid hormone levels. These results suggest a relation between high parathormone levels and uremic neuropathy and implicate parathyroid hormone as a uremic toxin.

Adult↗
PubMed1999

Falls relate to vitamin D and parathyroid hormone in an Australian nursing home and hostel.

OBJECTIVES: To determine whether falling relates to serum levels of vitamin D and parathyroid hormone. DESIGN: A cross-sectional study with retrospective analysis. SETTING: An aged-care institution in Melbourne Australia. PARTICIPANTS: Ambulant nursing home and hostel residents (n = 83). MEASUREMENTS: Frequency of falling, frequency of going outdoors, use of cane or walker, age, sex, weight, type of accommodation, and duration of residence. Serum concentrations of 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and parathyroid hormone (PTH). Plasma concentrations of albumin, calcium, phosphate, and creatinine. Use of furosemide or non-benzodiazepine anticonvulsants. RESULTS: Median age of residents was 84 years. The cohort was vitamin D deficient with a median (interquartile range) 25-hydroxyvitamin D level of 27 (18-37) nmol/L (one-third the reference range median), P < .001. The median (interquartile range) PTH of 5.2 (3.8-7.7) pmol/L exceeded the reference range median, P < .001. Residents who fell (n = 33) had lower serum 25-hydroxyvitamin D levels than other residents (medians 22 vs 29 nmol/L, P = .02) and higher serum PTH levels (medians 6.2 vs 4.8 pmol/L, P < .01). Sixty residents lived in the hostel (72%), and 41 (49%) walked without any walking aid. In a multiple logistic regression for falling, higher serum PTH remained independently associated with falling, with an odds ratio (95% confidence interval) for falling of 5.6 (1.7-18.5) per unit of the natural logarithm of serum PTH. Other terms in the regression were hostel accommodation, odds ratio .04 (.01-.25), and ability to walk without aids, odds ratio .07 (.01-.37). CONCLUSIONS: In ambulant nursing home and hostel residents, residents who fall have lower serum 25-hydroxyvitamin D and higher serum parathyroid hormone levels than other residents. The association between falling and serum PTH persists after adjustment for other variables.

Accidental Falls↗
PubMed1998

Parathyroid-hormone-related protein in sarcoidosis.

Parathyroid-hormone-related protein (PTHrP) is the main mediator of the humoral hypercalcemia of malignancy. It is also detected in many normal adult and fetal tissues. Altered calcium metabolism occurs in sarcoidosis, and two cases of sarcoidosis with hypercalcemia and elevated plasma PTHrP are described. An archival study of 20 lymph node biopsies with the pathological diagnosis of sarcoidosis was performed. Immunohistochemistry using a polyclonal antiserum to human PTHrP and in situ hybridization using a riboprobe to human PTHrP were performed on the lymph node biopsies. Immunohistochemistry for PTHrP was also performed on the biopsies from the two cases with elevated plasma levels. Immunohistochemical analysis detected PTHrP in macrophages within granulomata in 17 of the 20 (85%) biopsies. In situ hybridization detected a positive signal for messenger RNA in the granulomata of 11 of 19 (58%) biopsies. PTHrP immunoreactivity and PTHrP gene expression are present in sarcoid granulomata. PTHrP may contribute to the hypercalcemia of sarcoidosis.

Adult↗
PubMedDate not supplied

Regulation of phosphate transport in the renal tubule through parathyroid hormone receptor: unexpected pathways.

The recent molecular identification of parathyroid hormone (PTH) receptors, on the one hand, and Napi cotransporters, on the other hand, has enabled the development of powerful tools to boost the study of the regulation of renal Pi transport by PTH, a regulation which stands at a crucial point in the physiology and pathophysiology of Pi homeostasis. The aim of this review is to summarize these recent findings.

Animals↗
PubMed1973

Activation of renal cortical adenylate cyclase by circulating immunoreactive parathyroid hormone fragments.

Three distinct immunoreactive species of parathyroid hormone (PTH) are present in human serum. One has an estimated mol wt of 9,500 and probably represents glandular hormone, the second 7,000-7,500 mol wt, and the third 4,500-5,000 mol wt. In order to assess the biological activity of these circulating forms of PTH, we determined their ability to activate renal cortical adenylate cyclase. The 9,500 mol wt and 4,500-5,000 mol wt fractions produced four- to sixfold increases in cyclic 3',5'-AMP accumulation above control; the 7,000-7,500 mol wt fraction was inactive. None of the fragments had any effects on phosphodiesterase activity. Antiserum to bovine PTH did not block the activation of adenylate cyclase by either the gragments or bovine PTH. The data suggest that a large proportion of circulating immunoreactive human PTH is biologically active and that the biologically and immunologically active sites of the hormone are distinct.

Adenylyl Cyclases↗
PubMed1988

Vitamin D and parathyroid hormone and bone mineralisation in adults with cystic fibrosis.

Vitamin D and parathyroid hormone concentrations were assessed in 31 adults with cystic fibrosis (mean age 24, range 17-52 years), in 28 of whom the bone mineral index in the forearm was also determined. Serum 25-hydroxyvitamin D was subnormal in eight patients, of whom five were receiving vitamin D supplements in standard doses. 1,25-dihydroxyvitamin D and parathyroid hormone concentrations showed no consistent abnormalities. The bone mineral index was lower in patients with cystic fibrosis (p less than 0.02) than in controls. Five patients with unequivocally reduced bone mineral index had a subnormal mean serum 25-hydroxyvitamin D and significantly worse lung function than the other patients. There was a positive correlation between age and bone mineral index (r = 0.68, p less than 0.001). Thus a significant proportion of patients with cystic fibrosis living in a temperate climate are at risk of vitamin D deficiency. Osteopenia is common and is probably related to a combination of hypovitaminosis D, delay in puberty, hypo-oestrogenism in women, and reduced physical activity, rather than to secondary hyperparathyroidism. Since most patients with deficiency of 25-hydroxyvitamin D were receiving oral supplements, parenteral vitamin D supplementation may be appropriate for selected patients who are unable to maintain adequate 25-hydroxyvitamin D concentrations despite oral vitamin D supplements.

Adolescent↗
PubMed1997

Residues in the membrane-spanning and extracellular loop regions of the parathyroid hormone (PTH)-2 receptor determine signaling selectivity for PTH and PTH-related peptide.

The parathyroid hormone (PTH)-2 receptor displays strong ligand selectivity in that it responds fully to PTH but not at all to PTH-related peptide (PTHrP). In contrast, the PTH-1 receptor (PTH/PTHrP receptor) responds fully to both ligands. Previously it was shown that two divergent residues in PTH and PTHrP account for PTH-2 receptor selectivity; position 23 (Trp in PTH and Phe in PTHrP) determines binding selectivity and position 5 (Ile in PTH and His in PTHrP) determines signaling selectivity. To identify sites in the PTH-2 receptor involved in discriminating between His5 and Ile5, we constructed PTH-2 receptor/PTH-1 receptor chimeras, expressed them in COS-7 cells, and tested for cAMP responsiveness to [Trp23] PTHrP-(1-36), and to the nondiscriminating peptide [Ile5, Trp23]PTHrP-(1-36) (the Phe23 --> Trp modification enabled high affinity binding of each ligand to the PTH-2 receptor). The chimeras revealed that the membrane-spanning/loop region of the receptor determined His5/Ile5 signaling selectivity. Subsequent analysis of smaller cassette substitutions and then individual point mutations led to the identification of two single residues that function as major determinants of residue 5 signaling selectivity. These residues, Ile244 at the extracellular end of transmembrane helix 3, and Tyr318 at the COOH-terminal portion of extracellular loop 2, are replaced by Leu and Ile in the PTH-1 receptor, respectively. The results thus indicate a functional interaction between two residues in the core region of the PTH-2 receptor and residue 5 of the ligand.

Amino Acid Sequence↗
PubMedDate not supplied

Parathyroid hormone: another pregnancy protein present in human seminal plasma and amniotic fluid.

Parathyroid hormone (PTH) has been found in human seminal plasma at concentrations of 302 +/- 65 (222-482) pmol l-1 (n = 16), which is about 5 times the concentration in human blood serum. Concentrations in human amniotic fluid at 16-22 weeks of gestation were 43 +/- 9 (28-65) pmol l-1 (n = 24), which is about 80% of the concentration in blood serum. The Amersham assay uses an antiserum raised against the synthetic middle piece of the PTH molecule from the parathyroid glands. It estimates amino acids 44-68 of the 84 amino acid intact molecule, together with fragments containing this part of the chain. It is considered that a placental type of parathyroid hormone was being measured, some of which escapes into the amniotic fluid. The placenta contains a complete PTH-dihydroxyvitamin D3 system that causes the absorption of more calcium from the gut for foetal needs during pregnancy. It is postulated that the seminal vesicles also contain a PTH-dihydroxyvitamin D3 system that has a paracrine action in passing large amounts of calcium into the ejaculate.

Amniotic Fluid↗
PubMed1999

Effect of rate of calcium reduction and a hypocalcemic clamp on parathyroid hormone secretion: a study in dogs.

BACKGROUND: The parathyroid hormone (PTH) calcium curve is used to evaluate parathyroid function in clinical studies. However, unanswered questions remain about whether PTH secretion is affected by the rate of calcium reduction and how the maximal PTH response to hypocalcemia is best determined. We performed studies in normal dogs to determine whether (a) the rate of calcium reduction affected the PTH response to hypocalcemia and (b) the reduction in PTH values during a hypocalcemic clamp from the peak PTH value observed during the nadir of hypocalcemia was due to a depletion of stored PTH. METHODS: Fast (30 min) and slow (120 min) ethylenediamine-tetraacetic acid (EDTA) infusions were used to induce similar reductions in ionized calcium. In the fast EDTA infusion group, serum calcium was maintained at the hypocalcemic 30-minute value for an additional 90 minutes (hypocalcemic clamp). To determine whether the reduction in PTH values during the hypocalcemic clamp represented depletion of PTH stores, three subgroups were studied. Serum calcium was rapidly reduced from established hypocalcemic levels in the fast-infusion group at 30 and 60 minutes (after 30 min of a hypocalcemic clamp) and in the slow-infusion group at 120 minutes. RESULTS: At the end of the fast and slow EDTA infusions, serum ionized calcium values were not different (0.84 +/- 0.02 vs. 0.82 +/- 0.03 mM), but PTH values were greater in the fast-infusion group (246 +/- 19 vs. 194 +/- 13 pg/ml, P < 0.05). During the hypocalcemic clamp, PTH rapidly decreased (P < 0.05) to value of approximately 60% of the peak PTH value obtained at 30 minutes. A rapid reduction in serum calcium from established hypocalcemic levels at 30 minutes did not stimulate PTH further, but also PTH values did not decrease as they did when a hypocalcemic clamp was started at 30 minutes. At 60 minutes, the reduction in serum calcium increased (P < 0.05) PTH to peak values similar to those before the hypocalcemic clamp. The reduction in serum calcium at 120 minutes in the slow EDTA infusion group increased PTH values from 224 +/- 11 to 302 +/- 30 pg/ml (P < 0.05). CONCLUSIONS: These results suggest that (a) the reduction in PTH values during the hypocalcemic clamp may not represent a depletion of PTH stores. (b) The use of PTH values from the hypocalcemic clamp as the maximal PTH may underestimate the maximal secretory capacity of the parathyroid glands and also would change the analysis of the PTH-calcium curve, and (c) the PTH response to similar reductions in serum calcium may be less for slow than fast reductions in serum calcium.

Animals↗
PubMed1992

Thallium-technetium subtraction scintigraphy of enlarged parathyroid glands after calcitonin stimulation of parathyroid hormone secretion.

To improve the sensitivity of thallium-technetium subtraction scintigraphy for preoperative localization procedure of enlarged parathyroid glands in primary hyperparathyroidism, we administered calcitonin intramuscularly 4 hours before the scintigraphy in 14 consecutive patients. Injection of calcitonin reduced plasma levels of ionized calcium from 1.47 +/- 0.10 mmol/l to 1.41 +/- 0.09 mmol/l (p less than 0.01). Concomitantly, serum levels of intact parathyroid hormone increased from 6.4 +/- 2.5 pmol/l to 7.9 +/- 2.6 pmol/l (p less than 0.001). The scintigram after calcitonin injection visualized 11 adenomas (sensitivity 78%) compared to only 9 (sensitivity 64%) in conventional scintigrams. In addition, 5 of the adenomas were more distinctly imaged in the scintigram after calcitonin injection, whereas in only one patient was the conventional scintigram better. Thus, the calcitonin injection improved the scintigram in 7 cases and was inferior in only one case (p = 0.031). We conclude that stimulation of parathyroid hormone secretion with calcitonin results in a better preoperative localization of enlarged parathyroid glands in primary hyperparathyroidism.

Adenoma↗
PubMed1976

Parathyroid hormone plasma level in untreated chronic renal failure and in hemodialyzed patients.

In 42 untreated patients at various stages of chronic renal failure, plasma level of parathyroid hormone was directly proportional to the degree of renal failure and inversely proportional to the serum calcium level. Plasma parathyroid hormone levels were frequently elevated in 21 patients undergoing regular dialysis treatment, in spite of normal levels of serum total calcium and magnesium. Serum-ionized calcium levels measured in dialyzed patients were usually reduced and inversely correlated with the creatinine levels. Parathyroid hormone levels were correlated with the creatinine levels, but the inverse relationship with ionized calcium was not significant.

Adult↗
PubMed1991

Restructuring the translation initiation region of the human parathyroid hormone gene for improved expression in Escherichia coli.

Overexpression of native human parathyroid hormone in Escherichia coli was achieved by a modification of the 5' end of the genomic gene sequence, thereby adapting this part of the translation initiation region to the bacterial host. Some simple rules abstracted from optimization studies of translation initiation of a beta-interferon gene were applied. These included (a) extending complementarity of the mRNA to the anticodon loop of tRNAfMet by use of a codon with a purine nucleotide directly following the ATG, (b) avoidance of stable secondary structure in the mRNA by use of synonymous A/U-rich codons, (c) elimination of a potential second Shine-Dalgarno sequence. The appropriate silent changes led to a 20-fold increase in parathyroid hormone production resulting in 4.3% of total soluble protein. This result proves the validity of our simple approach for optimization of foreign gene expression in E. coli.

Base Sequence↗
PubMed1994

Immunoheterogeneity of parathyroid hormone after surgery for primary hyperparathyroidism.

Circulating parathyroid hormone (PTH) immunoheterogeneity is altered in primary hyperparathyroidism (pHPT). It is not known, however, whether the relative secretion of various PTH fragments differs between the adenomatous and the non-adenomatous glands in pHPT. We therefore examined the immunoheterogeneity of PTH in patients operated upon because of parathyroid adenoma pre- and 4 days postoperatively during an EDTA-infusion test. Following surgery, baseline levels of amino-terminal PTH (N-PTH) were reduced by a smaller degree than the levels of intact PTH (i-PTH) (P < 0.05) resulting in a higher N/i ratio postoperatively (P < 0.05). Furthermore, the increase in i-PTH and C-PTH fragments during the EDTA infusion test was lower postoperatively than preoperatively (P < 0.05), whereas the increase in N-PTH did not differ. The results therefore suggest that compared with the parathyroid adenoma, the non-adenomatous glands secrete relatively more N-terminal PTH.

Adult↗
PubMed1998

RNA-Protein binding and post-transcriptional regulation of parathyroid hormone gene expression by calcium and phosphate.

Parathyroid hormone (PTH) regulates serum calcium and phosphate levels, which, in turn, regulate PTH secretion and mRNA levels. PTH mRNA levels are markedly increased in rats fed low calcium diets and decreased after low phosphate diets, and this effect is post-transcriptional. Protein-PTH mRNA binding studies, with parathyroid cytosolic proteins, showed three protein-RNA bands. This binding was to the 3'-untranslated region (UTR) of the PTH mRNA and was dependent upon the terminal 60 nucleotides. Parathyroid proteins from hypocalcemic rats showed increased binding, and proteins from hypophosphatemic rats decreased binding, correlating with PTH mRNA levels. There is no parathyroid cell line; however, a functional role was provided by an in vitro degradation assay. Parathyroid proteins from control rats incubated with a PTH mRNA probe led to an intact transcript for 40 min; the transcript was intact with hypocalcemic proteins for 180 min and with hypophosphatemic proteins only for 5 min. A PTH mRNA probe without the 3'-UTR, or just the terminal 60 nucleotides, incubated with hypophosphatemic proteins, showed no degradation at all, indicating that the sequences in the 3'-UTR determine PTH mRNA degradation. Hypocalcemia and hypophosphatemia regulate PTH gene expression post-transcriptionally. This correlates with binding of proteins to the PTH mRNA 3'-UTR, which determines its stability.

Animals↗
PubMed1987

Characterization of a high-affinity antiserum specific for the amino-terminal sequence of human parathyroid hormone.

1. The present paper describes a detailed study of the specificity of high-affinity antibodies obtained from the yolk of eggs laid by a chicken successfully immunized with synthetic human parathyroid hormone (hPTH)-(1-34). 2. Using 125I-labelled bovine parathyroid hormone (bPTH)-(1-84) purified by high performance liquid chromatography (HPLC) as tracer, and hPTH-(1-34) as reference, we found superimposable curves with hPTH-(13-34), bPTH-(13-34) and bPTH-(1-34); the [Asp-76]hPTH-(1-84) peptide showed a molar percent cross-reactivity (calculated at 50% B/BO) of 73% and the bovine sequence 1-84 of 15%. 3. Studying amidated [Tyr-34] bovine PTH fragments we found the highest cross-reactivity with the peptide 7-34 (33%) followed by 20-34 (1.7%) and 25-34 (0.4%). The bovine sequence 1-25 showed a low reactivity (0.7%) and the 1-12 sequence none at all. Rat parathyroid hormone (rPTH)-(1-34) showed low cross-reactivity (3.1%), the same occurring with peptide [Tyr-34, Norleu-8,18] bPTH-(1-34) (1.5%). 4. The data suggest that the antibodies studied recognize epitopes in or near amino acids 18 to 25 of the sequence of the hPTH molecule. This region of the molecule is coincident with the antigenic determinant predicted by the analysis of the hydrophilicity plot of the hPTH-(1-34) peptide.

Amino Acid Sequence↗
PubMed1981

Parathyroid hormone stimulates bone formation and resorption in organ culture: evidence for a coupling mechanism.

We have developed an in vitro system, using embryonic chicken tibiae grown in a serum-free medium, which exhibits simultaneous bone formation and resorption. Tibiae from 8-day embryos increased in mean (+/- SD) length (4.0 +/- 0.4 to 11.0 +/- 0.3 mm) and dry weight (0.30 +/- 0.04 to 0.84 +/- 0.04 mg) during 12 days in vitro. There was increased incorporation of [3H]proline into hydroxyproline (120 +/- 20 to 340 +/- 20 cpm/mg of bone per 24 hr) as a measure of collagen synthesis, as well as a 62 +/- 5% increase in total calcium and 45Ca taken up as an indication of active mineralization. A physiologic concentration (1 pM) of parathyroid hormone was found to stimulate bone resorption over control levels in this system. Parathyroid hormone stimulated the release of [3H]hydroxyproline from the bone shafts but not from the cartilage ends, indicating the specificity of the response. With 1 pM parathyroid hormone we observed an acute inhibition of bone formation, followed (after 12-16 hr) by a chronic stimulation of bone formation during the 12-day incubation. Both mineral uptake and matrix formation were enhanced at approximately the same rate during the 12-day incubation. The chronic enhancement of formation required parathyroid hormone only for the initial 8-10 hr of incubation. These results could be explained by the production or release of a factor from bone to stimulate formation in response to the acute increase in resorption--a "coupling factor." Indeed, dialyzed culture medium conditioned by actively resorbing bones stimulated bone formation over controls when added to organ cultures at a 1:20 dilution. The factor is larger than 12,000 daltons as determined by dialysis. The factor is specific for the bone shaft and did not affect the cartilage ends.

Animals↗