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PubMed1991

[Immunohistochemical study of parathyroid hormone related protein (PTHrP) in renal cell carcinoma].

Parathyroid hormone related protein (PTHrP) is the main factor of humoral hypercalcemia of malignancy (HHM). Using anti-PTHrP monoclonal antibody 4B3, we investigated the immunohistochemical localization of PTHrP in human normal renal tissues and renal cell carcinomas. Among normal renal tissues, distal tubules and collecting ducts showed positive immunostaining. Among 36 cases of renal cell carcinoma, PTHrP was detected in 30 cases (83%), and there was no significant correlation between the degree of the immunostaining and the serum calcium levels of the patients. As for the histopathological types of the renal cell carcinomas, granular cell subtypes tended to be more strongly positive than clear cell ones. In conclusion, it was not uncommon that PTHrP was commonly presented by renal cell carcinoma, and HHM occurred when the PTHrP transgressed the homeostatic mechanisms.

Adult↗
PubMed2002

Parathyroid hormone is essential for normal fetal bone formation.

Parathyroid hormone (PTH) is a potent pharmacologic inducer of new bone formation, but no physiologic anabolic effect of PTH on adult bone has been described. We investigated the role of PTH in fetal skeletal development by comparing newborn mice lacking either PTH, PTH-related peptide (PTHrP), or both peptides. PTH-deficient mice were dysmorphic but viable, whereas mice lacking PTHrP died at birth with dyschondroplasia. PTH-deficient mice uniquely demonstrated diminished cartilage matrix mineralization, decreased neovascularization with reduced expression of angiopoietin-1, and reduced metaphyseal osteoblasts and trabecular bone. Compound mutants displayed the combined cartilaginous and osseous defects of both single mutants. These results indicate that coordinated action of both PTH and PTHrP are required to achieve normal fetal skeletal morphogenesis, and they demonstrate an essential function for PTH at the cartilage-bone interface. The effect of PTH on fetal osteoblasts may be relevant to its postnatal anabolic effects on trabecular bone.

Animals↗
PubMed2002

Parathyroid hormone concentrations during and after two periods of high intensity exercise with and without an intervening recovery period.

The purpose of this study was to examine the effect of a recovery period between two periods of exercise on bone metabolism and related hormones. Concentrations of serum parathyroid hormone ([PTH]), plasma ionized calcium ([Ca(2+)]) and total calcium were measured. A group of 12 healthy men aged 20-27 years participated in this study. They took part in two exercise protocols (P(1) and P(2)) on two separate weeks. The exercise in P(1) comprised two successive periods of 21 min each at 70% and 85% of maximal oxygen uptake; P(2) comprised two periods of exercise at the same intensities but separated by 40 min of recovery. Venous blood samples were collected 1 day before the sessions (control), before each protocol, during (7th and 21st min), at the end (42nd min in P(1) and 82nd min in P(2)) and after 24 h of recovery. The [PTH] was significantly elevated during the two protocols ( P<0.01), remained raised in P(1) after 24 h of recovery ( P<0.05) and was significantly lower ( P<0.01) at the end of P(2) when compared to P(1). The [Ca(2+)] decreased significantly during and at the end of the two protocols ( P<0.01) and had returned to control values after 24 h of recovery. Plasma lactate concentration increased during the two protocols ( P<0.01) and returned to control values after recovery. These results indicate firstly that [Ca(2+)] decreases during continuous exercise as [PTH] increases and remains raised after 24 h of recovery, secondly that a recovery period between two periods of exercise attenuates the variations in [Ca(2+)] and [PTH], and thirdly that recovery may have anabolic effects on bone. However, the small physiological changes observed prevent us from forming any firm conclusion about this.

Adult↗
PubMed1999

Molecular characterization of the receptor-ligand complex for parathyroid hormone.

Molecular models for the interaction of parathyroid hormone (PTH) with its G-protein-coupled receptors (PTH1 and PTH2) have been developed. The proposed ligand-receptor complex is based on experimental data from spectroscopic investigations of the hormone and receptor fragments as well as theoretical structure predictions based on homology analysis with proteins of known structure. From the insight afforded by the models, biochemical and pharmacological observations can be correlated with specific molecular or atomic interactions. The ligand selectivity of PTH2, specifically the lack of binding of His5-containing analogues, can be ascribed to unfavorable steric interactions (the binding pocket is markedly smaller in PTH2 than PTH1) as well as repulsive Coulombic forces between amino acids of like-charge (a positively charged H384 is located in the binding pocket in PTH2). The model of PTH1 suggests that the constitutive activity observed from the incorporation of a positively charged amino acid at position 223, found at the cytoplasmic end of TM2, is caused by a Coulombic attraction to E465, at the cytoplasmic end of TM7, leading to an association of TM2 and TM7 and thereby ligand-free activation. Additionally, a number of important interactions in the ligand-receptor complex are described along with predictions of the pharmacological profile which will result from specific modifications at these sites. In this regard, the models described here allow for atomic insight into the biochemical data currently available and allow targeting of future mutations to probe specific ligand/receptor interactions and thereby further our understanding of the functioning of this important hormone system.

Amino Acid Sequence↗
PubMed2002

Residue 19 of the parathyroid hormone: structural consequences.

Residue 19 of the parathyroid hormone (PTH) has been shown to play an important role in both binding to and activation of the PTH receptor; specifically, Arg(19)-containing analogues have improved biological function over similar Glu(19) peptides [Shimizu et al. (2002) Biochemistry 41, 13224-13233]. Additionally the juxtamembrane portion of the receptor is involved in the different biological responses. Here, we determine the conformational preferences of PTH analogues to provide a structural basis for their biological actions. On the basis of circular dichroism results, the Arg(19) --> Glu(19) mutations within the context of both PTH(1-20) and PTH(1-34) analogues lead to increases in helix content, ranging from a 8-15% increase. High-resolution structures as determined by (1)H NMR and NOE-restrained molecular dynamics simulations clearly illustrate the difference between Arg(19) and Glu(19)-PTH(1-20), particularly with the extent and stability of the C-terminal helix. The Arg(19)-containing analogue has a well defined, stable alpha-helix from Ser(4)-Arg(19), while the Glu(19) analogue is less ordered at the C-terminus. On the basis of these observations, we propose that position 19 of PTH(1-20) must be alpha-helical for optimal interaction with the juxtamembrane portion of the receptor. This mode of binding extends the current view of PTH binding (indeed ligand binding for all class B GPCRs), which invokes a bihelical ligand with the C-terminus of the ligand interacting with the N-terminus of the receptor (responsible for binding) and the N-terminus of the ligand interacting with the seven-helical bundle (leading to receptor activation).

Amino Acid Sequence↗
PubMed1991

The expression of parathyroid hormone messenger RNA in normal and abnormal parathyroid tissue.

The distribution and expression of preproparathyroid hormone (PTH) mRNA were investigated in parathyroid tissue from 57 parathyroidectomy specimens. PTH mRNA was detected by in situ hybridization using digoxigenin-labelled oligonucleotide probes. Cell morphology was seen to correlate with PTH mRNA expression. Strong expression of PTH mRNA was confined to cells which on haematoxylin and eosin staining had large vesicular nuclei. These included both vacuolated and non-vacuolated cells. Chief cells with small dark nuclei and scanty cytoplasm had little or no expression. In both adenoma and chief cell hyperplasia, the striking difference from normal was the greatly increased proportion of cells expressing PTH mRNA. In adenomas, the rim of uninvolved parathyroid tissue showed PTH mRNA expression similar to that of normal parathyroid. In hyperplasia, there was frequently concordance of staining within individual nodules. The findings establish morphological criteria for activity of parathyroid tissue and support current concepts of the different pathogenesis of hyperplasia and adenoma. The expression of PTH mRNA in oxyphil change and parathyroid carcinoma was also investigated.

Humans↗
PubMed1988

Recombinant human parathyroid hormone synthesized in Escherichia coli. Purification and characterization.

Recombinant human parathyroid hormone (hPTH) was expressed in Escherichia coli harboring a plasmid containing a synthetic human parathyroid hormone gene under the control of the E. coli lac promoter. Three major forms of the hormone were isolated by acid extraction and purified to homogeneity by high performance liquid chromatography. By amino acid analysis and NH2-terminal sequencing, these were identified as hPTH-(1-84), formyl-methionyl-hPTH-(1-84), and hPTH-(8-84). The recombinant hPTH-(1-84) was immunologically indistinguishable from a World Health Organization standard of extracted native hPTH-(1-84). Recombinant hPTH-(1-84) was also bioactive in renal and skeletal adenylate cyclase assays. In the skeletal bioassay performed in UMR 108 osteosarcoma cells its activity was identical to that of an hPTH-(1-84) standard. In this bioassay, formyl-methionyl-hPTH-(1-84) had 10% of the activity of hPTH-(1-84) and hPTH-(8-84) was inactive. The results demonstrate the importance of isolating hPTH-(1-84) from other recombinant forms and metabolites to achieve full hormonal bioactivity and indicate that purified recombinant hPTH-(1-84) can thereby be obtained which should be a useful source of hormone for both basic and clinical studies.

Adenylyl Cyclases↗
PubMed1983

Age-related changes in parathyroid hormone and 25 hydroxycholecalciferol levels.

Serum parathyroid hormone and 25 hydroxyvitamin D were measured in 124 normal subjects aged from 20 to 90 years. There was a significant progressive increase in serum parathyroid levels with age associated with a progressive decrease in total serum calcium. After the sixth decade there was a significant reduction of 25 hydroxyvitamin D serum levels. In each age group, there were no significant differences between men and women in all parameters measured. In normal elderly subjects there is an age-related decline of calcium absorption associated with reduced calcium intake and sun exposure leading to secondary hyperparathyroidism. These results emphasize the importance of calcium and vitamin D supplementation in elderly European population, not only in long-stay patients but in ambulatory normal people after 60 years.

25-Hydroxyvitamin D 2↗
PubMed1976

Failure of parathyroid hormone and cyclic AMP to inhibit renal carbonic anhydrase.

It has been suggested that the parathyroid hormone and cyclic AMP produce their bicarbonaturic effects through inhibition of renal carbonic anhydrase. In the present study, the incubation of renal carbonic anhydrase with parathyroid hormone or cyclic AMP in presence of ATP, Mg++ and K+ ions, did not produce any inhibition of the enzyme when the pH of the solution was maintained above 7. It is concluded, that parathyroid hormone and cyclic AMP produce urinary bicarbonate excretion by a mechanism independent of carbonic anhydrase inhibition.

Animals↗
PubMed1978

The effects of intravenous phosphate loading on salivary phosphate secretion and plasma parathyroid hormone levels in the sheep.

Adult sheep were given intravenous infusions of a solution of Na2HPO4 and the effects on parotid salivary composition and on plasma parathyroid hormone levels were studied. Infusion of the phosphate solution resulted in increases in the concentration of inorganic phosphate in the plasma and to proportional increases in the concentration and amount of phosphate secreted in the saliva. There was, however, no evidence that the salivary response was dependent upon a change in endogenous parathyroid hormone release. In other studies infusion of bovine parathyroid hormone or stimulation of endogenous hormone release through infusion of EDTA both led to a fall in the concentration of inorganic phosphate in the plasma and to a fall in the concentration and amount of phosphate secreted in the saliva. Taken together these results suggest that the major factor affecting salivary phosphate secretion in these studies was the concentration of inorganic phosphate in the plasma. Parathyroid hormone does not appear to have any direct effect on salivary phosphate secretion in the sheep though it may indirectly influence phosphate secretion through its effects on plasma inorganic phosphate level.

Animals↗
PubMed1976

Chemistry and physiology of parathyroid hormone.

Many recent studies, only a few of which are reviewed here (see Habener & Potts, 1976, for a detailed summary) have led to considerable clarification concerning critical features of the chemistry, biosynthesis, secretion and mode of action of parathyroid hormone. Certain of the confusion recently experienced in measurements of parathyroid hormone in blood is clearly explained by the heterogeneity arising from various forms of parathyroid hormone arising during biosynthesis and metabolism. Ultimately, as critical features of biosynthesis and metabolism of PTH as well as chemical definition of various molecular forms are achieved, considerable refinement in immunoassays should result. These advances in turn should provide better insights into the role of parathyroid dysfunction in various disorders of calcium and skeletal metabolism. From the physiological viewpoint, a clearer appreciation of the homeostatic role of parathyroid hormone in calcium metabolism is emerging as the essential features of biosynthesis, release, metabolism and action of the hormone are uncovered.

Amino Acid Sequence↗
PubMed1991

Parathyroid hormone secretion and target organ response in experimental acute pancreatitis.

To determine changes in parathyroid hormone secretion and target organ response caused by acute pancreatitis before the development of systemic toxic conditions, experimental acute pancreatitis was induced in rats with a choline-deficient, ethionine-supplemented diet. After 7 days, the rats were weighed and bled, and one kidney was assayed for 25-hydroxyvitamin D1 hydroxylase activity. Several manifestations of pancreatitis were observed in rats given the diet: weight loss (from 29.6 to 26.3 g vs that for control rats, from 29 to 52.8 g) and lower dietary intake (15.5 vs 47 g per rat per 7 days). Serum amylase levels fell from 1794 to 350 U/L in rats given the choline-deficient, ethionine-supplemented diet compared with levels of 1800 to 2100 U/L in control rats. The pancreases of rats given the choline-deficient, ethionine-supplemented diet showed degeneration, necrosis, and hemorrhaging. Serum levels of calcium, phosphorus, chloride, and parathyroid hormone did not change significantly throughout the experiment. Renal 25-hydroxyvitamin D1 hydroxylase activity was higher than in control rats (8.9 +/- 0.8 vs 7.6 +/- 0.6 fmol/mg of kidney per minute). Acute pancreatitis in this experimental animal model does not alter serum levels of calcium and parathyroid hormone or reduce target organ responsiveness to the hormone.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed2000

The N-terminal fragment of human parathyroid hormone receptor 1 constitutes a hormone binding domain and reveals a distinct disulfide pattern.

The N-terminal extracellular parts of human G-protein coupled receptor class B, for example, receptors for secretin, glucagon, or parathyroid hormone, are involved in ligand binding. To obtain structural and functional information on the N-terminal receptor fragment of human parathyroid hormone receptor 1 (PTHR1), the truncated receptor was expressed in the cytosol of Escherichia coli in the form of inclusion bodies. Oxidative refolding of inclusion body material resulted in stable, soluble, monomeric protein. Ligand binding was proved by surface plasmon resonance spectroscopy and isothermal titration calorimetry. Refolded receptor fragment was able to bind parathyroid hormone with an apparent dissociation constant of 3-5 microM. Far-UV circular dichroism spectra showed that the refolded polypeptide contained approximately 25% alpha-helical and 23% beta-sheet secondary structures. Analysis of the disulfide bond pattern of the refolded receptor fragment revealed disulfide bonds between Cys170 and Cys131, Cys148 and Cys108, and Cys117 and Cys48. These results demonstrate that the extracellular N-terminal domain of the parathyroid hormone receptor (PTHR1) possesses a well-defined, stable conformation, which shows a significant ligand binding activity.

Amino Acid Sequence↗
PubMed1988

Raised plasma intact parathyroid hormone concentrations in young people with mildly raised blood pressure.

To study the role of parathyroid gland activity in early primary hypertension plasma concentrations of intact parathyroid hormone were measured in 90 untreated young subjects, aged 16-29, with stable midly raised blood pressure and in 40 normotensive control subjects selected from the same population in Zoetermeer, The Netherlands. Intact parathyroid hormone concentration was significantly higher in the hypertensive than the normotensive group (2.34 (SE 0.11) pmol/l v 1.47 (0.13) pmol/l, respectively; difference 0.87 pmol/l; 95% confidence interval 0.55 to 1.21; p less than 0.0001). Serum total calcium concentration was 2.36 (0.01) mmol/l in the hypertensive group and 2.42 (0.01) mmol/l in the normotensive group (difference 0.06 mmol/l; 95% confidence interval 0.02 to 0.09; p = 0.02). Urinary calcium excretion over 24 hours did not differ significantly between the two groups (4.17 (0.28) mmol/24 h in the hypertensive group and 3.89 (0.39) mmol/24 h in the normotensive group; difference 0.28 mmol/24 h; 95% confidence interval -0.66 to 1.22). In the hypertensive group both systolic and diastolic blood pressures increased slightly though significantly with intact parathyroid hormone concentrations. No obvious associations between serum calcium concentration and blood pressure were observed. These findings support the view that enhanced activity of the parathyroid gland may play a part in the early stage of primary hypertension.

Adolescent↗
PubMed1987

Covalent labeling of a high-affinity, guanyl nucleotide sensitive parathyroid hormone receptor in canine renal cortex.

Putative parathyroid hormone (PTH) receptors in canine renal membranes were affinity labeled with 125I-bPTH(1-34) using the heterobifunctional cross-linking reagent N-hydroxysuccinimidyl 4-azidobenzoate. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed the presence of a major 85,000 molecular weight (Mr) PTH binding component, the labeling of which was inhibited by nanomolar concentrations of unlabeled PTH and by micromolar concentrations of 5'-guanylyl imidodiphosphate [Gpp-(NH)p]. Labeling was not influenced by the unrelated peptides insulin and arginine vasopressin. Minor PTH binding components of Mr 55,000 and 130,000 were also seen, and labeling of these was likewise sensitive to unlabeled PTH and to Gpp(NH)p. Omission of protease inhibitors during the isolation of plasma membranes resulted in the loss of the Mr 85,000 PTH binding species and the appearance of an Mr 70,000 form. Several minor PTH binding components also were observed. Equilibrium binding studies showed that such membranes had an affinity for PTH indistinguishable from that in membranes isolated with protease inhibitors and displaying a major Mr 85,000 PTH binding species. We conclude that the major form of the adenylate cyclase coupled PTH receptor in canine renal membranes is an Mr 85,000 protein. An endogenous enzyme, probably a lysosomal cathepsin, can cleave this form to produce an Mr 70,000 receptor that retains full functional activity with respect to high-affinity, guanyl nucleotide sensitive PTH binding. The ability to covalently label the PTH receptor in high yield represents a major step toward the structural characterization of this important detector molecule.

Animals↗
PubMedDate not supplied

Mithramycin effects on calcium, phosphorus and parathyroid hormone in osseous Paget's disease.

Six patients with symptomatic osseous Paget's disease were treated with a four-day course of mithramycin (25 mug/kg/day). The effects of treatment on the plasma calcium, phosphorus, parathyroid hormone, and the urinary fractional clearance of calcium and phosphorus were studied. Mithramycin produced significant hypocalcemia and hypophosphatemia, and also significantly and simultaneously increased the plasma parathyroid hormone concentration. Despite the increase in parathyroid hormone, the hypocalemia persisted because of the probable blocking effect which mithramycin exerted on the osteoclasts. The physiological response of the kidney to the elevated plasma parathyroid hormone appeared to be well preserved, as evidenced by the decreased fractional excretion of calcium and the increased fractional excretion of phosphorus in the urine; however, the fall in the clearance of calcium could be the result of the decreased filtered load.

Aged↗
PubMed1987

The biological properties of bovine parathyroid hormone (1-41), a fragment generated from the native hormone by human leukocytes.

Native bovine parathyroid hormone (bPTH) was found to be readily cleaved with human leukocyte elastase to yield the fragments bPTH(1-41) and bPTH(42-84). These were then isolated by reverse-phase HPLC and characterised by gas-phase sequencing and amino acid analysis. The biological activities of these fragments were assessed in an adenylate cyclase bioassay using the rat osteosarcoma cell line UMR106. bPTH(1-41) was found to have approximately twice the molar potency of the native hormone from which it was derived. bPTH(42-84) had no biological activity and did not modulate the adenylate cyclase response to these cells to the native hormone. The possible physiological significance of these observations is discussed.

Adenylyl Cyclases↗