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PubMed1991

Parathyroid hormone fragment 1-34 inhibits drug-induced inflammation in various experimental models.

We investigated the effect of the administration of rat parathyroid hormone-(1-34) on acute or chronic inflammatory processes in different experimental animal models. Fragment 1-34 of parathyroid hormone had an inhibitory effect in all inflammatory acute tests. The dose-response experiments showed that the maximal anti-inflammatory and anti-exudative effects appeared at the dose of 3.30 and 0.33 micrograms/kg, respectively. The anti-inflammatory effect was observed in the first phase of the inflammatory process. In the carrageenin-induced edema test the anti-inflammatory activity began to decline after 180 min. In contrast, this peptide was inactive in the inflammatory chronic test we used.

Acetates↗

PubMed1982

Model for parathyroid hormone secretion and metabolism in calves.

A model for parathyroid gland response to differing calcium and magnesium concentrations is proposed based on direct determinations of parathyroid hormone (PTH) secretion rate. A proportional control seems adequate for physiological variations of calcium and magnesium levels. At extreme hypocalcemia, nonlinearities are observed: a model involving the depletion of a storage compartment is proposed, the size of which is calculated. PTH distribution was studied in another group of animals; sampling was made from the saphenous artery and the thoracic duct. Concentrations of plasma and lymph-intact PTH and carboxy-terminal fragments were determined by means of two different radioimmunoassays. The analysis of the results leads to the formulation of a five-compartment model, which shows that the metabolism of intact PTH is only partly due to the formation of carboxy-terminal fragments, most being directly secreted or catabolized. Linking these models for secretion and distribution of PTH, simulation studies were undertaken and compared with published data. This model is then discussed in comparison with previous work concerning other polypeptide hormones.

Animals↗

PubMed1993

NMR solution structure of human parathyroid hormone(1-34).

The aqueous solution structure of the biologically-active N-terminal domain of human parathyroid hormone (residues 1-34) was studied by two-dimensional proton nuclear magnetic resonance (2D NMR) spectroscopy, distance geometry, and dynamic simulated annealing. Unambiguous NMR assignments of all backbone and side chain hydrogens were made with the aid of totally correlated spectroscopy experiments, which provided through-bond 1H-1H connectivities, and nuclear Overhauser effect spectroscopy, which provided through-space and sequential backbone connectivities. The NMR data acquired were utilized in a distance geometry algorithm to generate a family of structures which were then refined using dynamic simulated annealing. The major structural feature evident is alpha-helix extending from residues Glu4 to Lys13 and from Val21 to Gln29 with a turn incorporating Asn16-Glu19 resulting in a quite globular C-terminal domain with a hydrophobic core comprising Leu15, Leu18, Trp23, and Val31. Structure-activity studies are interpreted in terms of the deduced conformation of the PTH structure with particular reference to the likely PTH receptor binding site formed primarily by the bulk of the C-terminal helix.

Amino Acid Sequence↗

PubMed2004

Parathyroid hormone: a double-edged sword for bone metabolism.

Parathyroid hormone (PTH) is the major hormone regulating calcium metabolism. It is also the only FDA-approved drug for osteoporosis treatment that stimulates bone formation when injected daily. However, continuous infusion of PTH causes severe bone loss in line with its known catabolic effects. Many studies to understand the dual effects of PTH have been carried out, and in recent years a growing number of molecular and cellular mechanisms underlying these effects have emerged. Here, we outline the present knowledge and conclude that the kinetics of administration and subsequent signaling probably account for the divergent actions of the hormone.

Bone Density↗

PubMed1975

The effect of chronic ammonium chloride ingestion on parathyroid hormone function.

The purpose of this study was to examine the effect of ammonium chloride ingestion on the hypercalcemic effect of parathyroid hormone in vivo. Thyroparathyroidectomized rats were given 1.5% ammonium chloride for 5-6 days. Ingestion of ammonium chloride increased serum calcium, but also significantly enhanced the calcium elevating effect of injected parathyroid extract. This result is compatible with a proposed hypothesis that the calcium mobilizing function of the parathyroid hormone may be enhanced by the hormone's own influence on systemic hydrogen ion concentration.

Administration, Oral↗

PubMed2005

Bioactive N-terminal undecapeptides derived from parathyroid hormone: the role of alpha-helicity.

The N-terminal 1-34 segment of parathyroid hormone (PTH) is fully active in vitro and in vivo and it can reproduce all biological responses in bone characteristic of the native intact PTH. Recent studies have demonstrated that N-terminal fragments presenting the principal activating domain such as PTH(1-11) and PTH(1-14) with helicity-enhancing substitutions yield potent analogues with PTH(1-34)-like activity. To further investigate the role of alpha-helicity on biological potency, we designed and synthesized by solid-phase methodology the following hPTH(1-11) analogues substituted at positions 1 and/or 3 by the sterically hindered and helix-promoting C(alpha)-tetrasubstituted alpha-amino acids alpha-amino isobutyric acid (Aib), 1-aminocyclopentane-1-carboxylic acid (Ac(5)c) and 1-aminocyclohexane-1-carboxylic acid (Ac(6)c): Ac(5)c-V-Aib-E-I-Q-L-M-H-Q-R-NH(2) (I); Aib-V-Ac(5)c-E-I-Q-L-M-H-Q-R-NH(2) (II); Ac(6)c-V-Aib-E-I-Q-L-M-H-Q-R-NH(2) (III); Aib-V-Ac(6)c-E-I-Q-L-M-H-Q-R-NH(2) (IV); Aib-V-Aib-E-I-Q-L-M-H-Q-R-NH(2) (V); S-V-Aib-E-I-Q-L-M-H-Q-R-NH(2) (VI), S-V-Ac(5)c-E-I-Q-L-M-H-Q-R-NH(2) (VII); Ac(5)c-V-S-E-I-Q-L-M-H-Q-R-NH(2) (VIII); Ac(6)c-V-S-E-I-Q-L-M-H-Q-R-NH(2) (IX); Ac(5)c-V-Ac(5)c-E-I-Q-L-M-H-Q-R-NH(2) (X); Ac(6)c-V-Ac(6)c-E-I-Q-L-M-H-Q-R-NH(2) (XI). All analogues were biologically evaluated and conformationally characterized in 2,2,2-trifluoroethanol (TFE) solution by circular dichroism (CD). Analogues I-V, which cover the full range of biological activity observed in the present study, were further conformationally characterized in detail by nuclear magnetic resonance (NMR) and computer simulations studies. The results of ligand-stimulated cAMP accumulation experiments indicated that analogues I and II are active, analogues III, VI and VII are very weakly active and analogues IV, V, VIII-XI are inactive. The most potent analogue, I exhibits biological activity 3500-fold higher than that of the native PTH(1-11) and only 15-fold weaker than that of the native sequence hPTH(1-34). Remarkably, the two most potent analogues, I and II, and the very weakly active analogues, VI and VII, exhibit similar helix contents. These results indicate that the presence of a stable N-terminal helical sequence is an important but not sufficient condition for biological activity.

Amino Acid Sequence↗

PubMed1984

Parathyroid hormone does not inhibit platelet aggregation.

The suggestion that parathyroid hormone (PTH) is a major uraemic toxin was examined by testing the effects of synthetic human PTH fragments and synthetic bovine PTH on ADP-induced and collagen-induced platelet aggregation. Whereas the bovine parathyroid-gland extracts inhibited platelet aggregation in a dose-dependent manner, none of the synthetic compounds was effective even at high concentrations. It is suggested that the inhibition of platelet aggregation by extracts of bovine parathyroid glands is not caused by PTH fragments and is probably an effect of other constituents contained in the extract. These findings argue against a role of PTH in the pathogenesis of platelet dysfunction and bleeding tendency in uraemia and were supported by platelet-aggregation studies in 6 patients with primary hyperparathyroidism. Platelet aggregation was normal before and unchanged after surgery of the parathyroid glands.

Adenosine Diphosphate↗

PubMed1992

Estimated weight of the residual parathyroid gland after parathyroidectomy using plasma levels of the parathyroid hormone.

The possibility of estimating the total weight of the parathyroid glands based on the plasma concentration of the parathyroid hormone (PTH) would be of great help when searching for the parathyroid glands during surgery on patients with secondary hyperparathyroidism. Thus, we studied the relationship between the levels of carboxyl-terminal PTH (C-PTH), midportion PTH (M-PTH) and intact PTH, and the weight of the parathyroid glands resected for secondary hyperparathyroidism. The subjects studied were 11 patients with secondary hyperparathyroidism caused by chronic renal failure. The pre- and post-operative differences in the plasma C-PTH levels and plasma M-PTH levels were significantly correlated with the weight of the resected parathyroid glands (p less than 0.001 for both), but there was no correlation between the differences in the levels of intact PTH and the weight of the resected parathyroid glands. From these relationships we estimated the weight of the residual parathyroid gland after parathyroidectomy using the levels of each PTH. All patients in whom the residual parathyroid gland was estimated to be heavy based on the levels of M-PTH showed recurrence of hyperparathyroidism after the parathyroidectomy. We therefore found that estimation of the weight of the parathyroid glands from the levels of M-PTH is both possible and useful.

Adult↗

PubMed1982

Regulation of parathyroid hormone secretion in vitro by divalent cations and cellular metabolism.

Parathyroid hormone (PTH) secretion was investigated in intact cells isolated in vitro. Parathyroid cells from bovine parathyroid glands were obtained through tissue dispersion and cell purification through isotonic Percoll gradients, a newly developed protocol enhancing cell homogeneity and viability. Isolated cells maintained both metabolic viability and plasma membrane intactness for over 3 h at 37 degrees C, as shown by the large ATP/ADP ratios and the high intracellular K+ content (ouabain-sensitive) measured. The rate of PTH secretion was inversely related to the Ca2+ concentrations in the medium; secretion was 54 and 18 ng PTH/mg of protein/min when free Ca2+ in the buffer was 0.8 and 2 mM, respectively. At either Ca2+ concentration, PTH secretion was strongly dependent on cell metabolism; it was inhibited by 80-85% within 10 min when cells were suspended in glucose-free buffer containing either cyanide or oxidative phosphorylation uncoupler. Under these conditions, both cellular ATP production and calcium-dependent PTH release could be partially restored by addition of 5 mM glucose. La3+, Mn2+, Sr2+, Ba2+, and Mg2+ were each tested in a range of 0.5-2.5 mM for their effects in suppressing low calcium-stimulated secretion. La3+ and Mn2+ were about twice as effective as Ca2+ on a molar basis, Sr2+ was similar to Ca2+, Mg2+ was about half as effective, and Ba2+ had almost no effect. These results suggest that the Ca2+-dependent stimulus-secretion coupling of these cells is largely different from that established in other secretory cells and provide an in vitro system to further investigate the regulation of PTH secretion.

Adenosine Diphosphate↗

PubMed2001

[Effect of sequential application of calcitonin and parathyroid hormone on bone remodeling process, an experimental research].

OBJECTIVE: To investigate the effect of sequential application of calcitonin and parathyroid hormone (PTH) on bone remodeling process. METHODS: Twelve female rats were divided equally into 2 groups: experimental group and control group. 1 U/100 g of calcitonin was injected intramuscularly to 6 rats for two days, and rrPTH in dosage of 30 micrograms was injected intramuscularly in the fourth and fifth days. At the sixth day their lumbar vertebral bodies were resected. Undecalcified and decalcified bone sections were made to be observed by optical microscopy and electronic microscopy. Bone histomorphological parameters were measured. Normal saline and solvent of the same volume were injected intramuscularly to the controls. RESULTS: The OS/BS (%), O. Th (micron), N.Ob.S (cell/mm), and Vos/TV (%) were 19.9% +/- 6.2%, 3.4 microns +/- 0.4 micron, 37.6 cells/mm +/- 4.6 cells/mm, and 1.8% +/- 0.6% respectively in the experimental group, significantly higher than those in the control group (P < 0.05). After the PTH administration, more and plumper osteoblasts were observed. They were rich in rough endoplasmic reticulum, mitochondria, and Golgi apparatus. CONCLUSION: Sequential application of calcitonin and parathyroid hormone obviously promotes the bone formation process. Both sites of bone remodeling formation and sites of bone modeling formation, especially the latter, increase.

Animals↗

PubMed2001

A comparison of the anabolic effects of rat and bovine parathyroid hormone (1-34) in ovariectomized rats.

The current study was designed to compare the skeletal effects of comparable doses of rat parathyroid hormone 1-34 (rPTH) and bovine parathyroid hormone 1-34 (bPTH) in ovariectomized (OVX) rats. Female Sprague-Dawley rats were OVX or sham-operated at 6 months of age and maintained untreated for 28 days after surgery. Baseline control and OVX rats were sacrificed at the beginning of treatment. Beginning 28 days post-OVX, the remaining rats were subcutaneously injected daily with rPTH or bPTH at 0, 5, 25, or 50 microg/kg/d for 28 days. Bone area, bone mineral content (BMC), and bone mineral density (BMD) of the distal femoral metaphyses were determined ex vivo using dual energy X-ray absorptiometry. Quantitative bone histomorphometry was performed on undecalcified longitudinal sections of the proximal tibia from each rat. Baseline OVX rats exhibited osteopenia as demonstrated by their significantly reduced femoral BMD and proximal tibia cancellous bone volume compared with those of baseline sham controls. Both rPTH and bPTH restored bone in OVX rats by markedly stimulating bone formation in a dose-dependent manner. However, a difference in potency between the two forms of PTH was evident. The percentage increases of BMC, BMD, cancellous bone volume, trabecular thickness, mineralizing surface, and bone formation rate in the OVX rats treated with bPTH at 5 microg/kg/d were the same as or above those treated with rPTH at the 25 microg/kg/d dose level. A relative potency analysis showed that bPTH was approximately 4- to 6-fold relatively more potent than rPTH in increasing distal femoral BMD as well as cancellous bone volume, mineralizing surface, and bone formation rate of proximal tibial metaphyses at comparable dose levels and a given time. These results may serve as a reference for in vivo study design when rPTH or bPTH are to be the agents for studies on bone anabolism.

Journal Article↗

PubMed2001

Therapy of male osteoporosis with parathyroid hormone.

Definable causes of male osteoporosis account for only about 60% of the osteoporotic population. Those for whom no etiology is readily apparent are said to have primary or idiopathic male osteoporosis. In these individuals, histomorphometric studies indicate that this is a disorder that is more typically characterized by low turnover. Although antiresorptive agents such as alendronate have been shown to increase bone mass in men, the rationale for an anabolic agent that can stimulate bone formation is clear. The most attractive anabolic agent at this time is parathyroid hormone (PTH) administered in low dosage and intermittently. Such regimens in experimental animals have been associated with marked gains in bone mass. Slovik et al. showed that parathyroid hormone can increase vertebral bone mass in men with idiopathic osteoporosis. We have conducted the first controlled, randomized, double-blind study of PTH in men with idiopathic osteoporosis. Twenty-three men, 30-68 years old (50 +/- 1.9) with Z-scores less than -2.0 were assigned to a placebo (n = 13) or treatment (n = 10) arm. After 18 months, those who received PTH showed a 13.5 +/- 3% increase in bone mass, significantly greater than the placebo group whose bone density did not change. Femoral neck bone density increased significantly by 2.9 +/- 1.5%. The distal radius site did not change. During an open label extension for an additional 12 months, there was no further increase in bone density in the lumbar spine but the femoral neck continued to show gains. Markers of bone formation and resorption increased in the PTH arm reaching a peak between 9 and 12 months of therapy and declining thereafter. Parathyroid hormone was well tolerated. These results suggest that low-dose intermittent PTH may be an efficacious therapy for men with idiopathic osteoporosis.

Adult↗

PubMed1992

Bisphosphonate kinetics in patients undergoing continuous ambulatory peritoneal dialysis: relations to dynamic bone histomorphometry, osteocalcin and parathyroid hormone.

In the evaluation of renal osteodystrophy bone biopsy is often performed. However, a reliable noninvasive test could be very useful, and recently the estimation of osseous tracer uptake as an index of bone formation has been introduced-the bone bisphosphonate clearance (BBC). The aim of the present investigation therefore was to compare BBC with parameters of bone histology, serum levels of osteocalcin, alkaline phosphatase, and parathyroid hormone in patients (n = 8) undergoing continuous ambulatory peritoneal dialysis (CAPD). No significant correlations were found between BBC values and the bone histomorphometrical variables measured. A positive correlation was seen between serum osteocalcin and resorption and active resorption surface (p < 0.05), as well as tetracycline-labelled surface, bone formation rate, surfaces, volume and tissue referents, respectively (p < 0.01). Furthermore, levels of alkaline phosphatase showed significant correlations to mineral appositional rate, tetracycline-labelled surface and bone formation rate, volume referent (p < 0.05). Values of parathyroid hormone were significantly correlated to resorption surface (p < 0.02), active resorption surface, mineral appositional rate and mineralization lag time (p < 0.05). In conclusion, BBC was of no use in patients treated with CAPD as a noninvasive test for evaluation of bone histomorphometry. However, osteocalcin correlated best with resorption and bone dynamics indices. Levels of alkaline phosphatase and parathyroid hormone were of a more limited value.

Adult↗

PubMed2000

Crystal structure of human parathyroid hormone 1-34 at 0.9-A resolution.

The N-terminal fragment 1-34 of parathyroid hormone (PTH), administered intermittently, results in increased bone formation in patients with osteoporosis. PTH and a related molecule, parathyroid hormone-related peptide (PTHrP), act on cells via a common PTH/PTHrP receptor. To define more precisely the ligand-receptor interactions, we have crystallized human PTH (hPTH)-(1-34) and determined the structure to 0.9-A resolution. hPTH-(1-34) crystallizes as a slightly bent, long helical dimer. Analysis reveals that the extended helical conformation of hPTH-(1-34) is the likely bioactive conformation. We have developed molecular models for the interaction of hPTH-(1-34) and hPTHrP-(1-34) with the PTH/PTHrP receptor. A receptor binding pocket for the N terminus of hPTH-(1-34) and a hydrophobic interface with the receptor for the C terminus of hPTH-(1-34) are proposed.

Amino Acid Sequence↗

PubMed1994

E-cadherins identified in osteoblastic cells: effects of parathyroid hormone and extracellular calcium on localization.

The presence and regulation of cadherin localization in osteoblastic cells were examined. Monoclonal antibody (ECCD-1) that interferes with E-cadherin function prevented cell adhesion in UMR 106-H5 rat osteosarcoma cells and non-tumorigenic mouse calvarial MC3T3-E1 cells, whereas CCL39 fibroblast adhesion was not affected. Immunofluorescent antibodies (ECCD-2 and polyclonal L-CAMP P1) revealed cadherins are localized along the osteoblastic cell-cell boundaries. Exposure of UMR 106-H5 cells to bovine parathyroid hormone (1-84) (PTH; 10 ng/ml x 1 hr) or low calcium medium (1.0-0.025 mM) produced cellular retraction accompanied by intense immunofluorescence for cadherins throughout cells with a corresponding loss of punctate localization at remaining cell-cell adhesion points. Western immunoblot analysis indicated 108 kd and 115 kd cadherins are present, with a smaller 29.5 kd band that became predominantly associated with the cytosolic fraction of cells treated with parathyroid hormone or lowered calcium. The results demonstrate E-like cadherins are present in osteoblastic cells and implicate a regulatory role for parathyroid hormone and calcium in cadherin function and localization.

3T3 Cells↗

PubMed1972

The interactions of thiazide diuretics with parathyroid hormone and vitamin D. Studies in patients with hypoparathyroidism.

In order to clarify the mechanisms of thiazide diuretic-induced hypocalciuria, the effect of a thiazide was studied for 7 days in seven patients with hypoparathyroidism on Vitamin D and one on calcium infusion, and seven euparathyroid patients with hypercalciuria. In the control group, calcium excretion (mg/24 hr) fell by 44% from 415 to 232 within 4 days and remained at this level. Plasma total calcium corrected for total protein did not change. In the hypoparathyroid group, calcium excretion fell by 11% from 351 to 311 and then returned to the base line level. Plasma total calcium (mg/100 ml) increased from 10.09 to 10.88, 11.29 and 10.77 at the end of the 2nd, 4th, and 7th day of thiazide administration. In the patient having i.v. calcium and no Vitamin D, neither plasma nor urinary calcium changed significantly. In both groups sodium excretion increased on the first 2 days and fell to or below base line level thereafter. Urinary phosphate, magnesium, and potassium increased, plasma phosphate rose, and magnesium and potassium fell. It is concluded that: (a) The hypocalciuric effect of thiazides requires the presence of parathyroid hormone and is not solely a result of sodium depletion. (b) The hypercalcemic effect of thiazides in hypoparathyroidism is due to increased release of calcium from bone and requires the presence of a pharmacologic dose of Vitamin D. (c) Thiazides enhane the action of parathyroid hormone on bone and kidney; Vitamin D can replace parathyroid hormone in this interaction in bone but not in kidney.

Adult↗

PubMed1995

Multiple calcium channel transcripts in rat osteosarcoma cells: selective activation of alpha 1D isoform by parathyroid hormone.

Osteoblasts express calcium channels that are thought to be involved in the transduction of extracellular signals regulating bone metabolism. The molecular identity of the pore-forming subunit (alpha 1) of L-type calcium channel(s) was determined in rat osteosarcoma UMR-106 cells, which express an osteoblast phenotype. A homology-based reverse transcriptase-polymerase chain reaction cloning strategy was employed that used primers spanning the fourth domain. Three types of cDNAs were isolated, corresponding to the alpha 1S (skeletal), alpha 1C (cardiac), and alpha 1D (neuroendocrine) isoforms. In the transmembrane segment IVS3 and the extracellular loop formed by the IVS3-S4 linker, a single pattern of mRNA splicing was found that occurs in all three types of calcium channel transcripts. Northern blot analysis revealed an 8.6-kb mRNA that hybridized to the alpha 1C probe and 4.8- and 11.7-kb mRNAs that hybridized to the alpha 1S and alpha 1D probes. Antisense oligonucleotides directed to the calcium channel alpha 1D transcript, but not those directed to alpha 1S or alpha 1C transcripts, inhibited the rise of intracellular calcium induced by parathyroid hormone. However, alpha 1D antisense oligonucleotides had no effect on the accumulation of cAMP induced by parathyroid hormone. When L-type calcium channels were activated with Bay K 8644, antisense oligonucleotides to each of the three isoforms partially inhibited the rise of intracellular calcium. The present results provide evidence for the expression of three distinct calcium channel alpha 1-subunit isoforms in an osteoblast-like cell line. We conclude that the alpha 1D isoform is selectively activated by parathyroid hormone.

Animals↗

PubMed1990

Parathyroid hormone and the vascular response to norepinephrine.

Norepinephrine blood pressure reactivity is reduced in uremia, an effect attributed to excess parathyroid hormone (PTH). Most, but not all, animal and human studies support the theory that high PTH levels diminish the pressor response to norepinephrine. In hemodialysis patients in whom norepinephrine infusion tests were performed to determine the effect of parathyroidectomy on vascular responsiveness, the vascular response to norepinephrine (100 ng/kg/min) improved significantly (11.3 +/- 1.3 mm Hg before and 17.5 +/- 2.4 mm Hg after parathyroidectomy; P less than .01). Excess parathyroid hormone appears to play an active role in reduced vascular responsiveness to norepinephrine, although the mechanisms of this effect are unknown.

Animals↗