Parathyroid carcinoma: location of pelvic metastases by parathyroid hormone assay

A metastasis from a functioning parathyroid carcinoma was located by PTH radioimmunoassay and selective venous catheterization. The site of the metastasis, verified at autopsy, was in the right side of the pelvis. This is the most distant reported location for metastatic parathyroid carcinoma. The patient''s plasma immunoreactive PTH rose more than twofold in response to induced hypocalcemia. This suggests that relative hypocalcemia, induced therapeutically in such patients, may result in a higher chronic level of PTH secretion.     

Parathyroid hormone in sodium-dependent hypertension

Plasma parathyroid hormone (pPTH) levels have been assessed in three separate radioimmunoassay systems in samples from Wistar-Kyoto rats. The animals were subjected to one of three dietary regimens throughout the study period: Group 1 animals consumed normal rat chow and drank tap water; Group 2 animals consumed normal rat chow and tap water was replaced with 0.5% saline solution; Group 3 animals consumed normal rat chow to which 2.5% CaCO3 (by weight) had been added and also drank 0.5% saline solution. Animals had consumed these diets for approximately 7 months prior to sacrifice for blood collection. Blood pressure was measured by tail cuff plethysmography in these animals and, as previously reported, saline consuming animals showed a moderate hypertension (Gp 2) only when diets did not contain added calcium (Gp 3). In the week prior to sacrifice, mean blood pressures were: Gp 1: 128.0 +/- 3.46 mmHg; Gp 2: 140.2 +/- 3.15 mmHg; and Gp 3: 133.5 +/- 2.90 mmHg. Three assay systems were used to measure pPTH levels from trunk blood samples obtained by guillotine decapitation. One assay used an antiserum directed toward the vasoactive N terminal fragment 1-34 and produced pPTH measurements of 0.74 +/- 0.05 ng/ml in Gp 1 animals, 1.04 +/- 0.07 ng/ml in Gp 2 animals and 1.12 +/- 0.08 ng/ml in Gp 3 animals. This pattern was consistent with that obtained by another antiserum which had been raised against the intact 1-84 PTH molecule and produced values of 0.25 +/- 0.03 ng/ml in Gp 1 animals, 0.55 +/- 0.07 ng/ml in Gp 2 animals and 0.74 +/- 0.04 ng/ml in Gp 3 animals. Antiserum raised against the C-terminal did not show any difference in pPTH across groups. We conclude that saline consumption may increase some portions of circulating PTH. Such elevation of pPTH may not be a pathophysiological component in the sodium dependent elevation of blood pressure since animals concurrently consuming both saline and calcium supplemented diets retained elevated pPTH levels even though blood pressures did not differ from controls. Rather, elevation of circulating PTH levels may be a response to prolonged increases in sodium consumption.     

Parathyroid hormone in urinary stone patients

To evaluate the role of parathyroids in calculus disease, the parathyroid hormone levels were determined in 22 control subjects and 42 stone (14 with bladder stone and 28 with kidney stone) patients. Serum calcium, inorganic phosphate, alkaline phosphatase and parathyroid hormone and urinary excretion of calcium and inorganic phosphate were determined. It was found that normocalcemic and normocalciuric stone patients had slightly higher levelsss of parathyroid hormone (irrespective of the site of the stone) and the difference was not statistically significant as compared with control subjects although some of the patients with calculus disease were hyperparathyroid. Serum alkaline phosphatase was increased while there was an increase in urinary calcium excretion in kidney stone patients and oxalate in all patients as compared with control subjects. The increase in inorganic phosphate was, however, not different from the control subjects. The subclinical hyperparathyroidism and stone formation in these patients are not correlated.     

Parathyroid hormone binding sites in the brain

Parathyroid hormone (PTH) has been shown to have actions within the brain, suggesting the presence of central PTH receptors. This possibility was examined by determining the binding of ¹²⁵I-labeled [Nle^8,18,Tyr³⁴]bovine PTH to the plasma membranes of rat and rabbit brains. Specific binding of the tracer to membranes of the whole brain was time and tissue dependent, and was greater with membranes from the hypothalamus than with membranes from the cerebellum, cerebrum, or brain stem. The binding of the tracer to rat hypothalamic membranes was saturable and competitively displaced by unlabeled PTH(1–34), PTH(3–34), [Nle^8,18,Tyr³⁴]PTH(1–34), and by PTH-related protein, indicating the presence of a single class of high-affinity (dissociation constant = 2–5 nM), low-capacity (maximum binding capacity, B_max = 110–250 fmol/mg protein) binding site. The binding of radiolabeled PTH to these sites was not displaced by unrelated peptides of comparable molecular size (calcitonin, calcitonin-gene related peptide, adrenocorticotropin). The binding of PTH to these sites did not, however, appear to stimulate adenylate cyclase activity, as in peripheral PTH target sites. Thus, although these results indicate the presence of PTH receptors in the brain, these binding sites have a lower affinity than those in peripheral tissues and may utilize a different signal transduction system.     

Parathyroid hormone receptors in circulating human mononuclear leukocytes

In this article we demonstrate receptors for parathyroid hormone in circulating mononuclear leukocytes using the radioiodinated analogue (8,18 norleucine, 34 tyrosine) bPTH 1-34 (bovine parathyroid hormone 1-34). Specific binding, which is reversible and saturable, equilibrates within 5 min at 0-4 degrees C with a calculated KD of 8.9 X 10(-11) M. This binding has a pH maximum of 7.0, is magnesium-dependent, and is inversely related to medium calcium concentration. Such binding is completely inhibited by simultaneous addition of 4 ng/ml of bovine parathyroid hormone 1-34, 5 ng/ml of bovine parathyroid hormone 1-84, or 5 ng/ml (8,18 norleucine, 34 Tyr) of 3-34 bPTH, but is unaffected by a biologically inactive parathyroid hormone fragment or other unrelated peptide hormones. Cyclic AMP accumulation increases 3-fold after 5 min exposure of mononuclear leukocytes to bPTH 1-34 in concentrations as low as 1 X 10(-9) M. Lymphocytes appear to be the circulating cells which interact with PTH as indicated by the observations that: 1) lymphocyte-enriched preparations bind three times as much radioligand/cell as do mixed mononuclear leukocytes, 2) monocytes, platelets, granulocytes, and erythrocytes do not bind PTH, and 3) monocytes, but not lymphocytes, degrade the hormone.     

Parathyroid hormone gene with bone phenotypes in Chinese

Osteoporosis is a common disorder afflicting old people. The parathyroid hormone (PTH) gene is involved in bone remodeling and calcium homeostasis, and has been considered as an important candidate gene for osteoporosis. In this study, we simultaneously tested linkage and/or association of PTH gene with bone mineral density (BMD) and bone mineral content (BMC), two important risk factors for osteoporosis. A sample of 1263 subjects from 402 Chinese nuclear families was used. The families are composed of both parents and at least one healthy daughter aged from 20 to 45 years. All the subjects were genotyped at the polymorphic BstBI site inside the intron 2 of the PTH gene (a nucleotide substitution of G to A at the position +3244). BMD and BMC were measured at the lumbar spine and the hip region via dual-energy X-ray absorptiometry (DXA). Using QTDT (quantitative trait transmission disequilibrium test), we did not find significant results for association or linkage between the PTH gene and BMD or BMC variation at the spine or hip. Our data do not support the PTH gene as a quantitative trait locus (QTL) underlying the bone phenotypic variation in the Chinese population.     

Parathyroid hormone binding to cultured avian osteoclasts.

Parathyroid hormone (PTH) increases serum calcium concentration via a controversial cellular mechanism. We investigated whether PTH binds avian osteoclasts. Isolated hypocalcaemic hen osteoclasts were incubated with [125I]--bovine PTH (1-84). Specific binding of the hormone to the cells, which reached the equilibrium within 60 min, was observed. Half maximal binding was reached by 10 min. Binding was competitively inhibited by increasing doses of unlabeled PTH, and was about 55% displaced by adding, at the equilibrium, 10(-6) M unlabeled PTH. Autoradiography demonstrated specific label on the osteoclast. The cellular mechanism activated by the hormone remains to be elucidated.     

Parathyroid hormone stimulates adenylate cyclase in rat cerebral microvessels

We have studied the effect of parathyroid hormone (PTH) on adenylate cyclase of microvessels isolated from rat cerebral cortex. Native bovine (b) PTH-(1–84), the synthetic amino-terminal fragment bPTH-(1–34) and the synthetic analog [Nle⁸, Nle¹⁸, Tyr³⁴]-bPTH- (1–34) amide stimulated adenylate cyclase in a dose-dependent manner with apparent ED₅₀ values of 16 nM, 6.3 nM and 15 nM respectively. The stimulation by bPTH was greatly enhanced by guanosine triphosphate. The PTH antagonist, [Nle⁸, Nle¹⁸, Tyr³⁴]-bPTH-(3–34) amide inhibited the action of bPTH-(1–84) and bPTH-(1–34). In summary, PTH stimulated adenylate cyclase in rat cerebral microvessels in a very similar manner to its stimulation in the renal cortex.     

Parathyroid hormone mediates hematopoietic cell expansion through interleukin-6

Parathyroid hormone (PTH) stimulates hematopoietic cells through mechanisms of action that remain elusive. Interleukin-6 (IL-6) is upregulated by PTH and stimulates hematopoiesis. The purpose of this investigation was to identify actions of PTH and IL-6 in hematopoietic cell expansion. Bone marrow cultures from C57B6 mice were treated with fms-like tyrosine kinase-3 ligand (Flt-3L), PTH, Flt-3L plus PTH, or vehicle control. Flt-3L alone increased adherent and non-adherent cells. PTH did not directly impact hematopoietic or osteoclastic cells but acted in concert with Flt-3L to further increase cell numbers. Flt-3L alone stimulated proliferation, while PTH combined with Flt-3L decreased apoptosis. Flt-3L increased blasts early in culture, and later increased CD45(+) and CD11b(+) cells. In parallel experiments, IL-6 acted additively with Flt-3L to increase cell numbers and IL-6-deficient bone marrow cultures (compared to wildtype controls) but failed to amplify in response to Flt-3L and PTH, suggesting that IL-6 mediated the PTH effect. In vivo, PTH increased Lin(-) Sca-1(+)c-Kit(+) (LSK) hematopoietic progenitor cells after PTH treatment in wildtype mice, but failed to increase LSKs in IL-6-deficient mice. In conclusion, PTH acts with Flt-3L to maintain hematopoietic cells by limiting apoptosis. IL-6 is a critical mediator of bone marrow cell expansion and is responsible for PTH actions in hematopoietic cell expansion.     

Parathyroid hormone temporal effects on bone formation and resorption

Parathyroid hormone (PTH) paradoxically causes net bone loss (resorption) when administered in a continuous fashion, and net bone formation (deposition) when administered intermittently. Currently no pharmacological formulations are available to promote bone formation, as needed for the treatment of osteoporosis. The paradoxical behavior of PTH confuses endocrinologists, thus, a model bone resorption or deposition dependent on the timing of PTH administration would de-mystify this behavior and provide the basis for logical drug formulation. We developed a mathematical model that accounts for net bone loss with continuous PTH administration and net bone formation with intermittent PTH administration, based on the differential effects of PTH on the osteoblastic and osteoclastic populations of cells. Bone, being a major reservoir of body calcium, is under the hormonal control of PTH. The overall effect of PTH is to raise plasma levels of calcium, partly through bone resorption. Osteoclasts resorb bone and liberate calcium, but they lack receptors for PTH. The preosteoblastic precursors and preosteoblasts possess receptors for PTH, upon which the hormone induces differentiation from the precursor to preosteoblast and from the preosteoblast to the osteoblast. The osteoblasts generate IL-6; IL-6 stimulates preosteoclasts to differentiate into osteoclasts. We developed a mathematical model for the differentiation of osteoblastic and osteoclastic populations in bone, using a delay time of 1 hour for differentiation of preosteoblastic precursors into preosteoblasts and 2 hours for the differentiation of preosteoblasts into osteoblasts. The ratio of the number of osteoblasts to osteoclasts indicates the net effect of PTH on bone resorption and deposition; the timing of events producing the maximum ratio would induce net bone deposition. When PTH is pulsed with a frequency of every hour, the preosteoblastic population rises and decreases in nearly a symmetric pattern, with 3.9 peaks every 24 hours, and 4.0 peaks every 24 hours when PTH is administered every 6 hours. Thus, the preosteoblast and osteoblast frequency depends more on the nearly constant value of the PTH, rather than on the frequency of the PTH pulsations. Increasing the time delay gradually increases the mean value for the number of osteoblasts. The osteoblastic population oscillates for all intermittent administrations of PTH and even when the PTH infusion is constant. The maximum ratio of osteoblasts to osteoclasts occurs when PTH is administered in pulses of every 6 hours. The delay features in the model bear most of the responsibility for the occurrence of these oscillations, because without the delay and in the presence of constant PTH infusions, no oscillations occur. However, with a delay, under constant PTH infusions, the model generates oscillations. The osteoblast oscillations express limit cycle behavior. Phase plane analysis show simple and complex attractors. Subsequent to a disturbance in the number of osteoblasts, the osteoblasts quickly regain their oscillatory behavior and cycle back to the original attractor, typical of limit cycle behavior. Further, because the model was constructed with dissipative and nonlinear features, one would expect ensuing oscillations to show limit cycle behavior. The results from our model, increased bone deposition with intermittent PTH administration and increased bone resorption with constant PTH administration, conforms with experimental observations and with an accepted explanation for osteoporosis.