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Introduction
Features of hyperparathyroidism have long been associated with malignancy, and with the advent of sufficiently sensitive bioassays, parathyroid hormone (PTH)-like activity was recognised in extracts of tumours from patients suffering from humoral hypercalcaemia of malignancy (HHM) (Stewart et al. 1983). While these extracts exhibited actions on bone and kidney that were very similar to those of PTH, low or undetectable levels of immunoreactive PTH in patients' plasma and in the tumour extracts indicated that the substance was unique (Stewart et al. 1980, Rodan et al. 1983, Stewart et al. 1983, Strewler et al. 1983). Subsequently, parathyroid hormone-related protein (PTHrP) was purified, sequenced and cloned from a human lung cancer cell line derived from a patient with HHM (Moseley et al. 1987, Suva et al. 1987).
This protein, homologous with PTH in the amino-terminal region, acts through a common PTH/PTHrP receptor (Jüppner et al. 1991) to promote bone
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ABSTRACT
Five synthetic analogues of human parathyroid hormone (hPTH), (Tyr34)hPTH(3–34) amide, (5–34) amide, (7–34) amide, (8–34) amide and (9–34) amide, were tested for their ability to antagonize hPTH action specifically in intact cultured cells. Clonal rat osteogenic sarcoma cells were used (UMR 106–06 line) which respond to PTH with an increase in cyclic AMP (cAMP) formation. The most potent antagonists were (Tyr34)hPTH(3–34) amide and (5–34) amide, which inhibited the effect of hPTH(2·4 nmol/l) with half maximally effective concentrations of 0·1 μmol/l. When conditioned medium was used from a human lung cancer cell line producing osteoblast adenylate cyclase-stimulating activity, these two analogues were capable of inhibiting the increase in cAMP production. The specificity of the antagonism was indicated by the inability of the analogues to influence the effects of prostaglandin E2 or of calcitonin, which are alternative stimulators of cAMP production in the osteogenic sarcoma cells. Only (Tyr34)hPTH(3–34) amide showed some PTH-like agonist activity at high concentrations. These analogues should prove valuable in the investigation of PTH actions on target cells and of tumour products which appear to act through the PTH receptor.
J. Endocr. (1986) 108, 261–265
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ABSTRACT
The isolated perfused rat kidney was used to study the effects of parathyroid hormone-related protein (PTHrP) on renal cyclic AMP (cAMP) and electrolyte excretion. A perfusate of PTHrP(1–34) increased cAMP excretion from 0·14 ± 0·09 (s.e.m.) nmol/l glomerular filtrate (GF) in controls to 24·67 ± 5·14 (P < 0·01) and decreased calcium excretion from 0·278 ± 0·033 to 0·162 ± 0·011 μmol/l GF (P < 0·01). Human PTH(1–34) (0·7 nmol/l) caused no significant change in calcium excretion, whilst the rise in cAMP excretion was similar to that with PTHrP. PTHrP(1–34) (7 nmol/l further increased cAMP production to 366·7 ± 100·8 nmol/l GF (P < 0·01), higher than the rise with hPTH(1–34) (7 nmol/l) which was 76·7 ± 46·8 (P < 0·05). With the higher concentrations of both peptides (7 nmol/l), calcium excretion was further reduced to 0·090 ± 0·009 μmol/l GF (P < 0·01), whilst phosphate excretion increased with both PTHrP and PTH. PTHrP (7 nmol/l) caused a fall in urinary pH compared with controls (P < 0·05). At low and high concentrations of both hormones, urinary pH was lower with PTHrP than hPTH (P < 0·01). Thus PTHrP, like PTH, acts on the kidney to increase cAMP and phosphate excretion and reduce calcium excretion, but PTHrP may be more effective. Disparate effects on urinary pH could be reflected in the clinical features of humoral hypercalcaemia of malignancy.
Journal of Endocrinology (1989) 120, 45–50
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SUMMARY
Synthetic porcine calcitonin (α-calcitonin) and its methionine-sulphoxide derivative (β-calcitonin) were given by intravenous infusion to conscious male rats. α-Calcitonin inactivated by performic acid oxidation was used as a control.
Microgram doses of α-calcitonin produced a dose-dependent decrease in the renal excretion of magnesium. The effect was not due to a secondary release of parathyroid hormone since it was also seen in parathyroidectomized animals.
A marked increase in the renal excretion of inorganic phosphate, sodium and potassium preceded the change in magnesium excretion in parathyroidectomized rats. It is concluded that the phosphaturia and natriuresis previously described after administration of extracted calcitonin preparations are true effects of the hormone.
The effect of β-calcitonin was indistinguishable from that of α-calcitonin.
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ABSTRACT
Parathyroid hormone (PTH)-like bioactivity, assayed as adenylate cyclase response in UMR 106-01 osteogenic sarcoma cells, was present in extracts of sheep fetal and maternal parathyroid glands and placenta. Preincubation of extracts with PTH(1–34) antiserum inhibited approximately 40% of the bioactivity in fetal parathyroid extracts, 50% in maternal parathyroid extracts, but only 10% of the bioactivity in the placental extract. Partial purification of placental extracts by chromatography yielded fractions containing PTH-like bioactivity which were similar in behaviour to that of PTH-related protein (PTHrP) from a human lung cancer cell line (BEN). An antiserum against synthetic PTHrP(1–16) partially inhibited the bioactivity of the placental extract and synthetic PTHrP(1–34), but had no effect on the bioactivity of bovine PTH(1–34) or bovine PTH(1– 84). The placental PTH-like bioactivity was higher in mid- than in late gestation. Fetal parathyroid glands contained the highest PTH-like bioactivity.
Thyroparathyroidectomy of one fetal twin lamb in each of 16 ewes between 110 and 125 days of gestation resulted in decreases of the plasma calcium concentration and reversal of the placental calcium gradient that existed between the ewe and the intact fetus. Perfusion of the placenta of each twin in anaesthetized ewes was carried out sequentially with autologous fetal blood in the absence of the exsanguinated fetus. The plasma calcium concentration in the blood perfusing the placenta of each twin increased, but reached a plateau at a lower concentration in the perfusing blood of thyroparathyroidectomized fetuses than in that of the intact fetuses. Addition of extracts of fetal parathyroid glands or of partially purified PTHrP resulted in further increases in plasma calcium in the autologous blood perfusing the placentae of thyroparathyroidectomized fetuses, but addition of bovine PTH(1–84) or rat PTH(1–34) had no effect. The presence of this PTH-like protein in the fetal parathyroid gland and placenta may contribute to the relative hypercalcaemia of the fetal lamb. This protein, which is similar to PTHrP associated with humoral hypercalcaemia of malignancy, stimulates the placental calcium pump responsible for maintaining a relative fetal hypercalcaemia during gestation.
J. Endocr. (1988) 117, 261–271
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ABSTRACT
Classical pharmacological studies have shown that oestrogen dominance in humans and other animals can increase the responsiveness of the uterus to many locally acting peptides. Parathyroid hormone-related protein (PTHrP) has been shown to be expressed in the pregnant and non-pregnant rat uterus and exogenous PTHrP is known to relax uterine contraction in vitro. We investigated whether oestrogen dominance can influence the responsiveness of the uterine horn to PTHrP, and further studied the localization of PTHrP mRNA and protein in the rat uterine horn using in-situ hybridization and immunohistochemistry. Exogenous PTHrP(1–34) inhibited spontaneous and electrically induced contractions in uteri isolated from non-cycling rats. Pretreatment of non-cycling rats with oestradiol-17β increased uterine sensitivity to PTHrP: EC50 values for inhibition of spontaneous contractions by PTHrP were 0·33 nmol/l, 1·1 nmol/l, 2·6 nmol/l and 7800 nmol/l in uteri from animals treated for 2 days with oestradiol-17β alone, 2 days with oestradiol-17β+1 day progesterone, 1 day with oestradiol-17β alone and in untreated rats respectively. Similar EC50 values were obtained for electrically stimulated uteri. In agreement with these findings, uterine horns from cycling rats in pro-oestrous and oestrous phases of the cycle showed a higher responsiveness to PTHrP(1–34) when compared with uterine horns taken from rats in metoestrus and dioestrus. PTHrP mRNA and protein were detected in the endometrial epithelium lining of the lumen and the endometrial glands, as well as in the myometrium of rats which were either pretreated for 2 days with oestradiol-17β or untreated. This study suggests that PTHrP may act in an autocrine and/or paracrine manner to modulate uterine motility and function.
Journal of Endocrinology (1992) 134, 415–425
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ABSTRACT
In two experiments, the effects of i.v. infusions of various doses of bovine GH-releasing factor (GRF) on blood hormones and metabolites in lactating Holstein cows were determined.
In experiment 1, cows were infused with GRF (0, 3·125, 6·25, 12·5, 25·0 or 50·0 mg/cow per 24 h) for 24 h. Blood was sampled at −1, 5, 11, 15 and 23 h relative to the start of the infusion. The serum concentration of somatomedin C (SM-C) before infusion was 303 ± 8 (s.e.m.) μg/l. Doses of GRF of between 3·125 and 50·0 mg were equipotent in stimulating (P < 0·05) SM-C by 1·5- to 2·5-fold. GRF-induced increases in SM-C occurred by 11 h from the start of the infusion.
In experiment 2, primiparous cows were infused with GRF (0, 1 or 3 mg/24 h) for 20 days. Blood was sampled for 12 h on days 1, 10 and 19. The 1 mg dose of GRF increased (P < 0·05) blood concentrations of SM-C (on days 10 and 19) and glucose (on day 19), but did not affect blood concentrations of prolactin, insulin, cortisol, tri-iodothyronine (T3), thyroxine (T4), non-esterified fatty acids (NEFA) or glucose. The 3 mg dose of GRF increased (P < 0·05) blood concentrations of SM-C (on days 10 and 19), T3 (on days 10 and 19), insulin (on day 19), NEFA (on days 1, 10 and 19) and glucose (on day 19), but did not affect blood concentrations of prolactin, cortisol or T4.
We conclude that these data are consistent with the hypothesis that the galactopoietic effect of exogenous GRF in dairy cattle is mediated by increased secretion of GH.
Journal of Endocrinology (1989) 122, 671–679
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ABSTRACT
Peptides containing residues 1–34 of parathyroid hormone-related protein (PTHrP) and of bovine parathyroid hormone (bPTH), and recombinant full-length PTHrP(1–141) were infused i.v. into anaesthetized thyroparathyroidectomized rats to compare their action and potency on the renal handling of calcium, phosphate and cyclic AMP (cAMP) in vivo. All three peptides decreased the excretion of calcium and increased the excretion of phosphate and cAMP in the urine, with PTHrP(1–34) and PTHrP(1–141) having virtually equipotent effects. Thus the essential requirements for the major physiological activity of PTHrP on the kidney are contained within the 34 amino-terminal amino acids. For all three peptides, the lowest infusion rate that increased phosphate and cAMP excretion was 0·01 nmol/kg per h, whereas the lowest infusion rate that decreased calcium excretion was 0·025 nmol/kg per h for the PTHrP peptides and 0·1 nmol/kg per h for bPTH(1–34). The response to the PTHrP peptides was maximal at an infusion rate of 01 nmol/kg per h for both calcium and phosphate. Since the kidney is either equally sensitive to PTHrP and bPTH(1–34), or more sensitive to PTHrP than to bPTH(1–34), the hypercalcaemia of humoral hypercalcaemia of malignancy may develop because uncontrolled secretion of PTHrP increases the renal reabsorption of calcium to such an extent that even a modest increase in the inflow of calcium into the blood raises plasma calcium concentration.
Journal of Endocrinology (1989) 122, 229–235
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Abstract
Parathyroid hormone-related protein (PTHrP) gene expression and/or immunoreactive protein have previously been identified in the uterus and intrauterine gestational tissues. The putative roles of PTHrP during pregnancy include vasodilatation, regulation of placental calcium transfer, uterine smooth muscle relaxation and normal fetal development. The aims of this study were 1) to determine the tissue-specific and temporal expression of PTHrP mRNA and immunoreactive protein in human gestational tissues collected at preterm and term; and 2) to determine the effect of labour on PTHrP expression by collecting these tissues from women undergoing elective caesarean section (before labour), intra-partum caesarean section during spontaneous-onset labour (during labour), and women with spontaneous labour and normal vaginal delivery (after labour). Total RNA and protein were extracted from placenta, amnion (over placenta and reflected) and choriodecidua for analysis by Northern blot (using a specific human PTHrP cDNA probe), and by N-terminal PTHrP RIA respectively. In amnion over placenta, reflected amnion and choriodecidua both PTHrP mRNA relative abundance and immunoreactive protein were significantly elevated at term compared with preterm (P<0·01). At term, both PTHrP and its mRNA were significantly greater in amnion than in placenta and choriodecidua (P<0·05). Also, both PTHrP and its mRNA were significantly elevated in amnion over placenta compared with reflected amnion (P<0·05). The expression of PTHrP and its mRNA did not change in association with term labour or rupture of the fetal membranes, therefore this study provides no evidence for a specific PTHrP role in the onset and/or maintenance of term labour. However, the significant up-regulation of PTHrP mRNA and protein in the fetal membranes at term compared with preterm suggests an important role in late human pregnancy.
Journal of Endocrinology (1997) 154, 103–112