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PubMed1990

[Hypomagnesemia-induced hypocalcemia: functional hypoparathyroidism, parathyroid hormone- and vitamin D-resistant].

In four patients with severe hypomagnesemia, hypocalcemia, and functional hypoparathyroidism (three patients with shortened bowel, one with alcoholism), sequential measurements of parameters of calcium metabolism were performed before and during intravenous administration of magnesium. Parathyroid hormone was immeasurably or inadequately low in all patients before magnesium injection, but rapidly rose to elevated values thereafter. Even without calcium supplements, serum calcium rose to normal levels within 2-5 days, although 1,25(OH)2-Vitamin D levels did not rise significantly. In the patient with alcoholism, hypophosphatemia developed during the first days after admission; the rise of serum calcium preceded the elevation of cyclic adenosine monophosphate in urine. A transient rise of urinary calcium was observed in two patients after initiation of magnesium therapy, with a subsequent fall to subnormal levels in spite of normal serum calcium concentrations. The findings were considered to be due to partial parathyroid hormone resistance during the phase of magnesium replenishment.

Adult↗
PubMed2007

Minimally invasive parathyroidectomy without intraoperative parathyroid hormone monitoring in patients with primary hyperparathyroidism.

BACKGROUND: Minimally invasive parathyroidectomy (MIP) is the preferred operation for patients with primary hyperparathyroidism (HPT) and positive preoperative imaging. This non-randomized case series assessed the long-term results of MIP performed without the use of intraoperative parathyroid hormone (ioPTH) monitoring. METHODS: The study involved prospective collection of demographic, biochemical and operative details on a consecutive, unselected cohort of 298 patients who underwent surgery for non-familial primary HPT during a 5-year interval. The mean preoperative serum calcium level was 3.00 mmol/l with a mean parathyroid hormone concentration of 25.8 pmol/l. (99m)Tc-labelled sestamibi scanning and neck ultrasonography were performed in 262 patients. RESULTS: Sestamibi scan showed unilateral uptake in 182 patients and a single parathyroid adenoma was confirmed on ultrasonography in 161 patients. MIP was performed in 150 patients. The mean duration of operation was 25 (range 8-65) min. Four patients needed conversion to conventional neck exploration. There was one postoperative haematoma and three cases of temporary recurrent laryngeal nerve neuropraxia. All but four patients were normocalcaemic after MIP. All the parathyroid tumours removed were adenomas, with a mean weight of 1.3 (range 0.1-17.4) g. No patient developed recurrent HPT after a median follow-up of 16 (range 3-48) months. CONCLUSION: The outcome of MIP without ioPTH monitoring was comparable to that reported in series that used ioPTH monitoring.

Adolescent↗
PubMed1976

Comparative in vitro biological activity of 1-34 N-terminal synthetic fragments of human parathyroid hormone on bovine and porcine kidney membranes.

1-34 N-terminal fragments of human parathyroid hormone with sequences according to Brewer et al (hPTHB) and to Niall et al (hPTHN) were synthesized and compared for their ability to activate bovine and porcine kidney cortex membrane adenylate cyclase. Results show that these two hormone sequences are able to activate these membranes but at least in this in vitro assay, hPTHN is about 10 times more active than hPTHB on bovine as well as on porcine membranes. These "apparent potencies" with respect to the potency of bPTH 1-34 in bovine and porcine membrane assay systems are respectively 4% and 11% for hPTHB and 39% and 156% for hPTHN. These relative potencies may be interpreted as corresponding to species specificity of the hormone receptor structural relationships.

Adenylyl Cyclases↗
PubMed2002

Cis and trans acting factors in the regulation of parathyroid hormone (PTH) mRNA stability by calcium and phosphate.

Calcium and phosphate regulate parathyroid hormone (PTH) mRNA stability through differences in binding of parathyroid proteins to an element in its 3'-untranslated region. One of the proteins is AUF1 (A+U-rich element binding factor 1). An in vitro degradation assay showed that transcripts for PTH and chimeric growth hormone (GH)-PTH 63 nt, but not for native GH, were stabilized by PT proteins from rats on low calcium diets and destabilized by proteins from rats on low phosphate diets, correlating with PTH mRNA levels in vivo. In transfection experiments the 63 nt binding element destabilized mRNAs of reporter genes and this was prevented by over-expression of AUF1. Our results identified a functional cis element in PTH mRNA. Differences in protein binding to this element determine PTH mRNA stability and its regulation by calcium and phosphate.

3' Untranslated Regions↗
PubMed1997

Parathyroid hormone enhances early and suppresses late stages of osteogenic and chondrogenic development in a BMP-dependent mesenchymal differentiation system (C3H10T1/2).

The role of parathyroid hormone (PTH) upon osteo-/chondrogenic development was investigated in a bone morphogenetic protein (BMP)-dependent differentiation system involving the recombinant expression of BMPs in mesenchymal progenitor cells (C3H10T1/2). The constitutive expression of the PTH/PTH related protein receptor in this system led to a marked stimulation of chondrogenic and osteogenic development, while the permanent application of the ligand PTH(1-34) resulted in opposite responses by stimulating the early and suppressing the late stages of osteo-/chondrogenic development. These contrasting effects of PTH(1-34) on osteogenic and chondrocytic development seem, therefore, to depend on the cellular state of differentiation. The osteogenic and chondrocytic differentiation potential was substantiated histologically and by genetic analyses of marker genes like c-fos, alkaline phosphatase, osteocalcin, collagen alpha1(I), and collagen alpha1(II). The capacity to regulate osteogenic and chondrogenic development is located in the amino-terminal (1-34) region of the PTH molecule and seems to be mediated by the cyclic adenosine monophosphate signaling cascade. The application of other PTH domains like PTH(28-48) and PTH(53-84) did not exhibit significant responses. PTH acts as an essential factor in mesenchymal development controlling rates of differentiation into the osteogenic or chondrogenic lineage. The analysis of PTH effects in this system demonstrates the value of recombinant mesenchymal progenitor cells in the in vitro analysis of osteo-/chondrogenic development.

Bone Morphogenetic Proteins↗
PubMed2003

Mechanisms of down-regulation of the renal parathyroid hormone receptor in rats with chronic renal failure.

Hypocalcemia, hyperphosphatemia and resistance to the action of parathyroid hormone (PTH) are well-characterized features in advanced chronic renal failure (CRF). Their pathogenesis has been attributed to both PTH receptor (PTH-R) down-regulation and postreceptor abnormalities. In this study, we examined the renal expression of the PTH-R mRNA in CRF (5/6 nephrectomy) rats. Experiments were also performed to determine whether an acidic condition and PTH itself influence PTH-R mRNA expression. RT-competitive PCR was used to examine mRNA expression, and polyclonal antibody against PTH-R was used for Western blot. PTH-R mRNA expression was abundant in glomeruli, proximal convoluted and straight tubules (PCT, PST), small in medullary and cortical thick ascending limbs, and cortical collecting ducts and not detectable in outer and inner medullary collecting ducts. The expression was significantly decreased in PCT and PST in CRF rats. Decrease in PTH-R mRNA expression was observed 1 week after the induction of CRF. PTH-R protein was decreased at 2 (-23%) and 4 (-45%) weeks in renal cortex, but not in medulla in CRF rats. PTH-R mRNA expression in PST was decreased by low pH (7.1 or 6.7) incubation compared with that at pH 7.4. PTH(1-34) (10(-9) M) increased PTH-R mRNA expression in PST from control rats by 250%. The stimulatory effect of PTH on PTH-R mRNA expression was decreased by the incubation at low pH medium. In summary, renal PTH-R is down-regulated in CRF rats. The decrease in mRNA expression in PCT and PST causes the decrease in PTH-R protein. Metabolic acidosis may participate in the down-regulation of PTH-R in early stage of CRF. This abnormality could be important in the pathogenesis of secondary hyperparathyroidism of CRF.

Acidosis↗
PubMed1977

Phosphate excretion in chronic renal failure: evidence for a mechanism other than circulating parathyroid hormone.

The mechanism of the increased phosphaturia of chronic renal failure was investigated in seven patients with creatinine clearances ranging from 22 to 63 ml/min. Phosphorus deprivation for 2 to 7 weeks resulted in a marked and rapid reduction in urinary total and fractional phosphate excretion. Serum immunoreactive parathyroid hormone concentration initially remained unchanged and eventually decreased slowly from 330 +/- 50 microliterEq per ml (control) to 252 +/- 58 microliterEq per ml (P less than 0.025), but persisted substantially elevated above the normal range (10-60 microliterEq per ml). Thus, phosphate excretion in chronic renal failure can be regulated to a major extent by the dietary phosphorus intake independently of parathyroid hormone.

Adult↗
PubMed1980

Interaction between antidiuretic and parathyroid hormones on urine concentration.

Experiments were performed on 26 acutely thyroparathyroidectomized (TPTX) Sprague-Dawley rats undergoing maximum water diuresis to determine whether the rise in urinary osmolality (Uosmol) in response to a submaximal dose of antidiuretic hormone (ADH) is modified by exogenous administration of parathyroid hormone (PTH). During administration of a submaximal dose of PTH to 11 TPTX rats, the ADH-induced increase in Uosmol averaged 267 +/- 15 mosmol, or twice the average increment of 131 +/- 18 mosmol observed when the same dose of ADH was given prior to PTH infusion (P < 0.001). This difference could not be attributed to changes in endogenous ADH release, renal hemodynamics, or solute excretion, and was not observed in a second group of eight other water-diuretic TPTX rats given sham PTH infusion. A third group of seven water-diuretic TPTX rats were studied with verapamil, a compound known to antagonize calcium ion entry into cells. Pretreatment of these rats with intravenous verapamil abolished the PTH potentiation of the Uosmol response to ADH described above. We conclude, therefore, that PTH enhances the Uosmol response to ADH, perhaps via a mechanism requiring a PTH-mediated change in the cellular calcium concentration or content of cells important in the urinary concentrating process.

Animals↗
PubMed1994

Parathyroid hormone (PTH) and PTH-related protein stimulate surfactant phospholipid synthesis in rat fetal lung, apparently by a mesenchymal-epithelial mechanism.

We examined the effects of parathyroid hormone (PTH) and PTH-related protein (PTHrP) on rat fetal lung fibroblast and pneumocyte cell signalling. We also studied the effects of PTH and PTHrP on surfactant phospholipid synthesis to determine whether these peptides can modulate pulmonary maturation. Exposure of fibroblasts (gestational days 18-21) to PTH(1-34) or PTHrP(1-34) produced time- and dose-dependent stimulations of cAMP and inositol phosphate accumulation. Maximal stimulation of cAMP accumulation occurred with 1 x 10(-8) M of either peptide. These effects upon cAMP accumulation were competitively inhibited by the PTH antagonist, [Nle8, Nle18, Tyr34]bPTH(3-34)amide. Maximal stimulation of fibroblast inositol phosphates was reached at 1 x 10(-7) M of either peptide. In contrast, PTH and PTHrP at these concentrations produced no changes in cAMP or inositol phosphate metabolism in isolated type II pneumocytes. When pneumocytes were exposed to PTH or PTHrP and pulse-labelled with [methyl-3H]choline chloride, no hormone-stimulated changes in saturated phosphatidylcholine (PC) synthesis were detected. However, PTH and PTHrP stimulated saturated PC synthesis in rat fetal lung explants (gestational day 19-20) by 46% and 106%, respectively. When fibroblasts and pneumocytes were co-cultured, PTH and PTHrP again stimulated saturated PC synthesis by 45% and 73%, respectively. Taken together, these findings suggest that PTH and PTHrP may be endocrine and/or paracrine regulators of fetal lung development.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1994

Rapid desensitization of parathyroid hormone dependent adenylate cyclase in perifused human osteosarcoma cells (SaOS-2).

The pulsatile but not the continuous application of parathyroid hormone (PTH) increase bone mass in vivo. To study the effects of intermittent hormonal administration on bone-derived cells in vitro, we established a perifusion system using the human osteosarcoma cell line SaOS-2. Cells were grown in suspension culture attached to collagen beads and were then loaded into a 3 ml syringe for perifusion experiments. The application of PTH(1-34) resulted in a dose-dependent increase of cAMP release by SaOS-2 cells into the effluent medium. Cyclic AMP accumulation was rapidly desensitized by approx. 80% after 30 min of continuous exposure to PTH(1-34) (10(-7) M), while cells remained responsive to forskolin. The recovery of PTH responsiveness required at least 2 h of hormone-free perifusion. Desensitization in the experimental setting was dose-dependent (EC50 = 1 x 10(-10) M PTH(1-34)). Neither 8Br-cAMP (2 x 10(-4) M) nor PMA(1 x 10(-7) M) had an effect on the PTH(1-34)-induced desensitization of the adenylate cyclase. Radioreceptor assays showed that [125I]-[Tyr36]hPTHrP(1-36)amide binding to SaOS-2 cells was decreased by 60-70% by PTH(1-34) (1 x 10(-6) M), bPTH(1-84) (1.8 x 10(-6) M) and bPTH(3-34) (2 x 10(-6) M), whereas 8Br-cAMP (2 x 10(-4) M) had no effect on radioligand binding. PMA (1 x 10(-7) M) appeared to slightly increase [125I]PTHrP binding. This observation is consistent with a small (3-fold) increase in PTH-induced cAMP release as a result of PMA pre-treatment. Receptor internalization was dose-dependent EC50 = 3 x 10(-7) M PTH(1-34)). The maximal effect occurred after 10-30 min and was largely reversible within 2 h. Monensin (3 x 10(-5) M) inhibited the recovery from receptor internalization. We conclude that a perifusion system using SaOS-2 cells is a suitable model to study the effect of discontinuous application of PTH on cAMP release. A rapid, homologous desensitization of PTH(1-34) stimulated cAMP accumulation has been observed that does not appear to involve protein kinase A or C.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1988

Use of a new pulsatile perfused rat aorta preparation to study the characteristics of the vasodilator effect of parathyroid hormone.

Both the native hormone and the aminoterminal 1-34 peptide of parathyroid hormone [PTH-(1-34)] are potent vasodilators of the coronary and hepatic circulations and, relatedly, produce marked hypotensive effects in a variety of animal species. In this report, a new technique for studying vasoactive substances was used to determine the nature of the vasodilator response of the aminoterminal peptide. The technique, an alternative to classical cylindrical segment or helical strip approaches, involved perfusion of a 4 to 5 cm segment of rat thoracic aorta at a constant flow rate with a circumferentially applied pulsatile "systolic" pressure of 100 mm Hg. Changes in perfusion pressure were indicative of changes in vascular resistance. The perfusate consisted of oxygenated physiological salt solution. Aortas were precontracted with high [KCl], norepinephrine, phenylephrine or arginine vasopressin. PTH-(1-34) elicited a concentration-related relaxation of vessels precontracted with the alpha agonists or [arg8]-vasopressin, but did not inhibit high K+ (3.5 x 10(-2) M)-induced contractions over the same dose range. Inhibition of prostaglandin biosynthesis with indomethacin did not alter the vasorelaxant properties of the peptide fragment. Endothelium-dependency of the PTH-(1-34)-induced vasorelaxant effect was assessed in untreated aortas and in tissues pretreated with saponin. Aortas pretreated with saponin, in which both scanning and transmission electron microscopy revealed extensive damage to or loss of endothelium, relaxed in a manner indistinguishable from nontreated control vessels. Thus, PTH-(1-34) relaxed precontracted perfused rat aortas in dose-dependent fashion. The vasorelaxant effects of the peptide fragment involved preferential relaxation of pharmacomechanically coupled vessels, and were not mediated by vasodilator prostaglandins or other specific endothelium-dependent mechanisms.

Animals↗
PubMed2000

Rapid parathyroid hormone measurement during venous localization.

The development of a rapid format for intact parathyroid hormone (PTH) immunometric assays has facilitated the use of these assays intraoperatively as a guide to parathyroid surgery. The near real-time characteristics of this rapid PTH assay led us to evaluate its utility in the angiography suite in a patient who underwent venous localization for persistent primary hyperparathyroidism. The assay provided the angiographers with almost immediate feedback and thereby facilitated accurate parathyroid adenoma localization. We conclude that the performance characteristics of the rapid PTH assay extend its diagnostic utility to near real-time analysis of plasma PTH levels in patients undergoing venous catheterization for parathyroid localization.

Adult↗
PubMed2000

A novel Van91 I polymorphism in the 1st intron of the parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptor gene and its effect on the urinary cAMP response to PTH.

This study was designed to identify a parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptor gene polymorphism in a healthy Japanese population. All known 13 introns of this gene were amplified by PCR, except the 1st intron, which was amplified by the long-PCR method. No restriction fragment length polymorphisms (RFLPs) were detected by BsmI or XbaI in any of these introns. Twenty-one other restriction enzymes (Hind III, Bgl II, Sty I, Pvu II, Eco81 I, Van91 I, BstX I, Sse8387 I, EcoR I, BamH I, Mbo II, Tth111 I, PshA I, Eam1105 I, Not I, Srf I, Bgl I, Fok I, Sfi I, Apa I, Taq I) were tested on the 1st intron. Furthermore, digestion by Van911 (CCANNNNNTGG) identified a single, two-allele polymorphism with a fragment of approximately 3.5 kb (V allele) or a fragment of 3.1 and 0.4 kb (v allele). The frequency of the Van91 I polymorphism in 106 healthy Japanese volunteers was 77.4% for type vv, 19.8% for type Vv and 2.8% for type VV. In addition, the urinary cAMP response to exogenous [1-34]PTH was studied in 17 healthy volunteers and found to be significantly greater in persons with type Vv than type vv (p<0.05). In conclusion, the Van91 I polymorphism of the PTH/PTHrP receptor gene can be used to study the role of polymorphism in various disorders involving PTH or PTHrP.

Adult↗
PubMed1990

Differential effects of continuous and transient treatment with parathyroid hormone related peptide (PTHrp) on bone collagen synthesis.

Parathyroid hormone-related peptide (PTHrp), a polypeptide synthesized by tumors associated with hypercalcemia and known to cause bone resorption, was examined for its effects on bone formation in cultures of 21-day fetal rat calvariae. Continuous treatment with PTHrp for 24-72 h stimulated DNA synthesis, but inhibited [3H] proline incorporation into collagen by about 50%. In contrast, transient exposure to PTHrp at 0.1-1.0 nM for 24 h followed by removal of the factor for 48 h caused an increase in [3H]proline incorporation into collagen and noncollagen protein by 2- and 1.6-fold, respectively. The stimulatory effect was seen in the periosteum-free bone, and was decreased, but not prevented by hydroxyurea. PTHrp at 1-10 nM for 24 h increased medium insulin-like growth factor (IGF) I levels by 2.5-4.4-fold, and the effect was sustained 48 h after the removal of the agent. An IGF I neutralizing antibody prevented the stimulatory effect of PTHrp on bone collagen synthesis. PTH had the same stimulatory effects as those of PTHrp on bone collagen synthesis and IGF I concentrations, although slightly lower doses were needed to observe the enhancement of [3H]proline incorporation into collagen. It is concluded that continuous treatment with PTHrp inhibits, whereas transient treatment stimulates, collagen synthesis; the stimulatory effect appears mediated by an enhancement in the local production of IGF I.

Animals↗
PubMed1980

Effects of vitamin D metabolites on bovine parathyroid hormone release in vitro.

We evaluated the effects of 1 alpha,25-dihydroxycholecalciferol (1,25(OH)2D3), 24R,25-dihydroxycholecalciferol (24,25(OH)2D3), and 25-hydroxycholecalciferol (25(OH)D3) on the release of parathyroid hormone (PTH). Bovine parathyroid tissues were incubated in vitro for 4 h in low-calcium (1.0 mM) medium. 1,25(OH)2D3 ((10(-9)-10(-12)M), 24,25(OH)2D3 (10(-6)-10(-8)M), and 25(OH)D3 (5 X 10(-7)-5 X 10(-9)M) inhibited PTH release. Inhibition by all metabolites was concentration and time dependent. On a molar basis, 1,25(OH)2D3 was the most potent metabolite, being at least 100 times more potent than 24,25(OH)2D3 and 25(OH)D3; 24,25(OH)2D3 was about 5 times more potent than 25(OH)D3 at concentrations producing 65% inhibition. Inhibition by high concentrations of metabolites was evident by 1 h of incubation; inhibition was progressive throughout incubation, and maximal suppression to 30-40% of control occurred during the fourth and final hour of incubation. 1,25(OH)2D3 (10(-11) M), a low concentration that did not inhibit secretion, transiently stimulated release. In conclusion, under conditions of low-calcium-stimulated PTH release, 1,25(OH)2D3, 24,25(OH)2D3, and 25(OH)D3 inhibited PTH release, 1,25(OH)2D3 was the most potent inhibitor.

Animals↗
PubMed1982

Parathyroid-hormone-induced metabolic alkalosis in dogs.

We examined the effect of parathyroid hormone (PTH), administrated for 24-48 h, on acid-base homeostasis in dogs. Parathyroid extract (PTH), 15 IU/kg/day, given subcutaneously, caused metabolic alkalosis (control vs. experimental; mean +/- SEM): plasma HCO3, 21.3 +/- 0.3 vs. 24.2 +/- 0.5 mEq/l (p less than 0.001); plasma H+, 37.7 +/- 1.1 vs. 35.7 +/- 1.4 nEq/l (p less than 0.05), and net acid excretion, 48.6 +/- 2.0 vs. 65.1 +/- 4.0 mmol/day (p less than 0.01). PTH administered by continuous intravenous infusion had similar effects (control vs. experimental): plasma HCO3, 21.4 +/- 0.4 vs. 23.6 +/- 0.7 mEq/l (p less than 0.001) and net acid excretion, 54.0 +/- 3.5 vs. 68.3 +/- 5.7 mmol/day (p less than 0.05). PTH, 8 IU/kg/day, had qualitatively similar but quantitatively less profound consequences. Bicarbonaturia was not observed in any group. The effects of PTH were similar in adrenalectomized dogs maintained on hormone replacement. Indomethacin (150 mg/day) prevented the renal effects of PTH so that no increase in net acid secretion occurred. However, metabolic alkalosis still developed: control vs. experimental plasma HCO3, 21.8 +/- 0.5 vs. 23.9 +/- 0.5 mEq/l (p less than 0.001). Dichloromethanediphosphonate blunted both the renal and nonrenal effects of PTH, such that hypercalcemia, metabolic alkalosis and increased net acid excretion were quantitatively less and delayed in onset. In summary, PTH administration for 24-48 h causes metabolic alkalosis in dogs, the result of renal and nonrenal mechanisms.

Acid-Base Equilibrium↗
PubMed2004

Novel parathyroid hormone (PTH) antagonists that bind to the juxtamembrane portion of the PTH/PTH-related protein receptor.

Current antagonists for the parathyroid hormone (PTH)/PTH-related protein (PTHrP) receptor (PTHR) are N-terminally truncated or N-terminally modified analogs of PTH(1-34) or PTHrP(1-34) and are thought to bind predominantly to the N-terminal extracellular (N) domain of the receptor. We hypothesized that ligands that bind only to PTHR region comprised of the extracellular loops and seven transmembrane helices (the juxtamembrane or J domain) could also antagonize the PTHR. To test this, we started with the J domain-selective agonists [Gln(10),Ala(12),Har(11),Trp(14),Arg(19) (M)]PTH(1-21), [M]PTH(1-15), and [M]PTH(1-14), and introduced substitutions at positions 1-3 that were predicted to dissociate PTHR binding and cAMP signaling activities. Strong dissociation was observed with the tri-residue sequence diethylglycine (Deg)(1)-para-benzoyl-l-phenylalanine (Bpa)(2)-Deg(3). In HKRK-B7 cells, which express the cloned human PTHR, [Deg(1,3),Bpa(2),M]PTH(1-21), [Deg(1,3),Bpa(2),M]PTH(1-15), and [Deg(1,3),Bpa(2),M]PTH(1-14) fully inhibited (IC(50)s = 100-700 nm) the binding of (125)I-[alpha-aminoisobutyric acid(1,3),M]PTH(1-15) and were severely defective for stimulating cAMP accumulation. In ROS 17/2.8 cells, which express the native rat PTHR, [Deg(1,3),Bpa(2),M]PTH(1-21) and [Deg(1,3),Bpa(2),M]PTH(1-15) antagonized the cAMP-agonist action of PTH(1-34), as did PTHrP(5-36) (IC(50)s = 0.7 microm, 2.6 microm, and 36 nm, respectively). In COS-7 cells expressing PTHR-delNt, which lacks the N domain of the receptor, [Deg(1,3),Bpa(2), M]PTH(1-21) and [Deg(1,3),Bpa(2),M]PTH(1-15) inhibited the agonist actions of [alpha-aminoisobutyric acid(1,3)]PTH(1-34) and [M]PTH(1-14) (IC(50)s approximately 1 microm), whereas PTHrP(5-36) failed to inhibit. [Deg(1,3),Bpa(2),M]PTH(1-14) inhibited the constitutive cAMP-signaling activity of PTHR-tether-PTH(1-9), in which the PTH(1-9) sequence is covalently linked to the PTHR J domain, as well as that of PTHR(cam)H223R. Thus, the J-domain-selective N-terminal PTH fragment analogs can function as antagonists as well as inverse agonists for the PTHR. The new ligands described should be useful for further studies of the ligand binding and activation mechanisms that operate in the critical PTHR J domain.

Animals↗
PubMed2002

Parathyroid hormone related peptide and receptor expression in paired primary prostate cancer and bone metastases.

Parathyroid hormone-related peptide is a regulatory protein implicated in the pathogenesis of bone metastases, particularly in breast carcinoma. Parathyroid hormone-related peptide is widely expressed in primary prostate cancers but there are few reports of its expression in prostatic metastases. The aim of this study was to examine the expression of parathyroid hormone-related peptide and its receptor in matched primary and in bone metastatic tissue from patients with untreated adenocarcinoma of the prostate. Eight-millimetre trephine iliac crest bone biopsies containing metastatic prostate cancer were obtained from 14 patients from whom matched primary tumour tissue was also available. Histological grading was performed by an independent pathologist. The cellular location of mRNA for parathyroid hormone-related peptide and parathyroid hormone-related peptide receptor was identified using in situ hybridization with (35)S-labelled probe. Expression of parathyroid hormone-related peptide and its receptor was described as uniform, heterogenous or negative within the tumour cell population. Parathyroid hormone-related peptide expression was positive in 13 out of 14 primary tumours and in all 14 metastases. Receptor expression was evident in all 14 primaries and 12 out of 14 metastases. Co-expression of parathyroid hormone-related peptide and parathyroid hormone-related peptide receptor was common (13 primary tumours, 12 metastases). The co-expression of parathyroid hormone-related peptide and its receptor suggest that autocrine parathyroid hormone-related peptide mediated stimulation may be a mechanism of escape from normal growth regulatory pathways. The high frequency of parathyroid hormone-related peptide expression in metastases is consistent with a role in the pathogenesis of bone metastases.

Autoradiography↗