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At least 19 recordsLinked to original sources
PubMed1992

Relationships of parathyroid hormone, parathyroid secretory protein, parathyroid hormone messenger RNA, parathyroid secretory protein mRNA, and replication in human parathyroid adenoma and secondary hyperplasia tissues and cultures.

BACKGROUND: The purpose of this study was to clarify the relationships of extractable and secreted parathyroid hormone (PTH) and parathyroid secretory protein (PSP) in human parathyroid tumors to PTH messenger RNA (mRNA), PSP mRNA, and cell replication. METHODS AND RESULTS: In tissue cultures of seven adenomas and five secondary hyperplasias, we found a direct correlation for secreted PTH versus PSP for both adenomas and secondary hyperplasias. Secreted PTH:PSP was elevated for adenomas (11:1) compared to that of secondary hyperplasias (2:1), and adenomas secreted significantly more PTH and PSP than did secondary hyperplasias. In extracts of eight adenomas and six secondary hyperplasias, the ratio of PTH:PSP was unexpectedly low (2:1) and similar for both adenomas and secondary hyperplasias. The ratio of extractable PTH mRNA:PSP mRNA was extremely low for both adenomas (1:7) and for secondary hyperplasias (1:5). Flow cytometry indicated that percent replication was inversely correlated with PTH mRNA and PSP mRNA. CONCLUSIONS: Increased PTH secretion by adenomas cannot be attributed to increased biosynthetic capacity because it is less than expected. Hypersecretion of PTH by adenomas and coincident marked reductions in PTH mRNA suggest either a defect in cytoplasmic storage of PTH or impairment of normal posttranslational degradation of PTH. As parathyroid tumor cells increase replication, PTH mRNA is reduced. Possible explanations for this include decreased PTH gene transcription or decreased mRNA half-life.

Adenoma↗
PubMedDate not supplied

Vasodilator effects of parathyroid hormone, parathyroid hormone-related protein, and calcitonin gene-related peptide in the human fetal-placental circulation.

OBJECTIVE: The purpose of our study was to determine the vasoactivity of calcitonin gene-related peptide (CGRP), parathyroid hormone (PTH), and parathyroid hormone-related protein (PTHrP) in the human fetal-placental circulation in vitro. METHODS: Dually perfused placental cotyledons from term pregnancies were used in this study. RESULTS: Calcitonin gene-related peptide, PTHrP (both 10(-10)-10(-6) mol/L), and PTH (10(-8)-10(-6) mol/L) demonstrated a significant concentration-dependent vasodilator effect (P = .0007, P = .0172, P = .0063, respectively), following preconstriction with a thromboxane mimetic U46619. The CGRP-1 receptor inhibitor CGRP8-37 (10(-6) mol/L) significantly inhibited (P = .0131) the CGRP-induced vasodilator effect, while the nitric oxide synthesis inhibitor n-nitro-l-arginine showed no inhibitory effect. CONCLUSIONS: These results demonstrate the vasodilator effects of CGRP, PTH, and PTHrP in the human fetal-placental circulation. Calcitonin gene-related peptide and PTHrP were of equal potency, and both were approximately 100 times more potent than PTH. This study also suggests the CGRP may exert its vasodilator effect through two classes of receptors in the human placenta and may do so independently of nitric oxide.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1990

Effects of antidiuretic hormone, parathyroid hormone and glucagon on transepithelial voltage and resistance of the cortical and medullary thick ascending limb of Henle's loop of the mouse nephron.

The effect of antidiuretic hormone (arginine vasopressin, AVP, 10(-10) mol.l-1), parathyroid hormone (PTH, 10(-8) mol.l-1) and glucagon (10(-8) mol.l-1) on the transepithelial potential difference (PDte) and the transepithelial resistance (Rte) were tested in in vitro perfused cortical (cTAL) and medullary (mTAL) thick ascending limbs of Henle's loop of the mouse nephron. When compared with mTAL segments (PDte: 8.5 +/- 0.4 mV, n = 16), cTAL segments displayed a high PDte of 15.7 +/- 0.9 mV (n = 11) at the beginning of perfusion experiments which reached a value of 9.4 +/- 0.6 mV (n = 11) after 38 +/- 4 min perfusion. Simultaneously Rte increased significantly from 24 +/- 3 to 28 +/- 1 omega cm2 (n = 11). When PTH, AVP or glucagon were added to the bath solution, PDte increased with PTH from 10.3 +/- 0.8 to 15.2 +/- 0.8 mV (n = 13), with AVP from 10.2 +/- 0.5 to 15.0 +/- 0.7 mV (n = 24) and with glucagon from 11.3 +/- 1.9 to 15.3 +/- 2.1 mV (n = 8). At the same time Rte decreased from 30 +/- 3 to 23 +/- 2 omega cm2, from 28 +/- 1 to 23 +/- 1 omega cm2 and from 23 +/- 2 to 18 +/- 2 omega cm2, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

[Evaluation of physiological and pathological activity of osteoclasts and osteoblasts with special reference to calciotropic hormones: parathyroid hormone, calcitonin and calcitriol].

After introductory remarks concerning the pathophysiologic activities of osteoclasts and osteoblast, the author considers the three main pathologies: primary hyperparathyroidism, osteomalacia, and Paget's disease. These pathologies represent an excellent model for the pathophysiologic and clinico-therapeutic evaluation of some calciotropic hormones, viz. parathormone, calcitriol, and calcitonin.

Adolescent↗
PubMed2000

Six-month daily administration of parathyroid hormone and parathyroid hormone-related protein peptides to adult ovariectomized rats markedly enhances bone mass and biomechanical properties: a comparison of human parathyroid hormone 1-34, parathyroid hormone-related protein 1-36, and SDZ-parathyroid hormone 893.

Daily administration of parathyroid hormone (PTH) and PTH-related protein (PTHrP) peptides has been shown to increase bone mass and strength in animals and, for PTH, to increase bone mass in humans. Long-term direct comparison of multiple members of the PTH/PTHrP family in vivo has not been reported. We therefore selected three PTH/PTHrP molecules for direct comparison in vivo in an adult rat model of postmenopausal osteoporosis: PTH(1-34), PTHrP(1-36), and the PTH analog, SDZ-PTH 893 ¿Leu8, Asp10, Lys11, Ala16, Gln18, Thr33, Ala34 human PTH 1-34 [hPTH(1-34)]¿. A 6-month study was performed in which adult (6-month-old) vehicle-treated ovariectomized (OVX) and sham OVX rats were compared with OVX rats receiving 40 micrograms/kg per day of either PTH(1-34), PTHrP(1-36), or PTH-SDZ-893. Bone mass, as assessed by ash weight and densitometry, bone histomorphometry, biomechanical properties at trabecular and cortical sites, and indices of bone formation markedly increased in all three PTH/PTHrP peptide-treated groups as compared with controls. In general, this improvement followed a rank order of SDZ-PTH-893 > PTH > PTHrP. The adverse effect profile also was greatest with SDZ-PTH-893; these rats developed moderate hypercalcemia, marked renal calcium accumulation, and displayed a 13% mortality. These studies show that PTH(1-34), PTHrP(1-36), and PTH-SDZ-893 significantly and progressively increase bone mass and bone strength in this rat model of postmenopausal osteoporosis. The adverse effect profile correlates in general terms with efficacy. All three peptides show promise as skeletal anabolic agents. Further studies in humans will be required to define optimal efficacy-to-adverse effect ratios and relative efficacy for each peptide in human osteoporosis.

Animals↗
PubMed1998

[Activating mutations of the parathyroid hormone and parathyroid hormone related peptide].

Parathyroid hormone (PTH) and PTH related peptide (PTHrP) have a common main receptor: type I PTH-PTHrP receptor. PTH expresses its main metabolic actions, and PTHrP part of its autocrine or paracrine actions through this receptor. Jansen chondrodysplasia is a very rare disease mainly characterized by severe metaphyseal growth disorders leading to dwarfism and hypercalcemia. The group of Jüppner from the Massachusetts General Hospital in Boston recently demonstrated mutations on the gene of the type I PTH-PTHrP receptor in five patients with Jansen chondrodysplasia. These mutations result in permanent activation of the receptor responsible for the observed hypercalcemia and bone growth abnormalities due to the disease. Therefore Jansen chondrodysplasia appears as a remarkable clinical model outlining the major role of PTHrP in bone growth regulation.

Animals↗
PubMed1988

Effect of parathyroid hormone and parathyroid hormone fragments on the intracellular ionized calcium concentration in an osteoblast cell line.

In the present study the effect of parathyroid hormone and parathyroid hormone fragments on the intracellular ionized calcium concentration in an osteoblastic cell line (UMR 106-01) is examined. In these cells the intact hormone, bPTH(1-84) and three fragments (bPTH(1-34), hPTH(1-34) and bPTH(3-34) induce an initial increase of the ionized calcium concentration [( Ca2+]i). The increase of the [Ca2+]i due to bPTH(1-84) is more pronounced and of longer duration compared to the increase due to PTH fragments. For two parathyroid hormone fragments with a modified amino acid sequence [( Nle-8,Nle-18,Tyr-34]bPTH(1-34), [Nle-8,Nle-18,Tyr-34]bPTH(3-34], no effect was found. Our observations suggest: (1) a second messenger role for intracellular ionized calcium in the action of bPTH(1-84) in osteoblasts; (2) a functional role for the COOH-terminal part in the action of bPTH(1-84); and (3) the existence of a specific part of the hormone being responsible for the increase of the intracellular ionized calcium concentration.

Animals↗
PubMedDate not supplied

Parathyroid hormone and parathyroid hormone related protein assays in the investigation of hypercalcemic patients in hospital in a Chinese population.

There are many pathological causes and potential mechanisms for hypercalcemia. We measured intact parathyroid hormone (PTH) and parathyroid hormone related protein (PTHrP) in the hypercalcemic in-patients and attempted to evaluate the roles of PTH and PTHrP in hypercalcemia due to malignancy. We performed a prospective study of 178 patients with corrected serum calcium concentrations greater than 2.74 mmol/l in a hospital over a 3-year period. We measured calcium and albumin using a Hitachi 747 autoanalyzer, and we measured PTH and PTHrP by two-site immunoradiometric assays (IRMA). Hypercalcemia was attributed to malignancy alone in 93 patients (52.3%), primary hyperparathyroidism (HPT) alone in 28 patients (15.7%), uremia with hemodialysis in 23 patients (12.9%), unknown in 16 patients (9%), primary HPT coexisting with malignancy in 7 patients (3.9%) and other rare causes (6.2%). Plasma PTHrP levels were elevated in 71/93 (76.3%) patients with hypercalcemia due to malignancy, but the elevated PTHrP percentage differed for each kind of tumor. PTHrP levels were elevated in 100% of patients with squamous carcinomas (CA) in the lung, esophagus, skin, cholangiocarcinoma of liver, and breast CA. The positive bony metastatic rate was 44.1% (41/93). There was no correlation between high PTHrP and bony metastasis. There was a good correlation between the corrected serum calcium and PTHrP levels (r = 0.476, p < 0.001), but no correlation between survival time and serum calcium level or PTHrP level. There was no significant difference in life expectancy after cancer diagnosis between the high PTHrP group and normal PTHrP group, and there was no significant difference in life expectancy after the first occurrence of hypercalcemia between the two groups. Measurement of both PTH and PTHrP levels led to a change in the initial diagnosis in 7 patients. In routine practice, measurement of serum PTH alone is not enough. This study suggests that the appropriate combination of PTH and PTHrP assays results in a more accurate diagnosis of the hypercalcemic causes. In addition, especially high PTHrP levels should be screened for malignancy. However, the prognosis in cancer patients after hypercalcemia with high PTHrP group, as compared to those with the normal PTHrP group is not significantly different.

Adult↗
PubMed2000

Structure and activities of constrained analogues of human parathyroid hormone and parathyroid hormone-related peptide: implications for receptor-activating conformations of the hormones.

Parathyroid hormone (PTH) has a helix-bend-helix structure in solution. Part of the C-terminal helix, residues 21-31, is amphiphilic and forms a critical receptor-binding region. Stabilization of this alpha-helix by lactam formation between residues spaced i, i + 4 on the polar face was previously reported to increase adenylyl cyclase-stimulating (AC) activity if between residues 22 and 26 but to diminish it if between residues 26 and 30 [Barbier et al. (1997) J. Med. Chem. 40, 1373-1380]. This work reports the effects of other cyclizations on the polar face, differing in ring size or position, on alpha-helix conformation, as measured by circular dichroism, and on AC-stimulating activity. All analogues cyclized between residues 22 and 26 had at least a 1. 5-fold increase in activity, suggesting an alpha-helical structure between about residues 21 and 26. Cyclization between residues 25 and 29 or residues 26 and 30 diminished activity by 20-30%, despite stabilizing alpha-helix, suggesting that residues 25-31 bind to the receptor in a helical, but not classical alpha-helical, conformation. Analogues cyclized between residues 13 and 17 had slightly increased activity. A bicyclic analogue, with lactams between residues 13 and 17 and residues 22 and 26, had about the same activity as that cyclized only between 22 and 26. Parathyroid hormone-related peptide (PTHrP) may bind in a manner similar to the common receptor, but hydrophobic moment calculations suggest that it must bind as a tighter helix in order to optimally present its hydrophobic residues to the receptor. Both PTHrP analogues cyclized between either residues 22 and 26 or residues 26 and 30 had more stable alpha-helices but reduced AC activities, consistent with this hypothesis.

Adenylyl Cyclases↗
PubMed1990

Modifications of position 12 in parathyroid hormone and parathyroid hormone related protein: toward the design of highly potent antagonists.

Truncated N-terminal fragments of parathyroid hormone (PTH), [Tyr34]bovine PTH(7-34)NH2, and parathyroid hormone related protein (PTHrP), PTHrP(7-34)NH2, inhibit [Nle8,18,[125I]iodo-Tyr34]-bPTH(1-34)NH2 binding and PTH-stimulated adenylate cyclase in bone and kidney assays. However, the receptor interactions of these peptides are 2-3 orders of magnitude weaker than those of their agonist counterparts. To produce an antagonist with increased receptor-binding affinity but lacking agonist-like properties, structure-function studies were undertaken. Glycine at position 12 (present in all homologues of PTH and in PTHrP), which is predicted in both hormones to participate in a beta-turn, was examined by substituting conformational reporters, such as D- or L-Ala, Pro, and alpha-aminoisobutyric acid (Aib), in both agonist and antagonist analogues. Except for N-substituted amino acids, which substantially diminished potency, substitutions were well tolerated, indicating that this site can accept a wide latitude of modifications. To augment receptor avidity, hydrophobic residues compatible with helical secondary structure were introduced. Incorporation of the nonnatural amino acids D-Trp, D-alpha-naphthylalanine (D-alpha-Nal), or D-beta-Nal into either [Tyr34]bPTH(7-34)NH2 or [Nle8,18,Tyr34]bPTH(7-34)NH2 resulted in antagonists that were about 10-fold more active than their respective 7-34 parent compound. Similarly, [D-Trp12]PTHrP(7-34)NH2 was 6 times more potent than the unsubstituted peptide but retained partial agonistic properties, although markedly reduced, similar to PTHrP(7-34)NH2. The antagonistic potentiating effect was configurationally specific.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗
PubMed1990

Bioactivity of amino terminal fragments of parathyroid hormone and parathyroid hormone related peptide in rat kidney slices: no effect of dietary phosphate deprivation.

Humoral hypercalcemia of malignancy has been associated with the production of a recently cloned peptide human parathyroid hormone related protein (hPTHRP). One of the markers of this disease is an increased urinary excretion of cyclic AMP. The postreceptor mechanism of action and physiological role of hPTHRP remain obscure. To study the activity of hPTHRP 1-34 compared to rat and human parathyroid hormone (PTH) 1-34 we incubated these peptides with rat kidney slices and measured the cyclic AMP generated in the supernatant. hPTHRP 1-34 was equipotent with human PTH 1-34 but both were 5 times less active than rat PTH 1-34. Previous studies have suggested that a low dietary phosphate intake results in renal resistance to the phosphaturic action of PTH perhaps mediated by reduced adenylate cyclase activation by PTH. To determine whether, during dietary phosphate restriction, hPTHRP 1-34 has actions different from hPTH 1-34 we studied their effects following dietary phosphate deprivation. Dietary phosphate restriction had no significant effect on the cyclic AMP generating activity of any of the peptides. We conclude that hPTHRP 1-34 may be operating through similar mechanisms as human PTH 1-34 and that the previously observed effects of dietary phosphate deprivation on PTH mediated cyclic AMP generation in a broken cell preparation do not occur in intact cell preparations.

Adenylyl Cyclases↗
PubMed1978

Carboxyl-terminal fragments of human parathyroid hormone in parathyroid tumors: unique new source of immunogens for the production of antisera potentially useful in the radioimmunoassay of parathyroid hormone in human serum.

We have found large quantities of immunoreactive carboxyl-terminal fragments of human parathyroid hormone )hPTH) in a previously discarded fraction [the 7.5% trichloroacetic acid (TCA)supernate] generated during extraction of intact hPTH from hyperfunctioning parathyroid tissue by the urea-TCA procedure. It is well established that serum RIAs directed toward the carboxyl-terminal region of hPTH are superior to those directed toward the amino-terminal region in the differential diagnosis of patients with suspected chronic parathyroid dysfunction. However, antisera that react with the carboxyl-terminal region of hPTH are not yet available for general use for these assays because of a lack of suitable hPTH immunogens. We immunized seven guinea pigs and two goats with the desalted 7.5% TCA supernate (containing about 2% carboxyl-terminal hPTH fragments); three of the guinea pigs and one goat produced high affinity antisera with predominant specificity for the carboxyl-terminal region of PTH. One of the guinea pig antisera had affinity for hPTH equal to that of our laboratory's best antiserum (GP1M) used in diagnostic RIAs for serum PTH. The use of this byproduct fraction as an immunogen should permit a large scale immunization program in large animals to provide standardized, species-and sequence-specific antisera potentially useful in RIAs for diagnosis of parathyroid disease.

Adenoma↗