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PubMed1982

Independence of the acute acid-buffering response from endogenous parathyroid hormone.

Two recent reports have made the provocative suggestion that parathyroid hormone (PTH) and, by implication, bone play a critical role in the early phase of acid buffering. The purpose of the present study was to investigate the effect of PTH on the acute buffering process by examining the influence of thyroparathyroidectomy (TPTX) on acid-base parameters in nephrectomized rats following infusion of hydrochloric acid at two differing doses. To ensure hemodynamic and physiologic stability of the animals, the required surgical procedures were staged over several days. Additionally, the experimental protocol was carried out in awake and unrestrained animals. Non-TPTX (sham) animals underwent a sham operation to equalize the surgical stresses between the two groups. The decrements in plasma [HCO-3] observed following infusion of 3.5 mmol/kg HCl over 1 h did not differ between TPTX vs. sham animals at 1 h (-9.4 vs. -9.9 meq/liter), 3 h (-8.6 vs. 8.6 meq/liter), or 6 h (-8.6 vs. -8.5 meq/liter) from the start of the infusion. Similarly, virtually identical falls in plasma [HCO-3] were observed between TPTX vs. sham rats after infusion of 5 mmol/kg HCl over 30 min at 30 min (-13.6 vs. -14.2 meq/liter) and 3 h (-10.9 vs. -11.4 meq/liter) after the start of the infusion. At both doses, the resultant changes in plasma [H+] and PaCO2 were not different in the two groups. The observed mortality was comparable in both TPTX and sham groups. The data demonstrate that endogenous PTH is not necessary in the early phase of buffering of a mineral acid load.

Acid-Base Equilibrium↗
PubMed1984

Morphological and ultrastructural aspects of the activation of avian medullary bone osteoclasts by parathyroid hormone.

The activation of physiologically inactive medullary bone osteoclasts by parathyroid hormone (PTH) was examined using light and electron microscopy and histomorphometric methods. Medullary bone osteoclasts are functionally inactive during the avian egg-laying cycle when an egg shell is not being calcified in the shell gland. Japanese quail hens were given 0.5 IU/g PTH and the medullary bone osteoclasts were examined up to 90 min later. Administration of PTH results in rapid changes in osteoclast morphology and ultrastructure. Within 10 min ectoplasmic regions containing condensed-appearing material are evident in areas of the cell adjacent to bone surfaces. In tannic acid-fixed specimens, these ectoplasmic regions contain bundles of filaments extending perpendicularly from the osteoclast plasma membrane into the cytoplasm. It is in these areas that ruffled border development is initiated. Even at 10 min after PTH administration, mineral crystals are seen between the developing cell surface invaginations and folds. By 15 min after PTH administration, ruffled borders have appeared next to bone surfaces. The rapid development of ruffled borders on medullary bone osteoclasts after PTH is confirmed by electron microscope histomorphometry. By 30 min after PTH administration, ruffled borders are well developed and large endocytic vacuoles are beginning to appear in the osteoclast cytoplasm. Light microscope histomorphometric measurements indicate that osteoclasts are also increasing in size and spreading along bone surfaces with time after PTH administration. This study provides a morphologic and ultrastructural description of osteoclast activation by PTH. The results indicate that osteoclasts may effect rapid changes in bone resorption and mineral metabolism due to exogenous PTH in hens.

Animals↗
PubMed1984

Oxidized forms of parathyroid hormone with biological activity. Separation and characterization of hormone forms oxidized at methionine 8 and methionine 18.

Bovine parathyroid hormone (PTH) was oxidized with hydrogen peroxide, and the oxidation products were separated by reverse phase high performance liquid chromatography. Using a shallow gradient, four major peaks (peaks I-IV in order of elution) were identified and completely separated from one another. Peak IV co-eluted with fully reduced PTH. The earliest eluting peak (peak I) could be reduced with mercaptoethylamine to produce all three of the later eluting ones. The second peak could be reduced back to peak IV but not to peak III, while peak III could be oxidized to peak I but not to peak II. These data plus the kinetics of oxidation showed that peaks II and III are intermediate in the generation of I from IV or IV from I, but were not generated from one another. Amino acid analysis showed that peak I contains no methionine and two residues of methionine sulfoxide, peaks II and III one methionine sulfoxide each, and peak IV two residues of methionine and no sulfoxide. Study of the peptides produced from each form of PTH by cleavage with cyanogen bromide showed that peak II is oxidized at methionine 8 and peak III at methionine 18 while peak I is oxidized at both methionines. The biological activity of each peak was determined in the kidney membrane adenylyl cyclase assay. All forms were active but with widely varying potencies (peak IV greater than peak III greater than peak II greater than peak I).

Adenylyl Cyclases↗
PubMed2001

Fragment-specific actions of parathyroid hormone in isolated perfused rat hearts.

Different regions within the parathyroid hormone (PTH) molecule are known to have different biological activities. In the heart, the physiological actions of the intact PTH molecule are known as positive chronotropy and coronary vasodilatation. However, it is unclear which region of the PTH exerts which physiological action in the heart. Therefore, to clarify this point, we examined the hemodynamic effect of intact PTH(1-84) and selected PTH analogs, namely, PTH(1-34), PTH(2-34), [Nle8, 18Tyr34]PTH(3-34), PTH(4-34), [Tyr34]PTH(7-34), and PTH(13-34) in isolated perfused rat hearts. Both PTH(1-84) and PTH(1-34) significantly increased heart rate and decreased coronary perfusion pressure. In contrast, neither PTH(2-34) nor [Nle8,18Tyr34]PTH(3-34) increased heart rate, but they did decrease coronary perfusion pressure. Peptides further truncated at the amino terminus, PTH(4-34), [Tyr34]PTH(7-34), and PTH(13-34), had no effect on hemodynamics. Furthermore, the protein kinase A inhibitor H89, but not the protein kinase C inhibitor H7, attenuated the hemodynamic effects of PTH(1-34) or PTH(2-34), while it prevented those of [Nle8,18Tyr34]PTH(3-34). These results clearly demonstrate that the first amino acid of PTH is essential for its chronotropic property whereas the first 3 amino acids of PTH are involved in its coronary vasodilatory action. Furthermore, protein kinase A, but not protein kinase C, appears to be involved in the chronotropic and coronary vasodilatory actions of PTH.

Animals↗
PubMed1987

Indomethacin does not inhibit the anabolic effect of parathyroid hormone on the long bones of rats.

Chronic administration of parathyroid hormone, hPTH 1-34, increased bone mass in normocalcemic, young rats. Since PTH can stimulate prostaglandin E2 (PGE2) production in bone in vitro, and since PGE2 can stimulate bone formation, the anabolic effect of PTH could be mediated by PGE2. To test this hypothesis, experiments were done to determine if indomethacin, which blocks endogenous PG production, would inhibit the anabolic response of bone to PTH. In the first experiment, male Sprague-Dawley rats, 70-100 g, in groups of five, were treated for 12 days with either hPTH 1-34, 8 micrograms/100g/day; PTH vehicle; indomethacin, 2 mg/kg/day; or a combination of PTH and indomethacin. In the second experiment, groups of 6 rats each were given vehicle or hPTH 1-34, 8 micrograms/100g/day, in combination with indomethacin, 0, 1, 2, or 4 mg/kg/day. Subcutaneous injections of PTH wee given once daily and indomethacin was given orally in divided doses, twice a day. Rats were killed on day 12 in both experiments; their sera were analyzed and the trabecular and cortical bone of distal femurs processed to determine calcium (Ca) and hydroxyproline content and dry weight. PTH and indomethacin had no significant effect on serum Ca, phosphate, alkaline phosphatase, urea nitrogen and creatinine, or systemic and long-bone linear growth. In rats treated with PTH alone or in combination with indomethacin, bone Ca of distal femurs increased by 28-44%; dry weight by 29-41%, and hydroxyproline by 17-45%. Indomethacin alone had no effect on bone growth.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1977

Selective deficiency of 1,25-dihydroxycholecalciferol. A cause of isolated skeletal resistance to parathyroid hormone.

To investigate the role of vitamin D metabolites in the pathogenesis of pseudohypoparathyroidism, we studied an elderly man with a unique variant of the disease, which was characterized by hypocalcemia, elevated serum parathyroid hormone (513 +/- 13 pg per milliliter, mean +/- S.E.M., normal, less than 450) but normal renal responses (phosphate and cyclic AMP) to exogenous parathyroid extract. Treatment with parathyroid extract did not produce a calcemic effect, suggesting an isolated skeletal hyporesponsiveness to parathyroid hormone. Although 25-hydroxyvitamin D levels were not reduced, levels of 1,25-dihydroxycholecalciferol were extremely low (0.52 ng per deciliter; normal 3.3 +/- 0.06, S.D.). Treatment with 1,25-dihydroxycholecalciferol (1 microgram by mouth per day for four days) increased circulating levels to normal (4.60 ng per deciliter) and restored to normal the calcemic response to parathyroid (change in calcium 3.0 mg per deciliter). These data suggest that 1,25-dihydroxycholecalciferol deficiency may explain the skeletal resistance, but not the renal resistance, often present in classic pseudohypoparathyroidism.

Aged↗
PubMed1991

Analogues of parathyroid hormone modified at positions 3 and 6. Effects on receptor binding and activation of adenylyl cyclase in kidney and bone.

Predictive and spectroscopic methods were used to develop a model of the structures of the 1-34 peptides of parathyroid hormone (PTH) and the PTH-related protein (PTHrP). Circular dichroism (CD) studies of bovine PTH-(1-34) and human PTHrP-(1-34)amide in the presence of trifluoroethanol suggest the presence of 24-26 alpha-helical residues. For both peptides, interactions between amino- and carboxyl-region alpha-helices are predicted to result in a hydrophobic core with externally facing hydrophilic residues that include probable determinants of receptor binding and activation. Two such residues, Ser3 and Gln6, are conserved in all known members of the PTH/PTHrP family. We have synthesized 13 novel analogues of bovine PTH-(1-34) monosubstituted at positions 3 and 6 and have determined their biological activities in renal and bone cell radioreceptor and adenylyl cyclase assays. Position 3 analogues displayed biological activity that was reduced in direct proportion to the volume of the substituent side-chain. Position 6 analogues also displayed reduced biological activity, but no simple correlation with side-chain volume or hydrophobicity was evident. The analogues fully displaced labeled PTH from binding sites in renal membranes and bone cells, but [Phe3]bPTH-(1-34), [Tyr3]bPTH-(1-34), [Phe6] bPTH-(1-34), and [Ser6]bPTH-(1-34) were only partial agonists in one or both adenylyl cyclase assays. Of these, [Phe3]bPTH-(1-34) and [Phe6]bPTH-(1-34) were tested for antagonist activity and were found to inhibit the activation of adenylyl cyclase in response to bPTH-(1-34) or hPTHrP-(1-34)amide. These results indicate that positions 3 and 6 contribute important determinants of PTH receptor binding and activation. Modification at these positions represents a novel approach to the development of antagonists of PTH action.

Adenylyl Cyclases↗
PubMed2003

Parathyroid hormone and its fragments in children with chronic renal failure.

Parathyroid hormone (PTH) immunoradiometric assays (IRMA) exhibit cross-reactivity between 1-84 PTH and long carboxyl-terminal-PTH (C-PTH) molecules. C-PTH antagonizes the biological actions of 1-84 PTH and circulates in excess in chronic renal failure (CRF), partially explaining why supra-physiological PTH levels are recommended to maintain bone turnover. Furthermore, the ratio 1-84 PTH/C-PTH may be related to bone turnover. This study characterizes the 1-84 PTH/C-PTH ratio in children with varying severity of CRF and levels of PTH. Two hundred and forty-one children with CRF, managed with the aim of preventing the development of hyperparathyroidism, had PTH measured by 'intact' IRMA and a new more specific Cyclase-Activating-PTH (CAP) IRMA. C-PTH levels were calculated by subtracting CAP-IRMA from 'intact' IRMA. Fifty-three controls with normal renal function were also recruited. Mean 'intact' IRMA correlated with CAP-IRMA ( r=0.98), but was higher ( P<0.001). The mean 1-84 PTH/C-PTH ratio was lower than controls in dialysis patients ( P=0.022) and those with a glomerular filtration rate <30 ml/min per m(2 )( P=0.033). This ratio was comparable to controls when the PTH level was normal, but was lower with PTH levels outside the normal range ( P<0.01). These data suggest that CAP-IRMA gives a more accurate assessment of actual PTH levels than 'intact' IRMA in CRF. Maintenance of normal PTH levels throughout the course of CRF permits the maintenance of a normal 1-84 PTH/C-PTH ratio, the clinical significance of which requires further investigation in children.

Child↗
PubMed1993

Estrogen protection against bone resorbing effects of parathyroid hormone infusion. Assessment by use of biochemical markers.

OBJECTIVE: Because parathyroid hormone (PTH) stimulates bone resorption, resistance to its actions might help maintain bone mass. We tested the hypothesis that the effects of estrogen on bone are accomplished in part by decreasing the sensitivity of the skeleton to the resorbing effects of PTH. STUDY DESIGN: Comparison of response to PTH infusion in untreated and estrogen-treated postmenopausal women with osteoporosis. INTERVENTION: (1-34) human PTH, 0.55 U/(kg.h), was infused intravenously over 20 hours. SETTING: The inpatient clinical research unit of a referral hospital. PATIENTS: Women with primary postmenopausal osteoporosis who were untreated (n = 15) or treated with estrogen (n = 17). MAIN OUTCOME MEASURES: Skeletal turnover indices including hydroxyproline, deoxypyridinoline, pyridinoline, tartrate-resistant acid phosphatase, alkaline phosphatase, bone Gla protein, and insulin-like growth factor-1. RESULTS: All basal indices were higher in untreated than in estrogen-treated women, but statistical differences were seen only for deoxypyridinoline and pyridinoline. During the 20-hour infusion, hydroxyproline/creatinine increased 0.023 mumol/mumol in untreated women but only 0.010 mumol/mumol in estrogen-treated women (P < 0.05). Corresponding changes for deoxypyridinoline/creatinine were 14.6 mumol/mumol and 3.5 mumol/mumol (P = 0.06). Tartrate-resistant acid phosphatase and pyridinoline increased only in untreated group. A circadian rhythm in circulating bone Gla protein was seen in both groups without clear PTH-induced effects or differences between groups. Alkaline phosphatase levels decreased and insulin-like growth factor-1 levels increased in both groups with no distinction between untreated and estrogen-treated women [corrected]. CONCLUSION: The estrogenized postmenopausal osteoporotic skeleton is less sensitive to the bone resorbing effects of acutely administered PTH. There are no differential effects on bone formation.

Aged↗
PubMedDate not supplied

The renal response to exogenous parathyroid hormone in treated pseudohypoparathyroidism.

Resistance to the renal actions of parathyroid hormone (PTH) in pseudohypoparathyroidism (PsH) may be improved after treatment with vitamin D or its metabolites, but reports conflict. We have examined the renal response to infusion of 35 micrograms of 1-38 PTH in patients with PsH type I (n = 8) and PsH type II (n = 1) during treatment and related this to prevailing endogenous serum PTH and calcium levels. Nine patients with postsurgical or idiopathic hypoparathyroidism (HP) served as controls. The urinary cAMP increase (delta cAMP) was lower (p < 0.001) in the PsH type I (175 +/- 6.4 nmol/l glomerular filtrate) than in the HP group (3251 +/- 515 nmol/l glomerular filtrate). delta cAMP in the PsH type I subjects was dependent on endogenous PTH concentrations (r = -0.76; p = 0.046) and serum calcium (r = 0.74; p = 0.037). Phosphaturic responses (expressed as % decrease in TmPO4/glomerular filtration rate) were lower (p = 0.013) in the PsH type I (28.8 +/- 3.75) compared with those of the HP patients (43 +/- 3.48). The phosphaturic responses in the PsH type I patients were strongly dependent on endogenous PTH (r = 0.94; p < 0.001) and serum calcium levels (r = 0.94; p < 0.001) so that the responses of subjects with normal or low PTH levels were no different (p = 0.16) from the HP group. Renal handling of calcium and sodium in response to exogenous PTH was identical in patients with PsH (types I and II) and HP. Renal tubular reabsorption during a calcium infusion was normal in all patients with PsH. These results emphasise the importance of the modulatory effects due to associated biochemical abnormalities in PsH on the responses to exogenous PTH. They also confirm that renal handling of calcium and sodium is probably normal in treated PsH.

Adult↗
PubMed2006

Skeletal actions of intermittent parathyroid hormone: effects on bone remodelling and structure.

Intermittent administration of parathyroid hormone peptides has anabolic skeletal effects and reduces fracture risk in postmenopausal women with osteoporosis but the cellular and structural mechanisms by which these effects are mediated have not been fully established. In cancellous and endocortical bone, there is evidence that both modelling and remodelling-based formation contribute to the increase in bone mass although the contribution of these at different time points in the response to PTH has not been established. Despite the large increase in spine bone mineral density, however, significant increases in iliac crest cancellous bone volume and trabecular thickness have not been consistently demonstrated, possibly reflecting site-specific differences in PTH-induced skeletal effects and/or the large sampling and measurement variance associated with assessment of iliac crest cancellous bone volume and structure. In iliac crest cortical bone, increased cortical thickness has been demonstrated, due at least in part to increased endosteal bone formation; there is also some evidence for increased formation on periosteal surfaces. At some sites an increase in cortical porosity may also occur and the overall effects on cortical bone strength, particularly at the hip, remain to be established. Studies in iliac crest bone indicate a trend towards a lower mineralisation density of bone matrix and increased heterogeneity of mineralisation, consistent with new bone formation. In addition, there is a reduction in mineral crystallinity and a shift towards more divalent collagen cross-links, indicating a change towards a younger bone profile. The potential clinical implications of these effects on bone are currently unknown. The stimulatory effect of PTH peptides on bone formation may favour their use in low turnover bone disease and in states of advanced bone loss. Furthermore, if beneficial effects on cortical bone strength are confirmed, efficacy at non-vertebral sites might be superior to those observed with antiresorptive drugs. Better definition of the effects of intermittent PTH administration on cancellous and cortical bone remodelling and structure at different skeletal sites may inform these speculations and is an important area for future research.

Bone Density↗
PubMed2006

PGC-1alpha is induced by parathyroid hormone and coactivates Nurr1-mediated promoter activity in osteoblasts.

Parathyroid hormone (PTH) potently activates cAMP-protein kinase A (PKA)-driven molecular cascades in osteoblasts. The NR4A/NGFI-B orphan nuclear receptor (NR) Nurr1 is a PTH-induced, cAMP-responsive primary response gene (PRG) that transactivates osteocalcin (Ocn) expression through a putative NGFI-B response element (NBRE) in the proximal promoter. As a true orphan NR, Nurr1's expression level and coactivator recruitment regulate its transactivation capacity. We postulated that Nurr1's induction through cAMP-PKA signaling might favor a coactivator that is likewise cAMP-dependent. A possible candidate is the cAMP-inducible coactivator PPARgamma coactivator-1alpha (PGC-1alpha). We hypothesize that PGC-1alpha is a PTH-induced PRG that synergizes with Nurr1 to induce target gene transcription in osteoblasts. We show that 10 nM PTH for 2 h maximally induced PGC-1alpha mRNA in primary mouse osteoblasts (MOBs) and calvariae. Selective signaling agonists and antagonists demonstrated that PTH induced PGC-1alpha mRNA primarily through the cAMP-PKA pathway. Protein synthesis inhibition sustained PTH-induced PGC-1alpha expression. PGC-1alpha enhanced Nurr1-induced transactivation of a consensus 3xNBRE-luciferase construct and the rat (-1050)Ocn promoter-luciferase construct from 3.7- to 9.6- and 10.1-fold, respectively. This synergy required Nurr1-DNA binding, since a mutation of the Ocn promoter NBRE abolished both Nurr1- and Nurr1-PGC-1alpha-induced transactivation. Using GST pull-down assays, PGC-1alpha directly interacted with in vitro-generated and nuclear Nurr1. We conclude that PGC-1alpha is a PTH-induced, cAMP-dependent PRG that directly synergizes with Nurr1 to transactivate target genes in osteoblasts. Taken together with published data, our findings suggest that Nurr1 and PGC-1alpha may be pivotal mediators of cAMP-induced osteoblast gene expression and osteoblast function.

Animals↗
PubMed2004

Evidence that the amino-terminal composition of non-(1-84) parathyroid hormone fragments starts before position 19.

BACKGROUND: Non-(1-84) parathyroid hormone (PTH) fragments are large C-terminal fragments of PTH with a partially preserved N-terminal structure. They differ from other C-terminal PTH fragments, which do not have an N-terminal structure and do not react in intact PTH assays. We aimed to identify the minimal N-terminal structure common to all non-(1-84) PTH fragments. METHODS: Sera obtained from six healthy individuals and six patients with primary hyperparathyroidism, and six serum pools from dialysis patients with different PTH concentrations were fractionated by HPLC and analyzed by four different PTH assays. Each assay was characterized by saturation analysis of its detection antibody and capacity to react with different PTH fragments. Human PTH(1-84) [hPTH(1-84)] calibrators were normalized to an in-house hPTH(1-84) calibrator. RESULTS: The cyclase-activating PTH (CA-PTH) assay had an early (1, 2,) epitope and reacted only with hPTH(1-84). The other assays had epitopes in region (13-34). Total and intact PTH assays had epitopes proximal to position 18 and reacted equally well with hPTH(1-84) and hPTH(7-84), and the Elecsys PTH assay had an epitope distal to position 19, being saturable by hPTH(18-48) and also reacting with [Tyr(34)]hPTH(19-84). The HPLC profiles obtained with these assays showed that non-(1-84) PTH fragments did not react in the CA-PTH assay, as expected. The amount of non-(1-84) PTH detected by the other three assays was similar when the assay results were normalized to a common calibrator. CONCLUSIONS: The results suggest that the amount of non-(1-84) PTH detected by epitopes proximal or distal to position 19 of the PTH structure is identical, indicating a common minimum structure starting before position 19. This in turn points to a probable high-affinity interaction with the C-PTH receptor, as observed previously with [Tyr(34)]hPTH(19-84) in various cell lines and in mouse osteocytes with PTH/PTHrP type I receptor ablation.

Calibration↗
PubMed2000

Influence of glomerular filtration rate on non-(1-84) parathyroid hormone (PTH) detected by intact PTH assays.

BACKGROUND: Commercial intact parathyroid hormone (I-PTH) assays detect molecular form(s) of human PTH, non-(1-84) PTH, different from the 84-amino acid native molecule. These molecular form(s) accumulate in hemodialyzed patients. We investigated the importance of non-(1-84) PTH in the interpretation of the increased I-PTH in progressive renal failure. METHODS: Five groups were studied: 26 healthy individuals, 12 hemodialyzed patients, and 31 patients with progressive renal failure subdivided according to their glomerular filtration rate (GFR) into 11 with a GFR between 60 and 100 mL. min(-1). 1.73 m(-2), 12 with a GFR between 30 and 60 mL. min(-1). 1.73 m(-2), and 8 with a GFR between 5 and 30 mL. min(-1). 1.73 m(-2). We evaluated indicators of calcium and phosphorus metabolism and creatinine clearance (CrCl) in the progressive renal failure groups, and the HPLC profile of I-PTH and C-terminal PTH in all groups. RESULTS: Only patients with a GFR <30 mL. min(-1). 1.73 m(-2) and hemodialyzed patients had decreased Ca(2+) and 1,25-dihydroxyvitamin D, and increased phosphate. In patients with progressive renal failure, I-PTH was related to Ca(2+) (r = -0.66; P <0.0001), CrCl (r = -0.61; P <0.001), 1,25-dihydroxyvitamin D (r = -0.40; P <0.05), and 25-hydroxyvitamin D (r = -0.49; P <0.01) by simple linear regression. The importance of non-(1-84) PTH in the composition of I-PTH increased with each GFR decrease, being 21% in healthy individuals, 32% in progressive renal failure patients with a GFR <30 mL. min(-1). 1.73 m(-2), and 50% in hemodialyzed patients, with PTH(1-84) making up the difference. CONCLUSIONS: As I-PTH increases progressively with GFR decrease, part of the increase is associated with the accumulation of non-(1-84) PTH, particularly when the GFR is <30 mL. min(-1). 1.73 m(-2). Concentrations of I-PTH 1.6-fold higher than in healthy individuals are necessary in hemodialyzed patients to achieve PTH(1-84) concentrations similar to those in the absence of renal failure.

Adult↗
PubMed1988

Glucocorticoids increase parathyroid hormone receptors in rat osteoblastic osteosarcoma cells (ROS 17/2).

The effects of glucocorticoids on parathyroid hormone (PTH) receptors was studied using rat osteosarcoma-derived cells (ROS 17/2), which have an osteoblastic phenotype, and [125I][Nle8,Nle18,Tyr34]bovine(b)PTH-(1-34)amide as the radioligand. Treatment of cells with physiologic concentrations of hydrocortisone resulted in a time and dose-dependent increase in PTH binding. The increase in PTH binding could be observed by 10 h of exposure to hydrocortisone (2 x 10(-7) M), was maximally enhanced by 48 h, and was maintained for the subsequent 7 days of continuous exposure to the steroid. With removal of hydrocortisone, PTH receptor binding promptly returned toward control levels. The increase in PTH binding was attributed to an increase in the availability of receptor binding sites, not to altered receptor binding affinity, and was blocked by cycloheximide. PTH-stimulated adenylate cyclase was also enhanced by glucocorticoids, and a close correlation was observed between PTH binding and PTH-stimulated adenylate cyclase. However, hydrocortisone not only increased PTH binding but also enhanced the efficiency of postreceptor signaling: 5'-guanylimidodiphosphate [Gpp(NH)p]- and forskolin-stimulated adenylate cyclase activities were also increased. Thus, enhanced PTH stimulation of adenylate cyclase by glucocorticoids resulted from at least two effects--increased receptor availability and enhanced postreceptor efficiency of transmembranous signaling.

Adenylyl Cyclases↗
PubMed1993

Parathyroid hormone related peptide gene expression in human fetal and adult heart.

OBJECTIVE: The aim was to investigate the expression of parathyroid hormone related peptide (PTHrP) gene in the human fetal and adult heart. METHODS: Molecular biological techniques were employed as well as immunocytochemistry and western blot analysis using rabbit polyclonal anti-PTHrP(1-34) and anti-PTHrP (56-86) on normal human fetal and adult heart tissues. Northern blot analysis of both normal human fetal and adult heart total RNA, using a human full length cDNA probe, and polymerase chain reaction analysis of normal human fetal and adult heart cDNAs with exon specific oligonucleotides were carried out. RESULTS: Positive staining was detected with both anti-PTHrP(1-34) and anti-PTHrP(56-86) in fetal heart at 12 weeks of gestation. In both fetal and adult hearts, multiple putative PTHrP proteins were observed with apparent molecular mass of 14-125 kDa. Multiple hybridising PTHrP mRNA isoforms (1.4, 2.1, 3.2, and 4.5 kb) were detected in both fetal and adult heart total RNAs. The fetal and adult heart cDNAs amplified from the cDNA libraries showed the presence of the 5' non-coding exon II and coding exons III-IV but not the 5' non-coding exon Ic. CONCLUSIONS: PTHrP is expressed in normal human fetal and adult hearts suggesting that it has a function as an endogenous modulator of the cardiovascular system.

Adult↗
PubMed2006

Parathyroid hormone induces mitogen-activated kinase phosphatase 1 in murine osteoblasts primarily through cAMP-protein kinase A signaling.

BACKGROUND: Parathyroid hormone (PTH) regulates osteoblast function by binding to the PTH receptor 1 (PTHR1) to activate downstream signaling to induce expression of primary response genes (PRGs), which affect various aspects of the osteoblast phenotype. We previously identified PTH-induced PRGs in MC3T3-E1 cells, including mitogen-activated protein kinase (MAPK) phosphatase 1 (mkp1), which dephosphorylates members of the MAPK family. The aim of this study was to explore the molecular mechanisms of PTH's induction of mkp1 in primary mouse osteoblasts. METHODS: Northern and Western analyses were used to determine mkp1 mRNA and protein expression. In vivo experiments were also performed to determine PTH's effect on mkp1 in mouse calvariae and long bones. RESULTS: A total of 10 nM PTH and PTH-related protein (PTHrP) maximally induced mkp1 mRNA levels after 1 hour in osteoblasts. PTH also increased mkp1 protein expression, and induced mkp1 mRNA independent of new protein synthesis. PTHR1 triggers protein kinase A (PKA), PKC, and calcium pathways. Although PKA and PKC agonists induced mkp1 mRNA levels, only cyclic adenosine 3':5'-monophosphate (cAMP)-PKA inhibition blocked PTH-induced mkp1 mRNA levels. These data suggest that PTH-induced mkp1 mRNA levels are primarily mediated through the cAMP-PKA pathway. Further, prostaglandin E2 (PGE2), which activates cAMP-PKA and PKC, induced mkp1 mRNA to a greater extent than PGF2alpha and fluprostenol, which activate PKC signaling only. Finally, PTH maximally induced mkp1 mRNA levels in mouse calvariae and long bones in vivo at 0.5 hours. CONCLUSIONS: mkp1's in vitro and in vivo induction in PTH-target tissues suggests its involvement in some of the effects of PTH on osteoblast function. mkp1 may be an important target gene in the anabolic effect of PTH on osteoblasts.

Animals↗
PubMed1986

Parathyroid hormone and calcitonin in diabetes mellitus.

Forty patients with diabetes mellitus and a reference group of forty-five healthy controls have been studied. Significantly increased serum concentrations of parathyroid hormone and calcitonin were found in the diabetics as well as increased levels of alkaline phosphatase activity and phosphate independent of the duration of the diabetic state. No difference was found in serum calcium levels when compared with the healthy controls. Since these results cannot be explained by diabetes nephropathy an altered balance between parathyroid hormone and calcitonin in diabetes mellitus is postulated.

Adolescent↗