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Sample records for mediating parathyroid hormone

  1. Gallbladder adenocarcinoma and paraneoplastic parathyroid hormone mediated hypercalcemia

    PubMed Central

    Yogarajah, Meera; Sivasambu, Bhradeev; Shiferaw-Deribe, Zewge

    2016-01-01

    Parathyroid hormone mediated hypercalcemia is not always exclusively primary hyperparathyroidism and rarely could be due to ectopic parathyroid hormone secretion from tumor cells. We present a case of 86-year-old female with metastatic gall bladder adenocarcinoma diagnosed eight months back who presented with generalized fatigue and poor oral intake and was found to be hypercalcemic with elevated parathyroid hormone levels. Imaging with technetium 99 m sestamibi scintigraphy with dual phase, subtraction thyroid scan (dual isotope scintigraphy), magnetic resonance imaging and ultrasonography did not demonstrate any parathyroid lesion in normal or ectopic sites. We believe that the tumor cells were the source of ectopic parathyroid hormone secretion as we had excluded all the other possibilities with extensive combined imaging thereby increasing the sensitivity of our testing. We report the first case of metastatic gall bladder adenocarcinoma with paraneoplastic ectopic parathyroid hormone secretion. PMID:27081650

  2. Gallbladder adenocarcinoma and paraneoplastic parathyroid hormone mediated hypercalcemia.

    PubMed

    Yogarajah, Meera; Sivasambu, Bhradeev; Shiferaw-Deribe, Zewge

    2016-04-10

    Parathyroid hormone mediated hypercalcemia is not always exclusively primary hyperparathyroidism and rarely could be due to ectopic parathyroid hormone secretion from tumor cells. We present a case of 86-year-old female with metastatic gall bladder adenocarcinoma diagnosed eight months back who presented with generalized fatigue and poor oral intake and was found to be hypercalcemic with elevated parathyroid hormone levels. Imaging with technetium 99 m sestamibi scintigraphy with dual phase, subtraction thyroid scan (dual isotope scintigraphy), magnetic resonance imaging and ultrasonography did not demonstrate any parathyroid lesion in normal or ectopic sites. We believe that the tumor cells were the source of ectopic parathyroid hormone secretion as we had excluded all the other possibilities with extensive combined imaging thereby increasing the sensitivity of our testing. We report the first case of metastatic gall bladder adenocarcinoma with paraneoplastic ectopic parathyroid hormone secretion. PMID:27081650

  3. Signal transduction pathways mediating parathyroid hormone regulation of osteoblastic gene expression

    NASA Technical Reports Server (NTRS)

    Partridge, N. C.; Bloch, S. R.; Pearman, A. T.

    1994-01-01

    Parathyroid hormone (PTH) plays a central role in regulation of calcium metabolism. For example, excessive or inappropriate production of PTH or the related hormone, parathyroid hormone related protein (PTHrP), accounts for the majority of the causes of hypercalcemia. Both hormones act through the same receptor on the osteoblast to elicit enhanced bone resorption by the osteoclast. Thus, the osteoblast mediates the effect of PTH in the resorption process. In this process, PTH causes a change in the function and phenotype of the osteoblast from a cell involved in bone formation to one directing the process of bone resorption. In response to PTH, the osteoblast decreases collagen, alkaline phosphatase, and osteopontin expression and increases production of osteocalcin, cytokines, and neutral proteases. Many of these changes have been shown to be due to effects on mRNA abundance through either transcriptional or post-transcriptional mechanisms. However, the signal transduction pathway for the hormone to cause these changes is not completely elucidated in any case. Binding of PTH and PTHrP to their common receptor has been shown to result in activation of protein kinases A and C and increases in intracellular calcium. The latter has not been implicated in any changes in mRNA of osteoblastic genes. On the other hand activation of PKA can mimic all the effects of PTH; protein kinase C may be involved in some responses. We will discuss possible mechanisms linking PKA and PKC activation to changes in gene expression, particularly at the nuclear level.

  4. In experimental chronic kidney disease or cancer, parathyroid hormone is a novel mediator of cachexia.

    PubMed

    Wyatt, Christina M; Mitch, William E

    2016-05-01

    Hyperparathyroidism plays a central role in the disordered bone mineral metabolism of chronic kidney disease, and has been associated with increased cardiovascular morbidity and mortality in that setting. A recent study suggests a novel role for parathyroid hormone and its receptor in muscle wasting and cachexia occurring in advanced chronic kidney disease. PMID:27083271

  5. In experimental chronic kidney disease or cancer, parathyroid hormone is a novel mediator of cachexia.

    PubMed

    Wyatt, Christina M; Mitch, William E

    2016-05-01

    Hyperparathyroidism plays a central role in the disordered bone mineral metabolism of chronic kidney disease, and has been associated with increased cardiovascular morbidity and mortality in that setting. A recent study suggests a novel role for parathyroid hormone and its receptor in muscle wasting and cachexia occurring in advanced chronic kidney disease.

  6. Bovine Parathyroid Hormone: Amino Acid Sequence

    PubMed Central

    Brewer, H. Bryan; Ronan, Rosemary

    1970-01-01

    Bovine parathyroid hormone has been isolated in homogeneous form, and its complete amino acid sequence determined. The bovine hormone is a single chain, 84 amino acids long. It contains amino-terminal alanine, and carboxyl-terminal glutamine. The bovine parathyroid hormone is approximately three times the length of the newly discovered hormone, thyrocalcitonin, whose action is reciprocal to parathyroid hormone. Images PMID:5275384

  7. Small Molecule Inhibited Parathyroid Hormone Mediated cAMP Response by N–Terminal Peptide Binding

    PubMed Central

    Kumar, Amit; Baumann, Monika; Balbach, Jochen

    2016-01-01

    Ligand binding to certain classes of G protein coupled receptors (GPCRs) stimulates the rapid synthesis of cAMP through G protein. Human parathyroid hormone (PTH), a member of class B GPCRs, binds to its receptor via its N–terminal domain, thereby activating the pathway to this secondary messenger inside cells. Presently, GPCRs are the target of many pharmaceuticals however, these drugs target only a small fraction of structurally known GPCRs (about 10%). Coordination complexes are gaining interest due to their wide applications in the medicinal field. In the present studies we explored the potential of a coordination complex of Zn(II) and anthracenyl–terpyridine as a modulator of the parathyroid hormone response. Preferential interactions at the N–terminal domain of the peptide hormone were manifested by suppressed cAMP generation inside the cells. These observations contribute a regulatory component to the current GPCR–cAMP paradigm, where not the receptor itself, but the activating hormone is a target. To our knowledge, this is the first report about a coordination complex modulating GPCR activity at the level of deactivating its agonist. Developing such molecules might help in the control of pathogenic PTH function such as hyperparathyroidism, where control of excess hormonal activity is essentially required. PMID:26932583

  8. Parathyroid Hormone Levels and Cognition

    NASA Technical Reports Server (NTRS)

    Burnett, J.; Smith, S.M.; Aung, K.; Dyer, C.

    2009-01-01

    Hyperparathyroidism is a well-recognized cause of impaired cognition due to hypercalcemia. However, recent studies have suggested that perhaps parathyroid hormone itself plays a role in cognition, especially executive dysfunction. The purpose of this study was to explore the relationship of parathyroid hormone levels in a study cohort of elders with impaied cognition. Methods: Sixty community-living adults, 65 years of age and older, reported to Adult Protective Services for self-neglect and 55 controls matched (on age, ethnicity, gender and socio-economic status) consented and participated in this study. The research team conducted in-home comprehensive geriatric assessments which included the Mini-mental state exam (MMSE), the 15-item geriatric depression scale (GDS) , the Wolf-Klein clock test and a comprehensive nutritional panel, which included parathyroid hormone and ionized calcium. Students t tests and linear regression analyses were performed to assess for bivariate associations. Results: Self-neglecters (M = 73.73, sd=48.4) had significantly higher PTH levels compared to controls (M =47.59, sd=28.7; t=3.59, df=98.94, p<.01). There was no significant group difference in ionized calcium levels. Overall, PTH was correlated with the MMSE (r=-.323, p=.001). Individual regression analyses revealed a statistically significant correlation between PTH and MMSE in the self-neglect group (r=-.298, p=.024) and this remained significant after controlling for ionized calcium levels in the regression. No significant associations were revealed in the control group or among any of the other cognitive measures. Conclusion: Parathyroid hormone may be associated with cognitive performance.

  9. Parathyroid hormone - Secretion and metabolism in vivo.

    NASA Technical Reports Server (NTRS)

    Habener, J. F.; Powell, D.; Murray, T. M.; Mayer, G. P.; Potts, J. T., Jr.

    1971-01-01

    Gel filtration and radioimmunoassay were used to determine the molecular size and immunochemical reactivity of parathyroid hormone present in gland extracts, in the general peripheral circulation, and in parathyroid effluent blood from patients with hyperparathyroidism, as well as from calves and from cattle. It was found that parathyroid hormone secreted from the parathyroids in man and cattle is at least as large as the molecule extracted from normal bovine glands. However, once secreted into the circulation the hormone is cleaved, and one or more fragments, immunologically, dissimilar to the originally secreted hormone, constitute the dominant form of circulating immunoreactive hormone.

  10. Mechanism of parathyroid hormone-mediated suppression of calcification markers in human intervertebral disc cells.

    PubMed

    Madiraju, P; Gawri, R; Wang, H; Antoniou, J; Mwale, F

    2013-01-01

    In degenerative intervertebral discs (IVD), type X collagen (COL X) expression (associated with hypertrophic differentiation) and calcification has been demonstrated. Suppression of COL X expression and calcification during disc degeneration can be therapeutic. In the present study we investigated the potential of human parathyroid hormone 1-34 (PTH) in suppressing indicators of calcification potential (alkaline phosphatase (ALP), Ca(2+), inorganic phosphate (Pi)), and COL X expression. Further, we sought to elucidate the mechanism of PTH action in annulus fibrosus (AF) and nucleus pulposus (NP) cells from human lumbar IVDs with moderate to advanced degeneration. Mitogen activated protein kinase (MAPK) signalling and alterations in the markers of calcification potential were analysed. PTH increased type II collagen (COL II) expression in AF (~200 %) and NP cells (~163 %) and decreased COL X levels both in AF and NP cells (~75 %). These changes in the expression of collagens were preceded by MAPK phosphorylation, which was increased in both AF and NP cells by PTH after 30 min. MAPK signalling inhibitor U0126 and protein kinase-A inhibitor H-89 DCH attenuated PTH stimulated COL II expression in both cell types. PTH decreased ALP activity and increased Ca(2+) release only in NP cells. The present study demonstrates that PTH can potentially retard IVD degeneration by stimulating matrix synthesis and suppressing markers of calcification potential in degenerated disc cells via both MAPK and PKA signalling pathways. Inhibition of further mineral deposition may therefore be a viable therapeutic option for improving the status of degenerating discs.

  11. Aluminum, parathyroid hormone, and osteomalacia

    SciTech Connect

    Burnatowska-Hledin, M.A.; Kaiser, L.; Mayor, G.H.

    1983-01-01

    Aluminum exposure in man is unavoidable. The occurrence of dialysis dementia, vitamin D-resistant osteomalacia, and hypochromic microcytic anemia in dialysis patients underscores the potential for aluminum toxicity. Although exposure via dialysate and hyperalimentation leads to significant tissue aluminum accumulation, the ubiquitous occurrence of aluminum and the severe pathology associated with large aluminum burdens suggest that smaller exposures via the gastrointestinal tract and lungs could represent an important, though largely unrecognized, public health problem. It is clear that some aluminum absorption occurs with the ingestion of small amounts of aluminum in the diet and medicines, and even greater aluminum absorption is seen in individuals consuming large amounts of aluminum present in antacids. Aluminum absorption is enhanced in the presence of elevated circulating parathyroid hormone. In addition, elevated PTH leads to the preferential deposition of aluminum in brain and bone. Consequently, PTH is likely to be involved in the pathogenesis of toxicities in those organs. PTH excess also seems to lead to the deposition of aluminum in the parathyroid gland. The in vitro demonstration that aluminum inhibits parathyroid hormone release is consistent with the findings of a euparathyroid state in dialysis patients with aluminum related vitamin D-resistant osteomalacia. Nevertheless, it seems likely that hyperparathyroidism is at least initially involved in the pathogenesis of aluminum neurotoxicity and osteomalacia; the increases in tissue aluminum stores are followed by suppression of parathyroid hormone release, which is required for the evolution of osteomalacia. Impaired renal function is not a prerequisite for increased tissue aluminum burdens, nor for aluminum-related organ toxicity. Consequently, it is likely that these diseases will be observed in populations other than those with chronic renal disease.

  12. Dynein light chain binding to a 3′-untranslated sequence mediates parathyroid hormone mRNA association with microtubules

    PubMed Central

    Epstein, Eyal; Sela-Brown, Alin; Ringel, Israel; Kilav, Rachel; King, Stephen M.; Benashski, Sharon E.; Yisraeli, Joel K.; Silver, Justin; Naveh-Many, Tally

    2000-01-01

    The 3′-untranslated region (UTR) of mRNAs binds proteins that determine mRNA stability and localization. The 3′-UTR of parathyroid hormone (PTH) mRNA specifically binds cytoplasmic proteins. We screened an expression library for proteins that bind the PTH mRNA 3′-UTR, and the sequence of 1 clone was identical to that of the dynein light chain LC8, a component of the dynein complexes that translocate cytoplasmic components along microtubules. Recombinant LC8 binds PTH mRNA 3′-UTR, as shown by RNA electrophoretic mobility shift assay. We showed that PTH mRNA colocalizes with microtubules in the parathyroid gland, as well as with a purified microtubule preparation from calf brain, and that this association was mediated by LC8. To our knowledge, this is the first report of a dynein complex protein binding an mRNA. The dynein complex may be the motor that is responsible for transporting mRNAs to specific locations in the cytoplasm and for the consequent is asymmetric distribution of translated proteins in the cell. PMID:10683380

  13. Parathyroid hormone therapy for hypoparathyroidism.

    PubMed

    Cusano, Natalie E; Rubin, Mishaela R; Bilezikian, John P

    2015-01-01

    Hypoparathyroidism is a disease characterized by hypocalcemia and insufficient parathyroid hormone (PTH). It is a rare disorder that has been given an orphan disease designation in the United States and European Union. Hypoparathyroidism is the only endocrine deficiency disease for which the missing hormone, PTH, is not yet an approved therapy. Conventional therapy includes calcium and active vitamin D supplementation, often in large doses. Although serum calcium can be controlled with conventional therapy, it can be a challenge and, moreover, does not address other aspects of the disease, such as abnormal skeletal features and reduced quality of life. This review focuses on PTH replacement therapy in hypoparathyroidism, utilizing the full-length molecule PTH(1-84) as well as the fully active but truncated form PTH(1-34). PTH therapy addresses some aspects of the disease not ameliorated with conventional therapy.

  14. 21 CFR 862.1545 - Parathyroid hormone test system.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Parathyroid hormone test system. 862.1545 Section... Systems § 862.1545 Parathyroid hormone test system. (a) Identification. A parathyroid hormone test system is a device intended to measure the levels of parathyroid hormone in serum and plasma....

  15. 21 CFR 862.1545 - Parathyroid hormone test system.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Parathyroid hormone test system. 862.1545 Section... Systems § 862.1545 Parathyroid hormone test system. (a) Identification. A parathyroid hormone test system is a device intended to measure the levels of parathyroid hormone in serum and plasma....

  16. 21 CFR 862.1545 - Parathyroid hormone test system.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Parathyroid hormone test system. 862.1545 Section... Systems § 862.1545 Parathyroid hormone test system. (a) Identification. A parathyroid hormone test system is a device intended to measure the levels of parathyroid hormone in serum and plasma....

  17. 21 CFR 862.1545 - Parathyroid hormone test system.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Parathyroid hormone test system. 862.1545 Section... Systems § 862.1545 Parathyroid hormone test system. (a) Identification. A parathyroid hormone test system is a device intended to measure the levels of parathyroid hormone in serum and plasma....

  18. 21 CFR 862.1545 - Parathyroid hormone test system.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Parathyroid hormone test system. 862.1545 Section... Systems § 862.1545 Parathyroid hormone test system. (a) Identification. A parathyroid hormone test system is a device intended to measure the levels of parathyroid hormone in serum and plasma....

  19. Parathyroid Hormone, Calcitonin, and Vitamin D

    NASA Technical Reports Server (NTRS)

    Potts, J. T.

    1972-01-01

    Analyses of secretion of parathyroid hormone during tests of stimulation and suppression of hormone-secretory activity using infusions of EDTA and calcium, respectively, have established that, in contrast to previous views, secretion of the hormone is not autonomous in many patients that have adenomatous hyperparathyroidism, but is responsive to changes in blood-calcium concentration. These findings have led to a new understanding of the pathophysiology of hormone production in hyperparathy-roidism. A related application of the diagnostic use of the radioimmunoassay is the preoperative localization of parathyroid tumors and the distinction between adenomas and chief-cell hyperplasia. Work involving catheterization and radioimmunoassay of blood samples obtained from the subclavin and innominate veins and the venae cavae, led to localization in a high percentage of patients. However, this procedure has been adopted recently to detect hormone concentration in the small veins directly draining the parathyroid glands.

  20. Parathyroid hormone is a plausible mediator for the metabolic syndrome in the morbidly obese: a cross-sectional study

    PubMed Central

    2011-01-01

    Background The biological mechanisms in the association between the metabolic syndrome (MS) and various biomarkers, such as 25-hydroxyvitamin D (vit D) and magnesium, are not fully understood. Several of the proposed predictors of MS are also possible predictors of parathyroid hormone (PTH). We aimed to explore whether PTH is a possible mediator between MS and various possible explanatory variables in morbidly obese patients. Methods Fasting serum levels of PTH, vit D and magnesium were assessed in a cross-sectional study of 1,017 consecutive morbidly obese patients (68% women). Dependencies between MS and a total of seven possible explanatory variables as suggested in the literature, including PTH, vit D and magnesium, were specified in a path diagram, including both direct and indirect effects. Possible gender differences were also included. Effects were estimated using Bayesian path analysis, a multivariable regression technique, and expressed using standardized regression coefficients. Results Sixty-eight percent of the patients had MS. In addition to type 2 diabetes and age, both PTH and serum phosphate had significant direct effects on MS; 0.36 (95% Credibility Interval (CrI) [0.15, 0.57]) and 0.28 (95% CrI [0.10,0.47]), respectively. However, due to significant gender differences, an increase in either PTH or phosphate corresponded to an increased OR for MS in women only. All proposed predictors of MS had significant direct effects on PTH, with vit D and phosphate the strongest; -0.27 (95% CrI [-0.33,-0.21]) and -0.26 (95% CrI [-0.32,-0.20]), respectively. Though neither vit D nor magnesium had significant direct effects on MS, for women they both affected MS indirectly, due to the strong direct effect of PTH on MS. For phosphate, the indirect effect on MS, mediated through serum calcium and PTH, had opposite sign than the direct effect, resulting in the total effect on MS being somewhat attenuated compared to the direct effect only. Conclusion Our results

  1. Parathyroid hormone (PTH) blood test

    MedlinePlus

    ... not produce enough PTH ( hypoparathyroidism ) Low levels of magnesium in the blood Radiation to the parathyroid glands Sarcoidosis Excess vitamin D intake Other conditions for which the test may be ...

  2. The soluble interleukin-6 receptor is a mediator of hematopoietic and skeletal actions of parathyroid hormone.

    PubMed

    Cho, Sun Wook; Pirih, Flavia Q; Koh, Amy J; Michalski, Megan; Eber, Matthew R; Ritchie, Kathryn; Sinder, Benjamin; Oh, Seojin; Al-Dujaili, Saja A; Lee, JoonHo; Kozloff, Ken; Danciu, Theodora; Wronski, Thomas J; McCauley, Laurie K

    2013-03-01

    Both PTH and IL-6 signaling play pivotal roles in hematopoiesis and skeletal biology, but their interdependence is unclear. The purpose of this study was to evaluate the effect of IL-6 and soluble IL-6 receptor (sIL-6R) on hematopoietic and skeletal actions of PTH. In the bone microenvironment, PTH stimulated sIL-6R protein levels in primary osteoblast cultures in vitro and bone marrow in vivo in both IL-6(+/+) and IL-6(-/-) mice. PTH-mediated hematopoietic cell expansion was attenuated in IL-6(-/-) compared with IL-6(+/+) bone marrow, whereas sIL-6R treatment amplified PTH actions in IL-6(-/-) earlier than IL-6(+/+) marrow cultures. Blocking sIL-6R signaling with sgp130 (soluble glycoprotein 130 receptor) inhibited PTH-dependent hematopoietic cell expansion in IL-6(-/-) marrow. In the skeletal system, although intermittent PTH administration to IL-6(+/+) and IL-6(-/-) mice resulted in similar anabolic actions, blocking sIL-6R significantly attenuated PTH anabolic actions. sIL-6R showed no direct effects on osteoblast proliferation or differentiation in vitro; however, it up-regulated myeloid cell expansion and production of the mesenchymal stem cell recruiting agent, TGF-β1 in the bone marrow microenvironment. Collectively, sIL-6R demonstrated orphan function and mediated PTH anabolic actions in bone in association with support of myeloid lineage cells in the hematopoietic system.

  3. [Lithium induced dysfunction of the parathyroid hormone].

    PubMed

    Valeur, Nana; Andersen, Rikke Steen

    2002-01-28

    The prevalence of hyperparathyroidism (HPT) in patients treated with lithium is higher than that in controls. Lithium seems to affect calcium metabolism, by acting directly parathyroid hormone cells, and distal tubuli in the kidneys. Because hypercalcaemic HPT can cause psychiatric symptoms mistakenly attributed to the lithium treatment, ionised calcium should be a standard control.

  4. Pharmacological regulation of parathyroid hormone secretion.

    PubMed

    Nemeth, E F

    2002-01-01

    Parathyroid hormone (PTH) is the key endocrine factor regulating systemic Ca(2+) homeostasis. Elevated levels of circulating PTH increase bone turnover and, depending on the duration of elevation, will result in net anabolic or catabolic effects on the skeleton. Secretion of PTH from the parathyroid glands is regulated by small changes in circulating levels of Ca(2+) which are detected by a Ca(2+) receptor on the surface of parathyroid cells. This G protein-coupled receptor is the primary molecular entity used by parathyroid cells to regulate secretion of PTH. As such, the Ca(2+) receptor is a unique molecular target for new drugs capable of increasing or decreasing circulating levels of PTH. Compounds which activate the Ca(2+) receptor are termed calcimimetics and they inhibit the secretion of PTH; a calcimimetic compound is in late stage clinical trials for the treatment of both primary and secondary hyperparathyroidism. Conversely, calcilytic compounds, which are Ca(2+) receptor antagonists, stimulate secretion of PTH; a calcilytic compound is in early clinical development for the treatment of osteoporosis. PMID:12171519

  5. Parathyroid hormone levels predict posttotal thyroidectomy hypoparathyroidism.

    PubMed

    Rivere, Amy E; Brooks, Ashton J; Hayek, Genevieve A; Wang, Heng; Corsetti, Ralph L; Fuhrman, George M

    2014-08-01

    We hypothesized that parathyroid hormone (PTH) determination would be the most effective strategy to identify posttotal thyroidectomy hypoparathyroidism (PTTHP) compared with other clinical and laboratory parameters. We retrospectively reviewed our recent experience with total thyroidectomy. We recorded demographics, malignancy, thyroid weight, parathyroid autotransplantation, hospital stay, use of postoperative calcium and hormonally active vitamin D3 (calcitriol), and postoperative serum calcium and PTH levels. Patients were divided into two groups depending on whether supplemental calcitriol was required to maintain eucalcemia and therefore reflecting the diagnosis of PTTHP. From October 2010 to June 2013, a total of 202 total thyroidectomies were performed. Twenty-four patients (12%) developed PTTHP and required calcitriol replacement. Logistic regression analysis revealed that only postoperative calcium levels (P = 0.02) and PTH levels (P < 0.0001) statistically significantly predicted PTTHP. Twenty-two of 29 patients with PTH 13 pg/mL or less had PTTHP. Only two of 173 patients with a PTH level greater than 13 pg/mL were diagnosed with PTTHP. We recommend using PTH levels after total thyroidectomy to determine which patients will have hypoparathyroidism requiring calcitriol therapy. An early determination of PTTHP allows for prompt management that can shorten hospital stay and improve outcomes.

  6. Immunoprecipitation of the parathyroid hormone receptor

    SciTech Connect

    Wright, B.S.; Tyler, G.A.; O'Brien, R.; Caporale, L.H.; Rosenblatt, M.

    1987-01-01

    An /sup 125/I-labeled synthetic analog of bovine parathyroid hormone, (8-norleucine,18-norleucine,34-tyrosine)PTH-(1-34) amide ((Nle)PTH-(1-34)-NH/sub 2/), purified by high-pressure liquid chromatography (HPLC), was employed to label the parathyroid hormone (PTH) receptor in cell lines derived from PTH target tissues: the ROS 17/2.8 rat osteosarcoma of bone and the CV1 and COS monkey kidney lines. After incubation of the radioligand with intact cultured cells, the hormone was covalently attached to receptors by using either a photoaffinity technique or chemical (affinity) crosslinking. In each case, covalent labeling was specific, as evidenced by a reduction of labeling when excess competing nonradioactive ligand was present. After covalent attachment of radioligand, membranes were prepared form the cells and solubilized in the nonionic detergent Nonidet P-40 or octyl glucoside. Analysis of the immunoprecipitate on NaDod-SO/sub 4//polyacrylamide gel electrophoresis followed by autoradiography revealed the presence of a doublet of apparent molecular mass 69-70 kDa. Specifically labeled bands of approximate molecular mass 95 and 28 kDa were also observed. The anti-PTH IgG was affinity purified by passage over a PTH-Sepharose column and used to made an immunoaffinity column. These studies suggest that the use of an anti-PTH antiserum that binds receptor-bound hormone is likely to be a useful step in the further physicochemical characterization and purification of the PTH receptor.

  7. Active acromegaly enhances spontaneous parathyroid hormone pulsatility.

    PubMed

    Mazziotti, Gherardo; Cimino, Vincenzo; De Menis, Ernesto; Bonadonna, Stefania; Bugari, Giovanna; De Marinis, Laura; Veldhuis, Johannes D; Giustina, Andrea

    2006-06-01

    In healthy subjects, parathyroid hormone (PTH) is secreted in a dual fashion, with low-amplitude and high-frequency pulses superimposed on tonic secretion. These 2 components of PTH secretion seem to have different effects on target organs. The aim of our study was to evaluate whether growth hormone excess in acromegaly may modify the spontaneous pulsatility of PTH. Five male patients with newly diagnosed active acromegaly and 8 healthy subjects were evaluated by 3-minute blood sampling for 6 hours. Plasma PTH concentrations were evaluated by multiparameter deconvolution analysis. Plasma PTH release profiles were also subjected to an approximate entropy (ApEn) estimate, which provides an ensemble measure of the serial regularity or orderliness of the release process. In acromegalic patients, baseline serum PTH values were not significantly different from those measured in the healthy subjects, as well as tonic PTH secretion rate, number of bursts, fractional pulsatile PTH secretion, and ApEn ratio. Conversely, PTH pulse half-duration was significantly longer in acromegalic patients vs healthy subjects (11.8+/-0.95 vs 6.9+/-1.6 minutes; P=.05), whereas PTH pulse mass showed a tendency (P=.06) to be significantly greater in acromegalic patients. These preliminary data suggest that growth hormone excess may affect PTH secretory dynamics in patients with acromegaly. Potentially negative bone effects of the modifications of PTH secretory pattern in acromegaly should be investigated.

  8. Calcemic Fraction-A: Biosynthetic Peptide Precursor of Parathyroid Hormone

    PubMed Central

    Cohn, David V.; Macgregor, Ronal R.; Chu, Luke L. H.; Kimmel, Joe R.; Hamilton, James W.

    1972-01-01

    Calcemic fraction-A (CF-A) is a biologically active, hypercalcemic and bone resorptive peptide, which was detected in, and isolated from, bovine parathyroid glands [Hamilton et al. (1971) Endocrinology 89, 1440-1447]. It has been further purified, and its relationship to parathyroid hormone clarified. The peptide is present in fresh glands at a concentration of about 3 μg/g (parathyroid hormone, 100 μg/g). It contains 109 amino acids (hormone, 84), each of which is present in equal or greater molar ratio than in the hormone. Its molecular weight, calculated from amino-acid composition, is 12,144; determined by dodecyl sulfate-polyacrylamide gel electrophoresis, it is 12,500 (hormone, 9563). Per mole, it reacts with antiserum to parathyroid hormone to an extent of 7-10% that of the hormone, and is about 50% as active in its hypercalcemic and bone resorptive properties in the appropriate assays. Time course and pulse-chase experiments with parathyroid gland slices, in which the incorporation of amino acid into isolated peptide and hormone were measured, indicate that the hormone is made from a protein precursor; the patterns of incorporation of radioactivity are those that would be predicted from a precursor-product relationship. When the large peptide was incubated with parathyroid gland extracts it was partially converted to a molecule that appeared to be the hormone, as based upon its coelution with marker hormone from ion-exchange columns. Finally, tryptic digestion of the peptide increased the immunoreactivity of the sample in accord with the known greater immunoreactivity of the hormone than the peptide. On the basis of these results, it is proposed that the peptide is a biosynthetic precursor of the hormone in bovine parathyroid gland. PMID:4504366

  9. Hypoparathyroidism: Replacement Therapy with Parathyroid Hormone

    PubMed Central

    Underbjerg, Line; Sikjaer, Tanja

    2015-01-01

    Hypoparathyroidism (HypoPT) is characterized by low serum calcium levels caused by an insufficient secretion of parathyroid hormone (PTH). Despite normalization of serum calcium levels by treatment with activated vitamin D analogues and calcium supplementation, patients are suffering from impaired quality of life (QoL) and are at increased risk of a number of comorbidities. Thus, despite normalization of calcium levels in response to conventional therapy, this should only be considered as an apparent normalization, as patients are suffering from a number of complications and calcium-phosphate homeostasis is not normalized in a physiological manner. In a number of recent studies, replacement therapy with recombinant human PTH (rhPTH(1-84)) as well as therapy with the N-terminal PTH fragment (rhPTH(1-34)) have been investigated. Both drugs have been shown to normalize serum calcium while reducing needs for activated vitamin D and calcium supplements. However, once a day injections cause large fluctuations in serum calcium. Twice a day injections diminish fluctuations, but don't restore the normal physiology of calcium homeostasis. Recent studies using pump-delivery have shown promising results on maintaining normocalcemia with minimal fluctuations in calcium levels. Further studies are needed to determine whether this may improve QoL and lower risk of complications. Such data are needed before replacement with the missing hormone can be recommended as standard therapy. PMID:26394728

  10. Degradation of parathyroid hormone in macrophage endosomes

    SciTech Connect

    Diment, S.; Martin, K.J.; Stahl, P.D.

    1986-05-01

    Parathyroid hormone (PTH) is secreted as an 84 amino acid protein that is rapidly cleaved between amino acids 34 and 35 by Kupffer cells in liver. The resulting amino terminal peptide (1-34) is active at PTH target organs (kidney and bone). Cathepsin D can process PTH to 1-34 in vitro, and a cathepsin D-like protease, which may rapidly process proteins, is present in endosomes of alveolar macrophages. The authors set out to determine whether PTH is degraded to 1-34 in endosomes, and to elucidate the mechanism of hormone processing in vivo. Intracellular transport of /sup 125/I-PTH was assessed by binding to alveolar macrophages at 4/sup 0/C, followed by internalization at 37/sup 0/C. Distribution of PTH among plasma membranes, endosomes and lysosomes was determined by subcellular fractionation. Degradation of the ligand to TCA-soluble fragments in each compartment was assayed at neutral and acid pH. 1-34 in supernatants was separated from undergraded PTH by gel filtration and detected by bioassay on kidney membranes. The authors data suggest that: 1) macrophages rapidly degrade PTH to TCA-soluble fragments. 2) macrophages do not secrete proteases that degrade extracellular PTH. 3) PTH is internalized into endocytic vesicles after 5 mins, but not delivered to lysosomes within 30 mins. 4) A bioactive peptide is released into the extracellular medium after 20 mins. 5) PTH is degraded in endosomes at acid pH by a pepstatin-sensitive protease.

  11. Hypoparathyroidism: Replacement Therapy with Parathyroid Hormone.

    PubMed

    Rejnmark, Lars; Underbjerg, Line; Sikjaer, Tanja

    2015-12-01

    Hypoparathyroidism (HypoPT) is characterized by low serum calcium levels caused by an insufficient secretion of parathyroid hormone (PTH). Despite normalization of serum calcium levels by treatment with activated vitamin D analogues and calcium supplementation, patients are suffering from impaired quality of life (QoL) and are at increased risk of a number of comorbidities. Thus, despite normalization of calcium levels in response to conventional therapy, this should only be considered as an apparent normalization, as patients are suffering from a number of complications and calcium-phosphate homeostasis is not normalized in a physiological manner. In a number of recent studies, replacement therapy with recombinant human PTH (rhPTH(1-84)) as well as therapy with the N-terminal PTH fragment (rhPTH(1-34)) have been investigated. Both drugs have been shown to normalize serum calcium while reducing needs for activated vitamin D and calcium supplements. However, once a day injections cause large fluctuations in serum calcium. Twice a day injections diminish fluctuations, but don't restore the normal physiology of calcium homeostasis. Recent studies using pump-delivery have shown promising results on maintaining normocalcemia with minimal fluctuations in calcium levels. Further studies are needed to determine whether this may improve QoL and lower risk of complications. Such data are needed before replacement with the missing hormone can be recommended as standard therapy. PMID:26394728

  12. Genetics and epigenetics of parathyroid hormone resistance.

    PubMed

    Bastepe, Murat

    2013-01-01

    End-organ resistance to the actions of parathyroid hormone (PTH) is defined as pseudohypoparathyroidism (PHP). Described originally by Fuller Albright and his colleagues in early 1940s, this rare genetic disease is subclassified into two types according to the nephrogenous response to the administration of biologically active PTH. In type I, the PTH-induced urinary excretion of both phosphate and cyclic AMP (cAMP) is blunted. In type II, only the PTH-induced urinary excretion of phosphate is blunted, while the cAMP response is unimpaired. Different subtypes of PHP type I have been described based on the existence of additional clinical features, such as resistance to other hormones and Albright's hereditary osteodystrophy, and underlying molecular defects. Genetic mutations responsible for the different subtypes of PHP type I involve the GNAS complex locus, an imprinted gene encoding the α-subunit of the stimulatory G protein (Gsα) and several other transcripts that are expressed in a parent-of-origin specific manner. Mutations in Gsα-coding GNAS exons cause PHP-Ia and, in some cases, PHP-Ic, while mutations that disrupt the imprinting of GNAS lead to PHP-Ib. PHP type II is less well characterized with respect to its molecular cause. Recently, however, mutations in PRKAR1A, a regulatory subunit of the cAMP-dependent protein kinase, have been identified in several cases of PTH and other hormone resistance and skeletal dysplasia that are considered to be affected by PHP type II due to unimpaired urinary excretion of cAMP following PTH administration.

  13. Genetics and epigenetics of parathyroid hormone resistance.

    PubMed

    Bastepe, Murat

    2013-01-01

    End-organ resistance to the actions of parathyroid hormone (PTH) is defined as pseudohypoparathyroidism (PHP). Described originally by Fuller Albright and his colleagues in early 1940s, this rare genetic disease is subclassified into two types according to the nephrogenous response to the administration of biologically active PTH. In type I, the PTH-induced urinary excretion of both phosphate and cyclic AMP (cAMP) is blunted. In type II, only the PTH-induced urinary excretion of phosphate is blunted, while the cAMP response is unimpaired. Different subtypes of PHP type I have been described based on the existence of additional clinical features, such as resistance to other hormones and Albright's hereditary osteodystrophy, and underlying molecular defects. Genetic mutations responsible for the different subtypes of PHP type I involve the GNAS complex locus, an imprinted gene encoding the α-subunit of the stimulatory G protein (Gsα) and several other transcripts that are expressed in a parent-of-origin specific manner. Mutations in Gsα-coding GNAS exons cause PHP-Ia and, in some cases, PHP-Ic, while mutations that disrupt the imprinting of GNAS lead to PHP-Ib. PHP type II is less well characterized with respect to its molecular cause. Recently, however, mutations in PRKAR1A, a regulatory subunit of the cAMP-dependent protein kinase, have been identified in several cases of PTH and other hormone resistance and skeletal dysplasia that are considered to be affected by PHP type II due to unimpaired urinary excretion of cAMP following PTH administration. PMID:23392091

  14. Cytochemical bioassay of parathyroid hormone in maternal and cord blood.

    PubMed Central

    Allgrove, J; Adami, S; Manning, R M; O'Riordan, J L

    1985-01-01

    Parathyroid hormone and calcium were measured in plasma taken from pregnant women at term and from the umbilical veins of their infants at birth. Three assays were used to measure parathyroid hormone, a cytochemical bioassay of bioactivity and two immunoradiometric assays, one specific for the amino terminus, the other specific for the carboxy terminus of the parathyroid hormone molecule. Plasma calcium was significantly higher in the infants than in the mothers. Maternal parathyroid hormone bioactivity and the amino terminus were both slightly raised, but the carboxy terminus value was normal; these findings supported the view that late pregnancy is a time of mild physiological hyperparathyroidism. In the infants, the amino terminus was undetectable and the carboxy terminus was either undetectable or towards the lower end of the normal range: bioactivity of parathyroid hormone was considerably raised and was related to the gradient of calcium across the placenta. This suggests that the parathyroid glands are not suppressed during fetal life and that they may play an important part in the maintenance of high fetal plasma calcium concentrations. PMID:3977382

  15. SIKs control osteocyte responses to parathyroid hormone

    PubMed Central

    Wein, Marc N.; Liang, Yanke; Goransson, Olga; Sundberg, Thomas B.; Wang, Jinhua; Williams, Elizabeth A.; O'Meara, Maureen J.; Govea, Nicolas; Beqo, Belinda; Nishimori, Shigeki; Nagano, Kenichi; Brooks, Daniel J.; Martins, Janaina S.; Corbin, Braden; Anselmo, Anthony; Sadreyev, Ruslan; Wu, Joy Y.; Sakamoto, Kei; Foretz, Marc; Xavier, Ramnik J.; Baron, Roland; Bouxsein, Mary L.; Gardella, Thomas J.; Divieti-Pajevic, Paola; Gray, Nathanael S.; Kronenberg, Henry M.

    2016-01-01

    Parathyroid hormone (PTH) activates receptors on osteocytes to orchestrate bone formation and resorption. Here we show that PTH inhibition of SOST (sclerostin), a WNT antagonist, requires HDAC4 and HDAC5, whereas PTH stimulation of RANKL, a stimulator of bone resorption, requires CRTC2. Salt inducible kinases (SIKs) control subcellular localization of HDAC4/5 and CRTC2. PTH regulates both HDAC4/5 and CRTC2 localization via phosphorylation and inhibition of SIK2. Like PTH, new small molecule SIK inhibitors cause decreased phosphorylation and increased nuclear translocation of HDAC4/5 and CRTC2. SIK inhibition mimics many of the effects of PTH in osteocytes as assessed by RNA-seq in cultured osteocytes and following in vivo administration. Once daily treatment with the small molecule SIK inhibitor YKL-05-099 increases bone formation and bone mass. Therefore, a major arm of PTH signalling in osteocytes involves SIK inhibition, and small molecule SIK inhibitors may be applied therapeutically to mimic skeletal effects of PTH. PMID:27759007

  16. Circulating parathyroid hormone and calcitonin in rats after spaceflight

    NASA Technical Reports Server (NTRS)

    Arnaud, Sara B.; Fung, Paul; Popova, Irina A.; Morey-Holton, Emily R.; Grindeland, Richard E.

    1992-01-01

    Parathyroid hormone and calcithonin, two major calcium-regulating hormones, were measured in the plasma of five experimental groups of rats to evaluate postflight calcium homeostasis after the 14-day Cosmos 2044 flight. Parathyroid hormone values were slightly higher in the flight animals (F) than in the appropriate cage and diet controls (S) (44 +/- 21 vs 21 +/- 4 pg/ml, P less than 0.05), but they were the same as in the vivarium controls (V), which had different housing and feeding schedules. The difference in F and V (22 +/- 11 vs 49 +/- 16 pg/ml, P less than 0.05) was most likely due to failure of circulating calcitonin in F to show the normal age-dependent increase which was demonstrated in age-matched controls in a separate experiment. Basal values for parathyroid hormone and calcitonin were unchanged after 2 wk of hindlimb suspension, a flight simulation model, in age-matched and younger rats. From a time course experiment serum calcium was higher and parathyroid hormone lower after 4 wk than in ambulatory controls. Postflight circulating levels of parathyroid hormone appear to reflect disturbances in calcium homeostasis from impaired renal function of undetermined cause, whereas levels of calcitonin reflect depression of a normal growth process.

  17. Osteoblast hydraulic conductivity is regulated by calcitonin and parathyroid hormone

    NASA Technical Reports Server (NTRS)

    Hillsley, M. V.; Frangos, J. A.

    1996-01-01

    It is our hypothesis that osteoblasts play a major role in regulating bone (re)modeling by regulating interstitial fluid (ISF) flow through individual bone compartments. We hypothesize that osteoblasts of the blood-bone membrane lining the bone surfaces are capable of regulating transosseous fluid flow. This regulatory function of the osteoblasts was tested in vitro by culturing a layer of rat calvarial osteoblasts on porous membranes. Such a layer of osteoblasts subjected to 7.3 mm Hg of hydrostatic pressure posed a significant resistance to fluid flow across the cell layer similar in magnitude to the resistance posed by endothelial monolayers in vitro. The hydraulic conductivity, the volumetric fluid flux per unit pressure drop, of the osteoblast layer was altered in response to certain hormones. Hydraulic conductivity decreased approximately 40% in response to 33 nM parathyroid hormone, while it exhibited biphasic behavior in response to calcitonin: increased 40% in response to 100 nM calcitonin and decreased 40% in response to 1000 nM calcitonin. Further, activation of adenylate cyclase by forskolin dramatically increased the hydraulic conductivity, while elevation of intracellular calcium, [Ca2+]i, by the calcium ionophore A23187 initially decreased the hydraulic conductivity at 5 minutes before increasing conductivity by 30 minutes. These results suggest that cyclic adenosine monophosphate (cAMP) and [Ca2+]i may mediate changes in the osteoblast hydraulic conductivity. The increase in hydraulic conductivity in response to 100 nM calcitonin and the decrease in response to PTH suggest that the stimulatory and inhibitory effects on bone formation of calcitonin and parathyroid hormone, respectively, may be due in part to alterations in bone fluid flow.

  18. The Roles of Parathyroid Hormone-Like Hormone during Mouse Preimplantation Embryonic Development

    PubMed Central

    Guo, Lei; Qi, Shu-Tao; Miao, De-Qiang; Liang, Xing-Wei; Li, Hui; Ou, Xiang-Hong; Huang, Xin; Yang, Cai-Rong; Ouyang, Ying-Chun; Hou, Yi; Sun, Qing-Yuan; Han, Zhiming

    2012-01-01

    Parathyroid hormone-like hormone (PTHLH) was first identified as a parathyroid hormone (PTH)-like factor responsible for humoral hypercalcemia in malignancies in the 1980s. Previous studies demonstrated that PTHLH is expressed in multiple tissues and is an important regulator of cellular and organ growth, development, migration, differentiation, and survival. However, there is a lack of data on the expression and function of PTHLH during preimplantation embryonic development. In this study, we investigated the expression characteristics and functions of PTHLH during mouse preimplantation embryonic development. The results show that Pthlh is expressed in mouse oocytes and preimplantation embryos at all developmental stages, with the highest expression at the MII stage of the oocytes and the lowest expression at the blastocyst stage of the preimplantation embryos. The siRNA-mediated depletion of Pthlh at the MII stage oocytes or the 1-cell stage embryos significantly decreased the blastocyst formation rate, while this effect could be corrected by culturing the Pthlh depleted embryos in the medium containing PTHLH protein. Moreover, expression of the pluripotency-related genes Nanog and Pou5f1 was significantly reduced in Pthlh-depleted embryos at the morula stage. Additionally, histone acetylation patterns were altered by Pthlh depletion. These results suggest that PTHLH plays important roles during mouse preimplantation embryonic development. PMID:22808183

  19. Parathyroid Hormone and Physical Exercise: a Brief Review

    PubMed Central

    Bouassida, Anissa; Latiri, Imed; Bouassida, Semi; Zalleg, Dalenda; Zaouali, Monia; Feki, Youssef; Gharbi, Najoua; Zbidi, Abdelkarim; Tabka, Zouhair

    2006-01-01

    Parathyroid hormone (PTH) is the major hormone regulating calcium metabolism and is involved in both catabolic and anabolic actions on bone. Intermittent PTH exposure can stimulate bone formation and bone mass when PTH has been injected. In contrast, continuous infusion of PTH stimulates bone resorption. PTH concentration may be affected by physical exercise and our review was designed to investigate this relationship. The variation in PTH concentration appears to be influenced by both exercise duration and intensity. There probably exists a stimulation threshold of exercise to alter PTH. PTH regulation is also influenced by the initial bone mineral content, age, gender, training state, and other hormonal and metabolic factors (catecholamines, lactic acid and calcium concentrations). Key Points Physical exercise can improve PTH secretion. Parathyroid hormone has both anabolic and catabolic effects on bone: intermittent treatment of PTH is anabolic whereas continuous treatment is catabolic. PMID:24353453

  20. Negative regulation of parathyroid hormone-related protein expression by steroid hormones

    SciTech Connect

    Kajitani, Takashi; Tamamori-Adachi, Mimi; Okinaga, Hiroko; Chikamori, Minoru; Iizuka, Masayoshi; Okazaki, Tomoki

    2011-04-15

    Highlights: {yields} Steroid hormones repress expression of PTHrP in the cell lines where the corresponding nuclear receptors are expressed. {yields} Nuclear receptors are required for suppression of PTHrP expression by steroid hormones, except for androgen receptor. {yields} Androgen-induced suppression of PTHrP expression appears to be mediated by estrogen receptor. -- Abstract: Elevated parathyroid hormone-related protein (PTHrP) is responsible for humoral hypercalcemia of malignancy (HHM), which is of clinical significance in treatment of terminal patients with malignancies. Steroid hormones were known to cause suppression of PTHrP expression. However, detailed studies linking multiple steroid hormones to PTHrP expression are lacking. Here we studied PTHrP expression in response to steroid hormones in four cell lines with excessive PTHrP production. Our study established that steroid hormones negatively regulate PTHrP expression. Vitamin D receptor, estrogen receptor {alpha}, glucocorticoid receptor, and progesterone receptor, were required for repression of PTHrP expression by the cognate ligands. A notable exception was the androgen receptor, which was dispensable for suppression of PTHrP expression in androgen-treated cells. We propose a pathway(s) involving nuclear receptors to suppress PTHrP expression.

  1. Magnesium modulates parathyroid hormone secretion and upregulates parathyroid receptor expression at moderately low calcium concentration

    PubMed Central

    Rodríguez-Ortiz, Maria E.; Canalejo, Antonio; Herencia, Carmen; Martínez-Moreno, Julio M.; Peralta-Ramírez, Alan; Perez-Martinez, Pablo; Navarro-González, Juan F.; Rodríguez, Mariano; Peter, Mirjam; Gundlach, Kristina; Steppan, Sonja; Passlick-Deetjen, Jutta; Muñoz-Castañeda, Juan R.; Almaden, Yolanda

    2014-01-01

    Background The interest on magnesium (Mg) has grown since clinical studies have shown the efficacy of Mg-containing phosphate binders. However, some concern has arisen for the potential effect of increased serum Mg on parathyroid hormone (PTH) secretion. Our objective was to evaluate the direct effect of Mg in the regulation of the parathyroid function; specifically, PTH secretion and the expression of parathyroid cell receptors: CaR, the vitamin D receptor (VDR) and FGFR1/Klotho. Methods The work was performed in vitro by incubating intact rat parathyroid glands in different calcium (Ca) and Mg concentrations. Results Increasing Mg concentrations from 0.5 to 2 mM produced a left shift of PTH–Ca curves. With Mg 5 mM, the secretory response was practically abolished. Mg was able to reduce PTH only if parathyroid glands were exposed to moderately low Ca concentrations; with normal–high Ca concentrations, the effect of Mg on PTH inhibition was minor or absent. After 6-h incubation at a Ca concentration of 1.0 mM, the expression of parathyroid CaR, VDR, FGFR1 and Klotho (at mRNA and protein levels) was increased with a Mg concentration of 2.0 when compared with 0.5 mM. Conclusions Mg reduces PTH secretion mainly when a moderate low calcium concentration is present; Mg also modulates parathyroid glands function through upregulation of the key cellular receptors CaR, VDR and FGF23/Klotho system. PMID:24103811

  2. Catabolic and anabolic actions of parathyroid hormone on the skeleton.

    PubMed

    Silva, B C; Costa, A G; Cusano, N E; Kousteni, S; Bilezikian, J P

    2011-11-01

    PTH, an 84-amino acid peptide hormone synthesized by the parathyroid glands, is essential for the maintenance of calcium homeostasis.While in its traditional metabolic role, PTH helps to maintain the serum calcium concentration within narrow, normal limits and participates as a determinant of bone remodeling, more specific actions, described as catabolic and anabolic are also well known. Clinically, the catabolic effect of PTH is best represented by primary hyperparathyroidism (PHPT), while the osteoanabolic effect of PTH is best seen when PTH or its biological amino-terminal fragment [PTH(1-34)] is used as a therapy for osteoporosis. These dual functions of PTH are unmasked under very specific pathological (PHPT) or therapeutic conditions. At the cellular level, PTH favors bone resorption, mostly by affecting the receptor activator of nuclear factor κ-B (RANK) ligand (RANKL)-osteoprotegerin- RANK system, leading to an increase in osteoclast formation and activity. Increased bone formation due to PTH therapy is explained best by its ability to enhance osteoblastogenesis and/or osteoblast survival. The PTH-induced bone formation is mediated, in part, by a decrease in SOST/sclerostin expression in osteocytes. This review focuses on the dual anabolic and catabolic actions of PTH on bone, situations where one is enhanced over the other, and the cellular and molecular mechanisms by which these actions are mediated.

  3. Hair-cycle-dependent expression of parathyroid hormone-related protein and its type I receptor: evidence for regulation at the anagen to catagen transition.

    PubMed

    Cho, Yong Mee; Woodard, Grant L; Dunbar, Maureen; Gocken, Todd; Jimènez, Juan A; Foley, John

    2003-05-01

    The humoral hypercalcemia factor parathyroid hormone-related protein is a paracrine-signaling molecule that regulates the development of several organ systems, including the skin. In pathologic circumstances such as hypercalcemia and in development, parathyroid hormone-related protein signaling appears to be mediated by the type I parathyroid hormone/parathyroid hormone-related protein receptor. In order to clarify the role of the ligand and receptor pair in cutaneous biology, gene expression was monitored in a series of murine skin samples ranging from embryonic day 14 to 2 y with in situ hybridization and RNase protection. In all samples, high levels of parathyroid hormone-related protein transcripts were exclusively expressed in the developing and adult hair follicle but were not observed in the interfollicular epidermis. In the adult, parathyroid hormone-related protein mRNA expression was dynamically regulated as a function of the murine hair cycle in a way similar to other signaling molecules that regulate the anagen to catagen transition. PTH receptor transcripts were abundantly expressed in the developing dermis. In the adult skin, PTH receptor mRNA was markedly reduced, but again demonstrated hair-cycle-dependent expression. The dorsal skin of the keratin 14-parathyroid hormone-related protein mouse was used to evaluate the impact of overexpression of the peptide on the murine hair cycle. All types of hair were 30-40% shorter in adult keratin 14-parathyroid hormone-related protein mice as compared with wild-type littermates. This appeared to result from a premature entry into the catagen phase of the hair cycle. Finally, the relationship between parathyroid hormone-related protein signaling and other growth factors that regulate the hair cycle was examined by cross-breeding experiments employing keratin 14-parathyroid hormone-related protein mice and fibroblast growth factor-5-knockout mice. It appears that parathyroid hormone-related protein and

  4. Recombinant production of TEV cleaved human parathyroid hormone.

    PubMed

    Audu, Christopher O; Cochran, Jared C; Pellegrini, Maria; Mierke, Dale F

    2013-08-01

    The parathyroid hormone, PTH, is responsible for calcium and phosphate ion homeostasis in the body. The first 34 amino acids of the peptide maintain the biological activity of the hormone and is currently marketed for calcium imbalance disorders. Although several methods for the production of recombinant PTH(1-34) have been reported, most involve the use of cleavage conditions that result in a modified peptide or unfavorable side products. Herein, we detail the recombinant production of (15) N-enriched human parathyroid hormone, (15) N PTH(1-34), generated via a plasmid vector that gives reasonable yield, low-cost protease cleavage (leaving the native N-terminal serine in its amino form), and purification by affinity and size exclusion chromatography. We characterize the product by multidimensional, heteronuclear NMR, circular dichroism, and LC/MS. PMID:23794508

  5. Parathyroid hormone: a double-edged sword for bone metabolism.

    PubMed

    Qin, Ling; Raggatt, Liza J; Partridge, Nicola C

    2004-03-01

    Parathyroid hormone (PTH) is the major hormone regulating calcium metabolism. It is also the only FDA-approved drug for osteoporosis treatment that stimulates bone formation when injected daily. However, continuous infusion of PTH causes severe bone loss in line with its known catabolic effects. Many studies to understand the dual effects of PTH have been carried out, and in recent years a growing number of molecular and cellular mechanisms underlying these effects have emerged. Here, we outline the present knowledge and conclude that the kinetics of administration and subsequent signaling probably account for the divergent actions of the hormone. PMID:15036251

  6. Analysis of Parathyroid Hormone and Its Fragments in Rat Tissues

    PubMed Central

    D'Amour, Pierre; Segre, Gino V.; Roth, Sanford I.; Potts, John T.

    1979-01-01

    After intravenous injection of [125I]-iodo-parathyroid hormone in the rat, uptake of the hormone was greatest in the liver and kidneys. Uptake was rapid, reaching a maximal concentration by 4 and 8 min, respectively. Extracts, prepared from both these organs at intervals soon after the injection of intact hormone, showed three main radioactive peaks when samples were subjected to gel filtration under protein-denaturing conditions. The first peak coeluted with intact hormone. The second eluted at a position corresponding to the carboxy-terminal fragments previously described in plasma, and the last eluted at the salt volume of the column. Microsequence analysis of the radioiodinated fragments, a method that has proved valuable for chemically defining the circulating fragments resulting from metabolism of injected hormone, showed that extracts of liver and kidney, prepared at 4 and 8 min after injection of the intact hormone, contained different fragments. The radioiodinated fragments in liver extracts were identical to those previously reported in the plasma of rats and dogs, fragments resulting principally from proteolysis between positions 33 and 34, and 36 and 37 of the intact hormone. Although the same fragments were also present in the kidneys, they constituted less than 15% of the amount present in the liver. More than 50% of the labeled renal fragments consisted of a peptide whose amino-terminal amino acid was position 39 of the intact hormone, a fragment not present in plasma. The rate of appearance of radioiodinated fragments that were chemically identical to those in plasma was more rapid in the liver than in plasma. Correlation of these chemical analyses with studies of the localization of 125I by autoradiography showed that at the times when the intact hormone and the carboxy-terminal fragments comprised nearly all of the 125I-labeled moieties in the tissues, the proximal convoluted tubules of the kidney and sinusoidal lining cells of the liver, which

  7. Vitamin D metabolites and bioactive parathyroid hormone levels during Spacelab 2

    NASA Technical Reports Server (NTRS)

    Morey-Holton, Emily R.; Schnoes, Heinrich K.; Deluca, Hector F.; Phelps, Mary E.; Klein, Robert F.

    1988-01-01

    The effect of an 8-day space flight (Spacelab mission 2) on plasma levels of the vitamin D and parathyroid hormones is investigated experimentally in four crew members. The results are presented in tables and graphs and briefly characterized. Parathyroid hormone levels remained normal throughout the flight, whereas vitamin D hormone levels increased significantly on day 1 but returned to normal by day 7.

  8. Parathyroid hormone and growth in chronic kidney disease.

    PubMed

    Waller, Simon

    2011-02-01

    Growth failure is common in children with chronic kidney disease, and successful treatment is a major challenge in the management of these children. The aetiology is multi-factorial with "chronic kidney disease-metabolic bone disorder" being a key component that is particularly difficult to manage. Parathyroid hormone is at the centre of this mineral imbalance, consequent skeletal disease and, ultimately, growth failure. When other aetiologies are treated, good growth can be achieved throughout the course of the disease when parathyroid hormone (PTH) levels are in the normal range or slightly elevated. A direct correlation between PTH levels and growth has not been convincingly established, and the direct effect of PTH on growth has not been adequately described; furthermore, direct actions of PTH on the growth plate are unproven. The effects of PTH on growth stem from the pivotal role that PTH plays in the development of renal osteodystrophy. In severe secondary hyperparathyroidism, the growth plate is altered and growth is affected. At the other end of the spectrum, with an over-suppressed parathyroid gland, the rate of bone turnover and remodelling is markedly diminished, and some data suggest this is associated with poor growth. Most of the data available suggests that avoiding the development of significant bone disease through the strict control of PTH levels permits good growth. Absolute optimal ranges for PTH that maximise growth or minimise growth failure are not yet established.

  9. Structural Basis for Antibody Discrimination between Two Hormones That Recognize the Parathyroid Hormone Receptor

    SciTech Connect

    McKinstry, William J.; Polekhina, Galina; Diefenbach-Jagger, Hannelore; Ho, Patricia W.M.; Sato, Koh; Onuma, Etsuro; Gillespie, Matthew T.; Martin, T. John; Parker, Michael W.

    2009-08-18

    Parathyroid hormone-related protein (PTHrP) plays a vital role in the embryonic development of the skeleton and other tissues. When it is produced in excess by cancers it can cause hypercalcemia, and its local production by breast cancer cells has been implicated in the pathogenesis of bone metastasis formation in that disease. Antibodies have been developed that neutralize the action of PTHrP through its receptor, parathyroid hormone receptor 1, without influencing parathyroid hormone action through the same receptor. Such neutralizing antibodies against PTHrP are therapeutically effective in animal models of the humoral hypercalcemia of malignancy and of bone metastasis formation. We have determined the crystal structure of the complex between PTHrP (residues 1-108) and a neutralizing monoclonal anti-PTHrP antibody that reveals the only point of contact is an {alpha}-helical structure extending from residues 14-29. Another striking feature is that the same residues that interact with the antibody also interact with parathyroid hormone receptor 1, showing that the antibody and the receptor binding site on the hormone closely overlap. The structure explains how the antibody discriminates between the two hormones and provides information that could be used in the development of novel agonists and antagonists of their common receptor.

  10. Structural Basis for Antibody Discrimination between Two Hormones That Recognize the Parathyroid Hormone Receptor*

    PubMed Central

    McKinstry, William J.; Polekhina, Galina; Diefenbach-Jagger, Hannelore; Ho, Patricia W. M.; Sato, Koh; Onuma, Etsuro; Gillespie, Matthew T.; Martin, T. John; Parker, Michael W.

    2009-01-01

    Parathyroid hormone-related protein (PTHrP) plays a vital role in the embryonic development of the skeleton and other tissues. When it is produced in excess by cancers it can cause hypercalcemia, and its local production by breast cancer cells has been implicated in the pathogenesis of bone metastasis formation in that disease. Antibodies have been developed that neutralize the action of PTHrP through its receptor, parathyroid hormone receptor 1, without influencing parathyroid hormone action through the same receptor. Such neutralizing antibodies against PTHrP are therapeutically effective in animal models of the humoral hypercalcemia of malignancy and of bone metastasis formation. We have determined the crystal structure of the complex between PTHrP (residues 1–108) and a neutralizing monoclonal anti-PTHrP antibody that reveals the only point of contact is an α-helical structure extending from residues 14–29. Another striking feature is that the same residues that interact with the antibody also interact with parathyroid hormone receptor 1, showing that the antibody and the receptor binding site on the hormone closely overlap. The structure explains how the antibody discriminates between the two hormones and provides information that could be used in the development of novel agonists and antagonists of their common receptor. PMID:19346515

  11. Parathyroid hormone ablation alters erythrocyte parameters that are rescued by calcium-sensing receptor gene deletion.

    PubMed

    Romero, Jose R; Youte, Rodeler; Brown, Edward M; Pollak, Martin R; Goltzman, David; Karaplis, Andrew; Pong, Lie-Chin; Chien, Lawrence; Chattopadhyay, Naibedya; Rivera, Alicia

    2013-07-01

    The mechanisms by which parathyroid hormone (PTH) produces anemia are unclear. Parathyroid hormone secretion is regulated by the extracellular Ca2+ -sensing receptor. We investigated the effects of ablating PTH on hematological indices and erythrocytes volume regulation in wild-type, PTH-null, and Ca2+ -sensing receptor-null/PTH-null mice. The erythrocyte parameters were measured in whole mouse blood, and volume regulatory systems were determined by plasma membrane K+ fluxes, and osmotic fragility was measured by hemoglobin determination at varying osmolarities. We observed that the absence of PTH significantly increases mean erythrocyte volume and reticulocyte counts, while decreasing erythrocyte counts, hemoglobin, hematocrit, and mean corpuscular hemoglobin concentration. These changes were accompanied by increases in erythrocyte cation content, a denser cell population, and increased K+ permeability, which were in part mediated by activation of the K+ /Cl- cotransporter and Gardos channel. In addition we observed that erythrocyte osmotic fragility in PTH-null compared with wild-type mice was enhanced. When Ca2+ -sensing receptor gene was deleted on the background of PTH-null mice, we observed that several of the alterations in erythrocyte parameters of PTH-null mice were largely rescued, particularly those related to erythrocyte volume, K+ fluxes and osmotic fragility, and became similar to those observed in wild-type mice. Our results demonstrate that Ca2+ -sensing receptor and parathyroid hormone are functionally coupled to maintain erythrocyte homeostasis. PMID:23528155

  12. Use of parathyroid hormone in hypoparathyroidism.

    PubMed

    Cusano, N E; Rubin, M R; Irani, D; Sliney, J; Bilezikian, J P

    2013-12-01

    Hypoparathyroidism is a disorder characterized by hypocalcemia, deficient PTH, and abnormal bone remodeling. Standard treatment of hypoparathyroidism consists of oral calcium and vitamin D supplementation. However, maintaining serum calcium levels can be a challenge. In addition, concerns exist regarding hypercalciuria and ectopic calcifications that can be associated with such treatment. Hypoparathyroidism is the only classic endocrine deficiency disease for which the missing hormone, PTH, is not yet an approved treatment. This review focuses on the use of PTH in the treatment of hypoparathyroidism, in the form of teriparatide [PTH(1-34)] and the full-length molecule, PTH(1-84). Studies in hypoparathyroid subjects demonstrate that PTH(1-34) and PTH(1-84) lower or abolish supplemental calcium and vitamin D requirements as well as increase markers of bone turnover. Densitometric and histomorphometric studies in some subjects treated with PTH(1- 34) and PTH(1-84) show an improvement in bone-remodeling dynamics and return of bone metabolism toward normal levels. Given the chronic nature of hypoparathyroidism, and the expectation that PTH will be used for extended periods of time in hypoparathyroidism, further studies are needed to determine the long-term safety of PTH therapy in this population.

  13. Evolution of the parathyroid hormone family and skeletal formation pathways.

    PubMed

    Danks, Janine A; D'Souza, Damian G; Gunn, Haley J; Milley, Kristi M; Richardson, Samantha J

    2011-01-01

    Bone is considered to be a feature of higher vertebrates and one of the features that was required for the movement from water onto land. But there are a number of evolutionarily important species that have cartilaginous skeletons, including sharks. Both bony and cartilaginous fish are believed to have a common ancestor who had a bony skeleton. A number of factors and pathways have been shown to be involved in the development and maintenance of bony skeleton including the Wnt pathway and the parathyroid hormone gene family. The study of these pathways and factors in cartilaginous animals may shed light on the evolution of the vertebrate skeleton. PMID:21074535

  14. Heterogeneity of Parathyroid Hormone. CLINICAL AND PHYSIOLOGIC IMPLICATIONS

    PubMed Central

    Silverman, Robert; Yalow, Rosalyn S.

    1973-01-01

    When immunoreactive human parathyroid hormone (hPTH), extracted by three different solvents (20% acetone in 1% acetic acid, 8 M urea, or normal saline) from parathyroid glandular tissue was subjected to Sephadex G-100 gel filtration and immunoassay using two different antisera (273 and C-329), four distinct fractions were observed. The first (I), a void volume peak, was detected by both antisera with similar immunoreactivity, as was a second (II), which had the elution and sedimentation properties of highly purified bovine parathyroid hormone (bPTH); a third (III) eluted between [125I]growth hormone and [125I]insulin, sedimented with the velocity of a molecule of approximately 6,000 mol wt, and was detected primarily by antiserum 273; a final fraction (IV), detected primarily by C-329, eluted just prior to [125I]insulin. The elution profiles of the acetone-acetic acid and 8 M urea extracts were similar and contained fraction II as their major component. In saline extracts, however, fraction III predominated. Three fractions, having gel filtration and immunologic characteristics similar to fractions II, III, and IV, respectively, of saline glandular extracts, were detected in the plasma of patients with both primary (adenomatous or carcinomatous) and secondary hyperparathyroidism. The predominant component in every plasma was the intermediate fraction that, like III, was detected primarily by antiserum 273, while the least abundant form was consistently the final fraction, detected primarily by antiserum C-329. The first fraction, like II, was detected with about equal potency by both antisera and had an elution volume on Sephadex corresponding to that of intact bPTH. It bore a reciprocal relationship to serum calcium and disappeared from the plasma of a uremic patient during calcium infusion or following parathyroidectomy with a half-time of no more than 20 min. This component therefore probably represents biologically active hormone. The intermediate and final

  15. Molecular cloning of the gene encoding the mouse parathyroid hormone/parathyroid hormone-related peptide receptor.

    PubMed Central

    McCuaig, K A; Clarke, J C; White, J H

    1994-01-01

    The parathyroid hormone/parathyroid hormone-related peptide receptor (PTHR) is a G-protein-coupled receptor containing seven predicted transmembrane domains. We have isolated and characterized recombinant bacteriophage lambda EMBL3 genomic clones containing the mouse PTHR gene, including 10 kilobases of the promoter region. The gene spans > 32 kilobases and is divided into 15 exons, 8 of which contain the transmembrane domains. The PTHR exons containing the predicted membrane-spanning domains are heterogeneous in length and three of the exon-intron boundaries fall within putative transmembrane sequences, suggesting that the exons did not arise from duplication events. This arrangement is closely related to that of the growth hormone releasing factor receptor gene, particularly in the transmembrane region, providing strong evidence that the two genes evolved from a common precursor. Transcription is initiated principally at a series of sites over a 15-base-pair region. The proximal promoter region is highly (G+C)-rich and lacks an apparent TATA box or initiator element homologies but does contain CCGCCC motifs. The presumptive amino acid sequence of the encoded receptor is 99%, 91%, and 76% identical to those of the rat, human, and opossum receptors, respectively. There is no consensus polyadenylation signal in the 3' untranslated region. The poly(A) tail of the PTHR transcript begins 32 bases downstream of a 35-base-long A-rich sequence, suggesting that this region directs polyadenylylation. Images PMID:8197183

  16. Parathyroid hormone/parathyroid hormone-related peptide regulate osteosarcoma cell functions: Focus on the extracellular matrix (Review).

    PubMed

    Nikitovic, Dragana; Kavasi, Rafaela-Maria; Berdiaki, Aikaterini; Papachristou, Dionysios J; Tsiaoussis, John; Spandidos, Demetrios A; Tsatsakis, Aristides M; Tzanakakis, George N

    2016-10-01

    Osteosarcoma (OS) is a primary bone tumor of mesenchymal origin mostly affecting children and adolescents. The OS extracellular matrix (ECM) is extensively altered as compared to physiological bone tissue. Indeed, the main characteristic of the most common osteoblastic subtype of OS is non‑mineralized osteoid production. Parathyroid hormone (PTH) is a polypeptide hormone secreted by the chief cells of the parathyroid glands. The PTH-related peptide (PTHrP) may be comprised of 139, 141 or 173 amino acids and exhibits considerate N‑terminal amino acid sequence homology with PTH. The function of PTH/PTHrP is executed through the activation of the PTH receptor 1 (PTHR1) and respective downstream intracellular pathways which regulate skeletal development, bone turnover and mineral ion homeostasis. Both PTHR1 and its PTH/PTHrP ligands have been shown to be expressed in OS and to affect the functions of these tumor cells. This review aims to highlight the less well known aspects of PTH/PTHrP functions in the progression of OS by focusing on ECM-dependent signaling.

  17. Parathyroid hormone/parathyroid hormone-related peptide regulate osteosarcoma cell functions: Focus on the extracellular matrix (Review)

    PubMed Central

    Nikitovic, Dragana; Kavasi, Rafaela-Maria; Berdiaki, Aikaterini; Papachristou, Dionysios J.; Tsiaoussis, John; Spandidos, Demetrios A.; Tsatsakis, Aristides M.; Tzanakakis, George N.

    2016-01-01

    Osteosarcoma (OS) is a primary bone tumor of mesenchymal origin mostly affecting children and adolescents. The OS extracellular matrix (ECM) is extensively altered as compared to physiological bone tissue. Indeed, the main characteristic of the most common osteoblastic subtype of OS is non-mineralized osteoid production. Parathyroid hormone (PTH) is a polypeptide hormone secreted by the chief cells of the parathyroid glands. The PTH-related peptide (PTHrP) may be comprised of 139, 141 or 173 amino acids and exhibits considerate N-terminal amino acid sequence homology with PTH. The function of PTH/PTHrP is executed through the activation of the PTH receptor 1 (PTHR1) and respective downstream intracellular pathways which regulate skeletal development, bone turnover and mineral ion homeostasis. Both PTHR1 and its PTH/PTHrP ligands have been shown to be expressed in OS and to affect the functions of these tumor cells. This review aims to highlight the less well known aspects of PTH/PTHrP functions in the progression of OS by focusing on ECM-dependent signaling. PMID:27499459

  18. Vascular effects of parathyroid hormone and parathyroid hormone-related protein in the split hydronephrotic rat kidney.

    PubMed Central

    Endlich, K; Massfelder, T; Helwig, J J; Steinhausen, M

    1995-01-01

    1. The effects of locally applied parathyroid hormone-related protein (PTHRP), a putative autocrine/paracrine hormone, on vascular diameters and glomerular blood flow (GBF) in the split hydronephrotic rat kidney were studied. As PTHRP interacts with parathyroid hormone (PTH) receptors in all tissues tested so far, the effects of PTHRP were compared with those of PTH. 2. Preglomerular vessels dilated in a concentration- and time-dependent manner that was almost identical for PTH and PTHRP. A significant preglomerular vasodilation (5-17%) occurred at a threshold concentration of 10(-10) mol l-1 PTH or PTHRP, which raised GBF by 20 +/- 2 and 31 +/- 4%, respectively (means +/- S.E.M., n = 6). PTH or PTHRP (10(-7) mol l-1) increased preglomerular diameters (11-36%) and GBF (60 +/- 10 and 70 +/- 8%, respectively) to near maximum. The most prominent dilatation was located at the interlobular artery and at the proximal afferent arteriole. 3. Efferent arterioles were not affected by either PTH or PTHRP. 4. Estimated concentrations of half-maximal response (EC50) for preglomerular vasodilatation and GBF increase were in the nanomolar to subnanomolar range. 5. After inhibition of angiotensin I-converting enzyme by 2 x 10(-6) mol kg-1 quinapril I.V. (n = 6), 10(-8) mol l-1 PTHRP dilated preglomerular vessels and efferent arterioles (9 +/- 1% proximal and 6 +/- 1% distal). 6. We conclude that the renal vasculature of the hydronephrotic kidney is highly sensitive to vasodilatation by PTH and PTHRP, which, in addition, may constrict efferent arterioles by stimulating renin release.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7650615

  19. Dimeric Arrangement of the Parathyroid Hormone Receptor and a Structural Mechanism for Ligand-induced Dissociation

    SciTech Connect

    Pioszak, Augen A.; Harikumar, Kaleeckal G.; Parker, Naomi R.; Miller, Laurence J.; Xu, H. Eric

    2010-06-25

    The parathyroid hormone receptor (PTH1R) is a class B G protein-coupled receptor that is activated by parathyroid hormone (PTH) and PTH-related protein (PTHrP). Little is known about the oligomeric state of the receptor and its regulation by hormone. The crystal structure of the ligand-free PTH1R extracellular domain (ECD) reveals an unexpected dimer in which the C-terminal segment of both ECD protomers forms an {alpha}-helix that mimics PTH/PTHrP by occupying the peptide binding groove of the opposing protomer. ECD-mediated oligomerization of intact PTH1R was confirmed in living cells by bioluminescence and fluorescence resonance energy transfer experiments. As predicted by the structure, PTH binding disrupted receptor oligomerization. A receptor rendered monomeric by mutations in the ECD retained wild-type PTH binding and cAMP signaling ability. Our results are consistent with the hypothesis that PTH1R forms constitutive dimers that are dissociated by ligand binding and that monomeric PTH1R is capable of activating G protein.

  20. Anabolic action of parathyroid hormone regulated by the β2-adrenergic receptor.

    PubMed

    Hanyu, Ryo; Wehbi, Vanessa L; Hayata, Tadayoshi; Moriya, Shuichi; Feinstein, Timothy N; Ezura, Yoichi; Nagao, Masashi; Saita, Yoshitomo; Hemmi, Hiroaki; Notomi, Takuya; Nakamoto, Tetsuya; Schipani, Ernestina; Takeda, Shu; Kaneko, Kazuo; Kurosawa, Hisashi; Karsenty, Gerard; Kronenberg, Henry M; Vilardaga, Jean-Pierre; Noda, Masaki

    2012-05-01

    Parathyroid hormone (PTH), the major calcium-regulating hormone, and norepinephrine (NE), the principal neurotransmitter of sympathetic nerves, regulate bone remodeling by activating distinct cell-surface G protein-coupled receptors in osteoblasts: the parathyroid hormone type 1 receptor (PTHR) and the β(2)-adrenergic receptor (β(2)AR), respectively. These receptors activate a common cAMP/PKA signal transduction pathway mediated through the stimulatory heterotrimeric G protein. Activation of β(2)AR via the sympathetic nervous system decreases bone formation and increases bone resorption. Conversely, daily injection of PTH (1-34), a regimen known as intermittent (i)PTH treatment, increases bone mass through the stimulation of trabecular and cortical bone formation and decreases fracture incidences in severe cases of osteoporosis. Here, we show that iPTH has no osteoanabolic activity in mice lacking the β(2)AR. β(2)AR deficiency suppressed both iPTH-induced increase in bone formation and resorption. We showed that the lack of β(2)AR blocks expression of iPTH-target genes involved in bone formation and resorption that are regulated by the cAMP/PKA pathway. These data implicate an unexpected functional interaction between PTHR and β(2)AR, two G protein-coupled receptors from distinct families, which control bone formation and PTH anabolism. PMID:22538810

  1. Negative regulation of parathyroid hormone-related protein expression by steroid hormones.

    PubMed

    Kajitani, Takashi; Tamamori-Adachi, Mimi; Okinaga, Hiroko; Chikamori, Minoru; Iizuka, Masayoshi; Okazaki, Tomoki

    2011-04-15

    Elevated parathyroid hormone-related protein (PTHrP) is responsible for humoral hypercalcemia of malignancy (HHM), which is of clinical significance in treatment of terminal patients with malignancies. Steroid hormones were known to cause suppression of PTHrP expression. However, detailed studies linking multiple steroid hormones to PTHrP expression are lacking. Here we studied PTHrP expression in response to steroid hormones in four cell lines with excessive PTHrP production. Our study established that steroid hormones negatively regulate PTHrP expression. Vitamin D receptor, estrogen receptor α, glucocorticoid receptor, and progesterone receptor, were required for repression of PTHrP expression by the cognate ligands. A notable exception was the androgen receptor, which was dispensable for suppression of PTHrP expression in androgen-treated cells. We propose a pathway(s) involving nuclear receptors to suppress PTHrP expression.

  2. The neuroendocrine functions of the parathyroid hormone 2 receptor.

    PubMed

    Dobolyi, Arpád; Dimitrov, Eugene; Palkovits, Miklós; Usdin, Ted B

    2012-01-01

    The G-protein coupled parathyroid hormone 2 receptor (PTH2R) is concentrated in endocrine and limbic regions in the forebrain. Its endogenous ligand, tuberoinfundibular peptide of 39 residues (TIP39), is synthesized in only two brain regions, within the posterior thalamus and the lateral pons. TIP39-expressing neurons have a widespread projection pattern, which matches the PTH2R distribution in the brain. Neuroendocrine centers including the preoptic area, the periventricular, paraventricular, and arcuate nuclei contain the highest density of PTH2R-positive networks. The administration of TIP39 and an antagonist of the PTH2R as well as the investigation of mice that lack functional TIP39 and PTH2R revealed the involvement of the PTH2R in a variety of neural and neuroendocrine functions. TIP39 acting via the PTH2R modulates several aspects of the stress response. It evokes corticosterone release by activating corticotropin-releasing hormone-containing neurons in the hypothalamic paraventricular nucleus. Block of TIP39 signaling elevates the anxiety state of animals and their fear response, and increases stress-induced analgesia. TIP39 has also been suggested to affect the release of additional pituitary hormones including arginine-vasopressin and growth hormone. A role of the TIP39-PTH2R system in thermoregulation was also identified. TIP39 may play a role in maintaining body temperature in a cold environment via descending excitatory pathways from the preoptic area. Anatomical and functional studies also implicated the TIP39-PTH2R system in nociceptive information processing. Finally, TIP39 induced in postpartum dams may play a role in the release of prolactin during lactation. Potential mechanisms leading to the activation of TIP39 neurons and how they influence the neuroendocrine system are also described. The unique TIP39-PTH2R neuromodulator system provides the possibility for developing drugs with a novel mechanism of action to control neuroendocrine disorders.

  3. The Neuroendocrine Functions of the Parathyroid Hormone 2 Receptor

    PubMed Central

    Dobolyi, Arpád; Dimitrov, Eugene; Palkovits, Miklós; Usdin, Ted B.

    2012-01-01

    The G-protein coupled parathyroid hormone 2 receptor (PTH2R) is concentrated in endocrine and limbic regions in the forebrain. Its endogenous ligand, tuberoinfundibular peptide of 39 residues (TIP39), is synthesized in only two brain regions, within the posterior thalamus and the lateral pons. TIP39-expressing neurons have a widespread projection pattern, which matches the PTH2R distribution in the brain. Neuroendocrine centers including the preoptic area, the periventricular, paraventricular, and arcuate nuclei contain the highest density of PTH2R-positive networks. The administration of TIP39 and an antagonist of the PTH2R as well as the investigation of mice that lack functional TIP39 and PTH2R revealed the involvement of the PTH2R in a variety of neural and neuroendocrine functions. TIP39 acting via the PTH2R modulates several aspects of the stress response. It evokes corticosterone release by activating corticotropin-releasing hormone-containing neurons in the hypothalamic paraventricular nucleus. Block of TIP39 signaling elevates the anxiety state of animals and their fear response, and increases stress-induced analgesia. TIP39 has also been suggested to affect the release of additional pituitary hormones including arginine-vasopressin and growth hormone. A role of the TIP39-PTH2R system in thermoregulation was also identified. TIP39 may play a role in maintaining body temperature in a cold environment via descending excitatory pathways from the preoptic area. Anatomical and functional studies also implicated the TIP39-PTH2R system in nociceptive information processing. Finally, TIP39 induced in postpartum dams may play a role in the release of prolactin during lactation. Potential mechanisms leading to the activation of TIP39 neurons and how they influence the neuroendocrine system are also described. The unique TIP39-PTH2R neuromodulator system provides the possibility for developing drugs with a novel mechanism of action to control neuroendocrine disorders

  4. Thymus-associated parathyroid hormone has two cellular origins with distinct endocrine and immunological functions.

    PubMed

    Liu, Zhijie; Farley, Alison; Chen, Lizhen; Kirby, Beth J; Kovacs, Christopher S; Blackburn, C Clare; Manley, Nancy R

    2010-01-01

    In mammals, parathyroid hormone (PTH) is a key regulator of extracellular calcium and inorganic phosphorus homeostasis. Although the parathyroid glands were thought to be the only source of PTH, extra-parathyroid PTH production in the thymus, which shares a common origin with parathyroids during organogenesis, has been proposed to provide an auxiliary source of PTH, resulting in a higher than expected survival rate for aparathyroid Gcm2⁻/⁻ mutants. However, the developmental ontogeny and cellular identity of these "thymic" PTH-expressing cells is unknown. We found that the lethality of aparathyroid Gcm2⁻/⁻ mutants was affected by genetic background without relation to serum PTH levels, suggesting a need to reconsider the physiological function of thymic PTH. We identified two sources of extra-parathyroid PTH in wild-type mice. Incomplete separation of the parathyroid and thymus organs during organogenesis resulted in misplaced, isolated parathyroid cells that were often attached to the thymus; this was the major source of thymic PTH in normal mice. Analysis of thymus and parathyroid organogenesis in human embryos showed a broadly similar result, indicating that these results may provide insight into human parathyroid development. In addition, medullary thymic epithelial cells (mTECs) express PTH in a Gcm2-independent manner that requires TEC differentiation and is consistent with expression as a self-antigen for negative selection. Genetic or surgical removal of the thymus indicated that thymus-derived PTH in Gcm2⁻/⁻ mutants did not provide auxiliary endocrine function. Our data show conclusively that the thymus does not serve as an auxiliary source of either serum PTH or parathyroid function. We further show that the normal process of parathyroid organogenesis in both mice and humans leads to the generation of multiple small parathyroid clusters in addition to the main parathyroid glands, that are the likely source of physiologically relevant "thymic

  5. Parathyroid Hormone-Related Protein Analogs as Osteoporosis Therapies.

    PubMed

    Esbrit, Pedro; Herrera, Sabina; Portal-Núñez, Sergio; Nogués, Xavier; Díez-Pérez, Adolfo

    2016-04-01

    The only bone anabolic agent currently available for osteoporosis treatment is parathyroid hormone (PTH)-either its N-terminal 1-34 fragment or the whole molecule of 1-84 aminoacids-whose intermittent administration stimulates new bone formation by targeting osteoblastogenesis and osteoblast survival. PTH-related protein (PTHrP) is an abundant factor in bone which shows N-terminal homology with PTH and thus exhibits high affinity for the same PTH type 1 receptor in osteoblasts. Therefore, it is not surprising that intermittently administered N-terminal PTHrP peptides induce bone anabolism in animals and humans. Furthermore, the C-terminal region of PTHrP also elicits osteogenic features in vitro in osteoblastic cells and in various animal models of osteoporosis. In this review, we discuss the current concepts about the cellular and molecular mechanisms whereby PTHrP may induce anabolic actions in bone. Pre-clinical studies and clinical data using N-terminal PTHrP analogs are also summarized, pointing to PTHrP as a promising alternative to current bone anabolic therapies. PMID:26259869

  6. Parathyroid hormone is not an inhibitor of lipoprotein lipase activity.

    PubMed

    Arnadottir, M; Nilsson-Ehle, P

    1994-01-01

    The reduced lipoprotein lipase (LPL) activities in uraemia are reflected by increased serum triglyceride concentrations and reduced HDL cholesterol concentrations. Both hyperparathyroidism and circulating inhibitor(s) of LPL have been associated with the disturbances of lipid metabolism in uraemia. The aim of the present study was to investigate if parathyroid hormone (PTH) had an inhibitory effect on LPL activity. Plasma post-heparin LPL activities, plasma LPL inhibitory activities, serum PTHintact and serum PTHC-terminal concentrations were analysed in 20 patients on haemodialysis and 20 healthy controls. The effects of purified, human PTHintact and a carboxyterminal fragment of PTH (PTH39-84) on LPL activities in post-heparin plasma from healthy individuals and on the enzyme activity of purified, bovine milk LPL, activated with apolipoprotein CII, were studied. Patients had significantly higher plasma LPL inhibitory activities than controls, but there was no correlation between plasma LPL inhibitory activities and serum PTH concentrations. Neither PTHintact nor PTH39-84 had a significant effect on LPL activities in vitro. Thus there was no evidence of a direct inhibition of LPL activity by PTH under the present in-vivo or in-vitro conditions.

  7. Parathyroid hormone is not an inhibitor of lipoprotein lipase activity.

    PubMed

    Arnadottir, M; Nilsson-Ehle, P

    1994-01-01

    The reduced lipoprotein lipase (LPL) activities in uraemia are reflected by increased serum triglyceride concentrations and reduced HDL cholesterol concentrations. Both hyperparathyroidism and circulating inhibitor(s) of LPL have been associated with the disturbances of lipid metabolism in uraemia. The aim of the present study was to investigate if parathyroid hormone (PTH) had an inhibitory effect on LPL activity. Plasma post-heparin LPL activities, plasma LPL inhibitory activities, serum PTHintact and serum PTHC-terminal concentrations were analysed in 20 patients on haemodialysis and 20 healthy controls. The effects of purified, human PTHintact and a carboxyterminal fragment of PTH (PTH39-84) on LPL activities in post-heparin plasma from healthy individuals and on the enzyme activity of purified, bovine milk LPL, activated with apolipoprotein CII, were studied. Patients had significantly higher plasma LPL inhibitory activities than controls, but there was no correlation between plasma LPL inhibitory activities and serum PTH concentrations. Neither PTHintact nor PTH39-84 had a significant effect on LPL activities in vitro. Thus there was no evidence of a direct inhibition of LPL activity by PTH under the present in-vivo or in-vitro conditions. PMID:7870347

  8. Parathyroid Hormone-Related Protein Analogs as Osteoporosis Therapies.

    PubMed

    Esbrit, Pedro; Herrera, Sabina; Portal-Núñez, Sergio; Nogués, Xavier; Díez-Pérez, Adolfo

    2016-04-01

    The only bone anabolic agent currently available for osteoporosis treatment is parathyroid hormone (PTH)-either its N-terminal 1-34 fragment or the whole molecule of 1-84 aminoacids-whose intermittent administration stimulates new bone formation by targeting osteoblastogenesis and osteoblast survival. PTH-related protein (PTHrP) is an abundant factor in bone which shows N-terminal homology with PTH and thus exhibits high affinity for the same PTH type 1 receptor in osteoblasts. Therefore, it is not surprising that intermittently administered N-terminal PTHrP peptides induce bone anabolism in animals and humans. Furthermore, the C-terminal region of PTHrP also elicits osteogenic features in vitro in osteoblastic cells and in various animal models of osteoporosis. In this review, we discuss the current concepts about the cellular and molecular mechanisms whereby PTHrP may induce anabolic actions in bone. Pre-clinical studies and clinical data using N-terminal PTHrP analogs are also summarized, pointing to PTHrP as a promising alternative to current bone anabolic therapies.

  9. Two teenage males with hypocalcemia and elevated parathyroid hormone levels.

    PubMed

    Shoemaker, Ashley H; Bremer, Andrew A

    2012-04-01

    Vitamin D deficiency is not a rare disorder, particularly in minority groups. The Institute of Medicine recommends serum 25-hydroxyvitamin (OH)D levels >20 ng/mL and The Endocrine Society recommends levels >30 ng/mL for good health. In contrast, the 2003-2006 National Health and Nutrition Examination Survey reported average total 25-(OH)D concentrations of 25.6 ± 0.4 ng/mL in whites, 19.5 ± 0.5 ng/mL in Mexican Americans, and 14.8 ± 0.4 ng/mL in blacks. Pediatric patients with vitamin D deficiency may be asymptomatic or may present either with rickets, hypocalcemia, or seizures. Pseudohypoparathyroidism (PHP) is a rare disorder characterized by parathyroid hormone (PTH) resistance with (type 1a) or without (type 1b) the Albright Hereditary Os-teodystrophy (AHO) phenotype of short stature, brachydactyly, and mental retardation. Patients with PHP have elevated PTH levels and may have hyperphosphatemia and hypocalcemia. However, the same laboratory values can be seen in children with vitamin D deficiency, and diagnostic confusion is common. We report two cases of vitamin D deficiency with presentations suggestive of PHP.

  10. Parathyroid hormone impairs extrarenal potassium tolerance in the rat

    SciTech Connect

    Sugarman, A.; Kahn, T. City Univ. of New York, NY )

    1988-03-01

    The effect of parathyroid hormone (PTH) on the extrarenal disposition of an acute potassium load was examined in acutely nephrectomized rats infused with KCl alone or in combination with PTH, with serial monitoring of plasma potassium every 10 min. The rise in plasma potassium concentration ({Delta}PK) in the PTH group was higher than control. PTH was then administered along with KCl to two groups of nephrectomized and acutely thyroparathyroidectomized (TPTX) rats in doses of 1 and 0.25 U {center dot} kg{sup {minus}1} {center dot} min{sup {minus}1} for 90 min. {Delta}PK with PTH in both groups was higher than TPTX control. The two higher doses of PTH resulted in a decrease in mean arterial pressure from their respective controls. A similar reduction in arterial pressure in three groups of nephrectomized rats by administration of hydralazine or nitroprusside or by acute blood loss did not change {Delta}PK subsequent to potassium infusion from that in control rats. Furthermore, the lowest dose of PTH did not lower arterial pressure from its respective control. Therefore, hypotension is not a cause for the PTH-induced potassium intolerance. Serum levels of insulin, aldosterone, catecholamines, calcium, plasma HCO{sub 3} concentration, and pH were not different in PTH-infused vs. respective control rats. These data suggest that PTH impairs extrarenal potassium disposal in the rat. The effect of PTH may relate to enhanced calcium entry into cells.

  11. Bisphosphonates, vitamin D, parathyroid hormone, and osteonecrosis of the jaw. Could there be a missing link?

    PubMed Central

    Leizaola-Cardesa, Ignacio-Osoitz; Aguilar-Salvatierra, Antonio; Gonzalez-Jaranay, Maximino; Moreu, Gerardo; Sala-Romero, María-José

    2016-01-01

    It is estimated that over 190 million bisphosphonates have been prescribed worldwide. But this drug can produce adverse effects, of which osteonecrosis of the jaw and severe hypocalcemia are the most serious. It is evident that bisphosphonate administration affects multiple and diverse biochemical mediators related to bone metabolism. This review of literature investigates four basic parameters in patients treated with bisphosphonates - parathyroid hormone (PTH), bisphosphonates, vitamin D, calcium, and jaw osteonecrosis - which are fundamental for assessing bone metabolism and so the efficacy and correct use of the drug. The imbalances generated by vitamin D and calcium deficiencies, together with their multiple systemic repercussions, have been widely researched but the outcomes of these imbalances in relation to bisphosphonate administration are not well known, and some research has indicated that they may be associated with osteonecrosis of the jaw (ONJ). The present review set out to explain the functioning of bone metabolism, the importance of different chemical mediators, the imbalances produced by incorrect use of this drug, in order to forewarn against the possible relation of these parameters with ONJ, whose physiopathology remains unknown. Medical and dental clinics should keep detailed anamneses of the use of vitamin D and calcium supplements, as it is of vital importance to maintain their correct levels in blood, given that these are related to ONJ as well as other adverse effects; this procedure is also necessary in order to ensure the correct use of the drug. Key words:Bisphosphonate-related osteonecrosis of the jaw, vitamin D, parathyroid hor PMID:26827062

  12. Kinetics of parathyroid hormone after parathyroidectomy in chronic hemodialysis patients.

    PubMed

    Skalli, Z; Elouazzani, H; Alhamany, Z; Mattous, M; Benamar, L; Bayahia, R; Belkouchi, M; El Malki, HadjOmar; Ouzeddoun, N

    2015-11-01

    Secondary hyperparathyroidism is a common complication in chronic renal failure. The treatment in some cases requires parathyroidectomy. The kinetics of the parathyroid hormone (PTH) levels after surgery helps to evaluate the efficacy of parathyroidectomy. Prospective analysis was made of the kinetics of intact PTH (iPTH) after parathyroidectomy in 10 chronic hemodialysis (HD) patients who had secondary hyperparathyroidism. We determined the levels of iPTH before surgery and its evolution after parathyroidectomy at regular intervals: Day 0, D7, D15, D30 and D90. The mean age of our patients was 40 ± 13 years, with a sex ratio of 1. The mean duration on HD was 122 ± 63 months. The duration of secondary hyperparathyroidism varied from one year to 12 years. All patients had received medical treatment for hyperparathyroidism. The indications for parathyroidectomy included resistance to medical treatment in seven cases, development of brown tumors in two cases and soft tissue calcifications in one case. All patients had radiographic evidence of hyperparathyroidism. The parathyroidectomy was sub-total in all patients, 6/8 in four cases and 7/8 in six cases. The mean iPTH level was 2341 ± 1946 pg/mL before surgery. A sharp drop in this level was noticed on D0, with a median of 92 pg/mL and, thereafter, the levels were 79 pg/mL on D7, 25 pg/mL on D15 and 36 pg/mL after 1 month. At 3 months post-surgery, the mean iPTH level was 302 pg/mL. Histological examination of the resected gland showed parathyroid hyperplasia in all patients. In our series, the efficacy of sub-total parathyroidectomy was satisfactory with rapid normalization of PTH, which is consistent with the literature data. Sub-total parathyroidectomy still has a place in the treatment of secondary hyperparathyroidism in chronic renal failure. Its indications should be limited to cases resistant to medical treatment and, in particular, in cases with occurrence of complications. PMID:26586059

  13. Immunochemical Localization of Parathyroid Hormone in Cancer Tissue from Patients with Ectopic Hyperparathyroidism

    PubMed Central

    Palmieri, Genaro M. A.; Nordquist, Robert E.; Omenn, Gilbert S.

    1974-01-01

    Immunoreactive parathyroid hormone (PTH) in nonparathyroid malignant tumors associated with hypercalcemia and hypophosphatemia in the absence of demonstrable bone metastases was determined by radioimmunoassay and immunofluorescent techniques. Six of seven tumors contained material with immunological cross-reactivity to bovine PTH by radioimmunoassay and immunofluorescence. The intensity of the immunofluorescent stain varied considerably in the different tumors. From 15 to 90% of neoplastic cells were stained specifically with fluorescein-labeled anti-PTH. In contrast, normal parathyroid glands and parathyroid adenomas showed uniform distribution of immunofluorescence in all parenchymal cells. In one malignant tumor, PTH was localized also by immunoautoradiography. In every case PTH was detected only in the cytoplasm of parenchymal cells. One patient lacked detectable PTH in his tumor, yet showed regression of the hypercalcemia to normal values after removal of large masses of neoplastic tissue and recurrence of hypercalcemia when new growth occurred. Dilutional radioimmunoassay curves of nonparathyroid malignant tumors were in most cases different from those obtained with extracts of normal parathyroid glands and parathyroid adenomas. Although both nonparathyroid neoplasmas and parathyroid extracts demonstrated immunoheterogeneity by gel filtration, greater heterogeneity was found in nonparathyroid malignant tumors. In those tumors in which immunological cross-reactivity to PTH was detected, the capability of secreting PTH may be restricted to derepressed cell clones amidst other neoplastic cells, whereas the greater heterogeneity of ectopic PTH may reflect hormone cleavage by proteolytic enzymes in the tumor that is less specific than the Pro-PTH cleaving enzyme in the parathyroids. Images PMID:4364410

  14. Parathyroid hormone-related protein promotes epithelial-mesenchymal transition.

    PubMed

    Ardura, Juan Antonio; Rayego-Mateos, Sandra; Rámila, David; Ruiz-Ortega, Marta; Esbrit, Pedro

    2010-02-01

    Epithelial-mesenchymal transition (EMT) is an important process that contributes to renal fibrogenesis. TGF-beta1 and EGF stimulate EMT. Recent studies suggested that parathyroid hormone-related protein (PTHrP) promotes fibrogenesis in the damaged kidney, apparently dependent on its interaction with vascular endothelial growth factor (VEGF), but whether it also interacts with TGF-beta and EGF to modulate EMT is unknown. Here, PTHrP(1-36) increased TGF-beta1 in cultured tubuloepithelial cells and TGF-beta blockade inhibited PTHrP-induced EMT-related changes, including upregulation of alpha-smooth muscle actin and integrin-linked kinase, nuclear translocation of Snail, and downregulation of E-cadherin and zonula occludens-1. PTHrP(1-36) also induced EGF receptor (EGFR) activation; inhibition of protein kinase C and metalloproteases abrogated this activation. Inhibition of EGFR activation abolished these EMT-related changes, the activation of ERK1/2, and upregulation of TGF-beta1 and VEGF by PTHrP(1-36). Moreover, inhibition of ERK1/2 blocked EMT induced by either PTHrP(1-36), TGF-beta1, EGF, or VEGF. In vivo, obstruction of mouse kidneys led to changes consistent with EMT and upregulation of TGF-beta1 mRNA, p-EGFR protein, and PTHrP. Taken together, these data suggest that PTHrP, TGF-beta, EGF, and VEGF might cooperate through activation of ERK1/2 to induce EMT in renal tubuloepithelial cells.

  15. Adenyl cyclase and interleukin 6 are downstream effectors of parathyroid hormone resulting in stimulation of bone resorption.

    PubMed Central

    Greenfield, E M; Shaw, S M; Gornik, S A; Banks, M A

    1995-01-01

    Parathyroid hormone and other bone resorptive agents function, at least in part, by inducing osteoblasts to secrete cytokines that stimulate both differentiation and resorptive activity of osteoclasts. We previously identified two potentially important cytokines by demonstrating that parathyroid hormone induces expression by osteoblasts of IL-6 and leukemia inhibitory factor without affecting levels of 14 other cytokines. Although parathyroid hormone activates multiple signal transduction pathways, induction of IL-6 and leukemia inhibitory factor is dependent on activation of adenyl cyclase. This study demonstrates that adenyl cyclase is also required for stimulation of osteoclast activity in cultures containing osteoclasts from rat long bones and UMR106-01 rat osteoblast-like osteosarcoma cells. Since the stimulation by parathyroid hormone of both cytokine production and bone resorption depends on the same signal transduction pathway, we hypothesized that IL-6 might be a downstream effector of parathyroid hormone. We found that addition of exogenous IL-6 mimics the ability of parathyroid hormone to stimulate bone resorption. More importantly, an antibody directed against the IL-6 receptor blocks moderate stimulation of osteoclast activity induced by the hormone. Interestingly, strong stimulation of resorption overcomes this dependence on IL-6. Thus, parathyroid hormone likely induces multiple, redundant cytokines that can overcome the IL-6 requirement associated with moderate stimulation. Taken together with studies showing that many other bone resorptive agents also stimulate IL-6 production, our results suggest that IL-6 may be a downstream effector of these agents as well as of parathyroid hormone. Images PMID:7657797

  16. Bovine parathyroid hormone enhances osteoclast bone resorption by modulating V-ATPase through PTH1R

    PubMed Central

    LIU, SHUANGXIN; ZHU, WEIPING; LI, SIJIA; MA, JIANCHAO; ZHANG, HUITAO; LI, ZHONGHE; ZHANG, LI; ZHANG, BIN; LI, ZHUO; LIANG, XINLING; SHI, WEI

    2016-01-01

    The vacuolar-type H+ adenosine triphosphatase (V-ATPase) plays an important role in cellular acidification and bone resorption by osteoclasts. However, the direct effect of bovine parathyroid hormone (bPTH) on V-ATPase has not yet been elucidated. The aim of the present study was to assess the effects of bPTH on V-ATPase and osteoclasts. Osteoclasts from bone marrow (BM)-derived monocytes of C57BL/6 mice were cultured with or without bPTH. The mRNA and protein expression levels of the V-ATPase a3-subunit and d2-subunit (by RT-qPCR and western blot analysis), V-ATPase activity (using the V type ATPase Activity Assay kit) and the bone resorption function of osteoclasts (by bone resorption assay) were examined following treatment with various concentrations of bPTH (0.1, 1.0, 10 and 100 ng/ml) alone or with bPTH and its inhibitor, bafilomycin A1. Furthermore, the expression of parathyroid hormone (PTH) receptors in osteoclasts was also detected. The results revealed that the mRNA and protein expression levels of V-ATPase a3-subunit and d2-subunit increased in a dose-dependent manner, paralleling the level of bPTH present. In addition, an increase in the concentration of bPTH was accompanied by the increased resorption capability of osteoclasts, whereas bone resorption was inhibited in the presence of bafilomycin A1. In addition, we confirmed the existence of parathyroid hormone 1 receptor (PTH1R) in osteoclasts using three different methods (RT-qPCR, western blot analysis and immunofluorescence staining). We found that bPTH enhanced the bone resorption capability of osteoclasts by modulating the expression of V-ATPase subunits, intracellular acidification and V-ATPase activity. Thus, we propose that PTH has a direct effect on osteoblasts and osteoclasts, and that this effect is mediated through PTH1R, thus contributing to bone remodeling. PMID:26647715

  17. International Union of Basic and Clinical Pharmacology. XCIII. The parathyroid hormone receptors--family B G protein-coupled receptors.

    PubMed

    Gardella, Thomas J; Vilardaga, Jean-Pierre

    2015-01-01

    The type-1 parathyroid hormone receptor (PTHR1) is a family B G protein-coupled receptor (GPCR) that mediates the actions of two polypeptide ligands; parathyroid hormone (PTH), an endocrine hormone that regulates the levels of calcium and inorganic phosphate in the blood by acting on bone and kidney, and PTH-related protein (PTHrP), a paracrine-factor that regulates cell differentiation and proliferation programs in developing bone and other tissues. The type-2 parathyroid hormone receptor (PTHR2) binds a peptide ligand, called tuberoinfundibular peptide-39 (TIP39), and while the biologic role of the PTHR2/TIP39 system is not as defined as that of the PTHR1, it likely plays a role in the central nervous system as well as in spermatogenesis. Mechanisms of action at these receptors have been explored through a variety of pharmacological and biochemical approaches, and the data obtained support a basic "two-site" mode of ligand binding now thought to be used by each of the family B peptide hormone GPCRs. Recent crystallographic studies on the family B GPCRs are providing new insights that help to further refine the specifics of the overall receptor architecture and modes of ligand docking. One intriguing pharmacological finding for the PTHR1 is that it can form surprisingly stable complexes with certain PTH/PTHrP ligand analogs and thereby mediate markedly prolonged cell signaling responses that persist even when the bulk of the complexes are found in internalized vesicles. The PTHR1 thus appears to be able to activate the Gα(s)/cAMP pathway not only from the plasma membrane but also from the endosomal domain. The cumulative findings could have an impact on efforts to develop new drug therapies for the PTH receptors.

  18. International Union of Basic and Clinical Pharmacology. XCIII. The Parathyroid Hormone Receptors—Family B G Protein–Coupled Receptors

    PubMed Central

    Vilardaga, Jean-Pierre

    2015-01-01

    The type-1 parathyroid hormone receptor (PTHR1) is a family B G protein–coupled receptor (GPCR) that mediates the actions of two polypeptide ligands; parathyroid hormone (PTH), an endocrine hormone that regulates the levels of calcium and inorganic phosphate in the blood by acting on bone and kidney, and PTH-related protein (PTHrP), a paracrine-factor that regulates cell differentiation and proliferation programs in developing bone and other tissues. The type-2 parathyroid hormone receptor (PTHR2) binds a peptide ligand, called tuberoinfundibular peptide-39 (TIP39), and while the biologic role of the PTHR2/TIP39 system is not as defined as that of the PTHR1, it likely plays a role in the central nervous system as well as in spermatogenesis. Mechanisms of action at these receptors have been explored through a variety of pharmacological and biochemical approaches, and the data obtained support a basic “two-site” mode of ligand binding now thought to be used by each of the family B peptide hormone GPCRs. Recent crystallographic studies on the family B GPCRs are providing new insights that help to further refine the specifics of the overall receptor architecture and modes of ligand docking. One intriguing pharmacological finding for the PTHR1 is that it can form surprisingly stable complexes with certain PTH/PTHrP ligand analogs and thereby mediate markedly prolonged cell signaling responses that persist even when the bulk of the complexes are found in internalized vesicles. The PTHR1 thus appears to be able to activate the Gαs/cAMP pathway not only from the plasma membrane but also from the endosomal domain. The cumulative findings could have an impact on efforts to develop new drug therapies for the PTH receptors. PMID:25713287

  19. Differential effects of intermittent and continuous administration of parathyroid hormone on bone histomorphometry and gene expression

    NASA Technical Reports Server (NTRS)

    Lotinun, Sutada; Sibonga, Jean D.; Turner, Russell T.

    2002-01-01

    A mechanism explaining the differential skeletal effects of intermittent and continuous elevation of serum parathyroid hormone (PTH) remains elusive. Intermittent PTH increases bone formation and bone mass and is being investigated as a therapy for osteoporosis. By contrast, chronic hyperparathyroidism results in the metabolic bone disease osteitis fibrosa characterized by osteomalacia, focal bone resorption, and peritrabecular bone marrow fibrosis. Intermittent and continuous PTH have similar effects on the number of osteoblasts and bone-forming activity. Many of the beneficial as well as detrimental effects of the hormone appear to be mediated by osteoblast-derived growth factors. This hypothesis was tested using cDNA microgene arrays to compare gene expression in tibia of rats treated with continuous and pulsatile administration of PTH. These treatments result in differential expression of many genes, including growth factors. One of the genes whose steady-state mRNA levels was increased by continuous but not pulsatile administration was platelet-derived growth factor-A (PDGF-A). Administration of a PDGF-A antagonist greatly reduced bone resorption, osteomalacia, and bone marrow fibrosis in a rat model for hyperparathyroidism, suggesting that PDGF-A is a causative agent for this disease. These findings suggest that profiling changes in gene expression can help identify the metabolic pathways responsible for the skeletal responses to the hormone.

  20. Calcium-sensing receptor activation in chronic kidney disease: effects beyond parathyroid hormone control.

    PubMed

    Massy, Ziad A; Hénaut, Lucie; Larsson, Tobias E; Vervloet, Marc G

    2014-11-01

    Secondary hyperparathyroidism (SHPT) is an important complication of advanced chronic kidney disease (CKD). Cinacalcet, an allosteric modulator of the calcium-sensing receptor (CaSR) expressed in parathyroid glands, is the only calcimimetic approved to treat SHPT in patients on dialysis. By enhancing CaSR sensitivity for plasma extracellular calcium (Ca(2+)0), cinacalcet reduces serum parathyroid hormone, Ca(2+)0, and serum inorganic phosphorous concentrations, allowing better control of SHPT and CKD-mineral and bone disorders. Of interest, the CaSR also is expressed in a variety of tissues where its activation regulates diverse cellular processes, including secretion, apoptosis, and proliferation. Thus, the existence of potential off-target effects of cinacalcet cannot be neglected. This review summarizes our current knowledge concerning the potential role(s) of the CaSR expressed in various tissues in CKD-related disorders, independently of parathyroid hormone control.

  1. Minerals, vitamin D, and parathyroid hormone in continuous ambulatory peritoneal dialysis.

    PubMed

    Delmez, J A; Slatopolsky, E; Martin, K J; Gearing, B N; Harter, H R

    1982-06-01

    The effects of continuous ambulatory peritoneal dialysis on parathyroid hormone (PTH) and mineral metabolism were evaluated in ten patients. Utilizing a PTH radioimmunoassay, which measures both intact hormone and carboxyl-terminal PTH fragments, it was found that the mean clearance of immunoreactive parathyroid hormone was 1.5 +/- 0.73 ml/min (SEM) yielding a daily net removal of 13.6 +/- 3.2% of estimated total extracellular parathyroid hormone. Gel electrophoresis of the dialysate revealed the presence of both intact parathyroid hormone and fragments in a similar pattern to that of peripheral plasma. Normal levels of 25-(OH) vitamin D and vitamin D binding protein were observed prior to the initiation of continuous ambulatory peritoneal dialysis and following 6 months of treatment. Timed dialysate collections (N = 93) demonstrated a daily calcium influx of only 9.9 +/- 9.7 mg. The daily removal of phosphorus was 308.4 +/- 15.5 mg. Despite elevated serum magnesium levels in all patients, the net daily removal was inadequate (31.2 +/- 15.5 mg). It was concluded that: (1) Unlike chronic hemodialysis, continuous ambulatory peritoneal dialysis removes significant amounts of parathyroid hormone. (2) Normal 25-(OH) vitamin D and vitamin D binding protein levels are maintained with continuous ambulatory peritoneal dialysis despite large protein losses. (3) Substantial amounts of phosphorus are removed with continuous ambulatory peritoneal dialysis but not to an extent that precludes use of phosphorus binders. (4) Dialysate containing lower magnesium and possibly higher calcium concentrations should be made available to improve mineral homeostasis. PMID:6897087

  2. Bone density parathyroid hormone and 25-hydroxyvitamin D concentrations in middle aged women.

    PubMed Central

    Khaw, K. T.; Sneyd, M. J.; Compston, J.

    1992-01-01

    OBJECTIVE--To examine the relation between bone density and indices of calcium metabolism including parathyroid hormone and 25-hydroxyvitamin D concentrations in middle aged women. DESIGN--A cross sectional study. SETTING AND SUBJECTS--138 women volunteers aged 45-65 with no known osteoporosis and unselected for disease status recruited for a dietary assessment study from the community using general practice registers. Volunteer rate was 20%. MAIN OUTCOME MEASURE--Bone mineral density measured with dual energy x ray absorptiometry. RESULTS--Bone density at the lumbar spine and neck and trochanteric regions of the femur was inversely related to serum intact parathyroid hormone concentrations and positively related to serum 25-hydroxyvitamin D concentrations. These associations were independent of possible confounding factors, including age, body mass index, cigarette smoking habit, menopausal status, and use of diuretics and postmenopausal hormone replacement therapy. These associations were apparent throughout the whole distribution of bone density and 25-hydroxyvitamin D and parathyroid hormone concentrations within the normal range, suggesting a physiological relation. CONCLUSIONS--The findings are consistent with the hypothesis that parathyroid hormone and 25-hydroxyvitamin D concentrations influence bone density in middle aged women. Findings from this study together with other work suggest that the role of vitamin D in osteoporosis should not be neglected. The associations with parathyroid hormone also indicate plausible biological mechanisms. The roughly 5-10% difference in bone density between top and bottom tertiles of serum 25-hydroxyvitamin D concentrations, though not large in magnitude, may have considerable public health implications in terms of prevention of osteoporosis and its sequelae, fractures. PMID:1392857

  3. The control of calcium metabolism by parathyroid hormone, calcitonin and vitamin D

    NASA Technical Reports Server (NTRS)

    Potts, J. T., Jr.

    1976-01-01

    Advances in analysis of chemistry and physiology of parathyroid hormone, calcitonin, and Vitamin D are described along with development of techniques in radioassay methods. Emphasis is placed on assessment of normal and abnormal patterns of secretion of these hormones in specific relation to the physiological adaptations of weightlessness and space flight. Related diseases that involve perturbations in normal skeletal and calcium homeostasis are also considered.

  4. Lipoprotein receptor-related protein 6 is required for parathyroid hormone-induced Sost suppression.

    PubMed

    Li, Changjun; Wang, Weishan; Xie, Liang; Luo, Xianghang; Cao, Xu; Wan, Mei

    2016-01-01

    Parathyroid hormone (PTH) suppresses the expression of the bone formation inhibitor sclerostin (Sost) in osteocytes by inducing nuclear accumulation of histone deacetylases (HDACs) to inhibit the myocyte enhancer factor 2 (MEF2)-dependent Sost bone enhancer. Previous studies revealed that lipoprotein receptor-related protein 6 (LRP6) mediates the intracellular signaling activation and the anabolic bone effect of PTH. Here, we investigated whether LRP6 mediates the inhibitory effect of PTH on Sost using an osteoblast-specific Lrp6-knockout (LRP6-KO) mouse model. An increased level of Sost mRNA expression was detected in femur tissue from LRP6-KO mice, compared to wild-type littermates. The number of osteocytes expressing sclerostin protein was also increased in bone tissue of LRP6-KO littermates, indicating a negative regulatory role of LRP6 on Sost/sclerostin. In wild-type littermates, intermittent PTH treatment significantly suppressed Sost mRNA expression in bone and the number of sclerostin(+) osteocytes, while the effect of PTH was much less significant in LRP6-KO mice. Additionally, PTH-induced downregulation of MEF2C and 2D, as well as HDAC changes in osteocytes, were abrogated in LRP6-KO mice. These data indicate that LRP6 is required for PTH suppression of Sost expression.

  5. Molecular mechanisms of calmodulin action on TRPV5 and modulation by parathyroid hormone.

    PubMed

    de Groot, Theun; Kovalevskaya, Nadezda V; Verkaart, Sjoerd; Schilderink, Nathalie; Felici, Marco; van der Hagen, Eline A E; Bindels, René J M; Vuister, Geerten W; Hoenderop, Joost G

    2011-07-01

    The epithelial Ca(2+) channel transient receptor potential vanilloid 5 (TRPV5) constitutes the apical entry gate for active Ca(2+) reabsorption in the kidney. Ca(2+) influx through TRPV5 induces rapid channel inactivation, preventing excessive Ca(2+) influx. This inactivation is mediated by the last ∼30 residues of the carboxy (C) terminus of the channel. Since the Ca(2+)-sensing protein calmodulin has been implicated in Ca(2+)-dependent regulation of several TRP channels, the potential role of calmodulin in TRPV5 function was investigated. High-resolution nuclear magnetic resonance (NMR) spectroscopy revealed a Ca(2+)-dependent interaction between calmodulin and a C-terminal fragment of TRPV5 (residues 696 to 729) in which one calmodulin binds two TRPV5 C termini. The TRPV5 residues involved in calmodulin binding were mutated to study the functional consequence of releasing calmodulin from the C terminus. The point mutants TRPV5-W702A and TRPV5-R706E, lacking calmodulin binding, displayed a strongly diminished Ca(2+)-dependent inactivation compared to wild-type TRPV5, as demonstrated by patch clamp analysis. Finally, parathyroid hormone (PTH) induced protein kinase A (PKA)-dependent phosphorylation of residue T709, which diminished calmodulin binding to TRPV5 and thereby enhanced channel open probability. The TRPV5-W702A mutant exhibited a significantly increased channel open probability and was not further stimulated by PTH. Thus, calmodulin negatively modulates TRPV5 activity, which is reversed by PTH-mediated channel phosphorylation. PMID:21576356

  6. Comparison of renal and osseous binding of parathyroid hormone and hormonal fragments

    SciTech Connect

    Demay, M.; Mitchell, J.; Goltzman, D.

    1985-11-01

    The authors compared receptor binding and adenylate cyclase stimulation of intact bovine parathyroid hormone (bPTH)-(1-84) and the synthetic amino-terminal fragments, bPTH-(1-34) and rat PTH (rPTH)-(1-34). In both canine renal membranes and cloned rat osteosarcoma cells the amino-terminal fragments bound to a single order of sites; the affinity of rPTH-(1-34) exceeded that of bPTH-(1-34), correlating with its higher potency in stimulating adenylate cyclase. In studies with oxidized bPTH-(1--84), the middle and carboxyl regions of intact PTH were found to bind to both tissues but with higher affinity to osteosarcoma cells than to renal membranes. Our results demonstrate that rPTH-(1--34) is the most favorable probe of amino-terminal PTH binding and the most potent of the PTH peptides in stimulating renal and osseous adenylate cyclase. The results also show that midregion and carboxyl determinants within intact PTH contribute to hormone binding, which does not correlate with adenylate cyclase activation and appears more significant for skeletal than for renal binding.

  7. Intraoperative measurement of parathyroid hormone: A Copernican revolution in the surgical treatment of hyperparathyroidism.

    PubMed

    Gioviale, Maria Concetta; Damiano, Giuseppe; Altomare, Roberta; Maione, Carolina; Buscemi, Salvatore; Buscemi, Giuseppe; Lo Monte, Attilio Ignazio

    2016-04-01

    Intraoperative parathyroid hormone (PTH) monitoring in the setting of the operating room represents a valuable example of the rationale use of the laboratory diagnostic in a patient-oriented approach. Rapid intraoperative PTH (ioPTH) assay is a valid tool for an accurate evaluation of the success of parathyroid surgery. The reliability of the user-friendly portable systems as well as the collaboration between operators and surgical staff allow the one-site monitoring of the ioPTH decrements on the course of the surgical management of hyperparathyroidism. The rapid answer provided by an effective decrement of PTH during parathyroidectomy contributes dramatically to the efficacy of parathyroid surgery and the reduction of the number of re-operations. Therefore the dose of ioPTH is a valid and reliable support for the success of the intervention of parathyroidectomy at controlled costs. PMID:26708859

  8. Influence of daily calcium and vitamin D supplementation on parathyroid hormone secretion.

    PubMed

    Reginster, J Y; Zegels, B; Lejeune, E; Micheletti, M C; Taquet, A N; Albert, A

    2001-02-01

    Calcium and vitamin D supplementation have been shown to reduce secondary hyperparathyroidism and play a role in age-related osteoporosis. In order to define the optimal regimen of calcium and vitamin D supplementation to produce the maximal inhibition of parathyroid hormone secretion, we compared the administration of a calcium-vitamin D supplement as a single morning dose with the administration of two divided doses at 6-hour intervals. Twelve healthy male volunteers were assigned to three investigational procedures, which were alternated at weekly intervals. After a 'blank' control procedure, when they were not exposed to any supplements, they received one of two calcium-vitamin D supplement regimens: either two doses of Orocal D3 (500 mg calcium and 400 IU vitamin D3) with a 6-hour interval between doses, or one water-soluble effervescent powder pack of Cacit vitamin D3, taken in the morning (1000 mg calcium and 880 IU vitamin D3). During the three procedures (control and the two calcium-vitamin D supplementation protocols), veinous blood was drawn every 60 minutes for up to 9 hours, for serum calcium and parathyroid hormone measurements. The order of administration of the two calcium and vitamin D supplementation regimens was allocated by randomization. No significant changes in serum calcium were observed during the study. During the first 6 hours following calcium-vitamin D supplementation, a statistically significant decrease in serum parathyroid hormone was observed with both regimens, compared with baseline and the control procedure. During this first period, no differences were observed between the two treatment regimens. However, between the 6th and the 9th hour, serum parathyroid hormone levels remained significantly decreased compared to baseline with the twice-daily Orocal D3 administration, while they returned to baseline values with the once-daily Cacit D3 preparation. During this period, the percentage decrease in serum parathyroid hormone

  9. Model of the complex of Parathyroid hormone-2 receptor and Tuberoinfundibular peptide of 39 residues

    PubMed Central

    2010-01-01

    Background We aim to propose interactions between the parathyroid hormone-2 receptor (PTH2R) and its ligand the tuberoinfundibular peptide of 39 residues (TIP39) by constructing a homology model of their complex. The two related peptides parathyroid hormone (PTH) and parathyroid hormone related protein (PTHrP) are compared with the complex to examine their interactions. Findings In the model, the hydrophobic N-terminus of TIP39 is buried in a hydrophobic part of the central cavity between helices 3 and 7. Comparison of the peptide sequences indicates that the main discriminator between the agonistic peptides TIP39 and PTH and the inactive PTHrP is a tryptophan-phenylalanine replacement. The model indicates that the smaller phenylalanine in PTHrP does not completely occupy the binding site of the larger tryptophan residue in the other peptides. As only TIP39 causes internalisation of the receptor and the primary difference being an aspartic acid in position 7 of TIP39 that interacts with histidine 396 in the receptor, versus isoleucine/histidine residues in the related hormones, this might be a trigger interaction for the events that cause internalisation. Conclusions A model is constructed for the complex and a trigger interaction for full agonistic activation between aspartic acid 7 of TIP39 and histidine 396 in the receptor is proposed. PMID:20979597

  10. Parathyroid hormone modulates the response of osteoblast-like cells to mechanical stimulation

    NASA Technical Reports Server (NTRS)

    Ryder, K. D.; Duncan, R. L.

    2000-01-01

    Mechanical loading stimulates many responses in bone and osteoblasts associated with osteogenesis. Since loading and parathyroid hormone (PTH) activate similar signaling pathways in osteoblasts, we postulate that PTH can potentiate the effects of mechanical stimulation. Using an in vitro four-point bending device, we found that expression of COX-2, the inducible isoform of cyclooxygenase, was dependent on fluid forces generated across the culture plate, but not physiologic levels of strain in MC3T3-E1 osteoblast-like cells. Addition of 50 nM PTH during loading increased COX-2 expression at both subthreshold and threshold levels of fluid forces compared with either stimuli alone. We also demonstrated that application of fluid shear to MC3T3-E1 cells induced a rapid increase in [Ca(2+)](i). Although PTH did not significantly change [Ca(2+)](i) levels, flow and PTH did produce a significantly greater [Ca(2+)](i) response and increased the number of responding cells than is found in fluid shear alone. The [Ca(2+)](i) response to these stimuli was significantly decreased when the mechanosensitive channel inhibitor, gadolinium, was present. These studies indicate that PTH increases the cellular responses of osteoblasts to mechanical loading. Furthermore, this response may be mediated by alterations in [Ca(2+)](i) by modulating the mechanosensitive channel.

  11. Amphiregulin lacks an essential role for the bone anabolic action of parathyroid hormone.

    PubMed

    Jay, Freya F; Vaidya, Mithila; Porada, Sabrina M; Andrukhova, Olena; Schneider, Marlon R; Erben, Reinhold G

    2015-12-01

    Although parathyroid hormone (PTH) has long been known to act as a bone anabolic agent when administered intermittently, the exact underlying mechanisms remain largely unknown. Amphiregulin (AREG), a ligand of the epidermal growth factor receptor, has been identified to be a PTH target gene in vitro and in vivo. Here, we used female global AREG knockout (AREG-KO) mice to explore the role of AREG in mediating the bone anabolic effects of PTH. AREG-KO mice were characterized by unchanged distal femoral cancellous bone mass and only subtle decreases in bone mineral density (BMD) and cortical thickness at the femoral midshaft at 3 and 8 months of age, relative to wildtype controls. AREG deficiency was associated with complex changes in the mRNA expression of other EGFR ligands in femoral cancellous bone osteoblasts in situ in 3-week-old mice. To examine the bone anabolic effects of PTH in the absence and presence of AREG, we injected 3-month-old AREG-KO females and wildtype control littermates with 80 μg/kg PTH or vehicle 5 times per week over 4 weeks. Intermittent PTH treatment of AREG-KO mice led to increases in femoral trabecular and cortical BMD, cortical thickness, endocortical and periosteal bone formation, cancellous bone formation rate, and serum osteocalcin, comparable to those observed in wildtype control mice. In conclusion, our data indicate that the bone anabolic effects of PTH do not require AREG, at least in 3-month-old female mice.

  12. DLC1-dependent parathyroid hormone–like hormone inhibition suppresses breast cancer bone metastasis

    PubMed Central

    Wang, Yufeng; Lei, Rong; Zhuang, Xueqian; Zhang, Ning; Pan, Hong; Li, Gang; Hu, Jing; Pan, Xiaoqi; Tao, Qian; Fu, Da; Xiao, Jianru; Chin, Y. Eugene; Kang, Yibin; Yang, Qifeng; Hu, Guohong

    2014-01-01

    Bone metastasis is a frequent complication of breast cancer that is often accelerated by TGF-β signaling; however, little is known about how the TGF-β pathway is regulated during bone metastasis. Here we report that deleted in liver cancer 1 (DLC1) is an important regulator of TGF-β responses and osteolytic metastasis of breast cancer cells. In murine models, breast cancer cells lacking DLC1 expression exhibited enhanced capabilities of bone metastasis. Knockdown of DLC1 in cancer cells promoted bone metastasis, leading to manifested osteolysis and accelerated death in mice, while DLC1 overexpression suppressed bone metastasis. Activation of Rho-ROCK signaling in the absence of DLC1 mediated SMAD3 linker region phosphorylation and TGF-β–induced expression of parathyroid hormone–like hormone (PTHLH), leading to osteoclast maturation for osteolytic colonization. Furthermore, pharmacological inhibition of Rho-ROCK effectively reduced PTHLH production and breast cancer bone metastasis in vitro and in vivo. Evaluation of clinical breast tumor samples revealed that reduced DLC1 expression was linked to elevated PTHLH expression and organ-specific metastasis to bone. Overall, our findings define a stroma-dependent paradigm of Rho signaling in cancer and implicate Rho–TGF-β crosstalk in osteolytic bone metastasis. PMID:24590291

  13. Parathyroid Hormone-Related Protein, Its Regulation of Cartilage and Bone Development, and Role in Treating Bone Diseases.

    PubMed

    Martin, T John

    2016-07-01

    Although parathyroid hormone-related protein (PTHrP) was discovered as a cancer-derived hormone, it has been revealed as an important paracrine/autocrine regulator in many tissues, where its effects are context dependent. Thus its location and action in the vasculature explained decades-long observations that injection of PTH into animals rapidly lowered blood pressure by producing vasodilatation. Its roles have been specified in development and maturity in cartilage and bone as a crucial regulator of endochondral bone formation and bone remodeling, respectively. Although it shares actions with parathyroid hormone (PTH) through the use of their common receptor, PTHR1, PTHrP has other actions mediated by regions within the molecule beyond the amino-terminal sequence that resembles PTH, including the ability to promote placental transfer of calcium from mother to fetus. A striking feature of the physiology of PTHrP is that it possesses structural features that equip it to be transported in and out of the nucleus, and makes use of a specific nuclear import mechanism to do so. Evidence from mouse genetic experiments shows that PTHrP generated locally in bone is essential for normal bone remodeling. Whereas the main physiological function of PTH is the hormonal regulation of calcium metabolism, locally generated PTHrP is the important physiological mediator of bone remodeling postnatally. Thus the use of intermittent injection of PTH as an anabolic therapy for bone appears to be a pharmacological application of the physiological function of PTHrP. There is much current interest in the possibility of developing PTHrP analogs that might enhance the therapeutic anabolic effects. PMID:27142453

  14. Parathyroid Hormone-Related Protein, Its Regulation of Cartilage and Bone Development, and Role in Treating Bone Diseases.

    PubMed

    Martin, T John

    2016-07-01

    Although parathyroid hormone-related protein (PTHrP) was discovered as a cancer-derived hormone, it has been revealed as an important paracrine/autocrine regulator in many tissues, where its effects are context dependent. Thus its location and action in the vasculature explained decades-long observations that injection of PTH into animals rapidly lowered blood pressure by producing vasodilatation. Its roles have been specified in development and maturity in cartilage and bone as a crucial regulator of endochondral bone formation and bone remodeling, respectively. Although it shares actions with parathyroid hormone (PTH) through the use of their common receptor, PTHR1, PTHrP has other actions mediated by regions within the molecule beyond the amino-terminal sequence that resembles PTH, including the ability to promote placental transfer of calcium from mother to fetus. A striking feature of the physiology of PTHrP is that it possesses structural features that equip it to be transported in and out of the nucleus, and makes use of a specific nuclear import mechanism to do so. Evidence from mouse genetic experiments shows that PTHrP generated locally in bone is essential for normal bone remodeling. Whereas the main physiological function of PTH is the hormonal regulation of calcium metabolism, locally generated PTHrP is the important physiological mediator of bone remodeling postnatally. Thus the use of intermittent injection of PTH as an anabolic therapy for bone appears to be a pharmacological application of the physiological function of PTHrP. There is much current interest in the possibility of developing PTHrP analogs that might enhance the therapeutic anabolic effects.

  15. Parathyroid hormone-dependent signaling pathways regulating genes in bone cells

    NASA Technical Reports Server (NTRS)

    Swarthout, John T.; D'Alonzo, Richard C.; Selvamurugan, Nagarajan; Partridge, Nicola C.

    2002-01-01

    Parathyroid hormone (PTH) is an 84-amino-acid polypeptide hormone functioning as a major mediator of bone remodeling and as an essential regulator of calcium homeostasis. PTH and PTH-related protein (PTHrP) indirectly activate osteoclasts resulting in increased bone resorption. During this process, PTH changes the phenotype of the osteoblast from a cell involved in bone formation to one directing bone resorption. In addition to these catabolic effects, PTH has been demonstrated to be an anabolic factor in skeletal tissue and in vitro. As a result, PTH has potential medical application to the treatment of osteoporosis, since intermittent administration of PTH stimulates bone formation. Activation of osteoblasts by PTH results in expression of genes important for the degradation of the extracellular matrix, production of growth factors, and stimulation and recruitment of osteoclasts. The ability of PTH to drive changes in gene expression is dependent upon activation of transcription factors such as the activator protein-1 family, RUNX2, and cAMP response element binding protein (CREB). Much of the regulation of these processes by PTH is protein kinase A (PKA)-dependent. However, while PKA is linked to many of the changes in gene expression directed by PTH, PKA activation has been shown to inhibit mitogen-activated protein kinase (MAPK) and proliferation of osteoblasts. It is now known that stimulation of MAPK and proliferation by PTH at low concentrations is protein kinase C (PKC)-dependent in both osteoblastic and kidney cells. Furthermore, PTH has been demonstrated to regulate components of the cell cycle. However, whether this regulation requires PKC and/or extracellular signal-regulated kinases or whether PTH is able to stimulate other components of the cell cycle is unknown. It is possible that stimulation of this signaling pathway by PTH mediates a unique pattern of gene expression resulting in proliferation in osteoblastic and kidney cells; however, specific

  16. Parathyroid hormone-dependent signaling pathways regulating genes in bone cells.

    PubMed

    Swarthout, John T; D'Alonzo, Richard C; Selvamurugan, Nagarajan; Partridge, Nicola C

    2002-01-01

    Parathyroid hormone (PTH) is an 84-amino-acid polypeptide hormone functioning as a major mediator of bone remodeling and as an essential regulator of calcium homeostasis. PTH and PTH-related protein (PTHrP) indirectly activate osteoclasts resulting in increased bone resorption. During this process, PTH changes the phenotype of the osteoblast from a cell involved in bone formation to one directing bone resorption. In addition to these catabolic effects, PTH has been demonstrated to be an anabolic factor in skeletal tissue and in vitro. As a result, PTH has potential medical application to the treatment of osteoporosis, since intermittent administration of PTH stimulates bone formation. Activation of osteoblasts by PTH results in expression of genes important for the degradation of the extracellular matrix, production of growth factors, and stimulation and recruitment of osteoclasts. The ability of PTH to drive changes in gene expression is dependent upon activation of transcription factors such as the activator protein-1 family, RUNX2, and cAMP response element binding protein (CREB). Much of the regulation of these processes by PTH is protein kinase A (PKA)-dependent. However, while PKA is linked to many of the changes in gene expression directed by PTH, PKA activation has been shown to inhibit mitogen-activated protein kinase (MAPK) and proliferation of osteoblasts. It is now known that stimulation of MAPK and proliferation by PTH at low concentrations is protein kinase C (PKC)-dependent in both osteoblastic and kidney cells. Furthermore, PTH has been demonstrated to regulate components of the cell cycle. However, whether this regulation requires PKC and/or extracellular signal-regulated kinases or whether PTH is able to stimulate other components of the cell cycle is unknown. It is possible that stimulation of this signaling pathway by PTH mediates a unique pattern of gene expression resulting in proliferation in osteoblastic and kidney cells; however, specific

  17. Parathyroid hormone stimulates bone formation and resorption in organ culture: evidence for a coupling mechanism.

    PubMed Central

    Howard, G A; Bottemiller, B L; Turner, R T; Rader, J I; Baylink, D J

    1981-01-01

    We have developed an in vitro system, using embryonic chicken tibiae grown in a serum-free medium, which exhibits simultaneous bone formation and resorption. Tibiae from 8-day embryos increased in mean (+/- SD) length (4.0 +/- 0.4 to 11.0 +/- 0.3 mm) and dry weight (0.30 +/- 0.04 to 0.84 +/- 0.04 mg) during 12 days in vitro. There was increased incorporation of [3H]proline into hydroxyproline (120 +/- 20 to 340 +/- 20 cpm/mg of bone per 24 hr) as a measure of collagen synthesis, as well as a 62 +/- 5% increase in total calcium and 45Ca taken up as an indication of active mineralization. A physiologic concentration (1 pM) of parathyroid hormone was found to stimulate bone resorption over control levels in this system. Parathyroid hormone stimulated the release of [3H]hydroxyproline from the bone shafts but not from the cartilage ends, indicating the specificity of the response. With 1 pM parathyroid hormone we observed an acute inhibition of bone formation, followed (after 12-16 hr) by a chronic stimulation of bone formation during the 12-day incubation. Both mineral uptake and matrix formation were enhanced at approximately the same rate during the 12-day incubation. The chronic enhancement of formation required parathyroid hormone only for the initial 8-10 hr of incubation. These results could be explained by the production or release of a factor from bone to stimulate formation in response to the acute increase in resorption--a "coupling factor." Indeed, dialyzed culture medium conditioned by actively resorbing bones stimulated bone formation over controls when added to organ cultures at a 1:20 dilution. The factor is larger than 12,000 daltons as determined by dialysis. The factor is specific for the bone shaft and did not affect the cartilage ends. PMID:6942425

  18. Osteopontin deficiency enhances parathyroid hormone/ parathyroid hormone related peptide receptor (PPR) signaling-induced alteration in tooth formation and odontoblastic morphology.

    PubMed

    Morishita, Maki; Ono, Noriaki; Miyai, Kentano; Nakagawa, Tomomi; Hanyu, Ryo; Nagao, Masashi; Kamolratanakul, Paksinee; Notomi, Takuya; Rittling, Susan R; Denhardt, David T; Kronenberg, Henry M; Ezura, Yoichi; Hayata, Tadayoshi; Nakamoto, Tetsuya; Noda, Masaki

    2011-06-01

    Parathyroid hormone/parathyroid hormone-related protein receptor (PPR) signaling is known to be involved in tooth development. In bone, extracellular matrix protein osteopontin (OPN) is a negative regulator of PPR signaling in bone formation. However, the role of OPN in modulation of PPR action in tooth development is not understood. Therefore, we examined the tooth in double mutant mice. Constitutively active PPR was expressed specifically in the odontoblasts and osteoblasts (caPPR-tg) in the presence or absence of OPN. Radiographic analysis indicated that the length of the third molar (M3) and the incisor was decreased in the caPPR-tg mice compared to wild type, and such reduction in molar and incisor length was further enhanced in the absence of OPN (caPPR-tg OPN-KO). With respect to histology of incisors, caPPR-tg induced high cellularity and irregularity in odontoblastic shape and this was enhanced by the absence of OPN. These morphological observations suggest that OPN modulates PPR signaling that are involved in tooth formation.

  19. Current concepts of the metabolism and radioimmunoassay of parathyroid hormone

    SciTech Connect

    Slatopolsky, E.; Martin, K.; Morrissey, J.; Hruska, K.

    1982-03-01

    Two major hormonal system (PTH and vitamin D) and a minor system (calcitonin) are responsible for the regulation of calcium homeostasis. Serum ionized calcium is maintained within narrow limits by the intereactions of these hormonal systems and their effects on the intestine, the kidney, and the skeleton. The editorial describes in a succinct form, general aspects of PTH metabolism in view of recent information regarding the contributions of the liver, kidney, and bone to the degradation of PTH. On the basis of information accumulated concerning the peripheral metabolism of PTH, the different RIAs for PTH are also discussed.

  20. The secretory response of parathyroid hormone to acute hypocalcemia in vivo is independent of parathyroid glandular sodium/potassium-ATPase activity.

    PubMed

    Martuseviciene, Giedre; Hofman-Bang, Jacob; Clausen, Torben; Olgaard, Klaus; Lewin, Ewa

    2011-04-01

    The involvement of sodium/potassium-ATPase in regulating parathyroid hormone (PTH) secretion is inferred from in vitro studies. Recently, the α-klotho-dependent rapid recruitment of this ATPase to the parathyroid cell plasma membrane in response to low extracellular calcium ion was suggested to be linked to increased hormone secretion. In this study, we used an in vivo rat model to determine the importance of sodium/potassium-ATPase in PTH secretion. Glands were exposed and treated in situ with vehicle or ouabain, a specific inhibitor of sodium/potassium-ATPase. PTH secretion was significantly increased in response to ethylene glycol tetraacetic acid-induced acute hypocalcemia and to the same extent in both vehicle and ouabain groups. The glands were removed, and inhibition of the ATPase was measured by (86)rubidium uptake, which was found to be significantly decreased in ouabain-treated parathyroid glands, indicating inhibition of the ATPase. As ouabain induced systemic hyperkalemia, the effect of high potassium on hormone secretion was also examined but was found to have no effect. Thus, inhibition of the parathyroid gland sodium/potassium-ATPase activity in vivo had no effect on the secretory response to acute hypocalcemia. Hence, the suggested importance of this ATPase in the regulation of PTH secretion could not be confirmed in this in vivo model. PMID:21209610

  1. Ultrasensitive Impedimetric Biosensor Fabricated by a New Immobilisation Technique for Parathyroid Hormone.

    PubMed

    Özcan, Hakkı Mevlüt; Yildiz, Kübra; Çakar, Cansu; Aydin, Tuba; Asav, Engin; Sağiroğlu, Ayten; Sezgintürk, Mustafa Kemal

    2015-07-01

    This paper presents a novel ultrasensitive and rapid impedimetric biosensor with new immobilisation materials for parathyroid hormone (PTH) with the aim to determine the PTH level in serum for the diagnosis and monitoring of parathyroid diseases such as hyperparathyroidism, adenoma, and thyroid cancer. The interaction between PTH and the biosensor was investigated with an electrochemical method. The biosensor was based on the gold electrode modified by mercaptohexanol (6-MHL). Anti-parathyroid hormone (anti-PTH) was covalently immobilised onto a self-assembled monolayer (SAM) by using epiclorhidrina (EPI) with ethanolamine (EA). The EPI-EA interaction represents the first use of these for the construction of biosensors in published reports. The immobilisation of the anti-PTH was monitored by electrochemical impedance spectroscopy, cyclic voltammetry and scanning electron microscopy (SEM) techniques. After the optimisation studies of immobilisation materials such as 6-MHL, EPI, EA and glutaraldehyde, linearity, repeatability and sensitivity of biosensor were evaluated as the performance of biosensor. PTH was detected within a linear range of 0.1-0.6 pg/ml, and the detection limit was 0.1 fg/ml. The specificity of the biosensor was also investigated. Finally, the described biosensor was used to detect the PTH levels in artificial serum samples.

  2. Use of pre-operative Tc99m-Sestamibi scintigraphy and intraoperative parathyroid hormone monitoring to eliminate neck exploration in mediastinal parathyroid adenocarcinoma.

    PubMed

    Damadi, Amir; Harkema, James; Kareti, Rao; Saxe, Andrew

    2007-01-01

    A 66-year-old white woman was found to have an elevated serum calcium and parathyroid hormone (PTH) on routine health evaluation. Physical examination was unremarkable as was ultrasonography of the neck. A sestamibi parathyroid scan revealed abnormal uptake in the anterior mediastinum. Computed tomography of the chest demonstrated an anterior mediastinal mass compatible with a parathyroid adenoma but no neck masses. The patient underwent mediastinoscopy that was converted to a median sternotomy to fully access the mass. The mass was completely resected with surrounding thymus gland. Frozen section confirmed that excised tissue was parathyroid gland in origin. An intraoperative PTH obtained 20 minutes after specimen removal showed a decrease of more than 50% from preoperative levels. The strategy for initial surgery for hyperparathyroidism when a sestamibi scan is "positive" in the mediastinum (only) is a point of some controversy. Traditional recommendations have been to "clear the neck" of abnormal parathyroid tissue before undertaking a more morbid sternotomy. Mediastinoscopy was attempted to remove the mediastinal lesion and to avoid a sternotomy. Preoperative Tc99m sestamibi scintigraphy, frozen section histology, and intraoperative PTH monitoring permitted the authors to conclude that neck exploration was unnecessary.

  3. Parathyroid hormone regulates the expression of rat osteoblast and osteosarcoma nuclear matrix proteins.

    PubMed

    Bidwell, J; Feister, H; Swartz, D; Onyia, J; Holden, J; Hock, J

    1996-12-01

    Parathyroid hormone (PTH) alters osteoblast morphology. How these changes in cell shape modify nuclear structure and ultimately gene expression is not known. Chronic exposure to rat PTH (1-34) [10 nM] attenuated the expression of 200, 190, and 160 kD proteins in the nuclear matrix-intermediate filament subfraction of the rat osteosarcoma cells, ROS 17/2.8 [Bidwell et al. (1994b): Endocrinology 134:1738-1744]. Here, we determined that these same PTH-responsive proteins were expressed in rat metaphyseal osteoblasts. We identified the 200 kD protein as a non-muscle myosin. Although the molecular weights, subcellular distribution, and half-lives of the 190 and 160 kD proteins were similar to topoisomerase II-alpha and -beta, nuclear matrix enzymes that mediate DNA topology, the 190 and 160 kD proteins did not interact with topoisomerase antibodies. Nevertheless, the expression of topoisomerase II-alpha, and NuMA, a component of the nuclear core filaments, was also regulated by PTH in the osteosarcoma cells. The 190 kD protein was selectively expressed in bone cells as it was not observed in OK opossum kidney cells, H4 hepatoma cells, or NIH3T3 cells. PTH attenuated mRNA expression of the PTH receptor in our cell preparations. These results demonstrate that PTH selectively alters the expression of osteoblast membrane, cytoskeletal, and nucleoskeletal proteins. Topoisomerase II-alpha, NuMA, and the 190 and 160 kD proteins may direct the nuclear PTH signalling pathways to the target genes and play a structural role in osteoblast gene expression. PMID:8913889

  4. Parathyroid hormone induces the Nrna family of nuclear orphan receptors in vivo

    SciTech Connect

    Pirih, Flavia Q. . E-mail: fqpirih@ucla.edu; Aghaloo, Tara L. . E-mail: taghaloo@ucla.edu; Bezouglaia, Olga . E-mail: obezougl@ucla.edu; Nervina, Jeanne M. . E-mail: jnervina@ucla.edu; Tetradis, Sotirios; E-mail: sotirist@dent.ucla.edu

    2005-07-01

    Parathyroid hormone (PTH) has both anabolic and catabolic effects on bone metabolism, although the molecular mechanisms mediating these effects are largely unknown. Among the transcription factors induced by Pth in osteoblasts are the nerve growth factor-inducible factor B (NR4A; NGFI-B) family of orphan nuclear receptors: Nurr1, Nur77, and NOR-1. PTH induces NR4A members through the cAMP-protein kinase A (PKA) pathway in vitro. We report here that PTH rapidly and transiently induced expression of all three NR4A genes in PTH-target tissues in vivo. In calvaria, long bones, and kidneys, NR4A induction was maximal 0.5-1 h after a single intraperitoneal (i.p.) injection of 80 {mu}g/kg PTH. Nur77 demonstrated the highest expression, followed, in order, by Nurr1 and NOR-1. In calvaria and long bone, PTH-induced expression of each NR4A gene was detectable at 10 {mu}g/kg i.p. with maximum induction at 40-80 {mu}g/kg. PTH (3-34) did not induce NR4A mRNA levels in calvaria, long bone, and kidney in vivo, confirming our in vitro results that NR4A genes are induced primarily through the cAMP-PKA pathway. The magnitude of PTH-induced NR4A expression was comparable in vivo and in vitro. However, NR4A mRNA levels peaked and returned to baseline faster in vivo. Both in vivo and in vitro, PTH induced NR4A pre-mRNA levels suggesting that induction of these genes is, at least in part, through activation of mRNA synthesis. The in vivo induction of the NR4A family members by PTH suggests their involvement in, at least some, PTH-induced changes in bone metabolism.

  5. Conjugation of cell-penetrating peptides to parathyroid hormone affects its structure, potency, and transepithelial permeation.

    PubMed

    Kristensen, Mie; de Groot, Anne Marit; Berthelsen, Jens; Franzyk, Henrik; Sijts, Alice; Nielsen, Hanne Mørck

    2015-03-18

    Delivery of therapeutic peptides and proteins by the use of cell-penetrating peptides (CPPs) as carriers has been suggested as a feasible strategy. The aim of the present study was to investigate the effect of conjugating a series of well-known CPPs to the biologically active part of parathyroid hormone, i.e., PTH(1-34), and to evaluate the effect with regard to secondary structure, potency in Saos-2 cells, immunogenicity, safety, as well as the transepithelial permeation across monolayers by using the Caco-2 cell culture model. Further, co-administration of CPP and PTH(1-34) as an alternative to covalent conjugation was compared with regard to the transepithelial permeation. CPP-conjugated PTH(1-34) fusion peptides were successfully expressed in Escherichia coli and purified from inclusion bodies. No clear correlation between the degree of secondary structure of the CPP-conjugated PTH(1-34) fusion peptides and their potency was found, albeit a general decrease in permeation was observed for both N- and C-terminally CPP-conjugated PTH(1-34) as compared to native PTH(1-34). However, attachment of CPP to the N-terminus significantly increased permeation across Caco-2 cell monolayers as compared to the corresponding C-terminally CPP-conjugated PTH(1-34). In addition, the nonaarginine sequence proved to be the only CPP capable of increasing permeation when conjugated to PTH(1-34) as compared to co-administration of CPP and PTH(1-34). This enhancement effect was, however, associated with an unacceptably low level of cell viability. In conclusion, covalent conjugation of CPPs to PTH(1-34) influenced the secondary structure, potency, and transepithelial permeation efficiency of the resulting conjugate, and hence this approach appears not to be favorable as compared to co-administration when optimizing CPP-mediated permeation of PTH(1-34) across an intestinal epithelium.

  6. Prolonged signaling at the parathyroid hormone receptor by peptide ligands targeted to a specific receptor conformation

    PubMed Central

    Okazaki, Makoto; Ferrandon, Sebastien; Vilardaga, Jean-Pierre; Bouxsein, Mary L.; Potts, John T.; Gardella, Thomas J.

    2008-01-01

    The parathyroid hormone receptor (PTHR) is a class B G protein-coupled receptor that plays critical roles in bone and mineral ion metabolism. Ligand binding to the PTHR involves interactions to both the amino-terminal extracellular (N) domain, and transmembrane/extracellular loop, or juxtamembrane (J) regions of the receptor. Recently, we found that PTH(1–34), but not PTH-related protein, PTHrP(1–36), or M-PTH(1–14) (M = Ala/Aib1,Aib3,Gln10,Har11,Ala12,Trp14,Arg19), binds to the PTHR in a largely GTPγS-resistant fashion, suggesting selective binding to a novel, high-affinity conformation (R0), distinct from the GTPγS-sensitive conformation (RG). We examined the effects in vitro and in vivo of introducing the M substitutions, which enhance interaction to the J domain, into PTH analogs extended C-terminally to incorporate residues involved in the N domain interaction. As compared with PTH(1–34), M-PTH(1–28) and M-PTH(1–34) bound to R0 with higher affinity, produced more sustained cAMP responses in cells, formed more stable complexes with the PTHR in FRET and subcellular localization assays, and induced more prolonged calcemic and phosphate responses in mice. Moreover, after 2 weeks of daily injection in mice, M-PTH(1–34) induced larger increases in trabecular bone volume and greater increases in cortical bone turnover, than did PTH(1–34). Thus, the putative R0 PTHR conformation can form highly stable complexes with certain PTH ligand analogs and thereby mediate surprisingly prolonged signaling responses in bone and/or kidney PTH target cells. Controlling, via ligand analog design, the selectivity with which a PTH ligand binds to R0, versus RG, may be a strategy for optimizing signaling duration time, and hence therapeutic efficacy, of PTHR agonist ligands. PMID:18946036

  7. Parathyroid hormone, calcitonin, and vitamin D 1974: Present status of physiological studies and analysis of calcium homeostasis

    NASA Technical Reports Server (NTRS)

    Potts, J. T., Jr.; Swenson, K. G.

    1975-01-01

    The role of parathyroid hormone, calcitonin, and vitamin D in the control of calcium and bone metabolism was studied. Particular emphasis was placed on the physiological adaptation to weightlessness and, as a potential model for this purpose, on the immobilization characteristic of space flight or prolonged bed rest. The biosynthesis, control of secretion, and metabolism of these hormonal agents is considered.

  8. Nonlinear dynamics in pulsatile secretion of parathyroid hormone in normal human subjects

    NASA Astrophysics Data System (ADS)

    Prank, Klaus; Harms, Heio; Brabant, Georg; Hesch, Rolf-Dieter; Dämmig, Matthias; Mitschke, Fedor

    1995-03-01

    In many biological systems, information is transferred by hormonal ligands, and it is assumed that these hormonal signals encode developmental and regulatory programs in mammalian organisms. In contrast to the dogma of endocrine homeostasis, it could be shown that the biological information in hormonal networks is not only present as a constant hormone concentration in the circulation pool. Recently, it has become apparent that hormone pulses contribute to this hormonal pool, which modulates the responsiveness of receptors within the cell membrane by regulation of the receptor synthesis, movement within the membrane layer, coupling to signal transduction proteins and internalization. Phase space analysis of dynamic parathyroid hormone (PTH) secretion allowed the definition of a (in comparison to normal subjects) relatively quiet ``low dynamic'' secretory pattern in osteoporosis, and a ``high dynamic'' state in hyperparathyroidism. We now investigate whether this pulsatile secretion of PTH in healthy men exhibits characteristics of nonlinear determinism. Our findings suggest that this is conceivable, although on the basis of presently available data and techniques, no proof can be established. Nevertheless, pulsatile secretion of PTH might be a first example of nonlinear deterministic dynamics in an apparently irregular hormonal rhythm in human physiology.

  9. Parathyroid Disorders

    MedlinePlus

    ... PTH, you have hyperparathyroidism, and your blood calcium rises. In many cases, a benign tumor on a parathyroid gland makes it overactive. Or, the extra hormones can come from enlarged parathyroid glands. Very rarely, the cause is cancer. If you do not have enough PTH, you ...

  10. Parathyroid hyperplasia

    MedlinePlus

    Enlarged parathyroid glands; Osteoporosis - parathyroid hyperplasia; Bone thinning - parathyroid hyperplasia; Osteopenia - parathyroid hyperplasia; High calcium level - parathyroid hyperplasia; Chronic kidney disease - parathyroid hyperplasia; ...

  11. Severe hypercalcemic hyperparathyroidism developing in a patient with hyperaldosteronism and renal resistance to parathyroid hormone.

    PubMed

    Park-Sigal, Jennifer; Don, Burl R; Porzig, Anne; Recker, Robert; Griswold, Virginia; Sebastian, Anthony; Duh, Quan-Yang; Portale, Anthony A; Shoback, Dolores; Schambelan, Morris

    2013-03-01

    We evaluated an African American woman referred in 1986 at age 33 years because of renal potassium and calcium wasting and chronic hip pain. She presented normotensive, hypokalemic, hypocalcemic, normophosphatemic, and hypercalciuric. Marked hyperparathyroidism was evident. Urinary cyclic adenosine monophosphate (cAMP) excretion did not increase in response to parathyroid hormone (PTH) infusion, indicating renal resistance to PTH. X-rays and bone biopsy revealed severe osteitis fibrosa cystica, confirming skeletal responsiveness to PTH. Renal potassium wasting, suppressed plasma renin activity, and elevated plasma and urinary aldosterone levels accompanied her hypokalemia, suggesting primary hyperaldosteronism. Hypokalemia resolved with spironolactone and, when combined with dietary sodium restriction, urinary calcium excretion fell and hypocalcemia improved, in accord with the known positive association between sodium intake and calcium excretion. Calcitriol and oral calcium supplements did not suppress the chronic hyperparathyroidism nor did they reduce aldosterone levels. Over time, hyperparathyroid bone disease progressed with pathologic fractures and persistent pain. In 2004, PTH levels increased further in association with worsening chronic kidney disease. Eventually hypercalcemia and hypertension developed. Localizing studies in 2005 suggested a left inferior parathyroid tumor. After having consistently declined, the patient finally agreed to neck exploration in January 2009. Four hyperplastic parathyroid glands were removed, followed immediately by severe hypocalcemia, attributed to "hungry bone syndrome" and hypoparathyroidism, which required prolonged hospitalization, calcium infusions, and oral calcitriol. Although her bone pain resolved, hyperaldosteronism persisted.

  12. Parathyroid hormone secretory pattern, circulating activity, and effect on bone turnover in adult growth hormone deficiency.

    PubMed

    Ahmad, A M; Hopkins, M T; Fraser, W D; Ooi, C G; Durham, B H; Vora, J P

    2003-02-01

    Adult growth hormone deficiency (AGHD) is associated with osteoporosis. Reports have associated parathyroid hormone (PTH) circadian rhythm abnormalities with osteoporosis. Furthermore, there is evidence of relative PTH insensitivity in AGHD patients. Factors regulating PTH circadian rhythm are not fully understood. There is evidence that serum phosphate is a likely determinant of PTH rhythm. The aim of this study was to investigate PTH circadian rhythm and its circulating activity and association with bone turnover in untreated AGHD patients compared to healthy individuals. We sampled peripheral venous blood at 30-min and urine at 3-h intervals during the day over a 24-h period from 1400 h in 14 untreated AGHD patients (7 M, 7 W; mean age, 49.5 +/- 10.7 years) and 14 age (48.6 +/- 11.4 years; P = NS) and gender-matched controls. Cosinor analysis was performed to analyze rhythm parameters. Cross-correlational analysis was used to determine the relationship between variables. Serum PTH (1-84), phosphate, total calcium, urea, creatinine, albumin, type I collagen C-telopeptides (CT(x)), a bone resorption marker, and procollagen type I amino-terminal propeptide (PINP), a bone formation marker, were measured on all samples. Nephrogenous cyclic adenosine monophosphate (NcAMP), which reflects the renal activity of PTH, was calculated from plasma and urinary cAMP. Urinary calcium and phosphate were measured on all urine samples. Significant circadian rhythms were observed for serum PTH, phosphate, CT(x), and PINP in AGHD and healthy subjects (P < 0.001). No significant rhythm was observed for serum-adjusted calcium. PTH MESOR (rhythm-adjusted mean) was significantly higher (P < 0.05), whereas the MESOR values for phosphate, CT(x) (P < 0.05), and PINP (P < 0.001) were lower in AGHD patients than in controls. AGHD patients had significantly lower 24-h NcAMP (P < 0.001) and higher urinary calcium excretion (P < 0.05). Maximum cross-correlation between PTH and phosphate (r = 0

  13. [Rapid measurement of human parathyroid hormone-(1-84) by immunoradiometric assay for use in intraoperative determination of hyperfunctioning parathyroid glands].

    PubMed

    Kousaka, T; Shigeno, C; Kitamura, N; Iwamoto, N; Shiomi, K; Lee, K C; Sone, T; Kikuchi, H; Ohta, S; Yamamoto, I

    1990-02-01

    Rapid measurement of serum intact parathyroid hormone concentration was achieved by modification of an immunoradiometric assay for the hormone. Incubation of serum samples for 15 min at 37 degrees C under shaking gave optimal results in terms of assay variance and reproducibility: intra-assay CVs were less than 10% over the hormone concentrations of 11-1,600 pg/ml; intra- and inter-assay CVs for two control sera at different hormone levels were less than 12%. The minimal detectable hormone concentration was found at 27.8 pg/ml. The serum hormone levels of 43 subjects (31 health subjects, 9 patients with primary hyperparathyroidism, and 3 patients with secondary hyperparathyroidism) determined by either rapid or regular assay well correlated with each other (r2 = 0.979, p less than 0.001). In two patients with parathyroid adenoma serum intact PTH levels fell rapidly to 12.1% of the preoperative values 20 min after ligation of the vascular pedicle to the hyperfunctioning glands. We conclude that the modified assay protocol allows rapid, accurate, and simple estimation of intact PTH concentrations, and can be used as an intraoperative measure to aid both diagnosis and surgical cure of hyperparathyroidism.

  14. Molecular recognition of parathyroid hormone by its G protein-coupled receptor

    SciTech Connect

    Pioszak, Augen A.; Xu, H. Eric

    2008-08-07

    Parathyroid hormone (PTH) is central to calcium homeostasis and bone maintenance in vertebrates, and as such it has been used for treating osteoporosis. It acts primarily by binding to its receptor, PTH1R, a member of the class B G protein-coupled receptor (GPCR) family that also includes receptors for glucagon, calcitonin, and other therapeutically important peptide hormones. Despite considerable interest and much research, determining the structure of the receptor-hormone complex has been hindered by difficulties in purifying the receptor and obtaining diffraction-quality crystals. Here, we present a method for expression and purification of the extracellular domain (ECD) of human PTH1R engineered as a maltose-binding protein (MBP) fusion that readily crystallizes. The 1.95-{angstrom} structure of PTH bound to the MBP-PTH1R-ECD fusion reveals that PTH docks as an amphipathic helix into a central hydrophobic groove formed by a three-layer {alpha}-{beta}-{beta}{alpha} fold of the PTH1R ECD, resembling a hot dog in a bun. Conservation in the ECD scaffold and the helical structure of peptide hormones emphasizes this hot dog model as a general mechanism of hormone recognition common to class B GPCRs. Our findings reveal critical insights into PTH actions and provide a rational template for drug design that targets this hormone signaling pathway.

  15. Isolation and characterization of the human parathyroid hormone-like peptide gene

    SciTech Connect

    Mangin, M.; Ikeda, K.; Dreyer, B.E.; Broadus, A.E. )

    1989-04-01

    A parathyroid hormone-like peptide (PTH-LP) has recently been identified in human tumors associated with the syndrome of humoral hypercalcemia of malignancy. The peptide appears to be encoded by a single-copy gene that gives rise to multiple mRNAs that are heterogeneous at both their 5{prime} and their 3{prime} ends. Alternative RNA splicing is responsible for the 3{prime} heterogeneity and results in mRNAs encoding three different peptides, each with a unique C terminus. The authors have isolated and characterized the human PTHLP gene. The gene is a complex transcriptional unit spanning more than 12 kilobases of DNA and containing six exons. Two 5{prime} exons encode distinct 5{prime} untranslated regions and are separated by a putative promoter element, indicating that the gene either has two promoters or is alternatively spliced from a single promoter upstream of the first exon. The middle portion of the PTHLP gene, comprising exons 2-4, has an organizational pattern of introns and exons identical to that of the parathyroid hormone gene, consistent with a common ancestral origin of these two genes. Exon 4 of the PTHLP gene encodes the region common to all three peptides and the C terminus of the shortest peptide, and exons 5 and 6 encode the unique C termini of the other two peptides. Northern analysis of mRNAs from four human tumors of different histological types reveals the preferential use of 3{prime} splicing patterns of individual tumors.

  16. Endogenous parathyroid hormone-related protein compensates for the absence of parathyroid hormone in promoting bone accrual in vivo in a model of bone marrow ablation.

    PubMed

    Zhu, Qi; Zhou, Xichao; Zhu, Min; Wang, Qian; Goltzman, David; Karaplis, Andrew; Miao, Dengshun

    2013-09-01

    To assess the effect of hypoparathyroidism on osteogenesis and bone turnover in vivo, bone marrow ablation (BMXs) were performed in tibias of 8-week-old wild-type and parathyroid hormone-null (PTH(-/-)) mice and newly formed bone tissue was analyzed from 5 days to 3 weeks after BMX. At 1 week after BMX, trabecular bone volume, osteoblast numbers, alkaline phosphatase-positive areas, type I collagen-positive areas, PTH receptor-positive areas, calcium sensing receptor-positive areas, and expression of bone formation-related genes were all decreased significantly in the diaphyseal regions of bones of PTH(-/-) mice compared to wild-type mice. In contrast, by 2 weeks after BMX, all parameters related to osteoblastic bone accrual were increased significantly in PTH(-/-) mice. At 5 days after BMX, active tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts had appeared in wild-type mice but were undetectable in PTH(-/-) mice, Both the ratio of mRNA levels of receptor activator of NF-κB ligand (RANKL)/osteoprotegerin (OPG) and TRAP-positive osteoclast surface were still reduced in PTH(-/-) mice at 1 week but were increased by 2 weeks after BMX. The expression levels of parathyroid hormone-related protein (PTHrP) at both mRNA and protein levels were upregulated significantly at 1 week and more dramatically at 2 weeks after BMX in PTH(-/-) mice. To determine whether the increased newly formed bones in PTH(-/-) mice at 2 weeks after BMX resulted from the compensatory action of PTHrP, PTH(-/-) PTHrP(+/-) mice were generated and newly formed bone tissue was compared in these mice with PTH(-/-) and wild-type mice at 2 weeks after BMX. All parameters related to osteoblastic bone formation and osteoclastic bone resorption were reduced significantly in PTH(-/-) PTHrP(+/-) mice compared to PTH(-/-) mice. These results demonstrate that PTH deficiency itself impairs osteogenesis, osteoclastogenesis, and osteoclastic bone resorption, whereas subsequent upregulation of PTHr

  17. Endogenous parathyroid hormone-related protein compensates for the absence of parathyroid hormone in promoting bone accrual in vivo in a model of bone marrow ablation.

    PubMed

    Zhu, Qi; Zhou, Xichao; Zhu, Min; Wang, Qian; Goltzman, David; Karaplis, Andrew; Miao, Dengshun

    2013-09-01

    To assess the effect of hypoparathyroidism on osteogenesis and bone turnover in vivo, bone marrow ablation (BMXs) were performed in tibias of 8-week-old wild-type and parathyroid hormone-null (PTH(-/-)) mice and newly formed bone tissue was analyzed from 5 days to 3 weeks after BMX. At 1 week after BMX, trabecular bone volume, osteoblast numbers, alkaline phosphatase-positive areas, type I collagen-positive areas, PTH receptor-positive areas, calcium sensing receptor-positive areas, and expression of bone formation-related genes were all decreased significantly in the diaphyseal regions of bones of PTH(-/-) mice compared to wild-type mice. In contrast, by 2 weeks after BMX, all parameters related to osteoblastic bone accrual were increased significantly in PTH(-/-) mice. At 5 days after BMX, active tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts had appeared in wild-type mice but were undetectable in PTH(-/-) mice, Both the ratio of mRNA levels of receptor activator of NF-κB ligand (RANKL)/osteoprotegerin (OPG) and TRAP-positive osteoclast surface were still reduced in PTH(-/-) mice at 1 week but were increased by 2 weeks after BMX. The expression levels of parathyroid hormone-related protein (PTHrP) at both mRNA and protein levels were upregulated significantly at 1 week and more dramatically at 2 weeks after BMX in PTH(-/-) mice. To determine whether the increased newly formed bones in PTH(-/-) mice at 2 weeks after BMX resulted from the compensatory action of PTHrP, PTH(-/-) PTHrP(+/-) mice were generated and newly formed bone tissue was compared in these mice with PTH(-/-) and wild-type mice at 2 weeks after BMX. All parameters related to osteoblastic bone formation and osteoclastic bone resorption were reduced significantly in PTH(-/-) PTHrP(+/-) mice compared to PTH(-/-) mice. These results demonstrate that PTH deficiency itself impairs osteogenesis, osteoclastogenesis, and osteoclastic bone resorption, whereas subsequent upregulation of PTHr

  18. ALX 111: ALX1-11, parathyroid hormone (1-84) - NPS Allelix, PREOS, PTH, recombinant human parathyroid hormone, rhPTH (1-84).

    PubMed

    2003-01-01

    ALX 111 [parathyroid hormone (1-84) - NPS Allelix, recombinant human parathyroid hormone, rhPTH (1-84), PREOS] is a full-length, recombinant human parathyroid hormone. It has potential as an anti-osteoporotic agent, due to its properties as a bone formation stimulant. This profile has been selected from R&D Insight, a pharmaceutical intelligence database produced by Adis International Ltd. It has been recommended that ALX 111 should be given for 1 to 2 years and may be given in combination with an antiresorptive agent, such as estrogen or a bisphosphonate. In December 1999, Allelix Biopharmaceuticals merged with NPS Pharmaceuticals. This combined company is operating as NPS Pharmaceuticals in the US and as NPS Allelix in Canada. The merger has enabled a phase III study of ALX 111 to begin in the US, Europe and South America. NPS harmaceuticals has signed an agreement with Bio-Imaging Technologies, which will provide all image handling and analysis for this trial. Until 1994, Allelix Biopharmaceuticals and Glaxo in Canada were involved in a joint venture to investigate the efficacy of ALX 111 in osteoporosis. Allelix was subsequently, until September 1998, collaborating with Astra of Sweden in developing ALX 111. Astra had acquired exclusive worldwide rights to ALX 111 and was responsible for development of the agent. However, Astra returned all rights to ALX 111 to Allelix as a result of its merger with Zeneca to form AstraZeneca. In December 1999, Allelix Biopharmaceuticals merged with NPS Pharmaceuticals. This combined company is operating as NPS Pharmaceuticals in the US and as NPS Allelix in Canada. The merger has enabled a phase III study of ALX 111 to begin in the US, Europe and South America. The phase III trial of ALX 111 for the treatment of osteoporosis has completed patient enrolment, and phase II trials have been completed in Canada and the Netherlands. The 18-month, phase III, multicentre, placebo-controlled trial (Treatment of Osteoporosis with

  19. Restoration of parathyroid function after change of phosphate binder from calcium carbonate to lanthanum carbonate in hemodialysis patients with suppressed serum parathyroid hormone.

    PubMed

    Inaba, Masaaki; Okuno, Senji; Nagayama, Harumi; Yamada, Shinsuke; Ishimura, Eiji; Imanishi, Yasuo; Shoji, Shigeichi

    2015-03-01

    Control of phosphate is the most critical in the treatment of chronic kidney disease with mineral and bone disorder (CKD-MBD). Because calcium-containing phosphate binder to CKD patients is known to induce adynamic bone disease with ectopic calcification by increasing calcium load, we examined the effect of lanthanum carbonate (LaC), a non-calcium containing phosphate binder, to restore bone turnover in 27 hemodialysis patients with suppressed parathyroid function (serum intact parathyroid hormone [iPTH] ≦ 150 pg/mL). At the initiation of LaC administration, the dose of calcium-containing phosphate binder calcium carbonate (CaC) was withdrawn or reduced based on serum phosphate. After initiation of LaC administration, serum calcium and phosphate decreased significantly by 4 weeks, whereas whole PTH and iPTH increased. A significant and positive correlation between decreases of serum calcium, but not phosphate, with increases of whole PTH and iPTH, suggested that the decline in serum calcium with reduction of calcium load by LaC might increase parathyroid function. Serum bone resorption markers, such as serum tartrate-resistant acid phosphatase 5b, and N-telopeptide of type I collagen increased significantly by 4 weeks after LaC administration, which was followed by increases of serum bone formation markers including serum bone alkaline phosphatase, intact procollagen N-propeptide, and osteocalcin. Therefore, it was suggested that LaC attenuated CaC-induced suppression of parathyroid function and bone turnover by decreasing calcium load. In conclusion, replacement of CaC with LaC, either partially or totally, could increase parathyroid function and resultant bone turnover in hemodialysis patients with serum iPTH ≦ 150 pg/mL.

  20. Parathyroid hormone decreases HCO3 reabsorption in the rat proximal tubule by stimulating phosphatidylinositol metabolism and inhibiting base exit.

    PubMed Central

    Pastoriza-Munoz, E; Harrington, R M; Graber, M L

    1992-01-01

    The mechanism of inhibition of HCO3 transport by parathyroid hormone (PTH) in the proximal tubule is not clearly defined. Previous studies in vitro have suggested that this effect is mediated via cAMP generation, which acts to inhibit Na/H exchange, resulting in cell acidification. To examine this question in vivo, intracellular pH (pHi) was measured in the superficial proximal tubule of the rat using the pH-sensitive fluoroprobes 4-methylumbelliferone (4MU) and 2',7'-bis(carboxyethyl)-(5, and 6)-carboxyfluorescein (BCECF). PTH was found to alkalinize the cell. This alkalinization suggested inhibition of basolateral base exit, which was confirmed by in situ microperfusion studies: lowering HCO3 in peritubular capillaries acidified the cell, an effect blunted by PTH. Removal of luminal Na promoted basolateral base entry, alkalinizing the cell. This response was also blunted by PTH. Readdition of luminal Na stimulated the luminal Na/H exchanger, causing an alkalinization overshoot that was partially inhibited by PTH. cAMP inhibited luminal H secretion but did not alkalinize the cell. Stimulation of phosphatidylinositol-bis-phosphate turnover by PTH was suggested by the effect to the hormone to increase cell Ca. Blocking the PTH-induced rise in cell Ca blunted the effect of the hormone to alkalinize the cell, as did inhibition of phosphatidylinositol breakdown. Furthermore, stimulation of protein kinase C by a phorbol ester and a diacylglycerol applied basolaterally alkalinized the cell and inhibited luminal H secretion. The findings indicate that both arms of the phosphatidylinositol-bis-phosphate cascade play a role in mediating the effect of PTH on the cell pH. The results are consistent with the view that PTH inhibits base exit in the proximal tubule by activation of the phosphatidylinositol cascade. The resulting alkalinization may contribute, with cAMP, to inhibit apical Na/H exchange and the PTH-induced depression of proximal HCO3 reabsorption. PMID:1314850

  1. Is intraoperative parathyroid hormone monitoring necessary in symptomatic primary hyperparathyroidism with concordant imaging?

    PubMed Central

    Nair, C. Gopalakrishnan; Babu, Misha J. C.; Jacob, Pradeep; Menon, Riju; Mathew, Jimmy

    2016-01-01

    Introduction: Symptomatic primary hyperparathyroidism (PHPT) is still seen frequently in referral centers all over India. These patients require parathyroidectomy and this study aimed to assess the roll of intraoperative parathyroid hormone (PTH) assay when concordant results of two localization studies were available. Study Design: We analyzed the case records of patients who underwent parathyroidectomy for PHPT from January 2005 to June 2015. Results: Of 143 patients included in the study, technetium 99m methoxyisobutylisonitrate dual phase scintigraphy showed true positive images in 93.7% and high definition ultrasonography in 84.6% of patients. Concordance in localization studies was observed in 121 (84.6%) patients, successful parathyroidectomy was done in 117 (96.7%) patients with concordant localization studies. Intraoperative PTH monitoring showed 97.84% sensitivity and 75% specificity and predicted failure in 2 patients with concordant imaging. However, re-exploration was not successful in these patients. Conclusion: When concordant result is available between parathyroid scintigraphy and anatomical imaging surgical cure rate is high in trained hands. Re-exploration is unlikely to be successful since these patients require higher imaging. PMID:27366718

  2. Interrelationship between parathyroid hormone and insulin: effects on DNA synthesis in UMR-106-01 cells.

    PubMed

    Felsenfeld, A J; Iida-Klein, A; Hahn, T J

    1992-11-01

    UMR-106-01 osteoblast-like cells respond to high concentrations of parathyroid hormone (PTH) in vitro by decreasing thymidine incorporation, a marker of DNA synthesis and cell proliferation. This response is different from in vivo conditions, such as primary and secondary hyperparathyroidism, in which high PTH levels are associated with an increased number of osteoblasts. When the response of UMR-106-01 cells to PTH is evaluated in vitro, however, these cells are exposed to only a single hormone. The present study was designed to evaluate the combined effects of two hormones, PTH and insulin, on the DNA synthesis of UMR-106-01 cells. PTH is known to decrease and insulin to increase thymidine incorporation by UMR-106-01 cells. To examine the interaction of these hormones, acute studies, defined as a 24 h exposure to hormone, and chronic studies, defined as a 7 day exposure to hormone, were performed. Both acute and chronic exposure to 10(-9) M PTH decreased thymidine incorporation by UMR-106-01 cells, with suppression ranging from 27 to 81% (P < 0.05). Both acute and chronic exposure to 10(-8) M insulin (INS) increased thymidine incorporation by UMR-106-01 cells; this ranged from 26 to 58% (P < 0.05). However, chronic exposure to 10(-9) M PTH followed by an acute exposure to 10(-8) M INS resulted in a 710% increase in thymidine incorporation (P < 0.01). Reversing the sequence by chronically exposing UMR-106-01 cells to 10(-8) M INS followed by acute exposure to 10(-9) M PTH resulted in a 53% decrease in thymidine incorporation (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

  3. Development of monoclonal antibodies against parathyroid hormone: genetic control of the immune response to human PTH

    SciTech Connect

    Nussbaum, S.R.; Lin, C.S.; Potts, J.T. Jr.; Rosenthal, A.S.; Rosenblatt, M.

    1985-01-01

    Seventeen monocloanl antibodies against the aminoterminal portion of parathyroid hormone (PTH) were generated by using BALB/c mouse for immunization fully biologically active synthetic human PTH-(1-34) and bovine PTH-(1-84) as immunogens, monoclonal antibody methods, and a solid-phase screening assay. Isotypic analysis of these monoclonal antibodies was performed using affinity purified goat antimouse immunoglobulins specific for IgG heavy chains and ..mu..(IgM). All antibodies were IgM as evidenced by 40 times greater than background activity when 25,000 cpm of /sup 125/I-labelled goat anti-mouse IgM was used as second antibody in a radioimmunoassay.

  4. Modeling of the parathyroid hormone response after calcium intake in healthy subjects.

    PubMed

    Ahn, Jae Eun; Jeon, Sangil; Lee, Jongtae; Han, Seunghoon; Yim, Dong-Seok

    2014-06-01

    Plasma ionized calcium (Ca(2+)) concentrations are tightly regulated in the body and maintained within a narrow range; thus it is challenging to quantify calcium absorption under normal physiologic conditions. This study aimed to develop a mechanistic model for the parathyroid hormone (PTH) response after calcium intake and indirectly compare the difference in oral calcium absorption from PTH responses. PTH and Ca(2+) concentrations were collected from 24 subjects from a clinical trial performed to evaluate the safety and calcium absorption of Geumjin Thermal Water in comparison with calcium carbonate tablets in healthy subjects. Indirect response models (NONMEM Ver. 7.2.0) were fitted to observed Ca(2+) and PTH data, respectively, in a manner that absorbed but unobserved Ca(2+) inhibits the secretion of PTH. Without notable changes in Ca(2+) levels, PTH responses were modeled and used as a marker for the extent of calcium absorption. PMID:24976761

  5. Parathyroid hormone receptor signalling in osterix-expressing mesenchymal progenitors is essential for tooth root formation.

    PubMed

    Ono, Wanida; Sakagami, Naoko; Nishimori, Shigeki; Ono, Noriaki; Kronenberg, Henry M

    2016-04-12

    Dental root formation is a dynamic process in which mesenchymal cells migrate toward the site of the future root, differentiate and secrete dentin and cementum. However, the identities of dental mesenchymal progenitors are largely unknown. Here we show that cells expressing osterix are mesenchymal progenitors contributing to all relevant cell types during morphogenesis. The majority of cells expressing parathyroid hormone-related peptide (PTHrP) are in the dental follicle and on the root surface, and deletion of its receptor (PPR) in these progenitors leads to failure of eruption and significantly truncated roots lacking periodontal ligaments. The PPR-deficient progenitors exhibit accelerated cementoblast differentiation with upregulation of nuclear factor I/C (Nfic). Deletion of histone deacetylase-4 (HDAC4) partially recapitulates the PPR deletion root phenotype. These findings indicate that PPR signalling in dental mesenchymal progenitors is essential for tooth root formation, underscoring importance of the PTHrP-PPR system during root morphogenesis and tooth eruption.

  6. Evolution of Parathyroid Hormone Receptor Family and Their Ligands in Vertebrate

    PubMed Central

    On, Jason S. W.; Chow, Billy K. C.; Lee, Leo T. O.

    2015-01-01

    The presence of the parathyroid hormones in vertebrates, including PTH, PTH-related peptide (PTHrP), and tuberoinfundibular peptide of 39 residues (TIP39), has been proposed to be the result of two rounds of whole genome duplication in the beginning of vertebrate diversification. Bioinformatics analyses, in particular chromosomal synteny study and the characterization of the PTH ligands and their receptors from various vertebrate species, provide evidence that strongly supports this hypothesis. In this mini-review, we summarize recent advances in studies regarding the molecular evolution and physiology of the PTH ligands and their receptors, with particular focus on non-mammalian vertebrates. In summary, the PTH family of peptides probably predates early vertebrate evolution, indicating a more ancient existence as well as a function of these peptides in invertebrates. PMID:25806022

  7. Mass Spectrometric Immunoassay for Parathyroid Hormone Related Protein (PTHrP)

    SciTech Connect

    Zheng, K.; Rivera, J.D.; Vogel, J.S.; Buchholz, B.A.; Burton, D.W.; Deftos, L.J.; Herold, D.A.; Fitzgerald, R.L.

    2000-06-16

    Many cancers, including prostate, breast and lung express parathyroid hormone related protein (PTHrP). Despite the common tumor overexpression of PTHrP, serum levels of PTHrP are not commonly elevated in affected patients. They postulate that the reasons for the discrepancy between tissue and serum measurements of PTHrP are the inadequate sensitivity and specificity of current PTHrP serum assays. To improve the clinical value of PTHrP serum assays for the cancer patient, they are developing a new generation of novel and ultrasensitive PTHrP serum immunoassays based on immunoaffinity purification, nanospray liquid chromatography tandem mass spectrometry (LC/MS/MS) and accelerator mass spectrometry (AMS).

  8. Parathyroid hormone receptor signalling in osterix-expressing mesenchymal progenitors is essential for tooth root formation

    PubMed Central

    Ono, Wanida; Sakagami, Naoko; Nishimori, Shigeki; Ono, Noriaki; Kronenberg, Henry M.

    2016-01-01

    Dental root formation is a dynamic process in which mesenchymal cells migrate toward the site of the future root, differentiate and secrete dentin and cementum. However, the identities of dental mesenchymal progenitors are largely unknown. Here we show that cells expressing osterix are mesenchymal progenitors contributing to all relevant cell types during morphogenesis. The majority of cells expressing parathyroid hormone-related peptide (PTHrP) are in the dental follicle and on the root surface, and deletion of its receptor (PPR) in these progenitors leads to failure of eruption and significantly truncated roots lacking periodontal ligaments. The PPR-deficient progenitors exhibit accelerated cementoblast differentiation with upregulation of nuclear factor I/C (Nfic). Deletion of histone deacetylase-4 (HDAC4) partially recapitulates the PPR deletion root phenotype. These findings indicate that PPR signalling in dental mesenchymal progenitors is essential for tooth root formation, underscoring importance of the PTHrP–PPR system during root morphogenesis and tooth eruption. PMID:27068606

  9. Regulation of beta catenin signaling and parathyroid hormone anabolic effects in bone by the matricellular protein periostin.

    PubMed

    Bonnet, Nicolas; Conway, Simon J; Ferrari, Serge L

    2012-09-11

    Periostin (Postn) is a matricellular protein preferentially expressed by osteocytes and periosteal osteoblasts in response to mechanical stimulation and parathyroid hormone (PTH). Whether and how periostin expression influences bone anabolism, however, remains unknown. We investigated the skeletal response of adult Postn(-/-) and Postn(+/+) mice to intermittent PTH. Compared with Postn(+/+), Postn(-/-) mice had a lower bone mass, cortical bone volume, and strength response to PTH. PTH-stimulated bone-forming indices were all significantly lower in Postn(-/-) mice, particularly at the periosteum. Furthermore, in vivo stimulation of Wnt-β-catenin signaling by PTH, as evaluated in TOPGAL reporter mice, was inhibited in the absence of periostin (TOPGAL;Postn(-/-) mice). PTH stimulated periostin and inhibited MEF2C and sclerostin (Sost) expression in bone and osteoblasts in vitro. Recombinant periostin also suppressed Sost expression, which was mediated through the integrin αVβ3 receptor, whereas periostin-blocking antibody prevented inhibition of MEF2C and Sost by PTH. In turn, administration of a Sost-blocking antiboby partially restored the PTH-mediated increase in bone mass in Postn(-/-) mice. In addition, primary osteoblasts from Postn(-/-) mice showed a lower proliferation, mineralization, and migration, both spontaneously and in response to PTH. Osteoblastic gene expression levels confirmed a defect of Postn(-/-) osteoblast differentiation with and without PTH, as well as an increased osteoblast apoptosis in the absence of periostin. These data elucidate the complex role of periostin on bone anabolism, through the regulation of Sost, Wnt-β-catenin signaling, and osteoblast differentiation.

  10. Detection of parathyroid hormone using an electrochemical impedance biosensor based on PAMAM dendrimers.

    PubMed

    Özcan, Hakkı Mevlüt; Sezgintürk, Mustafa Kemal

    2015-01-01

    This paper presents a novel hormone-based impedimetric biosensor to determine parathyroid hormone (PTH) level in serum for diagnosis and monitoring treatment of hyperparathyroidism, hypoparathyroidism and thyroid cancer. The interaction between PTH and the biosensor was investigated by an electrochemical method. The biosensor was based on the gold electrode modified by 12-mercapto dodecanoic (12MDDA). Antiparathyroid hormone (anti-PTH) was covalently immobilized on to poly amidoamine dendrimer (PAMAM) which was bound to a 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide/N-hydroxysuccinimide (EDC/NHS) couple, self-assembled monolayer structure from one of the other NH2 sites. The immobilization of anti-PTH was monitored by electrochemical impedance spectroscopy, cyclic voltammetry and scanning electron microscope techniques. After the optimization studies of immobilization materials such as 12MDDA, EDC-NHS, PAMAM, and glutaraldehyde, the performance of the biosensor was investigated in terms of linearity, sensitivity, repeatability, and reproducibility. PTH was detected within a linear range of 10-60 fg/mL. Finally the described biosensor was used to monitor PTH levels in artificial serum samples.

  11. Structural Basis for Parathyroid Hormone-related Protein Binding to the Parathyroid Hormone Receptor and Design of Conformation-selective Peptides

    SciTech Connect

    Pioszak, Augen A.; Parker, Naomi R.; Gardella, Thomas J.; Xu, H. Eric

    2009-12-01

    Parathyroid hormone (PTH) and PTH-related protein (PTHrP) are two related peptides that control calcium/phosphate homeostasis and bone development, respectively, through activation of the PTH/PTHrP receptor (PTH1R), a class B G protein-coupled receptor. Both peptides hold clinical interest for their capacities to stimulate bone formation. PTH and PTHrP display different selectivity for two distinct PTH1R conformations, but how their binding to the receptor differs is unclear. The high resolution crystal structure of PTHrP bound to the extracellular domain (ECD) of PTH1R reveals that PTHrP binds as an amphipathic {alpha}-helix to the same hydrophobic groove in the ECD as occupied by PTH, but in contrast to a straight, continuous PTH helix, the PTHrP helix is gently curved and C-terminally 'unwound.' The receptor accommodates the altered binding modes by shifting the side chain conformations of two residues within the binding groove: Leu-41 and Ile-115, the former acting as a rotamer toggle switch to accommodate PTH/PTHrP sequence divergence, and the latter adapting to the PTHrP curvature. Binding studies performed with PTH/PTHrP hybrid ligands having reciprocal exchanges of residues involved in different contacts confirmed functional consequences for the altered interactions and enabled the design of altered PTH and PTHrP peptides that adopt the ECD-binding mode of the opposite peptide. Hybrid peptides that bound the ECD poorly were selective for the G protein-coupled PTH1R conformation. These results establish a molecular model for better understanding of how two biologically distinct ligands can act through a single receptor and provide a template for designing better PTH/PTHrP therapeutics.

  12. Effect of parathyroid hormone on transport by toad and turtle bladder

    SciTech Connect

    Sabatini, S.; Kurtzman, N.A.

    1987-01-01

    The authors recently demonstrated that parathyroid hormone (PTH) inhibited both vasopressin- and cyclic AMP-stimulated water transport in the toad bladder. This was associated with an increase in calcium uptake by isolated epithelial cells. They postulated that PTH exerts its action on H/sub 2/O transport by directly stimulating calcium uptake. The current study was designed to compare the effects of PTH and the calcium ionophore, A23187, on H/sub 2/O and Na transport and H..mu.. secretion in toad and turtle bladders. In toad bladder, PTH and A23187 decreased arginine vasopressin (AVP)-stimulated H/sub 2/O flow and short-circuit current (SCC) after 60 min serosal incubation. In turtle bladder A23187 decreased SCC to 79.3 +/- 3.6% of base line (P < 0.05), and significantly decreased RSCC as well. PTH had no effect on SCC or H/sup +/ secretion in turtle bladders. Both PTH and A23187 increased /sup 45/Ca uptake in toad bladder epithelial cells; only A23187 increased /sup 45/Ca uptake in the turtle bladder. The different action of PTH in these two membranes, compared with that of the calcium ionophore, illustrates the selectivity of PTH on membrane transport. PTH increases calcium uptake and decreases transport only in a hormone-sensitive epithelium, whereas the ionophore works in virtually all living membranes. The mode of action of these two agents to increase calcium uptake is, therefore likely different.

  13. Opuntia humifusa supplementation increased bone density by regulating parathyroid hormone and osteocalcin in male growing rats.

    PubMed

    Kang, Junyong; Park, Jinho; Choi, Seong Hee; Igawa, Shoji; Song, Youngju

    2012-01-01

    We investigated the effect of Opuntia humifusa (O. humifusa) supplementation on bone density and related hormone secretion in growing male rats. Sixteen six-week-old male Sprague-Dawley rats were randomly divided into two groups; control diet group (CG, n = 8), and experimental diet group (EG, n = 8). The rats in the CG were given a control diet and those in the EG were given 5% O. humifusa added to the control diet for eight weeks. The serum OC level of the EG was significantly higher than that of the CG, and the serum parathyroid hormone (PTH) level of EG was significantly lower than that of the CG. In addition, the femoral and tibial BMD of the EG were significantly higher values than those of the CG, and the tibial BMC of the EG was significantly higher than that of the CG. These results suggest that O. humifusa supplementation has a positive effect on bone density by suppressing PTH and increasing the OC level in growing male rats.

  14. Opuntia humifusa Supplementation Increased Bone Density by Regulating Parathyroid Hormone and Osteocalcin in Male Growing Rats

    PubMed Central

    Kang, Junyong; Park, Jinho; Choi, Seong Hee; Igawa, Shoji; Song, Youngju

    2012-01-01

    We investigated the effect of Opuntia humifusa (O. humifusa) supplementation on bone density and related hormone secretion in growing male rats. Sixteen six-week-old male Sprague-Dawley rats were randomly divided into two groups; control diet group (CG, n = 8), and experimental diet group (EG, n = 8). The rats in the CG were given a control diet and those in the EG were given 5% O. humifusa added to the control diet for eight weeks. The serum OC level of the EG was significantly higher than that of the CG, and the serum parathyroid hormone (PTH) level of EG was significantly lower than that of the CG. In addition, the femoral and tibial BMD of the EG were significantly higher values than those of the CG, and the tibial BMC of the EG was significantly higher than that of the CG. These results suggest that O. humifusa supplementation has a positive effect on bone density by suppressing PTH and increasing the OC level in growing male rats. PMID:22837661

  15. Quantitation of Parathyroid Hormone in Serum or Plasma by Liquid Chromatography-Tandem Mass Spectrometry.

    PubMed

    Ketha, Hemamalini; Singh, Ravinder J

    2016-01-01

    Parathyroid hormone (PTH), an 84 amino acid peptide hormone, is an important regulator of calcium homeostasis. Quantitation of PTH in serum is useful for the diagnosis of primary hyperparathyroidism, hypoparathyroidism, and for monitoring osteodystrophy in patients with renal failure. The biological activity of PTH arises from binding of PTH (N terminus) to its target receptor (D'Amour et al., Kidney Int 68: 998-1007, 2005). Several C-terminal and N-terminal fragments circulate in normal subjects. Recent studies have demonstrated that accurate quantitation of PTH fragments may be of clinical value. In this chapter a mass spectrometry based method for quantitation of PTH(1-84) is described. This method involves immunoaffinity capture of PTH followed by trypsinization and quantitation of PTH-specific tryptic peptides by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The N-terminal tryptic peptide, PTH(1-13) as surrogate of 1-84 PTH, is used for quantitation. PMID:26602132

  16. Parathyroid hormone depresses cytosolic pH and DNA synthesis in osteoblast-like cells

    SciTech Connect

    Reid, I.R.; Civitelli, R.; Avioli, L.V.; Hruska, K.A. )

    1988-07-01

    It has recently become apparent that a number of hormones and growth factors modulate cytosolic pH (pH{sub i}) and there is some evidence that this in turn may influence cell growth. The authors have examined the effects of parathyroid hormone (PTH) on both these parameters in an osteoblast-like cell line, UMR 106. Preliminary studies, using the pH-sensitive fluorescent probe 2{prime},7{prime}-bis(2-carboxyethyl)-5,(6)-carboxyfluorescein indicated that these cells regulate pH{sub i} by means of an amiloride-inhibitable Na{sup +}-H{sup +} exchanger. Rat PTH-(1-34) (rPTH) caused a progressive dose-related decrease in pH{sub i} with a half-maximal effect at 10{sup {minus}11} M. The diacylglycerol analogue, phorbol 12-myristate 13-acetate, increased both pH{sub i} and ({sup 3}H)thymidine incorporation, and amiloride reduced both indexes. However, rPTH remained a potent inhibitor of ({sup 3}H)thymidine incorporation in the presence of amiloride, even though it did not affect pH{sub i} in these circumstances. It is concluded that PTH decreases pH{sub i} and growth in UMR 106 cells but that these changes can be dissociated. Depression of pH{sub i} may have other important effects on bone metabolism, such as reducing cell-cell communication, and may be associated with alkalinization of the bone fluid compartment.

  17. Observations on the effect of parathyroid hormone on environmental blood lead concentrations in humans

    SciTech Connect

    Osterloh, J.D. )

    1991-02-01

    The effect of parathyroid hormone (PTH) on blood lead (Pb) concentrations was observed preliminarily in three different situations. Of 342 healthy bus drivers with no unusual exposure to Pb, 25 drivers with the highest and 25 with the lowest blood Pb were compared for serum PTH concentrations. There was no association between blood Pb and serum PTH concentrations. Eight women with postmenopausal osteoporosis enrolled in an experimental protocol to increase bone mass received daily PTH (1-34 fragment) for 1 week, calcitonin for the next 2 weeks, and oral calcium for the subsequent 10 weeks. This cycle was repeated four times during the year. Initial blood Pb concentrations averaged 6.0 micrograms/dl (range 2.1-8.9). Mean blood Pb concentrations decreased by 1.7 micrograms/dl over 1 year of therapy. The confidence interval for this change excluded zero, the mean change was significantly different from the mean change for comparative population (P less than 0.050), and paired changes were statistically significant (P = 0.045). Lastly, a single subject with hyperparathyroid disease and no unusual exposures to lead demonstrated stabilized blood Pb concentrations that were 50% lower after removal of his hyperplastic parathyroid glands. These observations suggest that the effect of PTH on increasing bone turnover and releasing Pb into blood is not easily detected at low physiologic amounts of PTH, but that with pathologic increases of PTH in hyperparathyroid disease, elevation of blood Pb from bone or increased gastrointestinal absorption may be possible. Likewise, either bone building therapies (PTH + calcitonin + calcium) may move Pb from blood into bone or supplemental calcium may decrease Pb gastrointestinal absorption, thereby explaining the observed lower blood Pb concentrations.

  18. Nucleolar localization of parathyroid hormone-related peptide enhances survival of chondrocytes under conditions that promote apoptotic cell death.

    PubMed Central

    Henderson, J E; Amizuka, N; Warshawsky, H; Biasotto, D; Lanske, B M; Goltzman, D; Karaplis, A C

    1995-01-01

    Parathyroid hormone-related peptide (PTHrP) is a mediator of cellular growth and differentiation as well as a cause of malignancy-induced hypercalcemia. Most of the actions of PTHrP have been attributed to its interaction with a specific cell surface receptor that binds the N-terminal domain of the protein. Here we present evidence that PTHrP promotes some of its cellular effects by translocating to the nucleolus. Localization of transiently expressed PTHrP to the nucleolus was dependent on the presence of a highly basic region at the carboxyl terminus of the molecule that bears homology to nucleolar targeting sequences identified within human retroviral (human immunodeficiency virus type 1 and human T-cell leukemia virus type 1) regulatory proteins. Endogenous PTHrP also localized to the nucleolus in osseous cells in vitro and in vivo. Moreover, expression of PTHrP in chondrocytic cells (CFK2) delayed apoptosis induced by serum deprivation, and this effect depended on the presence of an intact nucleolar targeting signal. The present findings demonstrate a unique intracellular mode of PTHrP action and a novel mechanism by which this peptide growth factor may modulate programmed cell death. PMID:7623802

  19. The effects of parathyroid hormone and estradiol on cadmium accumulation by Madin-Darby canine kidney cells

    SciTech Connect

    Flanagan, J.L.

    1990-01-01

    Chronic exposure to the toxic metal cadmium causes osteomalacia, osteoporosis, increased serum parathyroid hormone, renal stone formation, hypercalciuria and renal tubular dysfunction, reflecting one or more disturbances of calcium homeostasis. Since renal cadmium (Cd[sup 2+]) transport proceeds in both proximal and distal tubules and parathyroid hormone (PTH) regulates calcium reabsorption at distal nephron sites, it was postulated that PTH may also stimulate Cd[sup 2+] transport in distal tubules. Madin-Darby canine kidney (MDCK) cells, which express a distal phenotype including PTH-sensitive adenylate cyclase and calcium transport, were used as the cell model for the present study. Cadmium uptake was measured using [[sup 109]Cd[sup 2+

  20. Disruption of parathyroid hormone and parathyroid hormone-related peptide receptor phosphorylation prolongs ERK1/2 MAPK activation and enhances c-fos expression

    PubMed Central

    Abou-Samra, Abdul B.

    2012-01-01

    Previous studies have demonstrated that parathyroid hormone (PTH) binding to the PTH/PTH-related peptide receptor (PPR) stimulates G protein coupling, receptor phosphorylation, β-arrestin translocation, and internalization of the ligand/receptor complex. The extracellular signal-regulated mitogen-activated protein kinases 1/2 (ERK1/2 MAPK) are downstream effectors of PPR. In the current study, we investigated the role of PPR phosphorylation in the PTH regulation of the ERK1/2 MAPK pathway. Short treatment with PTH (0–40 min) of LLCP-K1 cells stably expressing a wild-type (WT) or a phosphorylation-deficient (PD) PPR (WT-PPR or PD-PPR cells, respectively) results in similar activation of ERK1/2. Interestingly, PTH stimulation of ERK1/2 in the WT-PPR cells then decreases as a result of longer PTH (60 min) treatment, and inhibition of ERK1/2 by PTH is observed at 90 min. Strikingly, the PD-PPR cells exhibit prolonged ERK1/2 activation up to 90 min of PTH treatment. An ERK1/2-dependent increase in c-fos expression is observed in the PD-PPR cells. Subsequently, c-fos expression in the WT-PPR and PD-PPR cells was markedly attenuated by a specific ERK1/2 pathway inhibitor. Further investigations revealed that PTH treatment causes a robust recruitment of a green fluorescent protein-tagged β-arrestin2 (β-arrestin2-GFP) in the WT-PPR cells. In contrast, β-arrestin2 recruitment was reduced in the PD-PPR cells. Importantly, expression of a receptor phosphorylation-independent β-arrestin2 (R169E) in the PD-PPR cells restored the biphasic effect of PTH on ERK1/2 as in the WT-PPR cells. The study reports a novel role for receptor phosphorylation and β-arrestin2 in the subsequent inhibition of the ERK1/2 pathway and in control of gene expression. PMID:22414806

  1. Effects of intermittent versus continuous parathyroid hormone administration on condylar chondrocyte proliferation and differentiation

    SciTech Connect

    Liu, Qi; Wan, Qilong; Yang, Rongtao; Zhou, Haihua; Li, Zubing

    2012-07-20

    Highlights: Black-Right-Pointing-Pointer Different PTH administration exerts different effects on condylar chondrocyte. Black-Right-Pointing-Pointer Intermittent PTH administration suppresses condylar chondrocyte proliferation. Black-Right-Pointing-Pointer Continuous PTH administration maintains condylar chondrocyte proliferating. Black-Right-Pointing-Pointer Intermittent PTH administration enhances condylar chondrocyte differentiation. -- Abstract: Endochondral ossification is a complex process involving chondrogenesis and osteogenesis regulated by many hormones and growth factors. Parathyroid hormone (PTH), one of the key hormones regulating bone metabolism, promotes osteoblast differentiation and osteogenesis by intermittent administration, whereas continuous PTH administration inhibits bone formation. However, the effects of PTH on chondrocyte proliferation and differentiation are still unclear. In this study, intermittent PTH administration presented enhanced effects on condylar chondrocyte differentiation and bone formation, as demonstrated by increased mineral nodule formation and alkaline phosphatase (ALP) activity, up-regulated runt-related transcription factor 2 (RUNX2), ALP, collagen type X (COL10a1), collagen type I (COL1a1), osteocalcin (OCN), bone sialoprotein (BSP), bone morphogenetic protein 2 (BMP2) and osterix (OSX) mRNA and/or protein expression. On the contrary, continuous PTH administration promoted condylar chondrocyte proliferation and suppressed its differentiation, as demonstrated by up-regulated collagen type II (COL2a1) mRNA expression, reduced mineral nodule formation and down-regulated expression of the mRNAs and/or proteins mentioned above. Our data suggest that PTH can regulate condylar chondrocyte proliferation and differentiation, depending on the type of PTH administration. These results provide new insight into the effects of PTH on condylar chondrocytes and new evidence for using local PTH administration to cure mandibular

  2. A tagged parathyroid hormone derivative as a carrier of antibody cargoes transported by the G protein coupled PTH1 receptor.

    PubMed

    Charest-Morin, Xavier; Fortin, Jean-Philippe; Lodge, Robert; Allaeys, Isabelle; Poubelle, Patrice E; Marceau, François

    2014-10-01

    Based on the known fact that the parathyroid hormone (PTH) might be extended at its C-terminus with biotechnological protein cargoes, a vector directing the secretion of PTH1-84 C-terminally fused with the antigenic epitope myc (PTH-myc) was exploited. The functional properties and potential of this analog for imaging PTH1R-expressing cells were examined. The PTH-myc construct was recombinantly produced as a conditioned medium (CM) of transfected HEK 293a cells (typical concentrations of 187nM estimated with ELISAs for PTH). PTH-myc CM induced cyclic AMP formations (10min), with a minor loss of potency relative to authentic PTH1-84, and c-Fos expression (1-3h). Treatment of recipient HEK 293a cells transiently expressing PTH1R with PTH-myc CM (supplemented with a fluorescent monoclonal anti-myc tag antibody, either 4A6 or 9E10) allowed the labeling of endosomal structures positive for Rab5 and/or for β-arrestin1 (microscopy, cytofluorometry). Authentic PTH was inactive in this respect, ruling out a non-specific form of endocytosis like pinocytosis. Using a horseradish peroxidase-conjugated secondary antibody, the endocytosis of the PTH-myc-based antibody complex by endogenous PTH1R was evidenced in MG-63 osteoblastoid cells. The secreted construct PTH-myc represents a bona fide agonist that supports the feasibility of transporting cargoes of considerable molecular weight inside cells using arrestin and Rab5-mediated PTH1R endocytosis. PTH-myc is also transported into cells that express PTH1R at a physiological level. Such tagged peptide hormones may be part of a cancer chemotherapy scheme exploiting a modular cytotoxic secondary antibody and the receptor repertoire expressed in a given tumor.

  3. Parathyroid hormone stimulates juxtaglomerular cell cAMP accumulation without stimulating renin release

    PubMed Central

    Atchison, Douglas K.; Harding, Pamela; Cecilia Ortiz-Capisano, M.; Peterson, Edward L.

    2012-01-01

    Parathyroid hormone (PTH) is positively coupled to the generation of cAMP via its actions on the PTH1R and PTH2R receptors. Renin secretion from juxtaglomerular (JG) cells is stimulated by elevated intracellular cAMP, and every stimulus that increases renin secretion is thought to do so via increasing cAMP. Thus we hypothesized that PTH increases renin release from primary cultures of mouse JG cells by elevating intracellular cAMP via the PTH1R receptor. We found PTH1R, but not PTH2R, mRNA expressed in JG cells. While PTH increased JG cell cAMP content from (log10 means ± SE) 3.27 ± 0.06 to 3.92 ± 0.12 fmol/mg protein (P < 0.001), it did not affect renin release. The PTH1R-specific agonist, parathyroid hormone-related protein (PTHrP), also increased JG cell cAMP from 3.13 ± 0.09 to 3.93 ± 0.09 fmol/mg protein (P < 0.001), again without effect on renin release. PTH2R receptor agonists had no effect on cAMP or renin release. PTHrP increased cAMP in the presence of both low and high extracellular calcium from 3.31 ± 0.17 to 3.83 ± 0.20 fmol/mg protein (P < 0.01) and from 3.29 ± 0.18 to 3.63 ± 0.22 fmol/mg protein (P < 0.05), respectively, with no effect on renin release. PTHrP increased JG cell cAMP in the presence of adenylyl cyclase-V inhibition from 2.85 ± 0.17 to 3.44 ± 0.14 fmol/mg protein (P < 0.001) without affecting renin release. As a positive control, forskolin increased JG cell cAMP from 3.39 ± 0.13 to 4.48 ± 0.07 fmol/mg protein (P < 0.01) and renin release from 2.96 ± 0.10 to 3.29 ± 0.08 ng ANG I·mg prot−1·h−1 (P < 0.01). Thus PTH increases JG cell cAMP via non-calcium-sensitive adenylate cyclases without affecting renin release. These data suggest compartmentalization of cAMP signaling in JG cells. PMID:22896038

  4. Parathyroid hormone stimulates juxtaglomerular cell cAMP accumulation without stimulating renin release.

    PubMed

    Atchison, Douglas K; Harding, Pamela; Cecilia Ortiz-Capisano, M; Peterson, Edward L; Beierwaltes, William H

    2012-10-15

    Parathyroid hormone (PTH) is positively coupled to the generation of cAMP via its actions on the PTH1R and PTH2R receptors. Renin secretion from juxtaglomerular (JG) cells is stimulated by elevated intracellular cAMP, and every stimulus that increases renin secretion is thought to do so via increasing cAMP. Thus we hypothesized that PTH increases renin release from primary cultures of mouse JG cells by elevating intracellular cAMP via the PTH1R receptor. We found PTH1R, but not PTH2R, mRNA expressed in JG cells. While PTH increased JG cell cAMP content from (log(10) means ± SE) 3.27 ± 0.06 to 3.92 ± 0.12 fmol/mg protein (P < 0.001), it did not affect renin release. The PTH1R-specific agonist, parathyroid hormone-related protein (PTHrP), also increased JG cell cAMP from 3.13 ± 0.09 to 3.93 ± 0.09 fmol/mg protein (P < 0.001), again without effect on renin release. PTH2R receptor agonists had no effect on cAMP or renin release. PTHrP increased cAMP in the presence of both low and high extracellular calcium from 3.31 ± 0.17 to 3.83 ± 0.20 fmol/mg protein (P < 0.01) and from 3.29 ± 0.18 to 3.63 ± 0.22 fmol/mg protein (P < 0.05), respectively, with no effect on renin release. PTHrP increased JG cell cAMP in the presence of adenylyl cyclase-V inhibition from 2.85 ± 0.17 to 3.44 ± 0.14 fmol/mg protein (P < 0.001) without affecting renin release. As a positive control, forskolin increased JG cell cAMP from 3.39 ± 0.13 to 4.48 ± 0.07 fmol/mg protein (P < 0.01) and renin release from 2.96 ± 0.10 to 3.29 ± 0.08 ng ANG I·mg prot(-1)·h(-1) (P < 0.01). Thus PTH increases JG cell cAMP via non-calcium-sensitive adenylate cyclases without affecting renin release. These data suggest compartmentalization of cAMP signaling in JG cells.

  5. Two Years of Cinacalcet Hydrochloride Treatment Decreased Parathyroid Gland Volume and Serum Parathyroid Hormone Level in Hemodialysis Patients With Advanced Secondary Hyperparathyroidism.

    PubMed

    Yamada, Shunsuke; Tokumoto, Masanori; Taniguchi, Masatomo; Toyonaga, Jiro; Suehiro, Takaichi; Eriguchi, Rieko; Fujimi, Satoru; Ooboshi, Hiroaki; Kitazono, Takanari; Tsuruya, Kazuhiko

    2015-08-01

    The long-term effect of cinacalcet hydrochloride treatment on parathyroid gland (PTG) volume has been scarcely investigated in patients with moderate to advanced secondary hyperparathyroidism (SHPT). The present study was a prospective observational study to determine the effect of cinacalcet treatment on PTG volume and serum biochemical parameters in 60 patients with renal SHPT, already treated with intravenous vitamin D receptor activator (VDRA). Measurement of biochemical parameters and PTG volumes were performed periodically, which were analyzed by stratification into tertiles across the baseline parathyroid hormone (PTH) level or PTG volume. We also determined the factors that can estimate the changes in PTG volume and the achievement of the target PTH range by multivariable analyses. Two years of cinacalcet treatment significantly decreased the serum levels of PTH, calcium, and phosphate, followed by the improvement of achieving the target ranges for these parameters recommended by the Japanese Society for Dialysis Therapy. Cinacalcet decreased the maximal and total PTG volume by about 30%, and also decreased the serum PTH level independent of the baseline serum PTH level and PTG volume. Ten out of 60 patients showed 30% increase in maximal PTG after 2 years. Multivariable analysis showed that patients with nodular PTG at baseline and patients with higher serum calcium and PTH levels at 1 year were likely to exceed the target range of PTH at two years. In conclusion, cinacalcet treatment with intravenous VDRA therapy decreased both PTG volume and serum intact PTH level, irrespective of the pretreatment PTG status and past treatment history.

  6. Regulation of beta catenin signaling and parathyroid hormone anabolic effects in bone by the matricellular protein periostin

    PubMed Central

    Bonnet, Nicolas; Conway, Simon J.; Ferrari, Serge L.

    2012-01-01

    Periostin (Postn) is a matricellular protein preferentially expressed by osteocytes and periosteal osteoblasts in response to mechanical stimulation and parathyroid hormone (PTH). Whether and how periostin expression influences bone anabolism, however, remains unknown. We investigated the skeletal response of adult Postn−/− and Postn+/+ mice to intermittent PTH. Compared with Postn+/+, Postn−/− mice had a lower bone mass, cortical bone volume, and strength response to PTH. PTH-stimulated bone-forming indices were all significantly lower in Postn−/− mice, particularly at the periosteum. Furthermore, in vivo stimulation of Wnt-β-catenin signaling by PTH, as evaluated in TOPGAL reporter mice, was inhibited in the absence of periostin (TOPGAL;Postn−/− mice). PTH stimulated periostin and inhibited MEF2C and sclerostin (Sost) expression in bone and osteoblasts in vitro. Recombinant periostin also suppressed Sost expression, which was mediated through the integrin αVβ3 receptor, whereas periostin-blocking antibody prevented inhibition of MEF2C and Sost by PTH. In turn, administration of a Sost-blocking antiboby partially restored the PTH-mediated increase in bone mass in Postn−/− mice. In addition, primary osteoblasts from Postn−/− mice showed a lower proliferation, mineralization, and migration, both spontaneously and in response to PTH. Osteoblastic gene expression levels confirmed a defect of Postn−/− osteoblast differentiation with and without PTH, as well as an increased osteoblast apoptosis in the absence of periostin. These data elucidate the complex role of periostin on bone anabolism, through the regulation of Sost, Wnt-β-catenin signaling, and osteoblast differentiation. PMID:22927401

  7. Skeletal unloading causes resistance of osteoprogenitor cells to parathyroid hormone and to insulin-like growth factor-I

    NASA Technical Reports Server (NTRS)

    Kostenuik, P. J.; Harris, J.; Halloran, B. P.; Turner, R. T.; Morey-Holton, E. R.; Bikle, D. D.

    1999-01-01

    Skeletal unloading decreases bone formation and osteoblast number in vivo and decreases the number and proliferation of bone marrow osteoprogenitor (BMOp) cells in vitro. We tested the ability of parathyroid hormone (PTH) to stimulate BMOp cells in vivo by treating Sprague Dawley rats (n = 32) with intermittent PTH(1-34) (1 h/day at 8 microg/100 g of body weight), or with vehicle via osmotic minipumps during 7 days of normal weight bearing or hind limb unloading. Marrow cells were flushed from the femur and cultured at the same initial density for up to 21 days. PTH treatment of normally loaded rats caused a 2.5-fold increase in the number of BMOp cells, with similar increases in alkaline phosphatase (ALP) activity and mineralization, compared with cultures from vehicle-treated rats. PTH treatment of hind limb unloaded rats failed to stimulate BMOp cell number, ALP activity, or mineralization. Hind limb unloading had no significant effect on PTH receptor mRNA or protein levels in the tibia. Direct in vitro PTH challenge of BMOp cells isolated from normally loaded bone failed to stimulate their proliferation and inhibited their differentiation, suggesting that the in vivo anabolic effect of intermittent PTH on BMOp cells was mediated indirectly by a PTH-induced factor. We hypothesize that this factor is insulin-like growth factor-I (IGF-I), which stimulated the in vitro proliferation and differentiation of BMOp cells isolated from normally loaded bone, but not from unloaded bone. These results suggest that IGF-I mediates the ability of PTH to stimulate BMOp cell proliferation in normally loaded bone, and that BMOp cells in unloaded bone are resistant to the anabolic effect of intermittent PTH therapy due to their resistance to IGF-I.

  8. [Osteoporosis in Rheumatoid Arthritis: role of the vitamin D/parathyroid hormone system].

    PubMed

    Bellan, Mattia; Pirisi, Mario; Sainaghi, Pier Paolo

    2015-01-01

    Osteoporosis is a well-established extra-articular feature of Rheumatoid Arthritis (RA). Systemic inflammation seems to play a crucial role in causing an alteration of multiple homeostatic systems implied in bone health, such as the RANK/RANKL/Osteoprotegerin and Wnt/β catenin pathways; several other causal factors have been called into question, including the chronic use of corticosteroids. Since vitamin D exerts important immune-regulatory roles, it has been claimed that derangement of the vitamin D/parathyroid hormone (PTH) system, a well-known determinant of bone health, may play a pathogenic role in autoimmunity; animal models and clinical data support this hypothesis. Furthermore, RA patients seem to be relatively refractory to vitamin D-induced PTH suppression. Therefore, the link between RA and osteoporosis might in part be due to alterations in the vitamin D/PTH system. A better understanding of the pathophysiology of this system may be crucial to prevent and cure osteoporosis in patients with inflammatory/autoimmune diseases. A major clinical correlate of the strict cooperation and interdependence between vitamin D and PTH is that correction of the vitamin D deficiency, at least in autoimmune diseases, should be targeted to PTH suppression.

  9. Intermittently Administered Parathyroid Hormone [1–34] Promotes Tendon-Bone Healing in a Rat Model

    PubMed Central

    Bi, Fanggang; Shi, Zhongli; Jiang, Shuai; Guo, Peng; Yan, Shigui

    2014-01-01

    The objective of this study was to investigate whether intermittent administration of parathyroid hormone [1–34] (PTH[1–34]) promotes tendon-bone healing after anterior cruciate ligament (ACL) reconstruction in vivo. A rat model of ACL reconstruction with autograft was established at the left hind leg. Every day, injections of 60 μg PTH[1–34]/kg subcutaneously were given to the PTH group rats (n = 10) for four weeks, and the controls (n = 10) received saline. The tendon-bone healing process was evaluated by micro-CT, biomechanical test, histological and immunohistochemical analyses. The effects of PTH[1–34] on serum chemistry, bone microarchitecture and expression of the PTH receptor (PTH1R) and osteocalcin were determined. Administration of PTH[1–34] significantly increased serum levels of calcium, alkaline phosphatase (AP), osteocalcin and tartrate-resistant acid phosphatase (TRAP). The expression of PTH1R on both osteocytes and chondrocyte-like cells at the tendon-bone interface was increased in the PTH group. PTH[1–34] also enhanced the thickness and microarchitecture of trabecular bone according to the micro-CT analysis. The results imply that systematically intermittent administration of PTH[1–34] promotes tendon-bone healing at an early stage via up-regulated PTH1R. This method may enable a new strategy for the promotion of tendon-bone healing after ACL reconstruction. PMID:25268612

  10. Studies on the use of cultured cells in a bioassay for parathyroid hormone.

    PubMed

    Armston, A E; Wood, P J

    1994-11-01

    Measurement of parathyroid hormone (PTH) is important for diagnosing hyper- and hypoparathyroidism. The move to two-site immunometric assays that detect the whole molecule has improved the discrimination of these conditions but these assays may be too restrictive because some PTH fragments that are biologically active may not be detected. In addition, PTH-like peptide of malignancy, an important cause of malignancy-associated hypercalcaemia, is not detected by the two-site assays. Experiments were performed to set up a simple, robust and inexpensive bioassay for PTH, exploiting a kidney cell line and using cyclic AMP or an eluted stain assay as the end point. Of the 12 cell lines tested, an opossum kidney (WOK) cell line showed the most promise. Despite optimization of the procedure to include pre-treatment with dexamethasone, insulin and PTH, followed by incubation in the presence of 5'-guanylimidodiphosphate, isobutyl-1-methylxanthine and forskolin, the WOK cells showed insufficient sensitivity for use in a cultured cell bioassay for PTH in human serum. In addition, the cells were less sensitive to PTH-like peptide precluding their use for an assay for this molecule. PMID:7829991

  11. Bone healing induced by local delivery of an engineered parathyroid hormone prodrug.

    PubMed

    Arrighi, Isabelle; Mark, Silke; Alvisi, Monica; von Rechenberg, Brigitte; Hubbell, Jeffrey A; Schense, Jason C

    2009-03-01

    Regenerative medicine requires innovative therapeutic designs to accommodate high morphogen concentrations in local depots, provide their sustained presence, and enhance cellular invasion and directed differentiation. Here we present an example for inducing local bone regeneration with a matrix-bound engineered active fragment of human parathyroid hormone (PTH(1-34)), linked to a transglutaminase substrate for binding to fibrin as a delivery and cell-invasion matrix with an intervening plasmin-sensitive link (TGplPTH(1-34)). The precursor form displays very little activity and signaling to osteoblasts, whereas the plasmin cleavage product, as it would be induced under the enzymatic influence of cells remodeling the matrix, was highly active. In vivo animal bone-defect experiments showed dose-dependent bone formation using the PTH-fibrin matrix, with evidence of both osteoconductive and osteoinductive bone-healing mechanisms. Results showed that this PTH-derivatized matrix may have potential utility in humans as a replacement for bone grafts or to repair bone defects.

  12. Deficiency of the calcium-sensing receptor in the kidney causes parathyroid hormone-independent hypocalciuria.

    PubMed

    Toka, Hakan R; Al-Romaih, Khaldoun; Koshy, Jacob M; DiBartolo, Salvatore; Kos, Claudine H; Quinn, Stephen J; Curhan, Gary C; Mount, David B; Brown, Edward M; Pollak, Martin R

    2012-11-01

    Rare loss-of-function mutations in the calcium-sensing receptor (Casr) gene lead to decreased urinary calcium excretion in the context of parathyroid hormone (PTH)-dependent hypercalcemia, but the role of Casr in the kidney is unknown. Using animals expressing Cre recombinase driven by the Six2 promoter, we generated mice that appeared grossly normal but had undetectable levels of Casr mRNA and protein in the kidney. Baseline serum calcium, phosphorus, magnesium, and PTH levels were similar to control mice. When challenged with dietary calcium supplementation, however, these mice had significantly lower urinary calcium excretion than controls (urinary calcium to creatinine, 0.31±0.03 versus 0.63±0.14; P=0.001). Western blot analysis on whole-kidney lysates suggested an approximately four-fold increase in activated Na(+)-K(+)-2Cl(-) cotransporter (NKCC2). In addition, experimental animals exhibited significant downregulation of Claudin14, a negative regulator of paracellular cation permeability in the thick ascending limb, and small but significant upregulation of Claudin16, a positive regulator of paracellular cation permeability. Taken together, these data suggest that renal Casr regulates calcium reabsorption in the thick ascending limb, independent of any change in PTH, by increasing the lumen-positive driving force for paracellular Ca(2+) transport.

  13. Full length parathyroid hormone (1–84) in the treatment of osteoporosis in postmenopausal women

    PubMed Central

    Jódar-Gimeno, Esteban

    2007-01-01

    Objective: To review the pharmacological properties and the available clinical data of full length parathyroid hormone (PTH) in post-menopausal osteoporosis. Sources: A MEDLINE search was completed, together with a review of information obtained from the manufacturer and from the medicine regulatory agencies. Study and data selection: Studies were selected according to relevance and availability. Relevant information (design, objectives, patients’ characteristics, outcomes, adverse events, dosing, etc) was analyzed. Results: Different studies have shown that, when administered intermittently as a subcutaneous injection in the abdomen, PTH increases bone mineral density (BMD) and prevents vertebral fractures. On completion of PTH therapy (up to 24 months), there is evidence that sequential treatment with alendronate is associated with a therapeutic benefit in terms of increase in BMD. Further trials are necessary to determine long-term safety and the role of PTH in combination with other treatments for osteoporosis and the effect of repeated cycles of PTH followed by an anti-catabolic agent. There are currently no completed comparative trials with other osteoporosis treatments. Conclusions: Full length PTH, given intermittently as an abdominal subcutaneous injection, appears to be a safe and efficacious treatment option for high risk osteoporosis. More data are needed to determine its specific role in osteoporosis treatment. PMID:18044089

  14. Regional responsiveness of the tibia to intermittent administration of parathyroid hormone as affected by skeletal unloading

    NASA Technical Reports Server (NTRS)

    Halloran, B. P.; Bikle, D. D.; Harris, J.; Tanner, S.; Curren, T.; Morey-Holton, E.

    1997-01-01

    To determine whether the acute inhibition of bone formation and deficit in bone mineral induced by skeletal unloading can be prevented, we studied the effects of intermittent parathyroid hormone (PTH) administration (8 micrograms/100 g/day) on growing rats submitted to 8 days of skeletal unloading. Loss of weight bearing decreased periosteal bone formation by 34 and 51% at the tibiofibular junction and tibial midshaft, respectively, and reduced the normal gain in tibial mass by 35%. Treatment with PTH of normally loaded and unloaded animals increased mRNA for osteocalcin (+58 and +148%, respectively), cancellous bone volume in the proximal tibia (+41 and +42%, respectively), and bone formation at the tibiofibular junction (+27 and +27%, respectively). Formation was also stimulated at the midshaft in unloaded (+47%, p < 0.05), but not loaded animals (-3%, NS). Although cancellous bone volume was preserved in PTH-treated, unloaded animals, PTH did not restore periosteal bone formation to normal nor prevent the deficit in overall tibial mass induced by unloading. We conclude that the effects of PTH on bone formation are region specific and load dependent. PTH can prevent the decrease in cancellous bone volume and reduce the decrement in cortical bone formation induced by loss of weight bearing.

  15. Tuberoinfundibular peptide of 39 residues (TIP39): molecular structure and activity for parathyroid hormone 2 receptor.

    PubMed

    Della Penna, K; Kinose, F; Sun, H; Koblan, K S; Wang, H

    2003-01-01

    The neuropeptide TIP39 was recently purified from bovine hypothalamus based on the ability of the peptide to activate the parathyroid hormone 2 receptor (PTH2R) ( Nat. Neurosci. 2 (1999) 941). PTH2R is abundantly expressed in the nervous system, and its expression pattern suggests that it may play a role in modulation of pituitary function and in nociception. Towards understanding the physiological role of TIP39 and PTH2R, we cloned human, mouse and rat TIP39 gene. Our results revealed that: (1) the mature peptide is processed from a precursor; (2) TIP39 peptide is highly conserved among species; and (3) TIP39 from all species activates adenylyl cyclase and elevates intracellular calcium levels through PTH2R. We also defined and compared the structure-activity relationship of TIP39 on both activation of adenylyl cyclase and calcium mobilization pathways through PTH2R, finding common and differential determinants of TIP39 that are required for these pathways. Furthermore, we observed that TIP39 elevates intracellular calcium levels in primary dorsal root ganglion neurons whereas the peptide inactive on PTH2R do not, suggesting that TIP39 may activate these neurons important for nociception in vivo through PTH2R-dependent mechanisms.

  16. Influence of Parathyroid Hormone-Loaded PLGA Nanoparticles in Porous Scaffolds for Bone Regeneration

    PubMed Central

    Gentile, Piergiorgio; Nandagiri, Vijay Kumar; Pabari, Ritesh; Daly, Jacqueline; Tonda-Turo, Chiara; Ciardelli, Gianluca; Ramtoola, Zebunnissa

    2015-01-01

    Biodegradable poly(lactide-co-glycolide) (PLGA) nanoparticles, containing human parathyroid hormone (PTH (1–34)), prepared by a modified double emulsion-solvent diffusion-evaporation method, were incorporated in porous freeze-dried chitosan-gelatin (CH-G) scaffolds. The PTH-loaded nanoparticles (NPTH) were characterised in terms of morphology, size, protein loading, release kinetics and in vitro assessment of biological activity of released PTH and cytocompatibility studies against clonal human osteoblast (hFOB) cells. Structural integrity of incorporated and released PTH from nanoparticles was found to be intact by using Tris-tricine SDS-PAGE. In vitro PTH release kinetics from PLGA nanoparticles were characterised by a burst release followed by a slow release phase for 3–4 weeks. The released PTH was biologically active as evidenced by the stimulated release of cyclic AMP from hFOB cells as well as increased mineralisation studies. Both in vitro and cell studies demonstrated that the PTH bioactivity was maintained during the fabrication of PLGA nanoparticles and upon release. Finally, a content of 33.3% w/w NPTHs was incorporated in CH-G scaffolds, showing an intermittent release during the first 10 days and, followed by a controlled release over 28 days of observation time. The increased expression of Alkaline Phosphatase levels on hFOB cells further confirmed the activity of intermittently released PTH from scaffolds. PMID:26343649

  17. High Parathyroid Hormone Level and Osteoporosis Predict Progression of Coronary Artery Calcification in Patients on Dialysis.

    PubMed

    Malluche, Hartmut H; Blomquist, Gustav; Monier-Faugere, Marie-Claude; Cantor, Thomas L; Davenport, Daniel L

    2015-10-01

    Coronary artery calcifications (CACs) are observed in most patients with CKD on dialysis (CKD-5D). CACs frequently progress and are associated with increased risk for cardiovascular events, the major cause of death in these patients. A link between bone and vascular calcification has been shown. This prospective study was designed to identify noninvasive tests for predicting CAC progression, including measurements of bone mineral density (BMD) and novel bone markers in adult patients with CKD-5D. At baseline and after 1 year, patients underwent routine blood tests and measurement of CAC, BMD, and novel serum bone markers. A total of 213 patients received baseline measurements, of whom about 80% had measurable CAC and almost 50% had CAC Agatston scores>400, conferring high risk for cardiovascular events. Independent positive predictors of baseline CAC included coronary artery disease, diabetes, dialysis vintage, fibroblast growth factor-23 concentration, and age, whereas BMD of the spine measured by quantitative computed tomography was an inverse predictor. Hypertension, HDL level, and smoking were not baseline predictors in these patients. Three quarters of 122 patients completing the study had CAC increases at 1 year. Independent risk factors for CAC progression were age, baseline total or whole parathyroid hormone level greater than nine times the normal value, and osteoporosis by t scores. Our results confirm a role for bone in CKD-associated CAC prevalence and progression. PMID:25838468

  18. Recombinant Human Parathyroid Hormone (1-84): A Review in Hypoparathyroidism.

    PubMed

    Kim, Esther S; Keating, Gillian M

    2015-07-01

    Full-length recombinant human parathyroid hormone [rhPTH (1-84); Natpara(®)] is approved in the USA as an adjunct to calcium and vitamin D therapy for control of hypocalcaemia in patients with hypoparathyroidism. This article reviews the clinical efficacy and tolerability of rhPTH (1-84) in hypoparathyroidism and summarizes its pharmacological properties. In a pivotal phase III trial, subcutaneous rhPTH (1-84) was effective in maintaining albumin-corrected total serum calcium levels while reducing/eliminating the need for oral calcium and active vitamin D. rhPTH (1-84) had a generally acceptable tolerability profile in this trial, with <3% of patients discontinuing treatment because of adverse events. Commonly occurring adverse reactions included hypocalcaemia, hypercalcaemia and hypercalciuria. As the first PTH replacement therapy for hypoparathyroid patients with hypocalcaemia, rhPTH (1-84) is an effective regimen, has generally acceptable tolerability and represents an important advance for the management of hypoparathyroidism.

  19. Parathyroid hormone 1-34 enhances extracellular matrix deposition and organization during flexor tendon repair.

    PubMed

    Lee, Daniel J; Southgate, Richard D; Farhat, Youssef M; Loiselle, Alayna E; Hammert, Warren C; Awad, Hani A; O'Keefe, Regis J

    2015-01-01

    Parathyroid hormone (PTH) 1-34 is known to enhance fracture healing. Tendon repair is analogous to bone healing in its dependence on the proliferation and differentiation of mesenchymal stem cells, matrix formation, and tissue remodeling.(1,2,3) We hypothesized that PTH 1-34 enhances tendon healing in a flexor digitorum longus (FDL) tendon repair model. C57Bl/6J mice were treated with either intraperitoneal PTH 1-34 or vehicle-control (PBS). Tendons were harvested at 3-28 days for histology, gene expression, and biomechanical testing. The metatarsophalangeal joint range of motion was reduced 1.5-2-fold in PTH 1-34 mice compared to control mice. The gliding coefficient, a measure of adhesion formation, was 2-3.5-fold higher in PTH 1-34 mice. At 14 days post-repair, the tensile strength was twofold higher in PTH 1-34 specimens, but at 28 days there were no differences. PTH 1-34 mice had increased fibrous tissue deposition that correlated with elevated expression of collagens and fibronectin as seen on quantitative PCR. PTH 1-34 accelerated the deposition of reparative tissue but increased adhesion formation.

  20. Influence of Parathyroid Hormone-Loaded PLGA Nanoparticles in Porous Scaffolds for Bone Regeneration.

    PubMed

    Gentile, Piergiorgio; Nandagiri, Vijay Kumar; Pabari, Ritesh; Daly, Jacqueline; Tonda-Turo, Chiara; Ciardelli, Gianluca; Ramtoola, Zebunnissa

    2015-08-28

    Biodegradable poly(lactide-co-glycolide) (PLGA) nanoparticles, containing human parathyroid hormone (PTH (1-34)), prepared by a modified double emulsion-solvent diffusion-evaporation method, were incorporated in porous freeze-dried chitosan-gelatin (CH-G) scaffolds. The PTH-loaded nanoparticles (NPTH) were characterised in terms of morphology, size, protein loading, release kinetics and in vitro assessment of biological activity of released PTH and cytocompatibility studies against clonal human osteoblast (hFOB) cells. Structural integrity of incorporated and released PTH from nanoparticles was found to be intact by using Tris-tricine SDS-PAGE. In vitro PTH release kinetics from PLGA nanoparticles were characterised by a burst release followed by a slow release phase for 3-4 weeks. The released PTH was biologically active as evidenced by the stimulated release of cyclic AMP from hFOB cells as well as increased mineralisation studies. in vitro and cell studies demonstrated that the PTH bioactivity was maintained during the fabrication of PLGA nanoparticles and upon release. Finally, a content of 33.3% w/w NPTHs was incorporated in CH-G scaffolds, showing an intermittent release during the first 10 days and, followed by a controlled release over 28 days of observation time. The increased expression of Alkaline Phosphatase levels on hFOB cells further confirmed the activity of intermittently released PTH from scaffolds.

  1. Parathyroid hormone and risk of heart failure in the general population

    PubMed Central

    Meng, Fanbo; Wang, Wei; Ma, Jianghong; Lin, Baisong

    2016-01-01

    Abstract Inconsistent findings have been reported on the association between the parathyroid hormone (PTH) level and risk of heart failure. We aimed to systematically evaluate the association between circulating level of PTH and risk of heart failure in the general population by conducting a meta-analysis. We made a comprehensive literature search in PubMed, Embase, VIP, CNKI, and Wanfang databases published until January 2016. Only prospective observational studies reporting the association between circulating level of PTH and risk of heart failure in the general population were selected. Pooled adjusted hazard ratio (HR) and corresponding 95% confidence intervals (CIs) were calculated for the highest versus lowest PTH category. Six studies with 25,207 participants identified. Higher circulating level of PTH was associated with an increased risk of heart failure (HR: 1.38; 95% CI 1.09–1.74) in a random effect model. Subgroup analyses revealed that the risk of heart failure was more pronounced among men (HR: 1.75; 95% CI 1.38–2.22) than in both genders. However, the risk increment was not statistically significant (HR: 1.12; 95% CI 0.76–1.66) in the middle-aged population. Higher PTH level is independently associated with an exacerbated risk of heart failure in the general population. PMID:27749533

  2. Distinctive Tooth-Extraction Socket Healing: Bisphosphonate Versus Parathyroid Hormone Therapy

    PubMed Central

    Kuroshima, Shinichiro; Mecano, Rodan B.; Tanoue, Ryuichiro; Koi, Kiyono; Yamashita, Junro

    2014-01-01

    Background Patients with osteoporosis who receive tooth extractions are typically on either oral bisphosphonate or parathyroid hormone (PTH) therapy. Currently, the consequence of these therapies on hard- and soft-tissue healing in the oral cavity is not clearly defined. The aim of this study is to determine the differences in the therapeutic effect on tooth-extraction wound healing between bisphosphonate and PTH therapies. Methods Maxillary second molars were extracted in Sprague Dawley rats (n = 30), and either bisphosphonate (zoledronate [Zol]), PTH, or saline (vehicle control [VC]) was administered for 10 days (n = 10 per group). Hard-tissue healing was evaluated by microcomputed tomography and histomorphometric analyses. Collagen, blood vessels, inflammatory cell infiltration, and cathepsin K expression were assessed in soft tissue using immunohistochemistry, quantitative polymerase chain reaction, and immunoblotting. Results Both therapies significantly increased bone fill and suppressed vertical bone loss. However, considerably more devital bone was observed in the sockets of rats on Zol versus VC. Although Zol increased the numbers of blood vessels, the total blood vessel area in soft tissue was significantly smaller than in VC. PTH therapy increased osteoblastic bone formation and suppressed osteoclasts. PTH therapy promoted soft-tissue maturation by suppressing inflammation and stimulating collagen deposition. Conclusion Zoledronate therapy deters whereas PTH therapy promotes hard- and soft-tissue healing in the oral cavity, and both therapies prevent vertical bone loss. PMID:23688101

  3. Response of parathyroid hormone to anaerobic exercise in adolescent female athletes.

    PubMed

    Takada, H; Washino, K; Nagashima, M; Iwata, H

    1998-02-01

    It has been shown that moderate exercise suppresses parathyroid hormone (PTH) secretion, while strenuous exercise is apt to induce continuous secretion, which has a negative effect on bone mineral densities (BMD). The present study investigated a typical response of PTH to brief exercise. The study group comprised six adolescent female basketball players whose BMD were within normal limits. Maximal anaerobic power by three-step cycling was loaded on each subject. The first blood sample was drawn 30 min prior to testing test, the second was immediately following, the third was 15 min after, and the fourth was 30 min after. The proportional change in plasma volume was -11.5% immediately following (P < 0.05), +2.1% 15 min after, and +5.5% at 30 min after exercise (P < 0.05). The expected value was calculated on the assumption of no effect, except changes in plasma volume, by exercise. The measured values of PTH and calcium (Ca) immediately after exercise were lower than each of the expected values (P < 0.05 for both). At 15 min after, there was no significant difference between expected and measured values of PTH, Ca and magnesium (Mg), respectively. At 30 min after, the measured value of Ca and Mg was higher than each expected value (P < 0.05 for both). It was concluded that PTH secretion is suppressed transiently immediately after maximal anaerobic exercise and is then stimulated during the recovery time in normal BMD subjects.

  4. Individual and combined effects of noise-like whole-body vibration and parathyroid hormone treatment on bone defect repair in ovariectomized mice.

    PubMed

    Matsumoto, Takeshi; Sato, Daisuke; Hashimoto, Yoshihiro

    2016-01-01

    The effectiveness of intermittent administration of parathyroid hormone and exposure to whole-body vibration on osteoporotic fracture healing has been previously investigated, but data on their concurrent use are lacking. Thus, we evaluated the effects of intermittent administration of parathyroid hormone, whole-body vibration, and their combination on bone repair in osteoporotic mice. Noise-like whole-body vibration with a broad frequency range was used instead of conventional sine-wave whole-body vibration at a specific frequency. Mice were ovariectomized at 9 weeks of age and subjected to drill-hole surgery in the right tibial diaphysis at 11 weeks. The animals were divided into four groups (n = 12 each): a control group, and groups treated with intermittent administration of parathyroid hormone, noise-like whole-body vibration, and both. From postoperative day 2, the groups treated with intermittent administration of parathyroid hormone and groups treated with both intermittent administration of parathyroid hormone and noise-like whole-body vibration were subcutaneously administered parathyroid hormone at a dose of 30 µg/kg/day. The groups treated with noise-like whole-body vibration and groups treated with both intermittent administration of parathyroid hormone and noise-like whole-body vibration were exposed to noise-like whole-body vibration at a root mean squared acceleration of 0.3g and frequency components of 45-100 Hz for 20 min/day. Following 18 days of interventions, the right tibiae were harvested, and the regenerated bone was analyzed by micro-computed tomography and nanoindentation testing. Compared with the control group, callus volume fraction was 40% higher in groups treated with intermittent administration of parathyroid hormone and 73% higher in groups treated with both intermittent administration of parathyroid hormone and noise-like whole-body vibration, and callus thickness was 35% wider in groups treated with both

  5. Individual and combined effects of noise-like whole-body vibration and parathyroid hormone treatment on bone defect repair in ovariectomized mice.

    PubMed

    Matsumoto, Takeshi; Sato, Daisuke; Hashimoto, Yoshihiro

    2016-01-01

    The effectiveness of intermittent administration of parathyroid hormone and exposure to whole-body vibration on osteoporotic fracture healing has been previously investigated, but data on their concurrent use are lacking. Thus, we evaluated the effects of intermittent administration of parathyroid hormone, whole-body vibration, and their combination on bone repair in osteoporotic mice. Noise-like whole-body vibration with a broad frequency range was used instead of conventional sine-wave whole-body vibration at a specific frequency. Mice were ovariectomized at 9 weeks of age and subjected to drill-hole surgery in the right tibial diaphysis at 11 weeks. The animals were divided into four groups (n = 12 each): a control group, and groups treated with intermittent administration of parathyroid hormone, noise-like whole-body vibration, and both. From postoperative day 2, the groups treated with intermittent administration of parathyroid hormone and groups treated with both intermittent administration of parathyroid hormone and noise-like whole-body vibration were subcutaneously administered parathyroid hormone at a dose of 30 µg/kg/day. The groups treated with noise-like whole-body vibration and groups treated with both intermittent administration of parathyroid hormone and noise-like whole-body vibration were exposed to noise-like whole-body vibration at a root mean squared acceleration of 0.3g and frequency components of 45-100 Hz for 20 min/day. Following 18 days of interventions, the right tibiae were harvested, and the regenerated bone was analyzed by micro-computed tomography and nanoindentation testing. Compared with the control group, callus volume fraction was 40% higher in groups treated with intermittent administration of parathyroid hormone and 73% higher in groups treated with both intermittent administration of parathyroid hormone and noise-like whole-body vibration, and callus thickness was 35% wider in groups treated with both

  6. 25-Hydroxyvitamin D and Parathyroid Hormone Levels Are Independently Associated with the Hemoglobin A1c Level of Korean Type 2 Diabetic Patients: The Dong-Gu Study

    PubMed Central

    Choi, Jin-Su; Rhee, Jung-Ae; Nam, Hae-Sung; Jeong, Seul-Ki; Park, Kyeong-Soo; Kim, Hee Nam; Shin, Min-Ho

    2016-01-01

    In type 2 diabetic patients, the relationships between 25-hydroxyvitamin D and parathyroid hormone levels, and glycemic control, remain unclear. We evaluated associations between 25-hydroxyvitamin D, parathyroid hormone, and hemoglobin A1c levels after adjusting for other covariates, including log transformed 25-hydroxyvitamin D levels and log transformed parathyroid hormone levels, in Korean patients with type 2 diabetes. In total, 1,175 patients with type 2 diabetes were selected from 8,857 individuals who completed the baseline survey of the Dong-gu study, conducted in Korea from 2007 to 2010. After adjusting for other covariates, we found that the mean hemoglobin A1c level was inversely associated with the 25-hydroxyvitamin D level (Q1: 7.47% [7.30–7.63], Q2: 7.25% [7.09–7.40], Q3: 7.17% [7.02–7.32], Q4: 7.19% [7.02–7.35]; p for trend = 0.021, p for between groups = 0.050) and the parathyroid hormone level (Q1: 7.35% [7.19–7.51], Q2: 7.34% [7.19–7.50], Q3: 7.28% [7.13–7.43], Q4: 7.09% [6.94–7.24]; p for trend = 0.022, p for between groups = 0.048). However, the mean fasting glucose level was not associated with either the 25-hydroxyvitamin D or parathyroid hormone level. In conclusion, inverse associations were evident between hemoglobin A1c, 25-hydroxyvitamin D and parathyroid hormone levels in Korean patients with type 2 diabetes. The associations remained significant after adjusting for other covariates, including the log transformed 25-hydroxyvitamin D levels and log transformed parathyroid hormone levels. PMID:27362844

  7. Parathyroid hormone inhibits TGF-β/Smad signaling and extracellular matrix proteins upregulation in rat mesangial cells.

    PubMed

    Peng, Fang-Fang; Xiao, Ze-Ling; Chen, Hong-Min; Chen, Yan; Zhou, Jian; Yu, Hong; Zhang, Bai-Fang

    2016-09-23

    Accumulation of glomerular matrix is a hallmark of diabetic nephropathy. TGF-β1 is a major cytokine mediating the production of various extracellular matrix (ECM) proteins. The aim of this study is to elucidate the effect of parathyroid hormone (PTH) on TGF-β1 and high glucose-induced upregulation of ECM proteins in primary mesangial cells from Sprague-Dawley rat. The results showed that PTH pretreatment prevented TGF-β1 and high glucose-induced Smad2/3 phosphorylation and consequent upregulation of fibronectin and type IV collagen within 4 h. The inhibitory effect of PTH is due to PTH1R activation, because knocking down PTH 1 receptor (PTH1R) by RNA interference reversed the inhibitory effect of PTH on TGF-β1 and high glucose-induced Smad2/3 phosphorylation and ECM upregulation. Furthermore, it is found that PTH1R associated with TGF-β type II receptor (TβR II) and both receptors internalized into the cytoplasm when mesangial cells were stimulated with PTH alone. The internalization of TβR II might reduce the amount of membrane TβR II, attenuate the sensitivity of mesangial cells to TGF-β1, and therefore inhibit Smad activation and ECM upregulation induced by TGF-β1 and high glucose. Further studies are needed to know whether the endocytic receptors are to be degraded or recycled, and evaluate the role of PTH in TGF-β1 signaling more comprehensively.

  8. Fibroblast Growth Factor Receptor 3 Deficiency Does Not Impair the Osteoanabolic Action of Parathyroid Hormone on Mice

    PubMed Central

    Xie, Yangli; Yi, Lingxian; Weng, Tujun; Huang, Junlan; Luo, Fengtao; Jiang, Wanling; Xian, Cory J; Du, Xiaolan; Chen, Lin

    2016-01-01

    Summary: PTH stimulates bone formation in Fgfr3 knockout mice through promotion of proliferation and differentiation in osteoblasts. Introduction: Previous studies showed that endogenous fibroblast growth factor 2 (FGF-2) is required for parathyroid hormone (PTH)-stimulated bone anabolic effects, however, the exact mechanisms by which PTH stimulate bone formation and the function of FGF receptors in mediating these actions are not fully defined. FGF receptor 3 (FGFR3) has been characterized as an important regulator of bone metabolism and is confirmed to cross-talk with PTH/PTHrP signal in cartilage and bone development. Methods: Fgfr3 knockout and wild-type mice at 2-month-old and 4-month-old were intraperitoneally injected with PTH intermittently for 4 weeks and then the skeletal responses to PTH were assessed by dual energy X-ray absorptiometry (DEXA), micro-computed tomography (μCT) and bone histomorphometry. Results: Intermittent PTH treatment improved bone mineral density (BMD) and femoral mechanical properties in both Fgfr3-/- and wild-type mice. Histomorphometric analysis showed that bone formation and bone resorption were increased in both genotypes following PTH treatment. PTH treatment increased trabecular bone volume (BV/TV) in WT and Fgfr3-deficient mice. The anabolic response in Fgfr3-deficient and wild-type bone is characterized by an increase of both bone formation and resorption-related genes following PTH treatment. In addition, we found that Fgfr3 null osteoblasts (compared to wild-type controls) maintained normal abilities to response to PTH-stimulated increase of proliferation, differentiation, expression of osteoblastic marker genes (Cbfa1, Osteopontin and Osteocalcin), and phosphorylation of Erk1/2. Conclusions: Bone anabolic effects of PTH were not impaired by the absence of FGFR3, suggesting that the FGFR3 signaling may not be required for osteoanabolic effects of PTH activities. PMID:27489502

  9. Consequences of Daily Administered Parathyroid Hormone on Myeloma Growth, Bone Disease, and Molecular Profiling of Whole Myelomatous Bone

    PubMed Central

    Pennisi, Angela; Ling, Wen; Li, Xin; Khan, Sharmin; Wang, Yuping; Barlogie, Bart; Shaughnessy, John D.; Yaccoby, Shmuel

    2010-01-01

    Background Induction of osteolytic bone lesions in multiple myeloma is caused by an uncoupling of osteoclastic bone resorption and osteoblastic bone formation. Current management of myeloma bone disease is limited to the use of antiresorptive agents such as bisphosphonates. Methodology/Principal Findings We tested the effects of daily administered parathyroid hormone (PTH) on bone disease and myeloma growth, and we investigated molecular mechanisms by analyzing gene expression profiles of unique myeloma cell lines and primary myeloma cells engrafted in SCID-rab and SCID-hu mouse models. PTH resulted in increased bone mineral density of myelomatous bones and reduced tumor burden, which reflected the dependence of primary myeloma cells on the bone marrow microenvironment. Treatment with PTH also increased bone mineral density of uninvolved murine bones in myelomatous hosts and bone mineral density of implanted human bones in nonmyelomatous hosts. In myelomatous bone, PTH markedly increased the number of osteoblasts and bone-formation parameters, and the number of osteoclasts was unaffected or moderately reduced. Pretreatment with PTH before injecting myeloma cells increased bone mineral density of the implanted bone and delayed tumor progression. Human global gene expression profiling of myelomatous bones from SCID-hu mice treated with PTH or saline revealed activation of multiple distinct pathways involved in bone formation and coupling; involvement of Wnt signaling was prominent. Treatment with PTH also downregulated markers typically expressed by osteoclasts and myeloma cells, and altered expression of genes that control oxidative stress and inflammation. PTH receptors were not expressed by myeloma cells, and PTH had no effect on myeloma cell growth in vitro. Conclusions/Significance We conclude that PTH-induced bone formation in myelomatous bones is mediated by activation of multiple signaling pathways involved in osteoblastogenesis and attenuated bone resorption

  10. Insulin-like growth factor I is required for the anabolic actions of parathyroid hormone on mouse bone

    NASA Technical Reports Server (NTRS)

    Bikle, Daniel D.; Sakata, Takeshi; Leary, Colin; Elalieh, Hashem; Ginzinger, David; Rosen, Clifford J.; Beamer, Wesley; Majumdar, Sharmila; Halloran, Bernard P.

    2002-01-01

    Parathyroid hormone (PTH) is a potent anabolic agent for bone, but the mechanism(s) by which it works remains imperfectly understood. Previous studies have indicated that PTH stimulates insulin-like growth factor (IGF) I production, but it remains uncertain whether IGF-I mediates some or all of the skeletal actions of PTH. To address this question, we examined the skeletal response to PTH in IGF-I-deficient (knockout [k/o]) mice. These mice and their normal littermates (NLMs) were given daily injections of PTH (80 microg/kg) or vehicle for 2 weeks after which their tibias were examined for fat-free weight (FFW), bone mineral content, bone structure, and bone formation rate (BFR), and their femurs were assessed for mRNA levels of osteoblast differentiation markers. In wild-type mice, PTH increased FFW, periosteal BFR, and cortical thickness (C.Th) of the proximal tibia while reducing trabecular bone volume (BV); these responses were not seen in the k/o mice. The k/o mice had normal mRNA levels of the PTH receptor and increased mRNA levels of the IGF-I receptor but markedly reduced basal mRNA levels of the osteoblast markers. Surprisingly, these mRNAs in the k/o bones increased several-fold more in response to PTH than the mRNAs in the bones from their wild-type littermates. These results indicate that IGF-I is required for the anabolic actions of PTH on bone formation, but the defect lies distal to the initial response of the osteoblast to PTH.

  11. Roles of parathyroid hormone (PTH) receptor and reactive oxygen species in hyperlipidemia-induced PTH resistance in preosteoblasts.

    PubMed

    Li, Xin; Garcia, Jamie; Lu, Jinxiu; Iriana, Sidney; Kalajzic, Ivo; Rowe, David; Demer, Linda L; Tintut, Yin

    2014-01-01

    Bioactive lipids initiate inflammatory reactions leading to pathogenesis of atherosclerosis. Evidence shows that they also contribute to bone loss by inhibiting parathyroid hormone receptor (PTH1R) expression and differentiation of osteoblasts. We previously demonstrated that bone anabolic effects of PTH(1-34) are blunted in hyperlipidemic mice and that these PTH effects are restored by antioxidants. However, it is not clear which osteoblastic cell developmental stage is targeted by bioactive lipids. To investigate the effects of hyperlipidemia at the cellular level, hyperlipidemic Ldlr(-/-) mice were bred with Col3.6GFPtpz mice, in which preosteoblasts/osteoblasts carry a topaz fluorescent label, and with Col2.3GFPcyan mice, in which more mature osteoblasts/osteocytes carry a cyan fluorescent label. Histological analyses of trabecular bone surfaces in femoral as well as calvarial bones showed that intermittent PTH(1-34) increased fluorescence intensity in WT-Tpz mice, but not in Tpz-Ldlr(-/-) mice. In contrast, PTH(1-34) did not alter fluorescence intensity in femoral cortical envelopes of either WT-Cyan or Ldlr(-/-)-Cyan mice. To test the mechanism of PTH1R downregulation, preosteoblastic MC3T3-E1 cells were treated with bioactive lipids and the antioxidant Trolox. Results showed that inhibitory effects of PTH1R levels by bioactive lipids were rescued by pretreatment with Trolox. The inhibitory effects on expression of PTH1R as well as on PTH-induced osteoblastic genes were mimicked by xanthine/xanthine oxidase, a known generator of reactive oxygen species. These findings suggest an important role of the preosteoblastic development stage as the target and downregulation of PTH receptor expression mediated by intracellular oxidant stress as a mechanism in hyperlipidemia-induced PTH resistance. PMID:24038594

  12. Pregnancy-associated plasma protein-A modulates the anabolic effects of parathyroid hormone in mouse bone.

    PubMed

    Clifton, Kari B; Conover, Cheryl A

    2015-12-01

    Intermittent parathyroid hormone (PTH) is a potent anabolic therapy for bone, and several studies have implicated local insulin-like growth factor (IGF) signaling in mediating this effect. The IGF system is complex and includes ligands and receptors, as well as IGF binding proteins (IGFBPs) and IGFBP proteases. Pregnancy-associated plasma protein-A (PAPP-A) is a metalloprotease expressed by osteoblasts in vitro that has been shown to enhance local IGF action through cleavage of inhibitory IGFBP-4. This study was set up to test two specific hypotheses: 1) Intermittent PTH treatment increases the expression of IGF-I, IGFBP-4 and PAPP-A in bone in vivo, thereby increasing local IGF activity. 2) In the absence of PAPP-A, local IGF activity and the anabolic effects of PTH on bone are reduced. Wild-type (WT) and PAPP-A knock-out (KO) mice were treated with 80 μg/kg human PTH 1-34 or vehicle by subcutaneous injection five days per week for six weeks. IGF-I, IGFBP-4 and PAPP-A mRNA expression in bone were significantly increased in response to PTH treatment. PTH treatment of WT mice, but not PAPP-A KO mice, significantly increased expression of an IGF-responsive gene. Bone mineral density (BMD), as measured by DEXA, was significantly decreased in femurs of PAPP-A KO compared to WT mice with PTH treatment. Volumetric BMD, as measured by pQCT, was significantly decreased in femoral midshaft (primarily cortical bone), but not metaphysis (primarily trabecular bone), of PAPP-A KO compared to WT mice with PTH treatment. These data suggest that stimulation of PAPP-A expression by intermittent PTH treatment contributes to PTH bone anabolism in mice.

  13. The administration of intermittent parathyroid hormone affects functional recovery from trochanteric fractured neck of femur

    PubMed Central

    Chesser, T. J. S.; Fox, R.; Harding, K.; Halliday, R.; Barnfield, S.; Willett, K.; Lamb, S.; Yau, C.; Javaid, M. K.; Gray, A. C.; Young, J.; Taylor, H.; Shah, K.; Greenwood, R.

    2016-01-01

    Aims We wished to assess the feasibility of a future randomised controlled trial of parathyroid hormone (PTH) supplements to aid healing of trochanteric fractures of the hip, by an open label prospective feasibility and pilot study with a nested qualitative sub study. This aimed to inform the design of a future powered study comparing the functional recovery after trochanteric hip fracture in patients undergoing standard care, versus those who undergo administration of subcutaneous injection of PTH for six weeks. Patients and Methods We undertook a pilot study comparing the functional recovery after trochanteric hip fracture in patients 60 years or older, admitted with a trochanteric hip fracture, and potentially eligible to be randomised to either standard care or the administration of subcutaneous PTH for six weeks. Our desired outcomes were functional testing and measures to assess the feasibility and acceptability of the study. Results A total of 724 patients were screened, of whom 143 (20%) were eligible for recruitment. Of these, 123 were approached and 29 (4%) elected to take part. However, seven patients did not complete the study. Compliance with the injections was 11 out of 15 (73%) showing the intervention to be acceptable and feasible in this patient population. Take home message: Only 4% of patients who met the inclusion criteria were both eligible and willing to consent to a study involving injections of PTH, so delivering this study on a large scale would carry challenges in recruitment and retention. Methodological and sample size planning would have to take this into account. PTH administration to patients to enhance fracture healing should still be considered experimental. Cite this article: Bone Joint J 2016;98-B:840–5. PMID:27235530

  14. Atherogenic phospholipids attenuate osteogenic signaling by BMP-2 and parathyroid hormone in osteoblasts.

    PubMed

    Huang, Michael S; Morony, Sean; Lu, Jinxiu; Zhang, Zina; Bezouglaia, Olga; Tseng, Wendy; Tetradis, Sotirios; Demer, Linda L; Tintut, Yin

    2007-07-20

    Cardiovascular disease, such as atherosclerosis, has been associated with reduced bone mineral density and fracture risk. A major etiologic factor in atherogenesis is believed to be oxidized phospholipids. We previously found that these phospholipids inhibit spontaneous osteogenic differentiation of marrow stromal cells, suggesting that they may account for the clinical link between atherosclerosis and osteoporosis. Currently, anabolic agents that promote bone formation are increasingly used as a new treatment for osteoporosis. It is not known, however, whether atherogenic phospholipids alter the effects of bone anabolic agents, such as bone morphogenetic protein (BMP)-2 and parathyroid hormone (PTH). Therefore we investigated the effects of oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (ox-PAPC) on osteogenic signaling induced by BMP-2 and PTH in MC3T3-E1 cells. Results showed that ox-PAPC attenuated BMP-2 induction of osteogenic markers alkaline phosphatase and osteocalcin. Ox-PAPC also inhibited both spontaneous and BMP-induced expression of PTH receptor. Consistently, pretreatment of cells with ox-PAPC inhibited PTH-induced cAMP production and expression of immediate early genes Nurr1 and IL-6. Results from immunofluorescence and Western blot analyses showed that inhibitory effects of ox-PAPC on BMP-2 signaling were associated with inhibition of SMAD 1/5/8 but not p38-MAPK activation. These effects appear to be due to ox-PAPC activation of the ERK pathway, as the ERK inhibitor PD98059 reversed ox-PAPC inhibitory effects on BMP-2-induced alkaline phosphatase activity, osteocalcin expression, and SMAD activation. These results suggest that atherogenic lipids inhibit osteogenic signaling induced by BMP-2 and PTH, raising the possibility that hyperlipidemia and atherogenic phospholipids may interfere with anabolic therapy. PMID:17522049

  15. Calcitriol, calcidiol, parathyroid hormone, and fibroblast growth factor-23 interactions in chronic kidney disease

    PubMed Central

    Brito Galvao, Joao F; Nagode, Larry A; Schenck, Patricia A; Chew, Dennis J

    2013-01-01

    Objective To review the inter-relationships between calcium, phosphorus, parathyroid hormone (PTH), parent and activated vitamin D metabolites (vitamin D, 25(OH)-vitamin D, 1,25(OH)2-vitamin D, 24,25(OH)2-vitamin D), and fibroblast growth factor-23 (FGF-23) during chronic kidney disease (CKD) in dogs and cats. Data Sources Human and veterinary literature. Human Data Synthesis Beneficial effects of calcitriol treatment during CKD have traditionally been attributed to regulation of PTH but new perspectives emphasize direct renoprotective actions independent of PTH and calcium. It is now apparent that calcitriol exerts an important effect on renal tubular reclamation of filtered 25(OH)-vitamin D, which may be important in maintaining adequate circulating 25(OH)-vitamin D. This in turn may be vital for important pleiotropic actions in peripheral tissues through autocrine/paracrine mechanisms that impact the health of those local tissues. Veterinary Data Synthesis Limited information is available reporting the benefit of calcitriol treatment in dogs and cats with CKD. Conclusions A survival benefit has been shown for dogs with CKD treated with calcitriol compared to placebo. The concentrations of circulating 25(OH)-vitamin D have recently been shown to be low in people and dogs with CKD and are related to survival in people with CKD. Combination therapy for people with CKD using both parental and activated vitamin D compounds is common in human nephrology and there is a developing emphasis using combination treatment with activated vitamin D and renin-angiotensin-aldosterone-system (RAAS) inhibitors. PMID:23566108

  16. Radioimmunoassay for amino- and carboxyl terminal parathyroid hormone: Its clinical application

    SciTech Connect

    Fukunaga, M.; Otsuka, N.; Sone, T.; Muranake, A.; Yanagimoto, S.; Tomomitsu, T.; Morita, R.; Yamamoto, I.; Torizuka, K.; Dokoh, S.

    1985-05-01

    It has been well known that the circulating parathyroid hormones are immunochemically heterogenous. The authors have employed the region-specific radioimmunoassays directed against N-PTH using (1-34) human PTH and C-PTH using (65-84) human PTH to evaluate its clinical usefulness. Serum N-PTH and C-PTH levels were measured in 50 normal subjects, 17 primary hyperparathyroidism (1/sup 0/ HPT), 14 hypercalcemia associated with cancer and 30 chronic renal failure (CRF) on dialysis. In 1/sup 0/ HPT, higher N-PTH levels were observed in 6, while higher C-PTH levels in 13. Among 1/sup 0/ HPT, patients with bone type (osteitis fibrosa), compared with stone or chemical type, showed significantly higher N-PTH and C-PTH levels (bone type vs. stone and chemical type; p<0.001 for N-PTH and p<0.01 for C-PTH). Neither N-PTH nor C-PTH assay could be differentiated 1/sup 0/ HPT from hypercalcemia associated with cancer. In CRF, the increased N-PTH levels were observed in 6, while the increased C-PTH levels in 30. Among CRF, patients with osteitis fibrosa showed significantly higher N-PTH and C-PTH (with vs. without osteitis fibrosa; p<0.001 for N-PTH and p<0.025 for C-PTH). In conclusion, each assay has its own value in clinical settings, with the N-PTH assay being used in evaluation of the biological effect of PTH (eg. the recognition of the existence of osteitis fibrosa in 1/sup 0/ HPT and CRF) and the C-PTH assay primarily serving the differential diagnosis of 1/sup 0/ HPT from normal subjects.

  17. Parathyroid hormone is predictive of low bone mass in Canadian aboriginal and white women.

    PubMed

    Weiler, Hope A; Leslie, William D; Bernstein, Charles N

    2008-03-01

    Canadian Aboriginal women have lower age- and weight-corrected bone mineral density (BMD) and lower vitamin D status than White women. This study was undertaken to describe the differences in biomarkers of bone metabolism and vitamin D in Aboriginal and non-Aboriginal women and to establish which biomarkers were predictive of BMD. In total, 41 rural Aboriginal, 212 urban Aboriginal and 182 urban White women were studied for BMD of the distal radius, calcaneus, lumbar spine, femoral neck, total hip and whole body using dual-energy X-ray absorptiometry. Serum biomarkers measured included calcium, phosphate, alkaline phosphatase (ALP), C-telopeptide of type 1 collagen (CTX), osteocalcin (OC), osteoprotegerin (OPG), parathyroid hormone (PTH) and 25(OH)D. Data were analyzed for differences among the three groups stratified by age (25 to 39, 40 to 59 and 60 to 75 y) using factorial ANOVA. Predictors of BMD including ethnicity, age and body weight were identified using step-wise regression. Unadjusted BMD of all sites declined with age regardless of ethnic grouping. Prediction models for 5 of 6 BMD sites included PTH accounting for age and body weight. Other predictors of BMD included OC for the radius and calcaneus; OPG for spine and total hip; and ALP for whole body and calcaneus. Serum 25(OH)D was not included in any model of BMD. After accounting for all variables in the regression equation, an average Aboriginal woman of 46 y and 79 kg was predicted to have 6% lower calcaneus BMD and 3% lower radius BMD compared to a White woman of the same age and weight. In conclusion, PTH is a better predictor of BMD than 25(OH)D in this population of Aboriginal and White women. PMID:18191628

  18. Exogenous Parathyroid Hormone-Related Peptide Promotes Fracture Healing in Lepr(-/-) Mice.

    PubMed

    Liu, Anlong; Li, Yishan; Wang, Yinhe; Liu, Li; Shi, Hongfei; Qiu, Yong

    2015-12-01

    Diabetic osteoporosis continues to surge worldwide, increasing the risk of fracture. We have previously demonstrated that haploinsufficiency of endogenous parathyroid hormone-related peptide (PTHrP) impairs fracture healing. However, whether an exogenous supply of PTHrP can repair bone damage and accelerate fracture healing remains unclear. This study aimed to assess the efficacy and safety of PTHrP in healing fractures. Standardized mid-diaphyseal femur fractures were generated in 12-week-old wild-type and leptin receptor null Lepr(-/-) mice. After administration of PTHrP for 2 weeks, callus tissue properties were analyzed by radiography, micro-computed tomography, histology, histochemistry, immunohistochemistry, and molecular biology techniques. At 2 weeks post-fracture, cartilaginous callus areas were reduced, while total callus and bony callus areas were increased in PTHrP-treated Lepr(-/-) animals and control wild-type mice, compared with vehicle-treated Lepr(-/-) mice. The following parameters were enhanced both in Lepr(-/-) mice after treatment with PTHrP and vehicle-treated wild-type animals, compared with vehicle-treated Lepr(-/-) mice: osteoblast numbers; tissue alkaline phosphatase (ALP) and Type I collagen immunopositive areas; mRNA levels of ALP, Type I collagen, osteoprotegerin, and receptor activator for nuclear factor-κ B ligand; protein levels of Runt-related transcription factor 2 and insulin-like growth factor-1; and the number and surface of osteoclasts. In conclusion, exogenous PTHrP by subcutaneous injection promotes fracture repair in Lepr(-/-) mice by increasing callus formation and accelerating cell transformation: upregulated osteoblastic gene and protein expression, increased endochondral bone formation, osteoblastic bone formation, and osteoclastic bone resorption. However, complete repair was not obtained in PTHrP-treated Lepr(-/-) mice as in control wild-type animals. PMID:26314884

  19. Early parathyroid hormone laboratory abnormalities related to therapeutic radiation of neck: an Egyptian experience.

    PubMed

    Aboelnaga, Mohamed M; Aboelnaga, Engy M

    2015-05-01

    The effect of neck radiation on parathyroid hormone (PTH) is studied on concern as late effect of radiotherapy for benign or malignant diseases. However, the early effect on PTH is still in debate and need further evaluations. We aimed, in our study, to assess early effect of neck radiation on PTH, and related calcium and phosphorus levels. Patients diagnosed with breast or head and neck cancer who planned to received radiotherapy to neck as a definite or a part of their treatment enrolled in this prospective single-arm study from June 2012 to June 2013. Laboratory assessment of PTH, serum calcium, phosphorus and albumin was obtained before starting radiotherapy, 3 weeks and 3 months after radiation. Fifty-two patients included 24 (46.2 %) males and 28(53.8 %) females. Median age of diagnosis was 55 years. Thirty-six patients had head and neck cancer, while 16 patients were diagnosed as breast cancer. The difference in PTH and calcium levels before and after radiotherapy was statistically significant (P = 0.014 and P = 0.001 for 3 weeks and P = 0.015 and P = 0.004 for 3 months, respectively); even after correction of calcium level according to albumin level, the same results were obtained, while there was no significant difference in their levels after 3 weeks in comparison with 3 months after radiotherapy. The variation of level of phosphorus was not significant. PTH and calcium can be affected early with neck radiation, so follow-up of calcium and PTH level is mandatory for cases that will receive neck radiotherapy. PMID:25904502

  20. Haploinsufficiency of endogenous parathyroid hormone-related peptide impairs bone fracture healing.

    PubMed

    Wang, Yin-He; Qiu, Yong; Han, Xiao-Dong; Xiong, Jin; Chen, Yi-Xin; Shi, Hong-Fei; Karaplis, Andrew

    2013-11-01

    Previous studies have demonstrated that endogenous parathyroid hormone-related peptide (PTHrP) plays a central role in the physiological regulation of bone formation. However, it is unclear whether endogenous PTHrP plays an important function in enhancing bone fracture healing. To determine whether endogenous PTHrP haploinsufficiency impaired bone fracture healing, closed mid-diaphyseal femur fractures were created in 8-week-old wild-type and Pthrp(+/-) mice. Callus tissue properties were analysed 1, 2 and 4 weeks after fracture by radiography, histology, histochemistry, immunohistochemistry and molecular biology. The size of the calluses was reduced 2 weeks after fracture, and the fracture repairs were poor 4 weeks after fractures, in Pthrp(+/-) compared with wild-type mice. Cartilaginous callus areas were reduced 1 week after fracture, but were increased 2 weeks after fracture in Pthrp(+/-) mice. There was a reduction in the number of ostoblasts, alkaline phosphatase (ALP)-positive areas, Type I collagen immunopositive areas, mRNA levels of ALP, Runt-related transcription factor 2 (Runx2) and Type I collagen, Runx2 and insulin-like growth factor-1 protein levels, the number of osteoclasts and the surface in callus tissues in Pthrp(+/-) compared with wild-type mice. These results demonstrate that endogenous PTHrP haploinsufficiency impairs the fracture repair process by reducing cartilaginous and bony callus formation, with downregulation of osteoblastic gene and protein expression and a reduction in endochondral bone formation, osteoblastic bone formation and osteoclastic bone resorption. Together, the results indicate that endogenous PTHrP plays an important role in fracture healing.

  1. Parathyroid Hormone (1-34) Transiently Protects Against Radiation-Induced Bone Fragility.

    PubMed

    Oest, Megan E; Mann, Kenneth A; Zimmerman, Nicholas D; Damron, Timothy A

    2016-06-01

    Radiation therapy for soft tissue sarcoma or tumor metastases is frequently associated with damage to the underlying bone. Using a mouse model of limited field hindlimb irradiation, we assessed the ability of parathyroid hormone (1-34) fragment (PTH) delivery to prevent radiation-associated bone damage, including loss of mechanical strength, trabecular architecture, cortical bone volume, and mineral density. Female BALB/cJ mice received four consecutive doses of 5 Gy to a single hindlimb, accompanied by daily injections of either PTH or saline (vehicle) for 8 weeks, and were followed for 26 weeks. Treatment with PTH maintained the mechanical strength of irradiated femurs in axial compression for the first eight weeks of the study, and the apparent strength of irradiated femurs in PTH-treated mice was greater than that of naïve bones during this time. PTH similarly protected against radiation-accelerated resorption of trabecular bone and transient decrease in mid-diaphyseal cortical bone volume, although this benefit was maintained only for the duration of PTH delivery. Overall, PTH conferred protection against radiation-induced fragility and morphologic changes by increasing the quantity of bone, but only during the period of administration. Following cessation of PTH delivery, bone strength and trabecular volume fraction rapidly decreased. These data suggest that PTH does not negate the longer-term potential for osteoclastic bone resorption, and therefore, finite-duration treatment with PTH alone may not be sufficient to prevent late onset radiotherapy-induced bone fragility.

  2. Optimal vitamin D status and serum parathyroid hormone concentrations in African American women123

    PubMed Central

    Aloia, John F; Talwar, Sonia A; Pollack, Simcha; Feuerman, Martin; Yeh, James K

    2009-01-01

    Background Optimal vitamin D status for the prevention of osteoporosis has been inferred from examinations of the serum 25-hydroxyvitamin D [25(OH)D] concentration below which there is an increase in serum parathyroid hormone (PTH). Objective The objectives of the study were to ascertain whether a threshold for serum 25(OH)D exists below which serum PTH increases and whether persons with 25(OH)D above this threshold have lower rates of bone loss than do persons with 25(OH)D below the threshold. Design The relation of serum 25(OH)D to serum PTH was analyzed in 208 African American women studied longitudinally for 3 y. These healthy women in midlife were randomly assigned to receive placebo or 800 IU vitamin D3/d; after 2 y, the vitamin D3 supplementation was increased to 2000 IU/d. Both groups received calcium supplements to ensure an adequate calcium intake. A systematic literature review found a wide range of threshold values in part due to varied calcium intake. Results A Loess plot suggested a breakpoint between 40 and 50 nmol/L for serum 25(OH)D. A line-line model was fitted to the data, and it showed a spline knot at 44 nmol/L. A heuristic approach verified that PTH does not decline as rapidly when the serum concentration of 25(OH)D is >40 nmol/L as when it is <40 nmol/L. We found no significant difference in rates of bone loss between persons with 25(OH)D concentrations above and below 40 nmol/L. Conclusion Although a threshold for 25(OH)D can be identified, we suggest that it should not be used to recommend optimal vitamin D status. PMID:16960175

  3. Parathyroid hormone-related protein is a gravisensor in lung and bone cell biology

    NASA Astrophysics Data System (ADS)

    Torday, J. S.

    2003-10-01

    Parathyroid Hormone-related Protein (PTHrP) has been shown to be essential for the development and homeostatic regulation of lung and bone. Since both lung and bone structure and function are affected by microgravity, we hypothesized that 0 × g down-regulates PTHrP signaling. To test this hypothesis, we suspended lung and bone cells in the simulated microgravity environment of a Rotating Wall Vessel Bioreactor, which simulates microgravity, for up to 72 hours. During the first 8 hours of exposure to simulated 0 × g, PTHrP expression fell precipitously, decreasing by 80-90%; during the subsequent 64 hours, PTHrP expression remained at this newly established level of expression. PTHrP production decreased from 12 pg/ml/hour to 1 pg/ml/hour in culture medium from microgravity-exposed cells. The cells were then recultured at unit gravity for 24hours, and PTHrP expression and production returned to normal levels. Based on these findings, we have obtained bones from rats flown in space for 2 weeks (Mission STS-58, SL-2). Analysis of PTHrP expression by femurs and tibias from these animals (n=5) revealed that PTHrP expression was 60% lower than in bones from control ground-based rats. Interestingly, there were no differences in PTHrP expression by parietal bone from space-exposed versus ground-based animals, indicating that the effect of weightlessness on PTHrP expression is due to the unweighting of weight-bearing bones. This finding is consistent with other studies of microgravity-induced osteoporosis. The loss of the PTHrP signaling mechanism may be corrected using chemical agents that up-regulate this pathway. In conclusion, PTHrP represents a stretch-sensitive paracrine signaling mechanism that may sense gravity.

  4. Parathyroid Hormone (1-34) Transiently Protects Against Radiation-Induced Bone Fragility.

    PubMed

    Oest, Megan E; Mann, Kenneth A; Zimmerman, Nicholas D; Damron, Timothy A

    2016-06-01

    Radiation therapy for soft tissue sarcoma or tumor metastases is frequently associated with damage to the underlying bone. Using a mouse model of limited field hindlimb irradiation, we assessed the ability of parathyroid hormone (1-34) fragment (PTH) delivery to prevent radiation-associated bone damage, including loss of mechanical strength, trabecular architecture, cortical bone volume, and mineral density. Female BALB/cJ mice received four consecutive doses of 5 Gy to a single hindlimb, accompanied by daily injections of either PTH or saline (vehicle) for 8 weeks, and were followed for 26 weeks. Treatment with PTH maintained the mechanical strength of irradiated femurs in axial compression for the first eight weeks of the study, and the apparent strength of irradiated femurs in PTH-treated mice was greater than that of naïve bones during this time. PTH similarly protected against radiation-accelerated resorption of trabecular bone and transient decrease in mid-diaphyseal cortical bone volume, although this benefit was maintained only for the duration of PTH delivery. Overall, PTH conferred protection against radiation-induced fragility and morphologic changes by increasing the quantity of bone, but only during the period of administration. Following cessation of PTH delivery, bone strength and trabecular volume fraction rapidly decreased. These data suggest that PTH does not negate the longer-term potential for osteoclastic bone resorption, and therefore, finite-duration treatment with PTH alone may not be sufficient to prevent late onset radiotherapy-induced bone fragility. PMID:26847434

  5. Alternative splicing of parathyroid hormone-related protein mRNA: expression and stability

    PubMed Central

    Sellers, R S; Luchin, A I; Richard, V; Brena, R M; Lima, D; Rosol, T J

    2011-01-01

    Parathyroid hormone-related protein (PTHrP) is a multifunctional protein that is often dysregulated in cancer. The human PTHrP gene is alternatively spliced into three isoforms, each with a unique 3′-untranslated region (3′-UTR), encoding 139, 173 and 141 amino acid proteins. The regulation of PTHrP mRNA isoform expression has not been completely elucidated, but it may be affected by transforming growth factor-β1 (TGF-β1). In this study, we examined differences in the PTHrP mRNA isoform expression in two squamous carcinoma cell lines (SCC2/88 and HARA), an immortalized keratinocyte cell line (HaCaT), and spontaneous human lung cancer with adjacent normal tissue. In addition, the effect of TGF-β1 on PTHrP mRNA isoform expression and stability was examined. Cell-type specific expression of PTHrP mRNA isoforms occurred between the various cell lines, normal human lung, and immortalized human keratinocytes (HaCaT). PTHrP isoform expression pattern was significantly altered between normal lung tissue and the adjacent lung cancer. In vitro studies revealed that TGF-β1 differentially altered the mRNA steady-state levels and mRNA stability of the PTHrP isoforms. Protein–RNA binding studies identified different proteins binding to the 3′-UTR of the PTHrP isoforms (139) and (141), which may be important in the differential mRNA stability and response to cytokines between the PTHrP isoforms. The data demonstrate that there is cell-type specific expression of PTHrP mRNA isoforms, and disruption of the normal regulation during cancer progression may in part be associated with TGF-β1-induced changes in PTHrP mRNA isoform expression and stability. PMID:15291755

  6. Glucocorticoid attenuates the anabolic effects of parathyroid hormone on fracture repair.

    PubMed

    Doyon, Anthony R; Ferries, Ian K; Li, Jiliang

    2010-07-01

    Long-term use of glucocorticoid (GC) not only reduces bone mass and strength, which leads to a greater risk of fracture, but also hinders fracture repair. In this study, we produced open fractures in GC-treated mice and investigated the effects of human parathyroid hormone 1-34 (hPTH) on fracture repair. Swiss-Webster mice were randomly divided into five groups. Three groups of GC-treated mice were given prednisolone, which was slowly released from subcutaneously implanted pellets at the rate of 1.4 mg/kg/day. Placebo pellets were implanted into the animals in two placebo groups. Three weeks later, osteotomies at the midshaft femora were performed and intramedullary pins were inserted to stabilize the fracture site under general anesthesia. Following fracture surgery, three GC groups were treated subcutaneously with vehicle, PTH at a low dose (40 ug/kg/day), and PTH at a high dose (80 ug/kg/day), respectively. Two placebo groups were given vehicle and PTH at a dose of 40 ug/kg/day, respectively. Radiographs, dual-energy X-ray absorptiometry, and mechanical testing (four-point bending) were used to evaluate fracture repair at 4 weeks after fracture surgery. Callus development, endochondral ossification, and recovery of mechanical strength at the fracture sites in GC animals treated with vehicle were significantly suppressed compared to placebo animals. Normally, PTH accelerates fracture repair. In GC-treated mice, PTH fails to improve endochondral ossification and mechanical properties compared to vehicle treatment, suggesting that the anabolic effect of PTH on fracture healing can be attenuated by GC administration in mice.

  7. Parathyroid hormone resets the cartilage circadian clock of the organ-cultured murine femur

    PubMed Central

    Okubo, Naoki; Fujiwara, Hiroyoshi; Minami, Yoichi; Kunimoto, Tatsuya; Hosokawa, Toshihiro; Umemura, Yasuhiro; Inokawa, Hitoshi; Asada, Maki; Oda, Ryo; Kubo, Toshikazu

    2015-01-01

    Background and purpose The circadian clock governs endogenous day-night variations. In bone, the metabolism and growth show diurnal rhythms. The circadian clock is based on a transcription-translation feedback loop composed of clock genes including Period2 (Per2), which encodes the protein period circadian protein homolog 2. Because plasma parathyroid hormone (PTH) levels show diurnal variation, we hypothesized that PTH could carry the time information to bone and cartilage. In this study, we analyzed the effect of PTH on the circadian clock of the femur. Patients and methods Per2::Luciferase (Per2::Luc) knock-in mice were used and their femurs were organ-cultured. The bioluminescence was measured using photomultiplier tube-based real-time bioluminescence monitoring equipment or real-time bioluminescence microscopic imaging devices. PTH or its vehicle was administered and the phase shifts were calculated. Immunohistochemistry was performed to detect PTH type 1 receptor (PTH1R) expression. Results Real-time bioluminescence monitoring revealed that PTH reset the circadian rhythm of the Per2::Luc activity in the femurs in an administration time-dependent and dose-dependent manner. Microscopic bioluminescence imaging revealed that Per2::Luc activity in the growth plate and the articular cartilage showed that the circadian rhythms and their phase shifts were induced by PTH. PTH1R was expressed in the growth plate cartilage. Interpretation In clinical practice, teriparatide (PTH (1-34)) treatment is widely used for osteoporosis. We found that PTH administration regulated the femoral circadian clock oscillation, particularly in the cartilage. Regulation of the local circadian clock by PTH may lead to a more effective treatment for not only osteoporosis but also endochondral ossification in bone growth and fracture repair. PMID:25765847

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

    PubMed

    Miller, S C; Bowman, B M; Myers, R L

    1984-02-01

    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.

  9. PTH (parathyroid hormone) elevates inositol polyphosphates and diacylglycerol in a rat osteoblast-like cell line

    SciTech Connect

    Civitelli, R.; Reid, I.R.; Westbrook, S.; Avioli, L.V.; Hruska, K.A. )

    1988-11-01

    Parathyroid hormone (PTH)-stimulated signal transduction through mechanisms alternate to adenosine 3{prime},5{prime}-cyclic monophosphate (cAMP) production were studied in UMR 106-01 cells, a cell line with an osteoblastic phenotype. PTH produced transient, dose-related increases in cytosolic calcium ((Ca{sup 2+}){sub i}), inositol trisphosphates, and diacylglycerol (DAG). Both inositol 1,4,5-trisphosphate (Ins-1,4,5P{sub 3}) and inositol 1,3,4-trisphosphate (Ins-1,3,4P{sub 3}) production were rapidly stimulated by PTH. Consistent with the production of Ins-1,3,4P{sub 3}, rapid stimulation of late eluting inositol tetrakisphosphate was observed. The effects on the inositol phosphates were induced rapidly, consistent with roles as signals for changes in (Ca{sup 2+}){sub i}. In saponin-permeabilized UMR 106-01 cells, Ins-1,4,5P{sub 3} stimulated {sup 45}Ca release from a nonmitochondrial intracellular pool. Thus the hypothesis that PTH-stimulated Ins-1,4,5P{sub 3} production initiates Ca{sup 2+} release and contributes to transient elevations of (Ca{sup 2+}){sub i} is supported. These data suggest that stimulation of cAMP production during PTH stimulation may negatively affect production of rises in (Ca{sup 2+}){sub i} during PTH stimulation. The inactivation of the inhibitory G protein of adenylate cyclase by pertussis toxin could explain its action similar to cAMP analogues. Cyclci nucleotides diminish the effects of PTH on (Ca{sup 2+}){sub i}, probably interacting on a biochemical step subsequent to or independent of Ins-1,4,5P{sub 3} release.

  10. [Parathyroid hormone values obtained with immunometric assays depend on the amino-terminal antibody specificity].

    PubMed

    Vieira, José Gilberto H; Nishida, Sônia K; Camargo, Maria Tereza; Obara, Leda H; Kunii, Ilda S; Ohe, Monique N; Hauache, Omar M

    2004-08-01

    Introduction of 2nd generation immunometric assays for the measurement of serum parathyroid hormone (PTH), turned them more available, simple and rapid. These methods, based on double identification of the PTH molecule, supposedly measure the intact, bioactive molecule, with the sequence 1-84. Recent works showed that they also measure forms with amino-terminal deletions, like the 7-84 form, which are not able to activate the traditional PTH receptor (PTH1R). Thus, an important practical aspect is the definition of the PTH forms measured by the immunometric assays, a fact that depends on the specificity of the antibodies employed. In this report we compare the results obtained with an in-house immunofluorometric assay that presents a cross-reactivity of 50% with the 7-84 PTH sequence, and two commercial 2nd generation assays, that react 100%. In a first study, 135 samples were measured using our assay and an electrochemiluminescent assay, resulting in a correlation coefficient of 0.961 (P<0.0001) and medians of 35.0 and 51.0 ng/L (P<0.0001). In a second study, 252 samples were analyzed using our assay and an immunochemiluminometric assay, resulting in a correlation of 0.883 (P<0.0001) and medians of 36.0 and 45.5 ng/L (P<0.0001). In both studies results obtained with the in-house assay were significantly lower, as expected by the specificity of the anti-amino-terminal antibody employed. Our data support the need of a precise description of the specificity of the amino-terminal antibodies employed in 2nd generation PTH assays in order to better compare results and define normal ranges.

  11. Parathyroid Hormone Responses to Catecholamines and to Changes of Extracellular Calcium in Cows

    PubMed Central

    Blum, Juerg W.; Fischer, Jan A.; Hunziker, Willi H.; Binswanger, U.; Picotti, Giovanni B.; Da Prada, Mosè; Guillebeau, Albin

    1978-01-01

    Modifications of the plasma level of immunoreactive parathyroid hormone (PTH) in cattle were induced by changes of the plasma concentrations of epinephrine, isoproterenol, or calcium. During abrupt hypocalcemia, PTH, obtained by infusions with ethylene glycol-bis (β-aminoethylether) N, N′-tetraacetate (EGTA), increased during the first 4-8 min. After a transient decline, the hormone levels rose again and remained elevated. Infusions of calcium suppressed the hypocalcemia-induced augmentation of PTH levels within a few minutes. Prolonged epinephrine (and isoproterenol) infusions also rapidly increased PTH levels, however, in this case, they returned to basal concentrations after 50-60 min. Additional epinephrine infusions could not further raise PTH values. Moreover, three short-lasting infusions of epinephrine (7 min each), given at 30-min intervals, increased PTH levels to the same extent, whereas additional infusions were much less effective. The PTH response to epinephrine was completely restored, when the interval after a prolonged epinephrine infusion had been prolonged to > 100 min. During moderate hypocalcemia, occurring at the end of EGTA infusions and lasting for 90 min, the PTH response to a short-lasting epinephrine infusion (7 min) was more pronounced than in normocalcemic animals. During severe hypocalcemia, in which superimposed short-lasting infusions of EGTA (7 min) led to an additional abrupt fall of plasma calcium concentrations but not to a corresponding additional rise of the PTH levels, epinephrine rapidly and further increased PTH concentrations. On the other hand, at the end of prolonged infusions of epinephrine, when additional infusions of epinephrine were ineffective in raising PTH levels, EGTA-induced hypocalcemia consistently increased PTH concentrations. The EGTA-induced augmentation of PTH levels was enhanced by epinephrine and isoproterenol but not by propranolol. The present findings indicate, that variations of the extracellular

  12. Cloning of a parathyroid hormone/parathyroid hormone-related peptide receptor (PTHR) cDNA from a rat osteosarcoma (UMR 106) cell line: Chromosomal assignment of the gene in the human, mouse, and rat genomes

    SciTech Connect

    Pausova, Z.; Bourdon, J.; Clayton, D.; Janicic, N.; Goltzman, D.; Hendy, G.N. ); Mattei, M.G. ); Seldin, M.F. ); Riviere, M.; Szpirer, J. )

    1994-03-01

    Complementary DNAs spanning the entire coding region of the rat parathyroid hormone/parathyroid hormone-related peptide receptor (PTHR) were isolated from a rat osteosarcoma (UMR 106) cell-line cDNA library. The longest of these clones (rPTHrec4) was used to chromosomally assign the PTHR gene in the human, rat, and mouse genomes. By somatic cell hybrid analysis, the gene was localized to human chromosome 3 and rat chromosome 8; by in situ hybridization, the gene was mapped to human chromosome 3p21.1-p22 and to mouse chromosome 9 band F; and by interspecific backcross analysis, the Pthr gene segregated with the transferrin (Trf) gene in chromosome 9 band F. Mouse chromosome 9 and rat chromosome 8 are known to be highly homologous and to also show synteny conservation with human chromosome 3. These three chromosomes share the transferrin gene (TF), the myosin light polypeptide 3 gene (MYL3), and the acelpeptide hydrolase gene (APEH). These results add a fourth gene, the PTHR gene, to the synteny group conserved in these chromosomes. 34 refs., 7 figs. 1 tab.

  13. The Efficacy of Parathyroid Hormone Analogues in Combination With Bisphosphonates for the Treatment of Osteoporosis

    PubMed Central

    Li, Wan; Chen, Wenjian; Lin, Yang

    2015-01-01

    Abstract Parathyroid hormone (PTH) analogues increase bone strength primarily by stimulating bone formation, whereas antiresorptive drugs (bisphosphonates) reduce bone resorption. Therefore, some studies have been designed to test the hypothesis that the concurrent administration of the 2 agents would increase bone density more than the use of either one alone. This meta-analysis aimed to determine whether combining PTH analogues with bisphosphonates would be superior to PTH alone. Electronic databases were searched to identify relevant publications up to March, 2014. Randomized controlled trials (RCTs) comparing PTH analogues combined bisphosphonates with PTH for osteoporosis were analyzed. According to the Cochrane Handbook for systematic Reviews of Interventions 5.2, we identified eligible studies, evaluated the methodological quality, and abstracted relevant data. Totally 7 studies involving 641 patients were included for meta-analysis. The pooled data showed that there were no significant differences in the percent change of spine BMD (MD1-year = −0.97, 95% CI −2.81 to 0.86, P = 0.30; MD2-year =  − 0.57, 95% CI −5.01 to 6.14, P = 0.84), femoral neck BMD (MD1-year = 0.60, 95% CI −0.91 to 2.10, P = 0.44; MD2-year = −0.73, 95% CI −4.97 to 3.51, P = 0.74), the risk of vertebral fracture (risk ratio [RR] = 1.27; 95% CI 0.29–5.57; P = 0.75), and the risk of nonvertebral fracture (RR = 0.97; 95% CI 0.40–2.35; P = 0.95) between the 2 groups, whereas combination group improves the percent change of hip BMD at 1 year (MD = 1.16, 95% CI 0.56–1.76; P < 0.01) than PTH analogues group. Our results showed that there was no evidence for the superiority of combination therapy, although significant change was found for hip BMD at 1 year in combination group. Further large multicenter randomized controlled trials are still needed to investigate the efficacy of combination therapy. PMID:26402797

  14. Cancer Diagnostics via Ultrasensitive Multiplexed Detection of Parathyroid Hormone-Related Peptides with a Microfluidic Immunoarray.

    PubMed

    Otieno, Brunah A; Krause, Colleen E; Jones, Abby L; Kremer, Richard B; Rusling, James F

    2016-09-20

    Parathyroid hormone-related peptide (PTHrP) is recognized as the major causative agent of humoral hypercalcemia of malignancy (HHM). The paraneoplastic PTHrP has also been implicated in tumor progression and metastasis of many human cancers. Conventional PTHrP detection methods like immunoradiometric assay (IRMA) lack the sensitivity required to measure target peptide levels prior to the development of hypercalcemia. In general, sensitive, multiplexed peptide measurement by immunoassay represents challenges that we address in this paper. We describe here the first ultrasensitive multiplexed peptide assay to measure intact PTHrP 1-173 as well as circulating N-terminal and C-terminal peptide fragments. This versatile approach should apply to almost any collection of peptides that are long enough to present binding sites for two antibodies. To target PTHrP, we employed a microfluidic immunoarray featuring a chamber for online capture of the peptides from serum onto magnetic beads decorated with massive numbers of peptide-specific antibodies and enzyme labels. Magnetic bead-peptide conjugates were then washed and sent to a detection chamber housing an antibody-modified 8-electrode array fabricated by inkjet printing of gold nanoparticles. Limits of detection (LODs) of 150 aM (∼1000-fold lower than IRMA) in 5 μL of serum were achieved for simultaneous detection of PTHrP isoforms and peptide fragments in 30 min. Good correlation for patient samples was found with IRMA (n = 57); r(2) = 0.99 assaying PTHrP 1-86 equiv fragments. Analysis by a receiver operating characteristic (ROC) plot gave an area under the curve of 0.96, 80-83% clinical sensitivity, and 96-100% clinical specificity. Results suggest that PTHrP1-173 isoform and its short C-terminal fragments are the predominant circulating forms of PTHrP. This new ultrasensitive, multiplexed assay for PTHrP and fragments is promising for clinical diagnosis, prognosis, and therapeutic monitoring from early to advanced

  15. Temporal trends and determinants of longitudinal change in 25-hydroxyvitamin D and parathyroid hormone levels.

    PubMed

    Berger, Claudie; Greene-Finestone, Linda S; Langsetmo, Lisa; Kreiger, Nancy; Joseph, Lawrence; Kovacs, Christopher S; Richards, J Brent; Hidiroglou, Nick; Sarafin, Kurtis; Davison, K Shawn; Adachi, Jonathan D; Brown, Jacques; Hanley, David A; Prior, Jerilynn C; Goltzman, David

    2012-06-01

    Vitamin D is essential for facilitating calcium absorption and preventing increases in parathyroid hormone (PTH), which can augment bone resorption. Our objectives were to examine serum levels of 25-hydroxyvitamin D [25(OH)D] and PTH, and factors related to longitudinal change in a population-based cohort. This is the first longitudinal population-based study looking at PTH and 25(OH)D levels. We analyzed 3896 blood samples from 1896 women and 829 men in the Canadian Multicentre Osteoporosis Study over a 10-year period starting in 1995 to 1997. We fit hierarchical models with all available data and adjusted for season. Over 10 years, vitamin D supplement intake increased by 317 (95% confidence interval [CI] 277 to 359) IU/day in women and by 193 (135 to 252) IU/day in men. Serum 25(OH)D (without adjustment) increased by 9.3 (7.3 to 11.4) nmol/L in women and by 3.5 (0.6 to 6.4) nmol/L in men but increased by 4.7 (2.4 to 7.0) nmol/L in women and by 2.7 (-0.6 to 6.2) nmol/L in men after adjustment for vitamin D supplements. The percentage of participants with 25(OH)D levels <50 nmol/L was 29.7% (26.2 to 33.2) at baseline and 19.8% (18.0 to 21.6) at year 10 follow-up. PTH decreased over 10 years by 7.9 (5.4 to 11.3) pg/mL in women and by 4.6 (0.2 to 9.0) pg/mL in men. Higher 25(OH)D levels were associated with summer, younger age, lower body mass index (BMI), regular physical activity, sun exposure, and higher total calcium intake. Lower PTH levels were associated with younger age and higher 25(OH)D levels in both women and men and with lower BMI and participation in regular physical activity in women only. We have observed concurrent increasing 25(OH)D levels and decreasing PTH levels over 10 years. Secular increases in supplemental vitamin D intake influenced both changes in serum 25(OH)D and PTH levels.

  16. Cancer Diagnostics via Ultrasensitive Multiplexed Detection of Parathyroid Hormone-Related Peptides with a Microfluidic Immunoarray

    PubMed Central

    2016-01-01

    Parathyroid hormone-related peptide (PTHrP) is recognized as the major causative agent of humoral hypercalcemia of malignancy (HHM). The paraneoplastic PTHrP has also been implicated in tumor progression and metastasis of many human cancers. Conventional PTHrP detection methods like immunoradiometric assay (IRMA) lack the sensitivity required to measure target peptide levels prior to the development of hypercalcemia. In general, sensitive, multiplexed peptide measurement by immunoassay represents challenges that we address in this paper. We describe here the first ultrasensitive multiplexed peptide assay to measure intact PTHrP 1-173 as well as circulating N-terminal and C-terminal peptide fragments. This versatile approach should apply to almost any collection of peptides that are long enough to present binding sites for two antibodies. To target PTHrP, we employed a microfluidic immunoarray featuring a chamber for online capture of the peptides from serum onto magnetic beads decorated with massive numbers of peptide-specific antibodies and enzyme labels. Magnetic bead-peptide conjugates were then washed and sent to a detection chamber housing an antibody-modified 8-electrode array fabricated by inkjet printing of gold nanoparticles. Limits of detection (LODs) of 150 aM (∼1000-fold lower than IRMA) in 5 μL of serum were achieved for simultaneous detection of PTHrP isoforms and peptide fragments in 30 min. Good correlation for patient samples was found with IRMA (n = 57); r2 = 0.99 assaying PTHrP 1-86 equiv fragments. Analysis by a receiver operating characteristic (ROC) plot gave an area under the curve of 0.96, 80–83% clinical sensitivity, and 96–100% clinical specificity. Results suggest that PTHrP1-173 isoform and its short C-terminal fragments are the predominant circulating forms of PTHrP. This new ultrasensitive, multiplexed assay for PTHrP and fragments is promising for clinical diagnosis, prognosis, and therapeutic monitoring from early to advanced

  17. Temporal trends and determinants of longitudinal change in 25-hydroxyvitamin D and parathyroid hormone levels.

    PubMed

    Berger, Claudie; Greene-Finestone, Linda S; Langsetmo, Lisa; Kreiger, Nancy; Joseph, Lawrence; Kovacs, Christopher S; Richards, J Brent; Hidiroglou, Nick; Sarafin, Kurtis; Davison, K Shawn; Adachi, Jonathan D; Brown, Jacques; Hanley, David A; Prior, Jerilynn C; Goltzman, David

    2012-06-01

    Vitamin D is essential for facilitating calcium absorption and preventing increases in parathyroid hormone (PTH), which can augment bone resorption. Our objectives were to examine serum levels of 25-hydroxyvitamin D [25(OH)D] and PTH, and factors related to longitudinal change in a population-based cohort. This is the first longitudinal population-based study looking at PTH and 25(OH)D levels. We analyzed 3896 blood samples from 1896 women and 829 men in the Canadian Multicentre Osteoporosis Study over a 10-year period starting in 1995 to 1997. We fit hierarchical models with all available data and adjusted for season. Over 10 years, vitamin D supplement intake increased by 317 (95% confidence interval [CI] 277 to 359) IU/day in women and by 193 (135 to 252) IU/day in men. Serum 25(OH)D (without adjustment) increased by 9.3 (7.3 to 11.4) nmol/L in women and by 3.5 (0.6 to 6.4) nmol/L in men but increased by 4.7 (2.4 to 7.0) nmol/L in women and by 2.7 (-0.6 to 6.2) nmol/L in men after adjustment for vitamin D supplements. The percentage of participants with 25(OH)D levels <50 nmol/L was 29.7% (26.2 to 33.2) at baseline and 19.8% (18.0 to 21.6) at year 10 follow-up. PTH decreased over 10 years by 7.9 (5.4 to 11.3) pg/mL in women and by 4.6 (0.2 to 9.0) pg/mL in men. Higher 25(OH)D levels were associated with summer, younger age, lower body mass index (BMI), regular physical activity, sun exposure, and higher total calcium intake. Lower PTH levels were associated with younger age and higher 25(OH)D levels in both women and men and with lower BMI and participation in regular physical activity in women only. We have observed concurrent increasing 25(OH)D levels and decreasing PTH levels over 10 years. Secular increases in supplemental vitamin D intake influenced both changes in serum 25(OH)D and PTH levels. PMID:22407786

  18. Vitamin D and parathyroid hormone status in a representative population living in Macau, China.

    PubMed

    Ke, L; Mason, R S; Mpofu, E; Dibley, M; Li, Y; Brock, K E

    2015-04-01

    Associations between documented sun-exposure, exercise patterns and fish and supplement intake and 25-hydroxyvitamin D (25OHD) and parathyroid hormone (PTH) were investigated in a random household survey of Macau residents (aged 18-93). Blood samples (566) taken in summer were analyzed for 25OHD and PTH. In this Chinese population, 55% were deficient (25OHD <50nmol/L: median (interquartile range)=47.7 (24.2) nmol/L). Vitamin D deficiency was greatest in those aged <50 years: median (interquartile range)=43.3 (18.2) nmol/L, females: median (interquartile range)=45.5 (19.4) nmol/L and those with higher educational qualifications: median (interquartile range)=43.1 (18.7) nmol/L. In the total Macau population, statistically significant (p<0.01) modifiable associations with lower 25OHD levels were sunlight exposure (β=0.06), physical activity (PA) (measured as hours(hrs)/day: β=0.08), sitting (measured as hrs/day β=-0.20), intake of fish (β=0.08) and calcium (Ca) supplement intake (β=0.06) [linear regression analysis adjusting for demographic risk factors]. On similar analysis, and after adjustment for 25OHD, the only significant modifiable associations in the total population with PTH were sitting (β=-0.17), Body Mass Index (β=0.07) and Ca supplement intake (β=-0.06). In this Macau population less documented sun exposure, fish and Ca supplement intake and exercise were associated with lower 25OHD levels, especially in the younger population, along with the interesting finding that more sitting was associated with both lower 25OHD and high PTH blood levels. In conclusion, unlike findings from Caucasian populations, younger participants were significantly more vitamin D deficient, in particular highly educated single females. This may indicate the desire of young females to be pale and avoid the sun. There are also big differences in lifestyle between the older generation and the younger, in particular with respect to sun exposure and PA. This article is part of

  19. Role of paraoxonase-1 in bone anabolic effects of parathyroid hormone in hyperlipidemic mice

    SciTech Connect

    Lu, Jinxiu; Cheng, Henry; Atti, Elisa; Shih, Diana M.; Demer, Linda L.; Tintut, Yin

    2013-02-01

    Highlights: ► Anabolic effects of PTH were tested in hyperlipidemic mice overexpressing PON1. ► Expression of antioxidant regulatory genes was induced in PON1 overexpression. ► Bone resorptive activity was reduced in PON1 overexpressing hyperlipidemic mice. ► PON1 restored responsiveness to intermittent PTH in bones of hyperlipidemic mice. -- Abstract: Hyperlipidemia blunts anabolic effects of intermittent parathyroid hormone (PTH) on cortical bone, and the responsiveness to PTH are restored in part by oral administration of the antioxidant ApoA-I mimetic peptide, D-4F. To evaluate the mechanism of this rescue, hyperlipidemic mice overexpressing the high-density lipoprotein-associated antioxidant enzyme, paraoxonase 1 (Ldlr{sup −/−}PON1{sup tg}) were generated, and daily PTH injections were administered to Ldlr{sup −/−}PON1{sup tg} and to littermate Ldlr{sup −/−} mice. Expression of bone regulatory genes was determined by realtime RT-qPCR, and cortical bone parameters of the femoral bones by micro-computed tomographic analyses. PTH-treated Ldlr{sup −/−}PON1{sup tg} mice had significantly greater expression of PTH receptor (PTH1R), activating transcription factor-4 (ATF4), and osteoprotegerin (OPG) in femoral cortical bone, as well as significantly greater cortical bone mineral content, thickness, and area in femoral diaphyses compared with untreated Ldlr{sup −/−}PON1{sup tg} mice. In contrast, in control mice (Ldlr{sup −/−}) without PON1 overexpression, PTH treatment did not induce these markers. Calvarial bone of PTH-treated Ldlr{sup −/−}PON1{sup tg} mice also had significantly greater expression of osteoblastic differentiation marker genes as well as BMP-2-target and Wnt-target genes. Untreated Ldlr{sup −/−}PON1{sup tg} mice had significantly greater expression of PTHR1 than untreated Ldlr{sup −/−} mice, whereas sclerostin expression was reduced. In femoral cortical bones, expression levels of transcription factors, Fox

  20. Influence of daily regimen calcium and vitamin D supplementation on parathyroid hormone secretion.

    PubMed

    Reginster, J-Y; Zegels, B; Lejeune, E; Micheletti, M C; Kvsaz, A; Seidel, L; Sarlet, N

    2002-02-01

    Calcium and vitamin D supplementation has been shown to reduce secondary hyperparathyroidism and play a role in the management of senile osteoporosis. In order to define the optimal regimen of calcium and vitamin D supplementation to produce the maximal inhibition of parathyroid hormone secretion, we have compared the administration of a similar amount of Ca and vitamin D, either as a single morning dose or split in two doses, taken 6 hours apart. Twelve healthy volunteers were assigned to three investigational procedures, at weekly intervals. After a blank control procedure, when they were not exposed to any drug intake, they received two calcium-vitamin D supplement regimens including either two doses of Orocal D3 (500 mg Ca and 400 IU vitamin D) 6 hours apart or one water-soluble effervescent powder pack of Cacit D3 in a single morning dose (1000 mg Ca and 880 IU vitamin D). During the three procedures (control and the two calcium-vitamin D supplementations), venous blood was drawn every 60 minutes for up to 9 hours, for serum Ca and serum PTH measurements. The order of administration of the two Ca and vitamin D supplementation sequences was allocated by randomization. No significant changes in serum Ca were observed during the study. During the 6 hours following Ca and vitamin D supplementation, a statistically significant decrease in serum PTH was observed with both regimens, compared with baseline and with the control procedure. Over this period of time, no differences were observed between the two treatment regimens. However, between the sixth and the ninth hour, serum PTH levels were still significantly decreased compared with baseline with split dose Orocal D3 administration, while they returned to baseline value with the Cacit D3 preparation. During this period, the percentage decrease in serum PTH compared with baseline was significantly more pronounced with Orocal D3 than with Cacit D3 (P = 0.0021). We therefore conclude that the administration of two

  1. The effect of parathyroid hormones on hair follicle physiology: implications for treatment of chemotherapy-induced alopecia.

    PubMed

    Skrok, Anna; Bednarczuk, Tomasz; Skwarek, Agata; Popow, Michał; Rudnicka, Lidia; Olszewska, Małgorzata

    2015-01-01

    Parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP) influence hair follicles through paracrine and intracrine routes. There is significant evidence that PTH and PTHrP influence the proliferation and differentiation of hair follicle cells. The PTH/PTHrP receptor signalling plays an important role in the hair follicle cycle and may induce premature catagen-telogen transition. Transgenic mice with an overexpression or blockade (PTH/PTHrP receptor knockout mice) of PTHrP activity revealed impaired or increased hair growth, respectively. Some findings also suggest that PTHrP may additionally influence the hair cycle by inhibiting angiogenesis. Antagonists of the PTH/PTHrP receptor have been shown to stimulate proliferation of hair follicle cells and hair growth. A hair-stimulating effect of a PTH/PTHrP receptor antagonist applied topically to the skin has been observed in hairless mice, as well as in mice treated with cyclophosphamide. These data indicate that the PTH/PTHrP receptor may serve as a potential target for new (topical) hair growth-stimulating drugs, especially for chemotherapy-induced alopecia.

  2. Parathyroid adenoma

    MedlinePlus

    Hyperparathyroidism - parathryoid adenoma; Overactive parathyroid gland - parathyroid adenoma ... The parathyroid glands in the neck help control calcium use and removal by the body. They do this by producing parathyroid ...

  3. Dexamethasone downregulates the expression of parathyroid hormone-related protein (PTHrP) in mesenchymal stem cells.

    PubMed

    Ahlström, Mikael; Pekkinen, Minna; Lamberg-Allardt, Christel

    2009-02-01

    Parathyroid hormone-related protein (PTHrP) has been shown to have anabolic effects in women with postmenopausal osteoporosis. PTHrP promotes the recruitment of osteogenic cells and prevents apoptotic death of osteoblasts and osteocytes. The receptor responsible for the effects of PTHrP is the common PTH/PTHrP receptor (PTH1R). Glucocorticoids (GC) are commonly used as drugs to treat inflammatory diseases. Long-term GC treatments are often associated with bone loss which can lead to GC-induced osteoporosis. The aim of this work was to study the effects of the glucocorticoid dexamethasone (Dex) on the expression of PTHrP and PTH1R in adult human mesenchymal stem cells, the progenitor cells of osteoblasts. Adult human mesenchymal stem cells (hMSC) were cultured and differentiated by standard methods. The expression of PTHrP and PTH1R mRNA was assayed by real-time qPCR. The PTHrP release into the culture media was measured by an immunoradiometric assay. Treatment with Dex (10 nM) resulted in an 80% drop in the PTHrP release within 6 h. A 24 h Dex treatment also reduced the expression of PTHrP mRNA by up to 90%. The expression of PTH1R receptor mRNA was simultaneously increased up to 20-fold by 10 nM Dex. The effects of Dex on PTHrP and PTH1R were dose-dependent and experiments with the GC-receptor antagonist mifepristone showed an involvement of GC-receptors in these effects. In addition to the Dex-induced effects on PTHrP and PTH1R, Dex also increased mineralization and the expression of the osteoblast markers Runx2 and alkaline phosphatase. In our studies, we show that dexamethasone decreases the expression of PTHrP and increases the expression of the PTH1R receptor. This could have an impact on PTHrP-mediated anabolic actions on bone and could also affect the responsiveness of circulating PTH. The results indicate that glucocorticoids affect the signalling pathway of PTHrP by regulating both PTHrP and PTH1R expression and these mechanisms could be involved in

  4. Evidence of associations between feto-maternal vitamin D status, cord parathyroid hormone and bone-specific alkaline phosphatase, and newborn whole body bone mineral content

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In spite of a high prevalence of vitamin D inadequacy in pregnant women and neonates, relationships among vitamin D status [25(OH)D], parathyroid hormone (PTH), bone specific alkaline phosphatase (BALP), and whole body bone mineral content (WBBMC) in the newborn are poorly characterized. The purpose...

  5. Vitamin D3 decreases parathyroid hormone in HIV-infected youth being treated with tenofovir: a randomized, placebo-controlled trial

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Objective: To determine the effect of vitamin D (VITD) supplementation on tubular reabsorption of phosphate (TRP), serum parathyroid hormone (PTH), bone alkaline phosphatase (BAP), and C telopeptide (CTX) in HIV-infected youth receiving and not receiving tenofovir-containing cART (TDF). Design: Ra...

  6. An inflection point of serum 25-hydroxyvitamin D for maximal suppression of parathyroid hormone is not evident from multi-site pooled data in children and adolescents

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In adults, maximal suppression of serum parathyroid hormone (PTH) has commonly been used to determine the sufficiency of serum 25-hydroxyvitamin D [25(OH) D]. In children and adolescents, the relationship between serum 25(OH) D and PTH is less clear, and most studies reporting a relationship are der...

  7. Three-Phase Model Harmonizes Estimates of the Maximal Suppression of Parathyroid Hormone by 25-Hydroxyvitamin D in Persons 65 Years of Age and Older 1–3

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The concentration or threshold of 25-hydroxyvitamin D [25(OH)D] needed to maximally suppress intact serum parathyroid hormone (iPTH) has been suggested as a measure of optimal vitamin D status. Depending upon the definition of maximal suppression of iPTH and the 2-phase regression approach used, 2 d...

  8. Correlation of vitamin D, bone mineral density and parathyroid hormone levels in adults with low bone density

    PubMed Central

    Kota, Sunil; Jammula, Sruti; Kota, Siva; Meher, Lalit; Modi, Kirtikumar

    2013-01-01

    Background: Bone mineral densiy (BMD) is known to be affected by serum 25-hydroxyvitamin D (25(OH) D) levels, intact parathyroid hormone (iPTH) levels. Indian data pertinent to above observation is scant. Our study aimed to investigate the relationships between serum 25-hydroxyvitamin D (25(OH) D) levels, intact parathyroid hormone (iPTH) levels and bone mineral density (BMD) in a cohort of Indian patients. Materials and Methods: Adults with or without fragility fractures with low BMD at the hip or lumbar spine were evaluated clinically along with laboratory investigations. T-scores of the hip and spine were derived from BMD-DEXA (dual-energy X-ray absorptiometry). Multivariate regression models were used to investigate the relationships between serum 25(OH) D, iPTH and BMD. Results: Total of 102 patients (male:female = 38:64) with a mean age of 62.5 ± 6.4 years were included in the study. Forty-four patients had osteopenia. Osteoporosis was present in 58 patients. The mean values for serum 25(OH) D and iPTH levels were 21.3 ± 0.5 ng/ml and 53.1 ± 22.3 pg/ml, respectively. In 84.3% of patients, serum 25(OH) D levels were below 30 ng/ml (Normal = 30-74 ng/ml), confirming vitamin D deficiency. There was no association between 25(OH) D levels and BMD at the hip or lumbar spine (P = 0.473 and 0.353, respectively). Both at the hip and lumbar spine; iPTH levels, male gender, body mass index (BMI) and age were found to be significant predictors of BMD. Patients with higher BMI had significantly lower BMD and T-score. At levels <30 ng/ml, 25(OH) D was negatively associated with iPTH (P = 0.041). Conclusion: Among our cohort of patients with low BMD, no direct relationship between serum 25(OH) D levels and BMD was observed. However, a negative correlation between iPTH and 25(OH) D at serum 25(OH) D concentrations <30 ng/ml. Serum iPTH levels showed a significant negative association with BMD at the hip and lumbar spine. Our findings underscore the critical role of

  9. Effects of maintenance lithium treatment on serum parathyroid hormone and calcium levels: a retrospective longitudinal naturalistic study

    PubMed Central

    Albert, Umberto; De Cori, David; Aguglia, Andrea; Barbaro, Francesca; Lanfranco, Fabio; Bogetto, Filippo; Maina, Giuseppe

    2015-01-01

    Objective The aim of this retrospective longitudinal naturalistic study was to evaluate the effects of maintenance lithium treatment on parathyroid hormone (PTH) and calcium levels. Methods A retrospective longitudinal naturalistic study design was used. Data were collected from the database of a tertiary psychiatric center covering the years 2010–2014. Included were bipolar patients who had never been exposed to lithium and had lithium started, and who had PTH, and total and ionized calcium levels available before and during lithium treatment. Paired t-tests were used to analyze changes in PTH and calcium levels. Linear regressions were performed, with mean lithium level and duration of lithium exposure as independent variables and change in PTH levels as dependent variable. Results A total 31 patients were included. The mean duration of lithium treatment was 18.6±11.4 months. PTH levels significantly increased during lithium treatment (+13.55±14.20 pg/mL); the rate of hyperparathyroidism was 12.9%. Neither total nor ionized calcium increased from baseline to follow-up; none of our patients developed hypercalcemia. Linear regressions analyses did not show an effect of duration of lithium exposure or mean lithium level on PTH levels. Conclusion Lithium-associated stimulation of parathyroid function is more common than assumed to date. Among parameters to be evaluated prior to lithium implementation, calcium and PTH should be added. PMID:26229473

  10. Regulation of parathyroid hormone gene expression by hypocalcemia, hypercalcemia, and vitamin D in the rat.

    PubMed Central

    Naveh-Many, T; Silver, J

    1990-01-01

    In vivo in the rat 1,25(OH)2D3 decreases and a low calcium increases PTH mRNA levels. We now report the effect of 3 and 8 wk of changes in dietary vitamin D and calcium on PTH mRNA levels. PTH mRNA levels were increased by 3 wk of calcium deficiency (five times), a vitamin D-deficient diet (two times), and combined deficiency (10 times), but not changed by high calcium. Vitamin D-deficient-diet rats' PTH mRNA did not decrease after a single large dose of 1,25(OH)2D3, but did decrease partially after repeated daily doses of 1,25(OH)2D3. Rats after a vitamin D-, calcium-deficient (-D-Ca) diet did not respond to changes in serum calcium at 1 h. Flow cytometry of isolated cells from parathyroid-thyroid tissue separated the smaller parathyroid from the larger thyroid cells and allowed an analysis of parathyroid cell number. In normal vitamin D/normal calcium (NDNCa) rats the parathyroid cells were 24.7 +/- 3.4% (n = 6) of the total cell number, whereas in -D-Ca rats they were 41.8 +/- 6.6% (n = 6) (P less than 0.05). That is, -D-Ca rats had 1.7 times the number of cells, whereas they had 10 times the amount of PTH mRNA, indicating the major contribution (6 times) of increased PTH gene expression per cell. Moreover, a calcium-deficient, more so than a vitamin D-deficient diet, amplifies the expression of the PTH gene, and vitamin D is necessary for an intact response of PTH mRNA to 1,25(OH)2D3 or calcium. Images PMID:2212016

  11. Nonfunctional parathyroid carcinoma.

    PubMed Central

    Giessler, G. A.; Beech, D. J.

    2001-01-01

    Parathyroid carcinoma is a rare entity accounting for 0.5% to 5% of parathyroid neoplasia. Most of these malignancies present as functional hormone-producing masses with elevated serum levels of parathormone and calcium. These tumors may also be nonfunctional. Clinical detection of nonfunctioning parathyroid malignancies preoperatively is primarily based on symptoms of an expanding neck mass. This ominous complaint is typically accompanied with an advanced stage of the disease at initial diagnosis. Because there is a paucity of data in the literature regarding nonfunctioning parathyroid carcinoma, prognosis can not be readily assessed. In both functional and nonfunctional parathyroid carcinoma, early surgery has proven to be the only curative treatment approach whereas both chemotherapy and radiation therapy fail to produce systemic or regional benefit when used alone. Hence, parathyroid cancer should be considered in every patient evaluated for a neck mass regardless of the blood calcium and blood parathormone level. PMID:11491274

  12. Antagonist minigenes identify genes regulated by parathyroid hormone through G protein-selective and G protein co-regulated mechanisms in osteoblastic cells.

    PubMed

    Wang, J; Gilchrist, A; Stern, P H

    2011-02-01

    Parathyroid hormone (PTH) is the major hormone regulating bone remodeling. Binding of PTH to the PTH1 receptor (PTH1R), a heterotrimeric G protein coupled receptor (GPCR), can potentially trigger multiple signal transduction pathways mediated through several different G proteins. In this study, we employed G protein antagonist minigenes inhibiting Gα(s), Gα(q) or Gα₁₂ to selectively dissect out which of these G proteins were responsible for effects of PTH(1-34) in targeted signaling and osteogenesis arrays consisting of 159 genes. Among the 32 genes significantly regulated by 24h PTH treatment in UMR-106 osteoblastic cells, 9 genes were exclusively regulated through G(s), 6 genes were solely mediated through G(q), and 3 genes were only controlled through G₁₂. Such findings support the concept that there is some absolute specificity in downstream responses initiated at the G protein level following binding of PTH to the PTH1R. On the other hand, 6 PTH-regulated genes were regulated by both G(s) and G(q), 3 genes were regulated by both G(s) and G₁₂, and 3 genes were controlled by G(s), G(q) and G₁₂. These findings indicate potential overlapping or sequential interactions among different G protein-mediated pathways. In addition, two PTH-regulated genes were not regulated through any of the G proteins examined, suggesting that additional signaling mechanisms may be involved. Selectivity was largely maintained over a 2-48-hour time period. The minigene effects were mimicked by downstream inhibitors. The dissection of the differential effects of multiple G protein pathways on gene regulation provides a more complete understanding of PTH signaling in osteoblastic cells.

  13. The roles of parathyroid hormone in bone remodeling: prospects for novel therapeutics.

    PubMed

    Lombardi, G; Di Somma, C; Rubino, M; Faggiano, A; Vuolo, L; Guerra, E; Contaldi, P; Savastano, S; Colao, A

    2011-07-01

    The aim of this review is to focus on the roles of PTH in bone remodeling. PTH plays a central role in regulating calcium-phosphate metabolism and its production increases in response to low serum calcium levels. A continue hypersecretion of PTH, as occurs in primary hyperparathyroidism, leads to bone resorption. On the other hand, there is clear evidence of the anabolic properties of PTH.When administered at a low dose and intermittently, this hormone seems to be able to exert positive effects on bone volume and microarchitecture. The effects of PTH are mediated by PTH/PTH-related protein receptor, a G protein that can activate the cAMP-dependent protein kinase (PK)A and calcium-dependent PKC; the activation of PKA account for most of the PTH anabolic action. The anabolic actions of PTH involve direct effects on osteoblasts and indirect effects mediated by activation of skeletal growth factors (IGF-I) and inhibition of growth factor antagonists, such as sclerostin. PTH enhances the number and the activation of osteoblast through 4 pathways: increasing osteoblast proliferation and differentiation, decreasing osteoblast apoptosis and reducing the negative effects of peroxisome proliferator activator (PPAR)γ receptor on osteoblast differentiation. Moreover PTH enhances the Wnt-β catenin pathway, that is central to osteogenesis and bone formation, inhibiting sclerostin. Finally, PTH induces the synthesis of IGF-I and, due to its prodifferentiating and pro-survival effects on osteoblasts, this could be a key mediator of PTH effect on osteoblasts. In conclusion, the intermittent administration of PTH has a pleiotropic anabolic effect on bone; further studies about mechanisms of action of PTH could be a starting point to new osteoporosis treatments. PMID:21985975

  14. A rare complication of transitional cell carcinoma of the renal pelvis: parathyroid hormone-related peptide-induced hypercalcaemia.

    PubMed

    O Sullivan, Eoin; Plant, William

    2014-01-01

    We describe a rare occurrence of parathyroid hormone-related peptide (PTHrp) associated hypercalcaemia with a recurrence of transitional cell carcinoma of the renal pelvis. Our patient presented with serum calcium of 3.9 mmol/L, PTH of 5 ng/L and a PTHrp of 9.8 pmol/L (<2 pmol/L). He had no evidence of metastatic disease. His hypercalcaemia responded to bisphosphonate therapy. He chose to be treated conservatively and died 5 weeks after presentation. This is the seventh such case described in the literature. PTHrp-induced hypercalcaemia is associated with a grave prognosis, with a mean survival of 65 days from presentation. PMID:24951595

  15. Alterations in vitamin D metabolite, parathyroid hormone and fibroblast growth factor-23 concentrations in sclerostin-deficient mice permit the maintenance of a high bone mass.

    PubMed

    Ryan, Zachary C; Craig, Theodore A; McGee-Lawrence, Meghan; Westendorf, Jennifer J; Kumar, Rajiv

    2015-04-01

    Humans with mutations of the sclerostin (SOST) gene, and knockout animals in which the Sost gene has been experimentally deleted, exhibit an increase in bone mass. We review the mechanisms by which Sost knockout mice are able to accrete increased amounts of calcium and phosphorus required for the maintenance of a high bone mass. Recently published information from our laboratory, shows that bone mass is increased in Sost-deficient mice through an increase in osteoblast and a decrease in osteoclast activity, which is mediated by activation of β-catenin and an increase in prostacyclin synthesis in osteocytes and osteoblasts. The increases in calcium and phosphorus retention required for enhanced bone mineral accretion are brought about by changes in the vitamin D endocrine system, parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF-23). Thus, in Sost knockout mice, concentrations of serum 1,25-dihydroxyvitamin D (1,25(OH)2D) are increased and concentrations of FGF-23 are decreased thereby allowing a positive calcium and phosphorus balance. Additionally, in the absence of Sost expression, urinary calcium is decreased, either through a direct effect of sclerostin on renal calcium handling, or through its effect on the synthesis of 1,25(OH)2D. Adaptations in vitamin D, PTH and FGF-23 physiology occur in the absence of sclerostin expression and mediate increased calcium and phosphorus retention required for the increase in bone mineralization. This article is part of a Special Issue entitled '17th Vitamin D Workshop'.

  16. ATF936, a novel oral calcilytic, increases bone mineral density in rats and transiently releases parathyroid hormone in humans.

    PubMed

    John, Markus R; Widler, Leo; Gamse, Rainer; Buhl, Thomas; Seuwen, Klaus; Breitenstein, Werner; Bruin, Gerard J M; Belleli, Rossella; Klickstein, Lloyd B; Kneissel, Michaela

    2011-08-01

    Parathyroid hormone (PTH), when injected daily as either the intact hormone PTH(1-84) or the active fragment PTH(1-34) (teriparatide), is an efficacious bone anabolic treatment option for osteoporosis patients. Injections lead to rapid and transient spikes in hormone exposure levels, a profile which is a prerequisite to effectively form bone. Oral antagonists of the calcium-sensing receptor (calcilytics) stimulate PTH secretion and represent thus an alternative approach to elevate hormone levels transiently. We report here on ATF936, a novel calcilytic, which triggered rapid, transient spikes in endogenous PTH levels when given orally in single doses of 10 and 30mg/kg to growing rats, and of 1mg/kg to dogs. Eight weeks daily oral application of 30mg/kg of ATF936 to aged female rats induced in the proximal tibia metaphysis increases in bone mineral density, cancellous bone volume and cortical and trabecular thickness as evaluated by computed tomography. In healthy humans, single oral doses of ATF936 produced peak PTH levels in plasma after a median time of 1h and levels returned to normal at 24-h post-dose. The average maximum PTH concentration increase from baseline was 1.9, 3.6, and 6.0-fold at doses of 40, 70, and 140mg. ATF936 was well tolerated. The sharp, transient increase in PTH levels produced by the oral calcilytic ATF936 was comparable to the PTH profile observed after subcutaneous administration of teriparatide. In conclusion, ATF936 might hold potential as an oral bone-forming osteoporosis therapy.

  17. Parathyroid hormone (PTH)/PTH-related peptide type 1 receptor (PPR) signaling in osteocytes regulates anabolic and catabolic skeletal responses to PTH.

    PubMed

    Saini, Vaibhav; Marengi, Dean A; Barry, Kevin J; Fulzele, Keertik S; Heiden, Erica; Liu, Xiaolong; Dedic, Christopher; Maeda, Akira; Lotinun, Sutada; Baron, Roland; Pajevic, Paola Divieti

    2013-07-12

    Parathyroid hormone (PTH) is the only Food and Drug Administration-approved anabolic agent to treat osteoporosis; however, the cellular targets of PTH action in bone remain controversial. PTH modulates bone turnover by binding to the PTH/PTH-related peptide (PTHrP) type 1 receptor (PPR), a G-protein-coupled receptor highly expressed in bone and kidneys. Osteocytes, the most abundant cells in adult bone, also express PPR. However, the physiological relevance of PPR signaling in osteocytes remains to be elucidated. Toward this goal, we generated mice with PPR deletion in osteocytes (Ocy-PPRKO). Skeletal analysis of these mice revealed a significant increase in bone mineral density and trabecular and cortical bone parameters. Osteoblast activities were reduced in these animals, as demonstrated by decreased collagen type I α1 mRNA and receptor activator of NF-κB ligand (RANKL) expression. Importantly, when subjected to an anabolic or catabolic PTH regimen, Ocy-PPRKO animals demonstrated blunted skeletal responses. PTH failed to suppress SOST/Sclerostin or induce RANKL expression in Ocy-PPRKO animals compared with controls. In vitro, osteoclastogenesis was significantly impaired in Ocy-PPRKO upon PTH administration, indicating that osteocytes control osteoclast formation through a PPR-mediated mechanism. Taken together, these data indicate that PPR signaling in osteocytes is required for bone remodeling, and receptor signaling in osteocytes is needed for anabolic and catabolic skeletal responses.

  18. Role of parathyroid hormone-related protein in the pro-inflammatory and pro-fibrogenic response associated with acute pancreatitis

    PubMed Central

    Bhatia, Vandanajay; Kim, Sung O.K.; Aronson, Judith F.; Chao, Celia; Hellmich, Mark R.; Falzon, Miriam

    2012-01-01

    Pancreatitis is a common and potentially lethal necro-inflammatory disease with both acute and chronic manifestations. Current evidence suggests that the accumulated damage incurred during repeated bouts of acute pancreatitis (AP) can lead to chronic disease, which is associated with an increased risk of pancreatic cancer. While parathyroid hormone-related protein (PTHrP) exerts multiple effects in normal physiology and disease states, its function in pancreatitis has not been previously addressed. Here we show that PTHrP levels are transiently elevated in a mouse model of cerulein-induced AP. Treatment with alcohol, a risk factor for both AP and chronic pancreatitis (CP), also increases PTHrP levels. These effects of cerulein and ethanol are evident in isolated primary acinar and stellate cells, as well as in the immortalized acinar and stellate cell lines AR42J and irPSCc3, respectively. Ethanol sensitizes acinar and stellate cells to the PTHrP-modulating effects of cerulein. Treatment of acinar cells with PTHrP (1-36) increases expression of the inflammatory mediators interleukin-6 (IL-6) and intracellular adhesion protein (ICAM-1), suggesting a potential autocrine loop. PTHrP also increases apoptosis in AR42J cells. Stellate cells mediate the fibrogenic response associated with pancreatitis; PTHrP (1-36) increases procollagen I and fibronectin mRNA levels in both primary and immortalized stellate cells. The effects of cerulein and ethanol on levels of IL-6 and procollagen I are suppressed by the PTH1R antagonist, PTHrP (7-34). Together these studies identify PTHrP as a potential mediator of the inflammatory and fibrogenic responses associated with alcoholic pancreatitis. PMID:22280800

  19. [Chronic kidney disease (CKD) and bone. Targets of serum calcium, phosphate, and parathyroid hormone levels and their controls in maintenance dialysis patients].

    PubMed

    Akiba, Takashi

    2009-04-01

    Introduction of CKD-MBD changed clinical attitudes for the therapy of metabolic bone disease in maintenance dialysis therapy as the systemic diseases of calcium phosphate metabolism. We present the variation of target serum calcium, phosphate and parathyroid hormone levels in the guidelines of US and European countries. We also review the management of drug use especially concomitant active vitamin D metabolites and calcium carbonate to cinacalcet prescription.

  20. Serum parathyroid hormone (PTH) in pregnant women determined by an immunoradiometric assay for intact PTH

    SciTech Connect

    Davis, O.K.; Hawkins, D.S.; Rubin, L.P.; Posillico, J.T.; Brown, E.M.; Schiff, I.

    1988-10-01

    Most studies of circulating PTH levels using traditional RIAs have supported the concept of physiological hyperparathyroidism of pregnancy, with pregnant women having serum immunoreactive PTH levels significantly higher than those in nonpregnant subjects. However, such RIAs are insensitive and often detect inactive PTH fragments, so that the correlation between PTH immunoreactivity and bioactivity is poor. Employing a new intact PTH immunoradiometric assay (Allegro-Nichols), we reassessed the effects of pregnancy on parathyroid function. The mean serum PTH level in 81 pregnant women was 14.4 +/- 6.3 (+/- SD) compared to 24.8 +/- 9.0 ng/L in 11 normally cycling nonpregnant women (P less than 0.001). The mean serum total and ionized calcium levels in the 2 groups were similar. In 5 of the pregnant women, serum bioactive PTH, determined by cytochemical bioassay, was slightly lower (7.7 +/- 3.4 ng/L) than in normal individuals (11.1 +/- 1.9 ng/L). Our findings suggest, in contrast with the results of most previous studies, that serum intact PTH may decline during pregnancy.

  1. Gata3 cooperates with Gcm2 and MafB to activate parathyroid hormone gene expression by interacting with SP1.

    PubMed

    Han, Song-Iee; Tsunekage, Yukino; Kataoka, Kohsuke

    2015-08-15

    Haploinsufficiency of the Gata3 gene, which encodes a zinc-finger transcription factor, is associated with the disorder hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome in humans. However, the roles of Gata3 in transcriptional regulation in the parathyroid glands are not well-understood. In this study, we show that Gata3 activates transcription of parathyroid hormone (PTH), which is secreted from parathyroid glands and is critical for regulating serum calcium and phosphate homeostasis. Gata3 interacted with Gcm2 and MafB, two known transcriptional regulators of parathyroid development, and synergistically stimulated the PTH promoter. An SP1-binding element (GC box) located within the PTH-promoter proximal region was critical for activating transcription by Gata3. In addition, the ubiquitous transcription factor SP1 also interacted with Gata3 as well as MafB and Gcm2, and HDR syndrome-associated Gata3 mutants were defective in activating the PTH promoter. These results suggest that Gata3 is a critical regulator of PTH gene expression. PMID:25917456

  2. Osseous Consolidation of an Aseptic Delayed Union of a Lower Leg Fracture after Parathyroid Hormone Therapy – A Case Report

    PubMed Central

    Radmer, Sebastian; Andresen, Reimer; Schober, Hans-Christof

    2016-01-01

    The absence of osseous consolidation of a fracture within the normal time period is defined as delayed union or non-union. Both for the patient and from a socio-economic point of view, impaired fracture healing represents a major problem. Risk factors for a delayed fracture healing are insufficient immobilisation, poor adaptation of the fracture surfaces, interposition of soft tissue in the fracture gap, as well as circulation disturbances, metabolic disease, smoking and infections. In animal studies, a positive effect of parathyroid hormone (PTH) on fracture healing has been shown. PTH has a direct stimulatory effect on osteoblasts and osteoclasts. In addition, it appears to influence the effect of osseous growth factors. Few cases with the empiric off-label use of PTH that showed a tendency to support delayed or non-union fractures have been published. We report about a patient with a fracture of the lower leg and no osseous consolidation after 7 months. Four Months after therapy with 20 μg teriparatide per day for 8 weeks the fracture was consolidated and the patient had regained full and pain free weight bearing capacity of the leg with no reported side effects. PMID:27630919

  3. Polyamine and differentiation: induction of ornithine decarboxylase by parathyroid hormone is a good marker of differentiated chondrocytes.

    PubMed Central

    Takigawa, M; Ishida, H; Takano, T; Suzuki, F

    1980-01-01

    The activity of ornithine decarboxylase (OD-Case:L-ornithine carboxy-lyase, EC 4.1.1.17) in rabbit costal chondrocytes in culture increased markedly after addition of parathyroid hormone (PTH), reaching a maximum 4 to 5 hr after PTH addition. The increase in ODCase activity was followed by increase in the intracellular concentrations of polyamines, especially putrescine, which increased in 6 hr to about 3-fold that of untreated cultures. The induction of ODCase by PTH was not observed in L, 3T3, HeLa, buffalo rat liver, or BHK cells. Retinyl acetate and retinoic acid both inhibited expression of the differentiated phenotype of chondrocytes by rabbit costal chondrocytes in culture within 3 days after their addition, as judged by morphological change and decrease in sulfate incorporation into glycosaminoglycans but did not inhibit cell proliferation. PTH could not induce an increase in ODCase in de-differentiated cells that had been pretreated with retinyl acetate or retinoic acid for 3 days. but 4 days after removal of the retinoids, these de-differentiated cells regained the ability to synthesize ODCase in response to PTH. These facts suggest that the induction of ODCase and the formation of putrescine by PTH are good markers of the differentiated phenotype of cultured chondrocytes. Images PMID:6929498

  4. A sensitive electrochemical sensor for in vitro detection of parathyroid hormone based on a MoS2-graphene composite

    NASA Astrophysics Data System (ADS)

    Kim, Hyeong-U.; Kim, Hye Youn; Kulkarni, Atul; Ahn, Chisung; Jin, Yinhua; Kim, Yeongseok; Lee, Kook-Nyung; Lee, Min-Ho; Kim, Taesung

    2016-10-01

    This paper reports a biosensor based on a MoS2-graphene (MG) composite that can measure the parathyroid hormone (PTH) concentration in serum samples from patients. The interaction between PTH and MG was analysed via an electrochemical sensing technique. The MG was functionalized using L-cysteine. Following this, PTH could be covalently immobilized on the MG sensing electrode. The properties of MG were evaluated using scanning electron microscopy, high-resolution transmission electron microscopy, X-ray diffraction, Raman spectroscopy, X-ray photoelectron spectroscopy, and Fourier transform infrared spectrometry. Following optimization of immobilized materials—such as MG, PTH, and alkaline phosphatase (ALP)—the performance of the MG sensor was investigated via cyclic voltammetry, to assess its linearity, repeatability, and reproducibility. Electrochemical impedance spectroscopy was performed on graphene oxide (GO) and MG-modified electrodes to confirm the capture of a monoclonal antibody (MAb) targeting PTH. Furthermore, the ALP-PTH-MG sensor exhibits a linear response towards PTH from artificial serum over a range of 1–50 pg mL‑1. Moreover, patient sera (n = 30) were evaluated using the ALP-PTH-MG sensor and compared using standard equipment (Roche E 170). The P-value is less than 0.01 when evaluated with a t-test using Welch’s correction. This implies that the fabricated sensor can be deployed for medical diagnosis.

  5. Oral phosphorus supplementation secondarily increases circulating fibroblast growth factor 23 levels at least partially via stimulation of parathyroid hormone secretion.

    PubMed

    Takasugi, Satoshi; Akutsu, Miho; Nagata, Masashi

    2014-01-01

    Oral phosphorus supplementation stimulates fibroblast growth factor 23 (FGF23) secretion; however, the underlying mechanism remains unclear. The aim of this study was to investigate the involvement of parathyroid hormone (PTH) in increased plasma FGF23 levels after oral phosphorus supplementation in rats. Rats received single dose of phosphate with concomitant subcutaneous injection of saline or human PTH (1-34) after treatment with cinacalcet or its vehicle. Cinacalcet is a drug that acts as an allosteric activator of the calcium-sensing receptor and reduces PTH secretion. Plasma phosphorus and PTH levels significantly increased 1 h after oral phosphorus administration and returned to basal levels within 3 h, while plasma FGF23 levels did not change up to 2 h post-treatment, but rather significantly increased at 3 h after administration and maintained higher levels for at least 6 h compared with the 0 time point. Plasma PTH and FGF23 levels were significantly lower in the cinacalcet-treated rats than in the vehicle-treated rats. Plasma phosphorus levels were significantly higher in the cinacalcet-treated rats than in the vehicle-treated rats at 2, 3, 4, and 6 h after oral phosphorus administration. Furthermore, rats treated with cinacalcet+human PTH (1-34) showed transiently but significantly higher plasma FGF23 levels at 3 h after oral phosphorus administration compared with cinacalcet-treated rats. These results suggest that oral phosphorus supplementation secondarily increases circulating FGF23 levels at least partially by stimulation of PTH secretion.

  6. Impacts of the N-terminal fragment analog of human parathyroid hormone on structure, composition and biomechanics of bone.

    PubMed

    Chunxiao, Wang; Yu, Zhang; Wentao, Liu; Jingjing, Liu; Jiahui, Ye; Qingmei, Chen

    2012-12-18

    Osteoporosis is a skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, and it is a serious threat to human lives. We previously showed that the N-terminal peptide analog of human parathyroid hormone (Pro-Pro-PTH(1-34)) enhanced plasma calcium concentration. In this paper, we study the impact of PTH N-terminal fragment analog on the structure, component, and mechanical properties of the rat bones. Daily subcutaneous injections of Pro-Pro-hPTH (1-34) induces 26.5-32.8% increase in femur bone mineral density (BMD), 23.0-34.2% decrease the marrow cavity or increase in trabecular bone area. The peptide also increases 16.0-59.5%, 28.8-48.2% and 14.0-17.8% of bone components of calcium, phosphorus and collagen, respectively. In terms of mechanic properties, administration of the peptide elevates the bone rigidity by 45.4-76.6%, decreases the flexibility by 23.0-31.6%, and improves modulus of elasticity by 32.8-63.4%. The results suggest that Pro-Pro-hPTH (1-34) has a positive effect on bone growth and strength, and possesses anti-fracture capability, thus a potential candidate for the application for the treatment of osteoporosis.

  7. Osseous Consolidation of an Aseptic Delayed Union of a Lower Leg Fracture after Parathyroid Hormone Therapy – A Case Report

    PubMed Central

    Radmer, Sebastian; Andresen, Reimer; Schober, Hans-Christof

    2016-01-01

    The absence of osseous consolidation of a fracture within the normal time period is defined as delayed union or non-union. Both for the patient and from a socio-economic point of view, impaired fracture healing represents a major problem. Risk factors for a delayed fracture healing are insufficient immobilisation, poor adaptation of the fracture surfaces, interposition of soft tissue in the fracture gap, as well as circulation disturbances, metabolic disease, smoking and infections. In animal studies, a positive effect of parathyroid hormone (PTH) on fracture healing has been shown. PTH has a direct stimulatory effect on osteoblasts and osteoclasts. In addition, it appears to influence the effect of osseous growth factors. Few cases with the empiric off-label use of PTH that showed a tendency to support delayed or non-union fractures have been published. We report about a patient with a fracture of the lower leg and no osseous consolidation after 7 months. Four Months after therapy with 20 μg teriparatide per day for 8 weeks the fracture was consolidated and the patient had regained full and pain free weight bearing capacity of the leg with no reported side effects.

  8. Alternative promoter usage and mRNA splicing pathways for parathyroid hormone-related protein in normal tissues and tumours.

    PubMed Central

    Southby, J.; O'Keeffe, L. M.; Martin, T. J.; Gillespie, M. T.

    1995-01-01

    The parathyroid hormone-related protein (PTHrP) gene consists of nine exons and allows the production of multiple PTHrP mRNA species via the use of three promoters and 5' and 3' alternative splicing; as a result of 3' alternative splicing one of three protein isoforms may be produced. This organisation has potential for tissue-specific splicing patterns. We examined PTHrP mRNA expression and splicing patterns in a series of tumours and normal tissues, using the sensitive reverse transcription-polymerase chain reaction (RT-PCR) technique. Use of promoter 3 and mRNA specifying the 141 amino acid PTHrP isoform were detected in all samples. Transcripts encoding the 139 amino acid isoform were detected in all but two samples. Use of promoters 1 and 2 was less widespread as was detection of mRNA encoding the 173 amino acid isoform. While different PTHrP splicing patterns were observed between tumours, no tissue- or tumour-specific transcripts were detected. In comparing normal and tumour tissue from the same patient, an increase in the number of promoters utilised was observed in the tumour tissue. Furthermore, mRNA for the PTH/PTHrP receptor was detected in all samples, thus the PTHrP produced by these tumours may potentially act in an autocrine or paracrine fashion. Images Figure 2 PMID:7669584

  9. Parathyroid Hormone is Related to Dysplasia and a Higher Rate of Distal Colorectal Adenoma in Women but Not Men.

    PubMed

    Aigner, Elmar; Stadlmayr, Andreas; Huber-Schönauer, Ursula; Zwerina, Jochen; Husar-Memmer, Emma; Niederseer, David; Eder, Sebastian K; Stickel, Felix; Pirich, Christian; Schett, Georg; Patsch, Wolfgang; Datz, Christian

    2015-08-01

    Molecular and clinical observations provide evidence for a potential role of parathyroid hormone (PTH) in colorectal cancer development. We therefore aimed to assess the association of PTH with regard to colorectal cancer precursor lesions. A cohort of 1432 participants, 777 men, 58.4 ± 9.6 years and 701 women, 59.1 ± 10.6 years, undergoing screening colonoscopy were allocated to PTH serum concentrations either above or below 55 ng/L. The number, localization, size, and histology of the polypoid lesions detected during screening colonoscopy were recorded according to PTH serum concentrations. Serum PTH concentrations were not different between men and women. Women with PTH serum concentrations above the cut-off had significantly more adenomas (13/40; 32.5%) of the distal colon compared to women below the cut-off (91/659; 13.8%; P = 0.001). Additionally, the rate of dysplasia in adenomas of the distal colon was higher in women with high compared to low PTH concentrations (P = 0.001). These findings remained robust after adjustments for serum vitamin D, age, plasma creatinine, BMI, diabetes, and liver steatosis. No associations were observed between serum PTH concentrations and colorectal lesions in men. These data suggest that elevated PTH serum concentrations might have a role in colorectal cancer development as indicated by higher rates of adenomas, specifically with dysplasia, in women. The role of PTH in colon carcinogenesis and its sex specificity deserve further study. PMID:26021763

  10. Variation in parathyroid hormone immunoassay results—a critical governance issue in the management of chronic kidney disease

    PubMed Central

    Sprague, Stuart M.; Metcalfe, Wendy

    2011-01-01

    Renal physicians strive to maintain parathyroid hormone (PTH) concentrations for patients with chronic kidney disease (CKD) within guideline limits, but poor method comparability means there is currently serious risk of clinical misclassification. The potential for under- or over-treatment is significant, representing a major challenge to patient safety. In the short-term, raising awareness of clinical implications of method-related differences in PTH is essential. Agreeing and adopting assay-specific PTH action limits for CKD patients as an interim measure is highly desirable and has been achieved in Scotland. Establishing pre-analytical requirements for PTH is also a priority. In the longer term, re-standardization of PTH methods in terms of an appropriate International Standard is required. Provided commutability can be demonstrated, the recently established IS 95/646 for PTH (1-84) is a suitable candidate. Establishment of a well-characterized panel of samples of defined clinical provenance to enable manufacturers to determine appropriate reference intervals and clinical decision points is also recommended and will provide an invaluable clinical resource. Recent developments in mass spectrometry mean that a candidate reference measurement procedure for PTH is now achievable and will represent major progress. Concurrently, evidence-based recommendations on clinical requirements and performance goals for PTH are required. Improving the comparability of PTH results requires support from many stakeholders but is achievable. PMID:22039013

  11. Plasma Parathyroid Hormone Is Independently Related to Nocturnal Blood Pressure in Hypertensive Patients: The Styrian Hypertension Study.

    PubMed

    Verheyen, Nicolas D; Kienreich, Katharina; Gaksch, Martin; van Ballegooijen, Adriana J; Grübler, Martin R; Hartaigh, Briain Ó; Schmid, Johannes; Fahrleitner-Pammer, Astrid; Kraigher-Krainer, Elisabeth; Colantonio, Caterina; Belyavskiy, Evgeny; Treiber, Gerlies; Catena, Cristiana; Brussee, Helmut; Pieske, Burkert; März, Winfried; Tomaschitz, Andreas; Pilz, Stefan

    2016-06-01

    High parathyroid hormone (PTH) has been linked with high blood pressure (BP), but the relationship with 24-hour ambulatory blood pressure monitoring is largely unknown. The authors therefore analyzed cross-sectional data of 292 hypertensive patients participating in the Styrian Hypertension Study (mean age, 61±11 years; 53% women). Median plasma PTH (interquartile range) determined after an overnight fast was 49 pg/mL (39-61), mean daytime BP was 131/80±12/9 mm Hg, and mean nocturnal BP was 115/67±14/9 mm Hg. In multivariate regression analyses adjusted for BP and PTH-modifying parameters, PTH was significantly related to nocturnal systolic and diastolic BP (adjusted β-coefficient 0.140 [P=.03] and 0.175 [P<.01], respectively). PTH was not correlated with daytime BP readings. These data suggest a direct interrelationship between PTH and nocturnal BP regulation. Whether lowering high PTH concentrations reduces the burden of high nocturnal BP remains to be shown in future studies. PMID:26456544

  12. Osseous Consolidation of an Aseptic Delayed Union of a Lower Leg Fracture after Parathyroid Hormone Therapy - A Case Report.

    PubMed

    Kastirr, Ilko; Radmer, Sebastian; Andresen, Reimer; Schober, Hans-Christof

    2016-07-01

    The absence of osseous consolidation of a fracture within the normal time period is defined as delayed union or non-union. Both for the patient and from a socio-economic point of view, impaired fracture healing represents a major problem. Risk factors for a delayed fracture healing are insufficient immobilisation, poor adaptation of the fracture surfaces, interposition of soft tissue in the fracture gap, as well as circulation disturbances, metabolic disease, smoking and infections. In animal studies, a positive effect of parathyroid hormone (PTH) on fracture healing has been shown. PTH has a direct stimulatory effect on osteoblasts and osteoclasts. In addition, it appears to influence the effect of osseous growth factors. Few cases with the empiric off-label use of PTH that showed a tendency to support delayed or non-union fractures have been published. We report about a patient with a fracture of the lower leg and no osseous consolidation after 7 months. Four Months after therapy with 20 μg teriparatide per day for 8 weeks the fracture was consolidated and the patient had regained full and pain free weight bearing capacity of the leg with no reported side effects. PMID:27630919

  13. Current perspectives on parathyroid hormone (PTH) and PTH-related protein (PTHrP) as bone anabolic therapies.

    PubMed

    Esbrit, Pedro; Alcaraz, María José

    2013-05-15

    Osteoporosis is characterized by low bone mineral density and/or poor bone microarchitecture leading to an increased risk of fractures. The skeletal alterations in osteoporosis are a consequence of a relative deficit of bone formation compared to bone resorption. Osteoporosis therapies have mostly relied on antiresorptive drugs. An alternative therapeutic approach for osteoporosis is currently available, based on the intermittent administration of parathyroid hormone (PTH). Bone anabolism caused by PTH therapy is mainly accounted for by the ability of PTH to increase osteoblastogenesis and osteoblast survival. PTH and PTH-related protein (PTHrP)-an abundant local factor in bone- interact with the common PTH type 1 receptor with similar affinities in osteoblasts. Studies mainly in osteoporosis rodent models and limited data in postmenopausal women suggest that N-terminal PTHrP peptides might be considered a promising bone anabolic therapy. In addition, putative osteogenic actions of PTHrP might be ascribed not only to its N-terminal domain but also to its PTH-unrelated C-terminal region. In this review, we discuss the underlying cellular and molecular mechanisms of the anabolic actions of PTH and the similar potential of PTH-related protein (PTHrP) to increase bone mass and improve bone regeneration.

  14. A sensitive electrochemical sensor for in vitro detection of parathyroid hormone based on a MoS2-graphene composite

    PubMed Central

    Kim, Hyeong-U; Kim, Hye Youn; Kulkarni, Atul; Ahn, Chisung; Jin, Yinhua; Kim, Yeongseok; Lee, Kook-Nyung; Lee, Min-Ho; Kim, Taesung

    2016-01-01

    This paper reports a biosensor based on a MoS2-graphene (MG) composite that can measure the parathyroid hormone (PTH) concentration in serum samples from patients. The interaction between PTH and MG was analysed via an electrochemical sensing technique. The MG was functionalized using l-cysteine. Following this, PTH could be covalently immobilized on the MG sensing electrode. The properties of MG were evaluated using scanning electron microscopy, high-resolution transmission electron microscopy, X-ray diffraction, Raman spectroscopy, X-ray photoelectron spectroscopy, and Fourier transform infrared spectrometry. Following optimization of immobilized materials—such as MG, PTH, and alkaline phosphatase (ALP)—the performance of the MG sensor was investigated via cyclic voltammetry, to assess its linearity, repeatability, and reproducibility. Electrochemical impedance spectroscopy was performed on graphene oxide (GO) and MG-modified electrodes to confirm the capture of a monoclonal antibody (MAb) targeting PTH. Furthermore, the ALP-PTH-MG sensor exhibits a linear response towards PTH from artificial serum over a range of 1–50 pg mL−1. Moreover, patient sera (n = 30) were evaluated using the ALP-PTH-MG sensor and compared using standard equipment (Roche E 170). The P-value is less than 0.01 when evaluated with a t-test using Welch’s correction. This implies that the fabricated sensor can be deployed for medical diagnosis. PMID:27694822

  15. Parathyroid hormone-related peptide (PTHrP): prokaryotic expression, purification, and preparation of a polyclonal antibody.

    PubMed

    Zheng, H L; Li, H; Sun, Y S; Yang, Z Y; Yu, Q

    2014-01-01

    Parathyroid hormone-related peptide (PTHrP) plays important roles in promoting cancer occurrence and in the development of bone metastases. To increase our knowledge of the biological functions of PTHrP, the prokaryotic expression vector pET-PTHrP was successfully constructed and the His-PTHrP fusion protein was expressed in Escherichia coli. Anti-PTHrP polyclonal antibody was then prepared from rabbits. Finally, the goat tissue expression profile of PTHrP was analyzed by Western blot with the anti-PTHrP polyclonal antibody. The results showed that the expression of PTHrP in goat mammary glands was significantly higher than that in other organs. This indicates that PTHrP may play important roles in the goat mammary gland. The antibody prepared will be a useful tool for detecting PTHrP and will be valuable in future studies investigating the role of PTHrP in calcium metabolism in the goat model. PMID:25158263

  16. Parathyroid Hormone is Related to Dysplasia and a Higher Rate of Distal Colorectal Adenoma in Women but Not Men.

    PubMed

    Aigner, Elmar; Stadlmayr, Andreas; Huber-Schönauer, Ursula; Zwerina, Jochen; Husar-Memmer, Emma; Niederseer, David; Eder, Sebastian K; Stickel, Felix; Pirich, Christian; Schett, Georg; Patsch, Wolfgang; Datz, Christian

    2015-08-01

    Molecular and clinical observations provide evidence for a potential role of parathyroid hormone (PTH) in colorectal cancer development. We therefore aimed to assess the association of PTH with regard to colorectal cancer precursor lesions. A cohort of 1432 participants, 777 men, 58.4 ± 9.6 years and 701 women, 59.1 ± 10.6 years, undergoing screening colonoscopy were allocated to PTH serum concentrations either above or below 55 ng/L. The number, localization, size, and histology of the polypoid lesions detected during screening colonoscopy were recorded according to PTH serum concentrations. Serum PTH concentrations were not different between men and women. Women with PTH serum concentrations above the cut-off had significantly more adenomas (13/40; 32.5%) of the distal colon compared to women below the cut-off (91/659; 13.8%; P = 0.001). Additionally, the rate of dysplasia in adenomas of the distal colon was higher in women with high compared to low PTH concentrations (P = 0.001). These findings remained robust after adjustments for serum vitamin D, age, plasma creatinine, BMI, diabetes, and liver steatosis. No associations were observed between serum PTH concentrations and colorectal lesions in men. These data suggest that elevated PTH serum concentrations might have a role in colorectal cancer development as indicated by higher rates of adenomas, specifically with dysplasia, in women. The role of PTH in colon carcinogenesis and its sex specificity deserve further study.

  17. Seasonal variations in calcidiol and parathyroid hormone levels in healthy children and adolescents in Navarre, Spain: a cross-sectional study

    PubMed Central

    Gallinas-Victoriano, Fidel

    2016-01-01

    Objective To analyze the seasonal variations in calcidiol and parathyroid hormone serum levels along a natural year in a paediatric population living in a region of the north of Spain considering a normal nutrition status. Design A cross-sectional study. Setting Navarra Hospital Complex, Pamplona, Spain. Participants A total of 413 Caucasian individuals (aged 3.1 to 15.4 years): 227 school children (96 males and 131 females) and 186 adolescents (94 males and 92 females), with normal nutritional status. Main outcome measures Clinical examination (sex, age, weight, height and body mass index) and blood testing (calcium, phosphate, alkaline phosphatase, calcidiol and parathyroid hormone) during the year 2014. Results Calcidiol levels were lower during spring (25.96 ± 6.64 ng/mL) and reached its maximum level in summer (35.33 ± 7.51 ng/mL); parathyroid hormone levels were lower in summer (27.13 ± 7.89 pg/mL) and reached maximum level in autumn (34.73 ± 15.38 pg/mL). Hypovitaminosis D prevalence was 14.3% in summer and 75.3% in spring. Parathyroid hormone levels were compatible with secondary hyperparathyroidism in eight individuals (1.9%). There is a correlation (p < 0.01) between calcidiol and parathyroid hormone (r = −0.336). Logistic regression showed significant increased risk of hypovitaminosis in females (OR:1.63) and adolescents (OR:1.77), and when blood samples taken in autumn (OR:12.22), winter (OR:8.54) and spring (OR:19.72). Conclusions There is a high prevalence of hypovitaminosis D in the paediatric population with a healthy nutrition situation in Navarre, mainly during the months of autumn and winter, and, especially, in spring time. Given the difficulties in maintaining a sufficient amount of body vitamin D content along the year, it should be considered to give vitamin supplements and/or increase the intake of its natural dietary sources or vitamin D fortified foods. PMID:27066262

  18. TIP39/parathyroid hormone type 2 receptor signaling is a potent inhibitor of chondrocyte proliferation and differentiation

    PubMed Central

    Panda, Dibiyendu; Goltzman, David; Jüppner, Harald

    2009-01-01

    Tuberoinfundibular peptide of 39 residues (TIP39) is a member of the parathyroid hormone (PTH) family of peptide hormones that exerts its function by interacting with the PTH type 2 receptor (PTH2R). Presently, no known function has been attributed to this signaling pathway in the developing skeleton. We observed that TIP39 and PTH2R were present in the newborn mouse growth plate, with the receptor localizing in the resting zone whereas ligand expression was restricted exclusively in prehypertrophic and hypertrophic chondrocytes. By 8 wk of life, PTH2R, and to a lesser degree TIP39, immunoreactivity was present in articular chondrocytes. We therefore sought to investigate the role of TIP39/PTH2R signaling in chondrocytes by generating stably transfected CFK2 chondrocytic cells overexpressing PTH2R (CFK2R). TIP39 treatment of CFK2R clones in culture inhibited their proliferation by restricting cells at the G0/G1 phase of the cell cycle, coupled with decreased expression and activity of cyclin-dependent kinases Cdk2 and Cdk4, while p21, an inhibitor of Cdks, was upregulated. In addition, TIP39 treatment decreased expression of differentiation markers in these cells associated with marked alterations in extracellular matrix and metalloproteinase expression. Transcription of Sox9, the master regulator of cartilage differentiation, was reduced in TIP39-treated CFK2R clones. Moreover, Sox9 promoter activity, as measured by luciferase reporter assay, was markedly diminished after TIP39 treatment. In summary, our results show that TIP39/PTH2R signaling inhibits proliferation and alters differentiation of chondrocytes by modulating SOX9 expression, thereby substantiating the functional significance of this signaling pathway in chondrocyte biology. PMID:19706789

  19. TIP39/parathyroid hormone type 2 receptor signaling is a potent inhibitor of chondrocyte proliferation and differentiation.

    PubMed

    Panda, Dibiyendu; Goltzman, David; Jüppner, Harald; Karaplis, Andrew C

    2009-11-01

    Tuberoinfundibular peptide of 39 residues (TIP39) is a member of the parathyroid hormone (PTH) family of peptide hormones that exerts its function by interacting with the PTH type 2 receptor (PTH2R). Presently, no known function has been attributed to this signaling pathway in the developing skeleton. We observed that TIP39 and PTH2R were present in the newborn mouse growth plate, with the receptor localizing in the resting zone whereas ligand expression was restricted exclusively in prehypertrophic and hypertrophic chondrocytes. By 8 wk of life, PTH2R, and to a lesser degree TIP39, immunoreactivity was present in articular chondrocytes. We therefore sought to investigate the role of TIP39/PTH2R signaling in chondrocytes by generating stably transfected CFK2 chondrocytic cells overexpressing PTH2R (CFK2R). TIP39 treatment of CFK2R clones in culture inhibited their proliferation by restricting cells at the G(0)/G(1) phase of the cell cycle, coupled with decreased expression and activity of cyclin-dependent kinases Cdk2 and Cdk4, while p21, an inhibitor of Cdks, was upregulated. In addition, TIP39 treatment decreased expression of differentiation markers in these cells associated with marked alterations in extracellular matrix and metalloproteinase expression. Transcription of Sox9, the master regulator of cartilage differentiation, was reduced in TIP39-treated CFK2R clones. Moreover, Sox9 promoter activity, as measured by luciferase reporter assay, was markedly diminished after TIP39 treatment. In summary, our results show that TIP39/PTH2R signaling inhibits proliferation and alters differentiation of chondrocytes by modulating SOX9 expression, thereby substantiating the functional significance of this signaling pathway in chondrocyte biology.

  20. Relationship between disease activity and serum levels of vitamin D metabolites and parathyroid hormone in ankylosing spondylitis.

    PubMed

    Lange, U; Jung, O; Teichmann, J; Neeck, G

    2001-12-01

    Vertebral fractures due to osteoporosis are a common but frequently unrecognized complication of ankylosing spondylitis (AS) and various factors may contribute to the development of osteoporosis in AS. It is known that inflammatory activity in rheumatic disease (i.e., proinflammatory cytokines) itself plays a possible role in the pathophysiology of bone loss. 1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) seems to be another possible candidate for mediatory function in regulating both the inflammatory process and bone turnover. The aim of this study was to evaluate the relation between disease activity, bone turnover and calciotropic hormones. In 70 patients with established AS and an age- and sex-matched control group, the relation between disease activity (erythrocyte sedimentation rate, C-reactive protein, Bath Ankylosing Spondylitis Disease Activity Index), and serum levels of vitamin D metabolites, parathyroid hormone (PTH), bone alkaline phosphatase (bAP) and urinary pyridinium cross-links were determined. Serum levels of 1,25(OH)2D3 (p<0.01) and PTH (p<0.01) were negatively correlated with disease activity, the excretion of urinary pyridinium crosslinks showed a positive correlation with disease activity (p<0.01), and 1,25(OH)2D3 and PTH were positively correlated with bAP (p<0.01). These results indicate that high disease activity in AS is associated with an alteration in vitamin D metabolism and increased bone resorption. Furthermore, the decreased levels of 1,25(OH)2D3 may contribute to a negative calcium balance and inhibition of bone formation. Our results suggest further research is necessary to determine whether low levels of 1,25(OH)2D3 as an endogenous immune modulator suppressing activated T cells and cell proliferation may accelerate the inflammation process in AS. PMID:11846329

  1. Effects of parathyroid hormone on puppies during development of Ca and vitamin D deficiency.

    PubMed

    Wong, K M; Klein, L; Hollis, B

    1985-12-01

    The acute effects of parathyroid extract (PTE) were studied repeatedly in young dogs (prelabeled with 45Ca and [3H]tetracycline) during the development of calcium (Ca) and vitamin D deficiency. Blood Ca and radioactivity changes were monitored sequentially after subcutaneous PTE, injected seven times over 63 days. In control dogs, all sequential responses to acute PTE challenges were constant in both magnitude of increase and time at which maximum response occurred over the entire experiment. Under chronic Ca and D deficiency, plasma 25-hydroxyvitamin D in experimental dogs decreased continuously to very low levels at 63 days, whereas 1,25-dihydroxyvitamin D initially increased to a maximum at 32 days and thereafter decreased. In response to an acute challenge of PTE, dogs on the deficient diet for 3 and 10 days showed a greater response of blood Ca and 45Ca than the controls but subsequently showed a smaller response than controls after 49 and 63 days on the deficient diet. Compared with control dogs, the time of maximal response of blood Ca and 45Ca to PTE occurred much earlier in dogs that were on the deficient diet for 35-63 days. The blood [3H]tetracycline response (index of bone resorption) to exogenous PTE in the deficient dogs, however, was constant and similar to that of the control dogs during the entire period. The data suggest that the bone resorption response to PTE was normal in Ca- and D-deficient puppies with hypocalcemia.(ABSTRACT TRUNCATED AT 250 WORDS)

  2. Parathyroid Hormone and the Use of Diuretics and Calcium-Channel Blockers: The Multi-Ethnic Study of Atherosclerosis.

    PubMed

    Zaheer, Sarah; de Boer, Ian; Allison, Matthew; Brown, Jenifer M; Psaty, Bruce M; Robinson-Cohen, Cassianne; Ix, Joachim H; Kestenbaum, Bryan; Siscovick, David; Vaidya, Anand

    2016-06-01

    Thiazide diuretic (TZ) use is associated with higher bone mineral density, whereas loop diuretic (LD) use is associated with lower bone density and incident fracture. Dihydropyridine-sensitive calcium channels are expressed on parathyroid cells and may play a role in parathyroid hormone (PTH) regulation. The potential for diuretics and calcium-channel blockers (CCBs) to modulate PTH and calcium homeostasis may represent a mechanism by which they influence skeletal outcomes. We hypothesized that the use of LD and dihydropyridine CCBs is associated with higher PTH, and TZ use is associated with lower PTH. We conducted cross-sectional analyses of participants treated for hypertension in the Multi-Ethnic Study of Atherosclerosis who did not have primary hyperparathyroidism or chronic kidney disease (n = 1888). We used adjusted regression models to evaluate the independent association between TZ, LD, and CCB medication classes and PTH. TZ use was associated with lower PTH when compared with non-TZ use (44.4 versus 46.9 pg/mL, p = 0.02), whereas the use of LD and CCBs was associated with higher PTH when compared with non-users of each medication class (LD: 60.7 versus 45.5 pg/mL, p < 0.0001; CCB: 49.5 versus. 44.4 pg/mL, p < 0.0001). Adjusted regression models confirmed independent associations between TZ use and lower PTH (β = -3.2 pg/mL, p = 0.0007), and LD or CCB use and higher PTH (LD: β = +12.0 pg/mL, p < 0.0001; CCB: +3.7 pg/mL, p < 0.0001). Among CCB users, the use of dihydropyridines was independently associated with higher PTH (β = +5.0 pg/mL, p < 0.0001), whereas non-dihydropyridine use was not (β = +0.58 pg/mL, p = 0.68). We conclude that in a large community-based cohort with normal kidney function, TZ use is associated with lower PTH, whereas LD and dihydropyridine CCB use is associated with higher PTH. These associations may provide a mechanistic explanation linking use of these

  3. A comparison of parathyroid hormone-related protein (1-36) and parathyroid hormone (1-34) on markers of bone turnover and bone density in postmenopausal women: the PrOP study.

    PubMed

    Horwitz, Mara J; Augustine, Marilyn; Khan, Leila; Kahn, Leila; Martin, Emily; Oakley, Christine C; Carneiro, Raquel M; Tedesco, Mary Beth; Laslavic, Angela; Sereika, Susan M; Bisello, Alessandro; Garcia-Ocaña, Adolfo; Gundberg, Caren M; Cauley, Jane A; Stewart, Andrew F

    2013-11-01

    Parathyroid hormone-related protein (PTHrP)(1-36) increases lumbar spine (LS) bone mineral density (BMD), acting as an anabolic agent when injected intermittently, but it has not been directly compared with parathyroid hormone (PTH)(1-34). We performed a 3-month randomized, prospective study in 105 postmenopausal women with low bone density or osteoporosis, comparing daily subcutaneous injections of PTHrP(1-36) to PTH(1-34). Thirty-five women were randomized to each of three groups: PTHrP(1-36) 400 µg/day; PTHrP(1-36) 600 µg/day; and PTH(1-34) 20 µg/day. The primary outcome measures were changes in amino-terminal telopeptides of procollagen 1 (PINP) and carboxy-terminal telopeptides of collagen 1 (CTX). Secondary measures included safety parameters, 1,25(OH)2 vitamin D, and BMD. The increase in bone resorption (CTX) by PTH(1-34) (92%) (p < 0.005) was greater than for PTHrP(1-36) (30%) (p < 0.05). PTH(1-34) also increased bone formation (PINP) (171%) (p < 0.0005) more than either dose of PTHrP(1-36) (46% and 87%). The increase in PINP was earlier (day 15) and greater than the increase in CTX for all three groups. LS BMD increased equivalently in each group (p < 0.05 for all). Total hip (TH) and femoral neck (FN) BMD increased equivalently in each group but were only significant for the two doses of PTHrP(1-36) (p < 0.05) at the TH and for PTHrP(1-36) 400 (p < 0.05) at the FN. PTHrP(1-36) 400 induced mild, transient (day 15) hypercalcemia. PTHrP(1-36) 600 required a dose reduction for hypercalcemia in three subjects. PTH(1-34) was not associated with hypercalcemia. Each peptide induced a marked biphasic increase in 1,25(OH)2 D. Adverse events (AE) were similar among the three groups. This study demonstrates that PTHrP(1-36) and PTH(1-34) cause similar increases in LS BMD. PTHrP(1-36) also increased hip BMD. PTH(1-34) induced greater changes in bone turnover than PTHrP(1-36). PTHrP(1-36) was associated with mild transient hypercalcemia

  4. A salt bridge between Arg-20 on parathyroid hormone (PTH) and Asp-137 on the PTH1 receptor is essential for full affinity.

    PubMed

    Weaver, Richard E; Wigglesworth, Mark J; Donnelly, Dan

    2014-11-01

    Parathyroid hormone (PTH) acts via the receptor PTH1 and plays an important role in calcium homeostasis. PTH's interaction with the N-terminal domain of PTH1 is mediated in part by Arg-20 on the peptide which forms a number of interactions with the receptor: a charge-charge interaction with Asp-137; hydrogen bonds with the backbone of Asp-29 and Met-32; and hydrophobic interactions with Met-32 and Gln-37. The aim of this work was to establish the importance of the charge-charge interaction through the combined use of modified peptide ligands, site-directed mutations of the receptor, and pharmacological assays. The substitution of Arg-20 with norleucine resulted in a 50-fold reduction in potency at PTH1 and Asp-137-Glu while, in contrast, both Asp-137-Asn and Asp-137-Ala receptors were largely insensitive to this ligand modification. The effect of this removal of the positive charge as position 20 could be partially rescued at PTH1 and Asp-137-Glu, but not Asp-137-Asn and Asp-137-Ala, through a substitution of peptide position 20 with ornithine. The latter two receptors, which have no negative charge at position 137, displayed potency for PTH that was reduced by 40- and 117-fold, respectively. These data demonstrate that a negative charge at residue-137 is important for interacting with ligands containing a positive charge at residue-20, and that the Arg-20 interaction with Asp-137, observed in the crystal structure of the isolated N-terminal domain of PTH1, is likely to be present in the full length receptor where it provides an important affinity- and potency-generating interaction through a salt bridge.

  5. Giant intrathyroidal parathyroid adenoma

    PubMed Central

    Vilallonga, Ramon; Zafón, Carlos; Migone, Raul; Baena, Juan Antonio

    2012-01-01

    Primary hyperparathyroidism (PHPT) is not an uncommon endocrine disorder. However, acute primary hyperparathyroidism, or parathyroid crisis (PC), is a rare clinical entity characterized by life-threatening hypercalcemia of a sudden onset in patients with PHPT. We describe a patient with PC who presented with acute worsening of depressive symptoms, nausea and vomiting, and required emergency surgery. Serum calcium, alkaline phosphatase, and parathyroid hormone were elevated and serum phosphorus was low. An emergency hemithyroidectomy was performed because of none medical control of hypercalcemia. A giant intrathyroidal parathyroid adenoma was diagnosed. PHTP can be a life-threatening situation for patients, requiring immediate surgical treatment. A giant intrathyroidal parathyroid adenoma is an uncommon cause of PC. PMID:22787355

  6. Enhanced responsiveness to parathyroid hormone and induction of functional differentiation of cultured rabbit costal chondrocytes by a pulsed electromagnetic field.

    PubMed

    Hiraki, Y; Endo, N; Takigawa, M; Asada, A; Takahashi, H; Suzuki, F

    1987-10-22

    Pulsed electromagnetic fields promote healing of delayed united and ununited fractures by triggering a series of events in fibrocartilage. We examined the effects of a pulsed electromagnetic field (recurrent bursts, 15.4 Hz, of shorter pulses of an average of 2 gauss) on rabbit costal chondrocytes in culture. A pulsed electromagnetic field slightly reduced the intracellular cyclic adenosine 3',5'-monophosphate (cAMP) level in the culture. However, it significantly enhanced cAMP accumulation in response to parathyroid hormone (PTH) to 140% of that induced by PTH in its absence, while it did not affect cAMP accumulation in response to prostaglandin E1 or prostaglandin I2. The effect on cAMP accumulation in response to PTH became evident after exposure of the cultures to the pulsed electromagnetic field for 48 h, and was dependent upon the field strength. cAMP accumulation in response to PTH is followed by induction of ornithine decarboxylase, a good marker of differentiated chondrocytes, after PTH treatment for 4 h. Consistent with the enhanced cAMP accumulation, ornithine decarboxylase activity induced by PTH was also increased by the pulsed electromagnetic field to 170% of that in cells not exposed to a pulsed electromagnetic field. Furthermore, stimulation of glycosaminoglycan synthesis, a differentiated phenotype, in response to PTH was significantly enhanced by a pulsed electromagnetic field. Thus, a pulsed electromagnetic field enhanced a series of events in rabbit costal chondrocytes in response to PTH. These findings show that exposure of chondrocytes to a pulsed electromagnetic field resulted in functional differentiation of the cells.

  7. Intermittent Administration of Parathyroid Hormone [1–34] Prevents Particle-Induced Periprosthetic Osteolysis in a Rat Model

    PubMed Central

    Bi, Fanggang; Shi, Zhongli; Zhou, Chenhe; Liu, An; Shen, Yue; Yan, Shigui

    2015-01-01

    We examined whether intermittent administration of parathyroid hormone [1–34] (PTH[1–34]; 60 μg/kg/day) can prevent the negative effects of titanium (Ti) particles on implant fixation and periprosthetic osteolysis in a rat model. Eighteen adult male rats (12 weeks old, bones still growing) received intramedullary Ti implants in their bilateral femurs; 6 rats from the blank group received vehicle injections, and 12 rats from the control group and PTH treatment group received Ti particle injections at the time of operation and intra-articular injections 2 and 4 weeks postoperatively. Six of the rats that received Ti particles from the PTH group also received PTH[1–34] treatment. Six weeks postoperatively, all specimens were collected for assessment by X-ray, micro-CT, biomechanical, scanning electron microscopy (SEM), and dynamic histomorphometry. A lower BMD, BV/TV, Tb.N, maximal fixation strength, and mineral apposition rate were observed in the control group compared to the blank group, demonstrating that a periprosthetic osteolysis model had been successfully established. Administration of PTH[1–34] significantly increased the bone mineral density of the distal femur, BV/TV, Tb.N, Tb.Th, Tb.Sp, Con.D, SMI, and maximal fixation strength in the PTH group compared to that in the control group. SEM revealed higher bone–implant contact, thicker lamellar bone, and larger trabecular bone area in the PTH group than in the control group. A higher mineral apposition rate was observed in the PTH group compared to both the blank and control groups. These findings imply that intermittent administration of PTH[1–34] prevents periprosthetic osteolysis by promoting bone formation. The effects of PTH[1–34] were evaluated at a suprapharmacological dosage to the human equivalent in rats; therefore, additional studies are required to demonstrate its therapeutic potential in periprosthetic osteolysis. PMID:26441073

  8. Preparation and in vivo evaluation of an orally available enteric-microencapsulated parathyroid hormone (1-34)-deoxycholic acid nanocomplex.

    PubMed

    Hwang, Seung Rim; Seo, Dong-Hyun; Byun, Youngro; Park, Jin Woo

    2016-01-01

    The N-terminal 34-amino-acid peptide fragment of human parathyroid hormone PTH (1-34), is used clinically to treat osteoporosis; however, it is currently administered by a once-daily subcutaneous injection, resulting in poor patient compliance. We have developed enteric microcapsules containing an ionic nanocomplex between PTH (1-34) and lysine-linked deoxycholic acid (LysDOCA) for the oral delivery of PTH (1-34). We measured the particle size of the PTH/LysDOCA complex and assessed its biological activity by determining the cAMP content in MC3T3-E1 cells. We also assessed its permeability across a Caco-2 cell monolayer and the bioavailability of the intrajejunally administered PTH/LysDOCA complex compared with PTH (1-34) in rats. In addition, the antiosteoporotic activity of the PTH/LysDOCA complex, encapsulated in an enteric carrier by coaxial ultrasonic atomization, was evaluated after it was orally administered to ovariectomized (OVX) rats. The formation of an ionic complex between PTH (1-34) and LysDOCA produced nanoparticles of diameter 33.0±3.36 nm, and the bioactivity of the complex was comparable with that of PTH (1-34). The Caco-2 cell permeability and AUClast value of the PTH/LysDOCA (1:10) nanocomplex increased by 2.87- and 16.3-fold, respectively, compared with PTH (1-34) alone. Furthermore, the OVX rats treated with oral PTH/LysDOCA-loaded enteric microcapsules showed an increase in bone mineral density (159%), bone volume fraction (175%), and trabecular number (174%) compared with those in the OVX control group. Therefore, the PTH/LysDOCA nanocomplex oral delivery system is a promising treatment modality for osteoporosis because it improves osteogenesis and trabecular connectivity. PMID:27621618

  9. Bone marrow ablation demonstrates that excess endogenous parathyroid hormone plays distinct roles in trabecular and cortical bone.

    PubMed

    Yan, Jun; Sun, Weiwei; Zhang, Jing; Goltzman, David; Miao, Dengshun

    2012-07-01

    Mice null for Cyp27b1, which encodes the 25-hydroxyvitamin D-1α-hydroxylase [1α(OH)ase(-/-) mice], lack 1,25-dihydroxyvitamin D [1,25(OH)(2)D] and have hypocalcemia and high parathyroid hormone (PTH) secretion. Intermittent, exogenous PTH is anabolic for bone. To determine the effect of the chronic excess endogenous PTH on osteogenesis and bone turnover, bone marrow ablations (BMX) were performed in tibiae and femurs of 6-week-old 1α(OH)ase(-/-) mice and in wild-type (WT) controls. Newly formed bone tissue was analyzed at 1, 2, and 3 weeks after BMX. BMX did not alter the higher levels of PTH in 1α(OH)ase(-/-) mice. In the marrow cavity, trabecular volume, osteoblast number, alkaline phosphatase-positive areas, type I collagen-positive areas, bone formation-related genes, and protein expression levels all increased significantly after BMX in 1α(OH)ase(-/-) mice, compared with WT. Osteoclast numbers and surface and ratio of RANKL/OPG-relative mRNA levels decreased significantly after BMX in 1α(OH)ase(-/-) mice, compared with WT. In the cortex, alkaline phosphatase-positive osteoblasts and osteoclast numbers increased significantly after BMX in 1α(OH)ase(-/-) mice, compared with WT. These results demonstrate that chronic excess endogenous PTH exerts an anabolic role in trabecular bone by stimulating osteogenic cells and reducing bone resorption, but plays a catabolic role in cortical bone by enhancing bone turnover with an increase in resorption. PMID:22640808

  10. Parathyroid hormone induction of cyclooxygenase-2 in murine osteoblasts: role of the calcium-calcineurin-NFAT pathway.

    PubMed

    Huang, Hechang; Chikazu, Daichi; Voznesensky, Olga S; Herschman, Harvey R; Kream, Barbara E; Drissi, Hicham; Pilbeam, Carol C

    2010-04-01

    Murine MC3T3-E1 and MC-4 cells were stably transfected with -371/+70 bp of the murine cyclooxygenase-2 (COX-2) promoter fused to a luciferase reporter (Pluc371) or with Pluc371 carrying site-directed mutations. Mutations were made in (1) the cAMP response element (CRE) at -57/-52 bp, (2) the activating protein-1 (AP-1)-binding site at -69/-63 bp, (3) the nuclear factor of activated T-cells (NFAT)-binding site at -77/-73 bp, and (4) both the AP-1 and NFAT sites, which comprise a composite consensus sequence for NFAT/AP-1. Single mutation of CRE, AP-1, or NFAT sites decreased parathyroid hormone (PTH)-stimulated COX-2 promoter activity 40% to 60%, whereas joint mutation of NFAT and AP-1 abrogated the induction. On electrophoretic mobility shift analysis, PTH stimulated binding of phosphorylated CREB to an oligonucleotide spanning the CRE and binding of NFATc1, c-Fos, and c-Jun to an oligonucleotide spanning the NFAT/AP-1 composite site. Mutation of the NFAT site was less effective than mutation of the AP-1 site in competing binding to the composite element, suggesting that cooperative interactions of NFATc1 and AP-1 are more dependent on NFAT than on AP-1. Both PTH and forskolin, an activator of adenylyl cyclase, stimulated NFATc1 nuclear translocation. PTH- and forskolin-stimulated COX-2 promoter activity was inhibited 56% to 80% by calcium chelation or calcineurin inhibitors and 60% to 98% by protein kinase A (PKA) inhibitors. These results indicate an important role for the calcium-calcineurin-NFAT signaling pathway in the PTH induction of COX-2 and suggest that cross-talk between the cAMP/PKA pathway and the calcium-calcineurin-NFAT pathway may play a role in other functions of PTH in osteoblasts.

  11. Parathyroid hormone-related protein in tissues of the emerging frog (Rana temporaria): immunohistochemistry and in situ hybridisation

    PubMed Central

    DANKS, J. A.; McHALE, J. C.; MARTIN, T. J.; INGLETON, P. M.

    1997-01-01

    Using antiserum to human parathyroid hormone-related protein (1–16) [PTHrP(1–16)] we have examined tissues of the common frog (Rana temporaria) for the presence of immunoreactive PTHrP (irPTHrP) at the stage of emergence from water to land. irPTHrP was detected in dorsal and ventral stratum granulosum of the skin, in the developing ovary, striated muscle and the choroid plexus epithelium of the brain as well as in the olfactory gland epithelium and olfactory lobe neurons of the brain. In the pituitary and hypothalamus irPTHrP protein could be demonstrated in the median eminence, infundibular stem and principally in the neural lobe and pars distalis of the pituitary with weak reaction in the pars intermedia. In situ hybridisation of the same tissues with an oligonucleotide probe to chicken PTHrP 55–65 clearly showed the presence of mRNA for PTHrP-like molecule in all the tissues containing irPTHrP. There was a major inconsistency in the pituitary in that the highest level of gene expression, assessed by in situ hybridisation, was found in the pars intermedia with only very low expression in the pars distalis and neural lobe and undetectable levels in the infundibular stem and median eminence. These observations suggest that tissues of the frog synthesise a PTHrP-like molecule but that in the pituitary the pars intermedia cells may export the protein to cells in other regions of the pituitary and hypothalamus. PMID:9061446

  12. DECREASED OXIDATIVE STRESS AND GREATER BONE ANABOLISM IN THE AGED, AS COMPARED TO THE YOUNG, MURINE SKELETON BY PARATHYROID HORMONE

    PubMed Central

    Jilka, R.L.; Almeida, M.; Ambrogini, E.; Han, L.; Roberson, P. K.; Weinstein, R.S.; Manolagas, S.C.

    2010-01-01

    Summary Because of recent insights into the pathogenesis of age-related bone loss, we investigated whether intermittent parathyroid hormone (PTH) administration antagonizes the molecular mechanisms of the adverse effects of aging on bone. PTH produced a greater increase in vertebral trabecular bone mineral density and bone volume as well as a greater expansion of the endocortical bone surface in the femur of 26 as compared to 6 month old female C57BL/6 mice. Moreover, PTH increased trabecular connectivity in vertebrae and the toughness of both vertebrae and femora in old, but not young, mice. PTH also increased the rate of bone formation and reduced osteoblast apoptosis to a greater extent in the old mice. Most strikingly, PTH reduced reactive oxygen species (ROS), p66Shc phosphorylation and expression of the lipoxygenase Alox15; and it increased glutathione and stimulated Wnt signaling in bone of old mice. PTH also antagonized the effects of oxidative stress on p66Shc phosphorylation, FoxO transcriptional activity, osteoblast apoptosis, and Wnt signaling in vitro. In contrast, administration of the antioxidants N-acetyl cysteine or pegylated catalase reduced osteoblast progenitors, and attenuated proliferation and Wnt signaling. These results suggest that PTH has a greater bone anabolic efficacy in old age because in addition to its other positive actions on bone formation it antagonizes the age-associated increase in oxidative stress and its adverse effects on the birth and survival of osteoblasts. On the other hand, ordinary antioxidants cannot restore bone mass in old age because they slow remodeling and attenuate osteoblastogenesis by interfering with Wnt signaling. PMID:20698835

  13. Defective postnatal endochondral bone development by chondrocyte-specific targeted expression of parathyroid hormone type 2 receptor

    PubMed Central

    Panda, Dibyendu Kumar; Goltzman, David

    2012-01-01

    The human parathyroid hormone type 2 receptor (PTH2R) is activated by PTH and by tuberoinfundibular peptide of 39 residues (TIP39), the latter likely acting as its natural ligand. Although the receptor is expressed at highest levels in the nervous system, we have observed that both PTH2R and TIP39 are expressed in the newborn mouse growth plate, with the receptor localizing in the resting zone and the ligand TIP39 localizing exclusively in prehypertrophic and hypertrophic chondrocytes. To address the role of PTH2R in postnatal skeletal growth and development, Col2a1-hPTH2R (PTH2R-Tg) transgenic mice were generated. The mice were viable and of nearly normal size at birth. Expression of the transgene in the growth plate was limited to chondrocytes. We found that chondrocyte proliferation was decreased, as determined by in vivo BrdU labeling of proliferating chondrocytes and CDK4 and p21 expression in the growth plate of Col2a1-hPTH2R transgenic mice. Similarly, the differentiation and maturation of chondrocytes was delayed, as characterized by decreased Sox9 expression and weaker immunostaining for the chondrocyte differentiation markers collagen type II and type X and proteoglycans. As well, there was altered expression of Gdf5, Wdr5, and β-catenin, factors implicated in chondrocyte maturation, proliferation, and differentiation.These effects impacted on the process of endochondral ossification, resulting in delayed formation of the secondary ossification center, and diminished trabecular bone volume. The findings substantiate a role for PTH2R signaling in postnatal growth plate development and subsequent bone mass acquisition. PMID:23092913

  14. Distribution of Tuberoinfundibular Peptide of 39 Residues and Its Receptor, Parathyroid Hormone 2 Receptor, in the Mouse Brain

    PubMed Central

    FABER, CATHERINE A.; DOBOLYI, ARPÁD; SLEEMAN, MARK; USDIN, TED B.

    2010-01-01

    Tuberoinfundibular peptide of 39 residues (TIP39) was identified as a potent parathyroid hormone 2 receptor (PTH2R) agonist. Existing anatomical data also support the suggestion that TIP39 is the PTH2R’s endogenous ligand, but a comprehensive comparison of TIP39 and PTH2R distributions has not been performed. In the present study, we compared the distributions of TIP39 and PTH2R on adjacent mouse brain sections. In addition, we determined the locations of PTH2R-expressing cell bodies by in situ hybridization histochemistry and by labeling β-galactosidase driven by the PTH2R promoter in knockin mice. An excellent correlation was found between the distributions of TIP39-containing fibers and PTH2R-containing cell bodies and fibers throughout the brain. TIP39 and the PTH2R are abundant in medial prefrontal, insular, and ectorhinal cortices, the lateral septal nucleus, the bed nucleus of the stria terminalis, the fundus striati, the amygdala, the ventral subiculum, the hypothalamus, midline and intralaminar thalamic nuclei, the medial geniculate body, the periaqueductal gray, the ventral tegmental area, the superior and inferior colliculi, the parabrachial nuclei, the locus coeruleus, subcoeruleus and periolivary areas, and the nucleus of the solitary tract. Furthermore, even the subregional distribution of TIP39- and PTH2R-immunoreactive fibers in these regions showed remarkable similarities, providing anatomical evidence that TIP39 may act on the PTH2R. Based on these observations and on previous pharmacological data, we propose that TIP39 is an endogenous ligand of the PTH2R and that they form a neuromodulator system, which is optimally positioned to regulate limbic, endocrine, and auditory brain functions. PMID:17394159

  15. Distribution of tuberoinfundibular peptide of 39 residues and its receptor, parathyroid hormone 2 receptor, in the mouse brain.

    PubMed

    Faber, Catherine A; Dobolyi, Arpád; Sleeman, Mark; Usdin, Ted B

    2007-06-01

    Tuberoinfundibular peptide of 39 residues (TIP39) was identified as a potent parathyroid hormone 2 receptor (PTH2R) agonist. Existing anatomical data also support the suggestion that TIP39 is the PTH2R's endogenous ligand, but a comprehensive comparison of TIP39 and PTH2R distributions has not been performed. In the present study, we compared the distributions of TIP39 and PTH2R on adjacent mouse brain sections. In addition, we determined the locations of PTH2R-expressing cell bodies by in situ hybridization histochemistry and by labeling beta-galactosidase driven by the PTH2R promoter in knockin mice. An excellent correlation was found between the distributions of TIP39-containing fibers and PTH2R-containing cell bodies and fibers throughout the brain. TIP39 and the PTH2R are abundant in medial prefrontal, insular, and ectorhinal cortices, the lateral septal nucleus, the bed nucleus of the stria terminalis, the fundus striati, the amygdala, the ventral subiculum, the hypothalamus, midline and intralaminar thalamic nuclei, the medial geniculate body, the periaqueductal gray, the ventral tegmental area, the superior and inferior colliculi, the parabrachial nuclei, the locus coeruleus, subcoeruleus and periolivary areas, and the nucleus of the solitary tract. Furthermore, even the subregional distribution of TIP39- and PTH2R-immunoreactive fibers in these regions showed remarkable similarities, providing anatomical evidence that TIP39 may act on the PTH2R. Based on these observations and on previous pharmacological data, we propose that TIP39 is an endogenous ligand of the PTH2R and that they form a neuromodulator system, which is optimally positioned to regulate limbic, endocrine, and auditory brain functions. Published 2007 Wiley-Liss, Inc.

  16. Recombinant human parathyroid hormone related protein 1-34 and 1-84 and their roles in osteoporosis treatment.

    PubMed

    Wang, Hua; Liu, Jingning; Yin, Ying; Wu, Jun; Wang, Zilu; Miao, Dengshun; Sun, Wen

    2014-01-01

    Osteoporosis is a common disorder characterized by compromised bone strength that predisposes patients to increased fracture risk. Parathyroid hormone related protein (PTHrP) is one of the candidates for clinical osteoporosis treatment. In this study, GST Gene Fusion System was used to express recombinant human PTHrP (hPTHrP) 1-34 and 1-84. To determine whether the recombinant hPTHrP1-34 and 1-84 can enhance renal calcium reabsorption and promote bone formation, we examined effects of recombinant hPTHrP1-34 and 1-84 on osteogenic lineage commitment in a primary bone marrow cell culture system and on osteoporosis treatment. Results revealed that both of recombinant hPTHrP1-34 and 1-84 increased colony formation and osteogenic cell differentiation and mineralization in vitro; however, the effect of recombinant hPTHrP1-84 is a little stronger than that of hPTHrP1-34. Next, ovariectomy was used to construct osteoporosis animal model (OVX) to test activities of these two recombinants in vivo. HPTHrP1-84 administration elevated serum calcium by up-regulating the expression of renal calcium transporters, which resulted in stimulation of osteoblastic bone formation. These factors contributed to augmented bone mass in hPTHrP1-84 treated OVX mice but did not affect bone resorption. There was no obvious bone mass alteration in hPTHrP1-34 treated OVX mice, which may be, at least partly, associated with shorter half-life of hPTHrP1-34 compared to hPTHrP1-84 in vivo. This study implies that recombinant hPTHrP1-84 is more effective than hPTHrP1-34 to enhance renal calcium reabsorption and to stimulate bone formation in vivo. PMID:24516619

  17. Serum phosphorus adds to value of serum parathyroid hormone for assessment of bone turnover in renal osteodystrophy.

    PubMed

    Gentry, Jimmy; Webb, Jonathan; Davenport, Daniel; Malluche, Hartmut H

    2016-07-01

    It is well-established that parathyroid hormone (PTH) correlates with the level of bone turnover in patients with chronic kidney disease stage 5D (CKD-5D). Hyperphosphatemia is a well-established complication of end-stage renal disease and is usually attributed to dietary intake. This study evaluates the relationship between serum phosphorus levels and bone turnover in patients with CKD-5D. 93 patients with CKD-5D from the Kentucky Bone Registry who had sequentially undergone anterior iliac bone biopsies were reviewed. Undecalcified bone sections were qualitatively assessed for turnover and placed into a group with low turnover and a group with non-low (normal/high) turnover. Results of PTH and phosphorus concentrations in blood drawn at the time of biopsies were compared between the groups. PTH and phosphorus levels were significantly higher in the non-low turnover group compared to the low turnover group. Cutoff levels for PTH and phosphorus were tested for predictive power of bone turnover. Both PTH and phosphorus correlated with turnover. Adding serum phosphorus to serum PTH enhanced predictive power of PTH for low turnover. The vast majority of patients with serum phosphorus levels ≥ 6.0 mg/dL had non-low turnover, while the majority of those with low turnover had phosphorus values < 6.0 mg/dL. Classification and regression-tree analysis showed that elevated serum phosphorus (> 6.2 mg/dL) in patients with PTH < 440 pg/mL was helpful in diagnosing nonlow turnover in this range of PTH. In patients with PTH ranges of 440 - 814 pg/mL, serum phosphorus levels > 4.55 mg/dL ruled out low turnover bone disease. This suggests that not only dietary intake but also bone affects serum phosphorus levels. PMID:27191663

  18. Preparation and in vivo evaluation of an orally available enteric-microencapsulated parathyroid hormone (1-34)-deoxycholic acid nanocomplex

    PubMed Central

    Hwang, Seung Rim; Seo, Dong-Hyun; Byun, Youngro; Park, Jin Woo

    2016-01-01

    The N-terminal 34-amino-acid peptide fragment of human parathyroid hormone PTH (1-34), is used clinically to treat osteoporosis; however, it is currently administered by a once-daily subcutaneous injection, resulting in poor patient compliance. We have developed enteric microcapsules containing an ionic nanocomplex between PTH (1-34) and lysine-linked deoxycholic acid (LysDOCA) for the oral delivery of PTH (1-34). We measured the particle size of the PTH/LysDOCA complex and assessed its biological activity by determining the cAMP content in MC3T3-E1 cells. We also assessed its permeability across a Caco-2 cell monolayer and the bioavailability of the intrajejunally administered PTH/LysDOCA complex compared with PTH (1-34) in rats. In addition, the antiosteoporotic activity of the PTH/LysDOCA complex, encapsulated in an enteric carrier by coaxial ultrasonic atomization, was evaluated after it was orally administered to ovariectomized (OVX) rats. The formation of an ionic complex between PTH (1-34) and LysDOCA produced nanoparticles of diameter 33.0±3.36 nm, and the bioactivity of the complex was comparable with that of PTH (1-34). The Caco-2 cell permeability and AUClast value of the PTH/LysDOCA (1:10) nanocomplex increased by 2.87- and 16.3-fold, respectively, compared with PTH (1-34) alone. Furthermore, the OVX rats treated with oral PTH/LysDOCA-loaded enteric microcapsules showed an increase in bone mineral density (159%), bone volume fraction (175%), and trabecular number (174%) compared with those in the OVX control group. Therefore, the PTH/LysDOCA nanocomplex oral delivery system is a promising treatment modality for osteoporosis because it improves osteogenesis and trabecular connectivity.

  19. Defective postnatal endochondral bone development by chondrocyte-specific targeted expression of parathyroid hormone type 2 receptor.

    PubMed

    Panda, Dibyendu Kumar; Goltzman, David; Karaplis, Andrew C

    2012-12-15

    The human parathyroid hormone type 2 receptor (PTH2R) is activated by PTH and by tuberoinfundibular peptide of 39 residues (TIP39), the latter likely acting as its natural ligand. Although the receptor is expressed at highest levels in the nervous system, we have observed that both PTH2R and TIP39 are expressed in the newborn mouse growth plate, with the receptor localizing in the resting zone and the ligand TIP39 localizing exclusively in prehypertrophic and hypertrophic chondrocytes. To address the role of PTH2R in postnatal skeletal growth and development, Col2a1-hPTH2R (PTH2R-Tg) transgenic mice were generated. The mice were viable and of nearly normal size at birth. Expression of the transgene in the growth plate was limited to chondrocytes. We found that chondrocyte proliferation was decreased, as determined by in vivo BrdU labeling of proliferating chondrocytes and CDK4 and p21 expression in the growth plate of Col2a1-hPTH2R transgenic mice. Similarly, the differentiation and maturation of chondrocytes was delayed, as characterized by decreased Sox9 expression and weaker immunostaining for the chondrocyte differentiation markers collagen type II and type X and proteoglycans. As well, there was altered expression of Gdf5, Wdr5, and β-catenin, factors implicated in chondrocyte maturation, proliferation, and differentiation.These effects impacted on the process of endochondral ossification, resulting in delayed formation of the secondary ossification center, and diminished trabecular bone volume. The findings substantiate a role for PTH2R signaling in postnatal growth plate development and subsequent bone mass acquisition.

  20. Role of parathyroid hormone-related protein in tubulointerstitial apoptosis and fibrosis after folic acid-induced nephrotoxicity.

    PubMed

    Ortega, Arantxa; Rámila, David; Ardura, Juan Antonio; Esteban, Vanesa; Ruiz-Ortega, Marta; Barat, Antonio; Gazapo, Rosa; Bosch, Ricardo J; Esbrit, Pedro

    2006-06-01

    Parathyroid hormone-related protein (PTHrP) is shortly upregulated in acute renal injury, but its pathophysiologic role is unclear. Investigated was whether PTHrP might act as a profibrogenic factor in mice that do or do not overexpress PTHrP in the proximal tubule after folic acid (FA) nephrotoxicity, a model of acute renal damage followed by partial regeneration and patchy tubulointerstitial fibrosis. It was found that constitutive PTHrP overexpression in these animals conveyed a significant increase in tubulointerstitial fibrosis, associated with both fibroblast activation (as alpha-smooth muscle actin staining) and macrophage influx, compared with control littermates at 2 to 3 wk after FA damage. Cell proliferation and survival was higher (P<0.01) in the renal interstitium of PTHrP-overexpressing mice than in control littermates within this period after injury. Moreover, the former mice had a constitutive Bcl-XL protein overexpression. In vitro studies in renal tubulointerstitial and fibroblastic cells strongly suggest that PTHrP (1-36) (100 nM) reduced FA-induced apoptosis through a dual mechanism involving Bcl-XL upregulation and Akt and Bad phosphorylation. PTHrP (1-36) also stimulated monocyte chemoattractant protein-1 expression in tubuloepithelial cells, as well as type-1 procollagen gene expression and fibronectin (mRNA levels and protein secretion) in these cells and renal fibroblastic cells. Our findings indicate that this peptide, by interaction with the PTH1 receptor, can increase tubulointerstitial cell survival and seems to act as a proinflammatory and profibrogenic factor in the FA-damaged kidney.

  1. Preparation and in vivo evaluation of an orally available enteric-microencapsulated parathyroid hormone (1-34)-deoxycholic acid nanocomplex

    PubMed Central

    Hwang, Seung Rim; Seo, Dong-Hyun; Byun, Youngro; Park, Jin Woo

    2016-01-01

    The N-terminal 34-amino-acid peptide fragment of human parathyroid hormone PTH (1-34), is used clinically to treat osteoporosis; however, it is currently administered by a once-daily subcutaneous injection, resulting in poor patient compliance. We have developed enteric microcapsules containing an ionic nanocomplex between PTH (1-34) and lysine-linked deoxycholic acid (LysDOCA) for the oral delivery of PTH (1-34). We measured the particle size of the PTH/LysDOCA complex and assessed its biological activity by determining the cAMP content in MC3T3-E1 cells. We also assessed its permeability across a Caco-2 cell monolayer and the bioavailability of the intrajejunally administered PTH/LysDOCA complex compared with PTH (1-34) in rats. In addition, the antiosteoporotic activity of the PTH/LysDOCA complex, encapsulated in an enteric carrier by coaxial ultrasonic atomization, was evaluated after it was orally administered to ovariectomized (OVX) rats. The formation of an ionic complex between PTH (1-34) and LysDOCA produced nanoparticles of diameter 33.0±3.36 nm, and the bioactivity of the complex was comparable with that of PTH (1-34). The Caco-2 cell permeability and AUClast value of the PTH/LysDOCA (1:10) nanocomplex increased by 2.87- and 16.3-fold, respectively, compared with PTH (1-34) alone. Furthermore, the OVX rats treated with oral PTH/LysDOCA-loaded enteric microcapsules showed an increase in bone mineral density (159%), bone volume fraction (175%), and trabecular number (174%) compared with those in the OVX control group. Therefore, the PTH/LysDOCA nanocomplex oral delivery system is a promising treatment modality for osteoporosis because it improves osteogenesis and trabecular connectivity. PMID:27621618

  2. Intermittent administration of parathyroid hormone improves the repairing process of rat calvaria defects: A histomorphometric and radiodensitometric study

    PubMed Central

    Silva, Eduardo-de-Paula; Marques, Marcelo-Rocha; Dias da Silva, Marco-Antônio; Manzi, Flávio-Ricardo; Barros, Silvana-Pereira

    2015-01-01

    Background The aim of this study was to evaluate the effects of intermittent treatment of parathyroid hormone (PTH (1-34)) on the bone regeneration of critically-sized rat calvarial bone defects. Material and Methods Thirty-two male rats were trephined (4mm fullthickness diameter), in the central part of the parietal bones and divided into 2 groups of 16. The PTH group received subcutaneous injections of PTH (1-34) at 40µg/kg, 3 times a week and the control (CTL) group received the vehicle in the same regimen. The rats were sacrificed at 4 weeks post-treatment regimen, the parietal bones were extracted and samples were evaluated through histomorphometry and radiodensitometry. Results The histological observations showed that the PTH group presented more “island-like” new bone between the defect margins with fibrous tissues than did the CTL group. The PTH group significantly exhibited greater histologic bone formation than did the CTL group (1.5mm ±0.7; 1.9 mm ± 0.6, p<0.05/ for residual bone defect). The radiodensitometry analysis revealed significant differences among the PTH and CTL groups (2.1 Al eq. ±0.04; 1.8Al eq. ±0.06, p<0.05), demonstrating an increase in bone mineral density. The PTH treatment contributed to the bone formation with a higher amount of mineral and/or fibrous tissue when compared with the CTL group. Conclusions The results suggest that it was possible to increase the process of bone regeneration by accelerating the healing process in rat calvarial defects through intermittent administration of the PTH treatment. Key words: Bone, skull, rats, bone regeneration, bone density. PMID:26034928

  3. Admixture mapping of serum vitamin D and parathyroid hormone concentrations in the African American-Diabetes Heart Study.

    PubMed

    Palmer, Nicholette D; Divers, Jasmin; Lu, Lingyi; Register, Thomas C; Carr, J Jeffrey; Hicks, Pamela J; Smith, S Carrie; Xu, Jianzhao; Judd, Suzanne E; Irvin, Marguerite R; Gutierrez, Orlando M; Bowden, Donald W; Wagenknecht, Lynne E; Langefeld, Carl D; Freedman, Barry I

    2016-06-01

    Vitamin D and intact parathyroid hormone (iPTH) concentrations differ between individuals of African and European descent and may play a role in observed racial differences in bone mineral density (BMD). These findings suggest that mapping by admixture linkage disequilibrium (MALD) may be informative for identifying genetic variants contributing to these ethnic disparities. Admixture mapping was performed for serum 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, vitamin D-binding protein (VDBP), bioavailable vitamin D, and iPTH concentrations and computed tomography measured thoracic and lumbar vertebral volumetric BMD in 552 unrelated African Americans with type 2 diabetes from the African American-Diabetes Heart Study. Genotyping was performed using a custom Illumina ancestry informative marker (AIM) panel. For each AIM, the probability of inheriting 0, 1, or 2 copies of a European-derived allele was determined. Non-parametric linkage analysis was performed by testing for association between each AIM using these probabilities among phenotypes, accounting for global ancestry, age, and gender. Fine-mapping of MALD peaks was facilitated by genome-wide association study (GWAS) data. VDBP levels were significantly linked in proximity to the protein coding locus (rs7689609, LOD=11.05). Two loci exhibited significant linkage signals for 1,25-dihydroxyvitamin D on 13q21.2 (rs1622710, LOD=3.20) and 12q13.2 (rs11171526, LOD=3.10). iPTH was significantly linked on 9q31.3 (rs7854368, LOD=3.14). Fine-mapping with GWAS data revealed significant known (rs7041 with VDBP, P=1.38×10(-82)) and novel (rs12741813 and rs10863774 with VDBP, P<6.43×10(-5)) loci with plausible biological roles. Admixture mapping in combination with fine-mapping has focused efforts to identify loci contributing to ethnic differences in vitamin D-related traits. PMID:27032714

  4. Parathyroid hormone 1 receptor is essential to induce FGF23 production and maintain systemic mineral ion homeostasis.

    PubMed

    Fan, Yi; Bi, Ruiye; Densmore, Michael J; Sato, Tadatoshi; Kobayashi, Tatsuya; Yuan, Quan; Zhou, Xuedong; Erben, Reinhold G; Lanske, Beate

    2016-01-01

    Parathyroid-hormone-type 1 receptor (PTH1R) is extensively expressed in key regulatory organs for systemic mineral ion homeostasis, including kidney and bone. We investigated the bone-specific functions of PTH1R in modulating mineral ion homeostasis by generating a novel mouse model in which PTH1R is ablated in the limb mesenchyme using Prx1Cre transgenic mice. Such ablation decreased FGF23 protein and serum levels by 50%, despite normal Fgf23 mRNA levels in long bones. Circulating calcium and PTH levels were unchanged, but inorganic phosphate and 1,25(OH)2D3 levels were significantly decreased and accompanied by elevated urinary calcium and phosphate wasting. Key renal genes for balancing mineral ion homeostasis, calbindinD28k, Klotho, and Napi2a were suppressed by 30-40%. Intermittent hPTH(1-34) injections increased Fgf23 mRNA (7.3-fold), Nurr1 mRNA (3.1-fold), and serum intact-FGF23 (1.6-fold) in controls, but failed to induce Fgf23, Nurr1 mRNA, or intact FGF23 production in mutants. Moreover, a significant elevation in serum C-terminal-FGF23 levels (4-fold) was detected in both genotypes. PTH markedly downregulated Galnt3 expression (2.7-fold) in controls but not in mutants. These results demonstrate the pivotal role of PTH1R in long bones to regulate systemic mineral ion homeostasis and the direct induction of FGF23 by PTH1R signaling.

  5. Intermittent Administration of Parathyroid Hormone [1-34] Prevents Particle-Induced Periprosthetic Osteolysis in a Rat Model.

    PubMed

    Bi, Fanggang; Shi, Zhongli; Zhou, Chenhe; Liu, An; Shen, Yue; Yan, Shigui

    2015-01-01

    We examined whether intermittent administration of parathyroid hormone [1-34] (PTH[1-34]; 60 μg/kg/day) can prevent the negative effects of titanium (Ti) particles on implant fixation and periprosthetic osteolysis in a rat model. Eighteen adult male rats (12 weeks old, bones still growing) received intramedullary Ti implants in their bilateral femurs; 6 rats from the blank group received vehicle injections, and 12 rats from the control group and PTH treatment group received Ti particle injections at the time of operation and intra-articular injections 2 and 4 weeks postoperatively. Six of the rats that received Ti particles from the PTH group also received PTH[1-34] treatment. Six weeks postoperatively, all specimens were collected for assessment by X-ray, micro-CT, biomechanical, scanning electron microscopy (SEM), and dynamic histomorphometry. A lower BMD, BV/TV, Tb.N, maximal fixation strength, and mineral apposition rate were observed in the control group compared to the blank group, demonstrating that a periprosthetic osteolysis model had been successfully established. Administration of PTH[1-34] significantly increased the bone mineral density of the distal femur, BV/TV, Tb.N, Tb.Th, Tb.Sp, Con.D, SMI, and maximal fixation strength in the PTH group compared to that in the control group. SEM revealed higher bone-implant contact, thicker lamellar bone, and larger trabecular bone area in the PTH group than in the control group. A higher mineral apposition rate was observed in the PTH group compared to both the blank and control groups. These findings imply that intermittent administration of PTH[1-34] prevents periprosthetic osteolysis by promoting bone formation. The effects of PTH[1-34] were evaluated at a suprapharmacological dosage to the human equivalent in rats; therefore, additional studies are required to demonstrate its therapeutic potential in periprosthetic osteolysis. PMID:26441073

  6. Serum Sclerostin Levels Negatively Correlate with Parathyroid Hormone Levels and Free Estrogen Index in Postmenopausal Women

    PubMed Central

    Mirza, Faryal S.; Padhi, I. Desmond; Raisz, Lawrence G.; Lorenzo, Joseph A.

    2010-01-01

    Context: Sclerostin is a negative regulator of bone formation. Objective: The aim of the study was to compare serum sclerostin levels in premenopausal and postmenopausal women and evaluate its relationship to estrogen, TH, bone turnover, and bone mass. Design, Setting, and Participants: We conducted a cross-sectional observational study of healthy community-dwelling pre- and postmenopausal women. Intervention(s): There were no interventions. Main Outcome Measure(s): We compared serum sclerostin levels in pre- and postmenopausal women and correlated sclerostin levels with female sex hormones, calciotropic hormones, bone turnover markers, and bone mineral density. Results: Premenopausal women were 26.8 yr old, and postmenopausal women were 56.8 yr old. Postmenopausal women had lower values for estradiol (30 ± 23 vs. 10 ± 4 pg/ml; P < 0.001), estrone (61 ± 24 vs. 29 ± 10 pg/ml; P <0.001), and free estrogen index (FEI) (6 ± 4 vs. 3 ± 2 pmol/nmol; P = 0.008) and significantly lower bone mineral density at all sites compared to premenopausal women, with no significant differences in levels of PTH, 25-hydroxy or 1,25-dihydroxy vitamin D levels. Postmenopausal women had significantly higher serum sclerostin levels (1.16 ± 0.38 ng/ml vs. 0.48 ± 0.15 ng/ml; P < 0.001). Because most of the premenopausal women were on oral contraceptives, subsequent analyses were limited to postmenopausal women. There were significant negative correlations between sclerostin and FEI and sclerostin and PTH in this group. Using multiple regression analysis, both FEI (β = −0.629; P = 0.002) and PTH (β = −0.554; P = 0.004) were found to be independent predictors of sclerostin levels in postmenopausal women. Conclusions: Our findings suggest that serum sclerostin levels are regulated by both estrogens and PTH in postmenopausal women. These findings need to be explored further in larger prospective studies. PMID:20156921

  7. The vitamin D, ionised calcium and parathyroid hormone axis of cerebral capillary function: therapeutic considerations for vascular-based neurodegenerative disorders.

    PubMed

    Lam, Virginie; Takechi, Ryusuke; Pallabage-Gamarallage, Menuka; Giles, Corey; Mamo, John C L

    2015-01-01

    Blood-brain barrier dysfunction characterised by brain parenchymal extravasation of plasma proteins may contribute to risk of neurodegenerative disorders, however the mechanisms for increased capillary permeability are not understood. Increasing evidence suggests vitamin D confers central nervous system benefits and there is increasing demand for vitamin D supplementation. Vitamin D may influence the CNS via modulation of capillary function, however such effects may be indirect as it has a central role in maintaining calcium homeostasis, in concert with calcium regulatory hormones. This study utilised an integrated approach and investigated the effects of vitamin D supplementation, parathyroid tissue ablation (PTX), or exogenous infusion of parathyroid hormone (PTH) on cerebral capillary integrity. Parenchymal extravasation of immunoglobulin G (IgG) was used as a marker of cerebral capillary permeability. In C57BL/6J mice and Sprague Dawley rats, dietary vitamin D was associated with exaggerated abundance of IgG within cerebral cortex (CTX) and hippocampal formation (HPF). Vitamin D was also associated with increased plasma ionised calcium (iCa) and decreased PTH. A response to dose was suggested and parenchymal effects persisted for up to 24 weeks. Ablation of parathyroid glands increased CTX- and HPF-IgG abundance concomitant with a reduction in plasma iCa. With the provision of PTH, iCa levels increased, however the PTH treated animals did not show increased cerebral permeability. Vitamin D supplemented groups and rats with PTH-tissue ablation showed modestly increased parenchymal abundance of glial-fibrillary acidic protein (GFAP), a marker of astroglial activation. PTH infusion attenuated GFAP abundance. The findings suggest that vitamin D can compromise capillary integrity via a mechanism that is independent of calcium homeostasis. The effects of exogenous vitamin D supplementation on capillary function and in the context of prevention of vascular

  8. The Vitamin D, Ionised Calcium and Parathyroid Hormone Axis of Cerebral Capillary Function: Therapeutic Considerations for Vascular-Based Neurodegenerative Disorders

    PubMed Central

    Lam, Virginie; Takechi, Ryusuke; Pallabage-Gamarallage, Menuka; Giles, Corey; Mamo, John C. L.

    2015-01-01

    Blood-brain barrier dysfunction characterised by brain parenchymal extravasation of plasma proteins may contribute to risk of neurodegenerative disorders, however the mechanisms for increased capillary permeability are not understood. Increasing evidence suggests vitamin D confers central nervous system benefits and there is increasing demand for vitamin D supplementation. Vitamin D may influence the CNS via modulation of capillary function, however such effects may be indirect as it has a central role in maintaining calcium homeostasis, in concert with calcium regulatory hormones. This study utilised an integrated approach and investigated the effects of vitamin D supplementation, parathyroid tissue ablation (PTX), or exogenous infusion of parathyroid hormone (PTH) on cerebral capillary integrity. Parenchymal extravasation of immunoglobulin G (IgG) was used as a marker of cerebral capillary permeability. In C57BL/6J mice and Sprague Dawley rats, dietary vitamin D was associated with exaggerated abundance of IgG within cerebral cortex (CTX) and hippocampal formation (HPF). Vitamin D was also associated with increased plasma ionised calcium (iCa) and decreased PTH. A response to dose was suggested and parenchymal effects persisted for up to 24 weeks. Ablation of parathyroid glands increased CTX- and HPF-IgG abundance concomitant with a reduction in plasma iCa. With the provision of PTH, iCa levels increased, however the PTH treated animals did not show increased cerebral permeability. Vitamin D supplemented groups and rats with PTH-tissue ablation showed modestly increased parenchymal abundance of glial-fibrillary acidic protein (GFAP), a marker of astroglial activation. PTH infusion attenuated GFAP abundance. The findings suggest that vitamin D can compromise capillary integrity via a mechanism that is independent of calcium homeostasis. The effects of exogenous vitamin D supplementation on capillary function and in the context of prevention of vascular

  9. The secretion of parathyroid hormone-related protein in the saliva of sheep and its effects on the salivary clearance of phosphate, calcium, magnesium, potassium and sodium ions.

    PubMed

    Dua, K; Abbas, S K; Care, A D

    1995-07-01

    Parathyroid hormone-related protein (PTHrP(1-34)) was infused into five sheep, each fitted with a large rumen cannula. After infusion, significant increases were observed in the total and ionized calcium concentrations in plasma but not in saliva. In contrast, significant decreases in the plasma concentrations of phosphate and potassium and corresponding increases in their salivary concentrations and clearance rates were observed. The salivary concentration of endogenous PTH1P(1-34) was significantly greater than that in plasma sampled simultaneously, but during the infusion of PTHrP(1-34) both plasma and salivary concentrations of PTHrP(1-34) increased.

  10. Parathyroid hormone induces c-fos and c-jun messenger RNA in rat osteoblastic cells

    NASA Technical Reports Server (NTRS)

    Clohisy, J. C.; Scott, D. K.; Brakenhoff, K. D.; Quinn, C. O.; Partridge, N. C.

    1992-01-01

    PTH is a potent regulator of osteoblast gene expression, yet the nuclear events that mediate PTH action are poorly understood. We were interested in identifying immediate early genes which may regulate PTH-altered gene expression in the osteoblast. Therefore, we examined the effects of PTH on c-fos and c-jun gene expression in a rat osteoblastic cell line (UMR 106-01). Under control conditions, c-fos and c-jun mRNAs were present at low basal levels. After PTH treatment, c-fos mRNA abundance dramatically increased, with a maximal and transient response at 30 min. PTH also stimulated an increase in c-jun mRNA, but in a biphasic manner, with maximal levels at 30 min and 2 h. These responses were dose dependent, not altered by cotreatment with the protein synthesis inhibitor cycloheximide, and preceded PTH-induced expression of matrix metallo-proteinase-1 mRNA. Nuclear run-on assays demonstrated an increased rate of c-fos and c-jun transcription after PTH exposure. To determine the signal transduction pathways involved, second messenger analogs were tested for their ability to mimic the effects of PTH. 8-Bromo-cAMP and phorbol 12-myristate 13-acetate (PMA) caused increases in the abundance of c-fos and c-jun transcripts. Ionomycin had no effect on the expression of these genes. Pretreatment of the cells with PMA resulted in a decrease in basal c-jun expression, but did not alter the PTH-mediated increase in c-fos, c-jun, or matrix metalloproteinase-1 mRNAs.(ABSTRACT TRUNCATED AT 250 WORDS).

  11. Parathyroid hormone inhibition of Na{sup +}/H{sup +} exchanger 3 transcription: Intracellular signaling pathways and transcription factor expression

    SciTech Connect

    Neri, Elida Adalgisa; Bezerra, Camila Nogueira Alves Queiroz-Leite, Gabriella Duarte; Polidoro, Juliano Zequini; Rebouças, Nancy Amaral

    2015-06-12

    The main transport mechanism of reabsorption of sodium bicarbonate and fluid in the renal proximal tubules involves Na{sup +}/H{sup +} exchanger 3 (NHE3), which is acutely and chronically downregulated by parathyroid hormone (PTH). Although PTH is known to exert an inhibitory effect on NHE3 expression and transcription, the molecular mechanisms involved remain unclear. Here, we demonstrated that, in opossum kidney proximal tubule (OKP) cells, PTH-induced inhibition of Nhe3 gene promoter occurs even in the core promoter that controls expression of the reporter gene. We found that inhibition of the protein kinase A (PKA) and Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways transformed PTH from an inhibitor of promoter activity into an activator of that same activity, as did point mutations in the EGR1, Sp1, and Sp3 binding consensus elements in the promoter. In nuclear extracts of PTH-treated OKP cells, we also observed increased expression of EGR1 mRNA and of some Sp3 isoforms. Electrophoretic mobility shift assay showed a supershift of the −61 to −42-bp probe with an anti-EGR1 antibody in PTH-treated cells, suggesting that EGR1 binding is relevant for the inhibitory activity of PTH. We conclude that PTH-induced inhibition of NHE3 transcription is related to higher EGR1 expression; to EGR1 binding to the proximal and core promoters; and to PKA and JAK/STAT pathway activation. This mechanism might be responsible, at least in part, for lower NHE3 expression and sodium reabsorption in renal proximal tubules in the presence of high PTH levels. - Highlights: • PTH regulation of Nhe3 promoter depends on EGR1 binding. • EGR1, PKA and JAK/STAT are involved in PTH inhibition of the Nhe3 promoter. • PTH alters expression of EGR1 and Sp3. • PTH inhibits the Nhe3 promoter by regulating PKA and JAK/STAT signaling.

  12. Influence of Vitamin D and Parathyroid Hormone on Bone and Metabolic Risk in Women with Previous Gestational Diabetes

    PubMed Central

    Serra, Monica C.; Ryan, Alice S.

    2016-01-01

    The purpose of this study was to compare plasma 25-hydroxy vitamin D (25(OH)D) and parathyroid hormone (PTH), VO2max, bone (by DXA), and metabolic outcomes across age and race-matched postmenopausal women (54±1 years; mean±SEM): 1) with previous gestational diabetes (GDM) (32±1 kg/m2; N=17), 2) without previous GDM, but with a similar BMI to GDM (32±1 kg/m2; N=17), and 3) without previous GDM, but with a higher BMI than GDM (36±1 kg/m2; N=17; P<0.01). The prevalence of 25(OH)D insufficiency and deficiency was high (~80%), but not different across groups, while PTH tended to be ~30% lower in women with a history of GDM (P=0.09). Women with a history of GDM had lower HDL cholesterol and higher diastolic blood pressure and fasting and 2-hr glucose levels (by oral glucose tolerance test) (vs. groups 2 and 3; P’s<0.05). Bone mineral density (BMD) tended to be slightly higher in women with prior GDM than the BMI matched women with no prior GDM (P=0.09). Overall, higher PTH was associated with lower femoral neck (r=−0.33) and (r=−0.38) (P’s<0.05), while lower 25(OH)D was associated with lower VO2max (r=0.25, P=0.05) and higher fasting glucose (r=−0.14) and insulin (r=−0.29 (P’s<0.05). We observe that the poor metabolic profiles of postmenopausal women with a history of GDM are independent of 25(OH)D and PTH. However, due to associations between 25(OH)D and PTH with bone and metabolic outcomes, maintaining recommended 25(OH)D and PTH concentrations is important regardless of a previous history of GDM. PMID:26882050

  13. Enhanced Individual Trabecular Repair and Its Mechanical Implications in Parathyroid Hormone and Alendronate Treated Rat Tibial Bone

    PubMed Central

    Altman, Allison R.; de Bakker, Chantal M. J.; Tseng, Wei-Ju; Chandra, Abhishek; Qin, Ling; Sherry Liu, X.

    2015-01-01

    Combined parathyroid hormone (PTH) and bisphosphonate (alendronate—ALN) therapy has recently been shown to increase bone volume fraction and plate-like trabecular structure beyond either monotherapy. To identify the mechanism through which plate-like structure was enhanced, we used in vivo microcomputed tomography (μCT) of the proximal tibia metaphysis and individual trabecular dynamics (ITD) analysis to quantify connectivity repair (incidences of rod connection and plate perforation filling) and deterioration (incidences of rod disconnection and plate perforation). Three-month-old female, intact rats were scanned before and after a 12 day treatment period of vehicle (Veh, n = 5), ALN (n = 6), PTH (n = 6), and combined (PTH+ALN, n = 6) therapy. Additionally, we used computational simulation and finite element (FE) analysis to delineate the contributions of connectivity repair or trabecular thickening to trabecular bone stiffness. Our results showed that the combined therapy group had greater connectivity repair (5.8 ± 0.5% connected rods and 2.0 ± 0.3% filled plates) beyond that of the Veh group, resulting in the greatest net gain in connectivity. For all treatment groups, increases in bone volume due to thickening (5–31%) were far greater than those due to connectivity repair (2–3%). Newly formed bone contributing only to trabecular thickening caused a 10%, 41%, and 69% increase in stiffness in the ALN, PTH, and PTH+ALN groups, respectively. Moreover, newly formed bone that led to connectivity repair resulted in an additional improvement in stiffness, with the highest in PTH+ALN (by an additional 12%), which was significantly greater than either PTH (5.6%) or ALN (4.5%). An efficiency ratio was calculated as the mean percent increase in stiffness divided by mean percent increase in BV for either thickening or connectivity repair in each treatment. For all treatments, the efficiency ratio of connectivity repair (ALN: 2.9; PTH: 3

  14. Human parathyroid hormone-(1-38) restores cancellous bone to the immobilized, osteopenic proximal tibial metaphysis in rats

    NASA Technical Reports Server (NTRS)

    Ma, Y. F.; Jee, W. S.; Ke, H. Z.; Lin, B. Y.; Liang, X. G.; Li, M.; Yamamoto, N.

    1995-01-01

    The purpose of this study was to determine if human parathyroid hormone-(1-38) (hPTH(1-38)) can restore cancellous bone mass to the established osteopenic, immobilized proximal tibial metaphyses of female rats. The right hindlimbs of 6-month-old female Sprague-Dawley rats were immobilized by bandaging the right hindlimbs to the abdomen. After 30 days of right hindlimb immobilization, the rats were subcutaneously injected with 200 micrograms hPTH(1-38)/kg/day for 15 days (short-term treatment) or 75 days (longer-term treatment). Static bone histomorphometry was performed on the primary spongiosa, and both static and dynamic histomorphometry were performed on the secondary spongiosa of the right proximal tibial metaphyses. Immobilization for 30 days without treatment decreased trabecular bone area, number, and thickness in both primary and secondary spongiosa, and induced an increase in eroded perimeter and a decrease in tissue referent-bone formation rate in the secondary spongiosa. These changes reached a new steady state thereafter. Treatment with 200 micrograms hPTH(1-38)/kg/day for 15 days, beginning 30 days after immobilization, significantly increased trabecular bone area, thickness, and number in both primary and secondary spongiosa despite continuous immobilization when compared with controls. The short-term PTH treatment (15 days) significantly increased labeling perimeter, mineral apposition rate, and tissue referent-bone formation rate in the secondary spongiosa and stimulated longitudinal bone growth as compared with the controls. Longer PTH treatment (75 days) further increased trabecular bone area, thickness, and number as compared with controls and groups given short-term PTH treatment (15 days). The bone formation indices in the secondary spongiosa of the longer-term treated rats were lower than those of the short-term treated group, but they were still higher than those of controls. Our findings indicate that PTH treatment stimulates cancellous bone

  15. Human parathyroid hormone-(1-38) restores cancellous bone to the immobilized, osteopenic proximal tibial metaphysis in rats

    NASA Technical Reports Server (NTRS)

    Ma, Y. F.; Jee, W. S. S.; Ke, H. Z.; Lin, B. Y.; Liang, X. G.; Li, M.; Yamamoto, N.

    1994-01-01

    The purpose of this study was to determine if human parathyroid hormone-(1-38) (PTH) can restore cancellous bone mass to the established osteopenic, immobilized proximal tibial metaphyses (PTM) of female rats. The right hindlimbs of six-month-old female Sprague-Dawley rats were immobilized by bandaging the right hindlimbs to the abdomen. After 30 days of right hindlimb immobilization (RHLI), the rats were subcutaneously injected with 200 microgram hPTH(1-38)/kg/day for 15 (short-term) or 75 (longer-term) days. Static bone histomorphometry was performed on the primary spongiosa, while both static and dynamic histomorphometry were performed on the secondary spongiosa of the right PTM. Immobilization for 30 days without treatment decreased trabecular bone area, number and thickness in both primary and secondary spongiosa, and induced an increase in eroded perimeter and a decrease in tissue referent-bone formation rate (BFR/TV) in the secondary spongios. These changes reached a new steady state thereafter. Treatment with 200 microgram hPTH(1-38)/kg/day for 15 days, beginning at 30 days post immobilization (IM), significantly increased trabecular bone area, thickness and number in both primary and secondary spongiosa despite continuous IM when compared to the age-related and IM controls. The short-term (15 days) PTH treatment significantly increased labeling perimeter, mineral apposition rate and BFR/TV in the secondary spongiosa and stimulated longitudinal bone growth as compared to the age-related and IM controls. PTH treatment for longer-term (75 days) further increased trabecular bone area, thickness and number as compared to aging and IM controls and short-term (15 days) PTH treated groups. The bone formation indices in the secondary spongiosa of these longer-term treated rats were lower than that of short-term (15 days) PTH treated group, but they were still higher than those of IM and age-related controls. Our findings indicate that PTH treatment stimulates

  16. Daily Parathyroid Hormone 1-34 Replacement Therapy for Hypoparathyroidism Induces Marked Changes in Bone Turnover and Structure

    PubMed Central

    Gafni, Rachel I.; Brahim, Jaime S.; Andreopoulou, Panagiota; Bhattacharyya, Nisan; Kelly, Marilyn H.; Brillante, Beth A.; Reynolds, James C.; Zhou, Hua; Dempster, David W.; Collins, Michael T.

    2012-01-01

    Parathyroid hormone (PTH) has variable actions on bone. Chronically increased PTH is catabolic leading to osteoporosis, yet intermittent administration is anabolic and increases bone mass. PTH deficiency is associated with decreased bone remodeling and increased bone mass. However, the effects of PTH replacement therapy on bone in hypoparathyroidism are not well known. We discontinued calcitriol therapy and treated five hypoparathyroid subjects (2 adults and 3 adolescents) with synthetic human PTH 1-34 (hPTH 1-34), injected 2-3 times daily for 18 months, with doses individualized to maintain serum calcium at 1.9-2.25 mmol/L. Biochemical markers and bone density (BMD) were assessed every 6 months; iliac-crest biopsies were performed before and after 1 year of treatment. hPTH 1-34 therapy significantly increased bone markers to supranormal levels. Histomorphometry revealed that treatment dramatically increased cancellous bone volume and trabecular number and decreased trabecular separation. Changes in trabecular width were variable, suggesting that the increase in trabecular number was due to the observed intratrabecular tunneling. Cortical width remained unchanged, however, hPTH 1-34 treatment increased cortical porosity. Cancellous bone remodeling was also stimulated, inducing significant changes in osteoid, mineralizing surface, and bone formation rate. Similar changes were seen in endocortical and intracortical remodeling. BMD Z-scores were unchanged at the spine and femoral neck. Total hip Z-scores increased, however, total body BMD Z-scores decreased during the first 6 months of treatment and then stabilized, remaining significantly decreased compared to baseline. Radial Z-scores also decreased with treatment; this was most pronounced in the growing adolescent. Daily hPTH 1-34 therapy for hypoparathyroidism stimulated bone turnover, increased bone volume, and altered bone structure in the iliac crest. These findings suggest that treatment with hPTH 1-34 in

  17. Parathyroid hormone-related protein(1-34) in gestational fluids and release from human gestational tissues.

    PubMed

    Farrugia, W; Ho, P W; Rice, G E; Moseley, J M; Permezel, M; Wlodek, M E

    2000-06-01

    Parathyroid hormone-related protein (PTHrP) is present in fetal and gestational tissues, in which its proposed roles include stimulation of epithelial growth and differentiation, vasodilatation of the uteroplacental vasculature, relaxation of uterine muscle and stimulation of placental calcium transport. The aim of this study was to determine whether the release of PTHrP from gestational tissue explants was tissue specific. In addition, PTHrP concentrations were measured in maternal plasma, umbilical artery and vein plasma, and amniotic fluid from term, uncomplicated pregnancies before the onset of labour. PTHrP was detected in low concentrations in the mother, fetus and placental tissue. Amniotic fluid had ten times the PTHrP concentration compared with that in the maternal or fetal circulations. Using late pregnant human gestational tissues in an in vitro explant system, we found that amnion over placenta, choriodecidua, reflected amnion, and placenta released PTHrP into culture medium in progressively greater amounts over 24 h (P<0.05). This release was not associated with a loss of cell membrane integrity, as indicated by measurement of the intracellular enzyme, lactate dehydrogenase, in the incubation media. After 24 h incubation, the fetal membranes released significantly (P<0.05) greater amounts of PTHrP than did the placenta (placenta 3. 7+/-0.5 pmol PTHrP/g protein). Amnion over placenta released significantly more PTHrP (139.3+/- 43.1 pmol PTHrP/g protein) than did reflected amnion (29.0+/-8.3 pmol PTHrP/g protein) (P<0.05). This study unequivocally demonstrated that human gestational tissues release PTHrP and it was concluded that the main contributors to PTHrP in amniotic fluid were the human fetal membranes, particularly amnion over placenta. Fetal membrane-derived and amniotic fluid PTHrP are proposed to have stimulatory effects on epithelial growth and differentiation in fetal lung, gut, skin and hair follicles and paracrine effects on placental

  18. The p27 Pathway Modulates the Regulation of Skeletal Growth and Osteoblastic Bone Formation by Parathyroid Hormone-Related Peptide.

    PubMed

    Zhu, Min; Zhang, Jing; Dong, Zhan; Zhang, Ying; Wang, Rong; Karaplis, Andrew; Goltzman, David; Miao, Dengshun

    2015-11-01

    Parathyroid hormone-related peptide (PTHrP) 1-84 knock-in mice (Pthrp KI) develop skeletal growth retardation and defective osteoblastic bone formation. To further examine the mechanisms underlying this phenotype, microarray analyses of differential gene expression profiles were performed in long bone extracts from Pthrp KI mice and their wild-type (WT) littermates. We found that the expression levels of p27, p16, and p53 were significantly upregulated in Pthrp KI mice relative to WT littermates. To determine whether p27 was involved in the regulation by PTHrP of skeletal growth and development in vivo, we generated compound mutant mice, which were homozygous for both p27 deletion and the Pthrp KI mutation (p27(-/-) Pthrp KI). We then compared p27(-/-) Pthrp KI mice with p27(-/-), Pthrp KI, and WT littermates. Deletion of p27 in Pthrp KI mice resulted in a longer lifespan, increased body weight, and improvement in skeletal growth. At 2 weeks of age, skeletal parameters, including length of long bones, size of epiphyses, numbers of proliferating cell nuclear antigen (PCNA)-positive chondrocytes, bone mineral density, trabecular bone volume, osteoblast numbers, and alkaline phosphatase (ALP)-, type I collagen-, and osteocalcin-positive bone areas were increased in p27(-/-) mice and reduced in both Pthrp KI and p27(-/-) Pthrp KI mice compared with WT mice; however, these parameters were increased in p27(-/-) Pthrp KI mice compared with Pthrp KI mice. As well, protein expression levels of PTHR, IGF-1, and Bmi-1, and the numbers of total colony-forming unit fibroblastic (CFU-f) and ALP-positive CFU-f were similarly increased in p27(-/-) Pthrp KI mice compared with Pthrp KI mice. Our results demonstrate that deletion of p27 in Pthrp KI mice can partially rescue defects in skeletal growth and osteoblastic bone formation by enhancing endochondral bone formation and osteogenesis. These studies, therefore, indicate that the p27 pathway may function downstream in the action

  19. Summer/winter differences in the serum 25-hydroxyvitamin D3 and parathyroid hormone levels of Japanese women

    NASA Astrophysics Data System (ADS)

    Nakamura, K.; Nashimoto, Mitsue; Yamamoto, Masaharu

    Serum 25-hydroxyvitamin D3 [25(OH)D3] is produced in the skin in response to exposure to ultraviolet radiation, and is a good indicator of vitamin D nutritional status. The aim of this study was to determine summer/winter differences in serum 25(OH)D3 and parathyroid hormone (PTH) in Japanese women and how the summer and winter values are related. The subjects were 122 healthy Japanese women aged 45-81 years (average age: 65.7 years). They were medically examined twice, in September 1997 and February 1999. Serum 25(OH)D3 and intact PTH were determined by high-performance liquid chromatography and a two-site immunoradiometric assay respectively. Lifestyle information was obtained through an interview. The seasonal differences (winter minus summer) in 25(OH)D3 [Δ25(OH)D3] and intact PTH concentrations were -18.8 nmol/l (SD 19.2, P<0.0001) and 0.98pmol/l (SD 1.02, P<0.0001) respectively. The correlation coefficient between summer (x) and winter (y) 25(OH)D3 levels was 0.462 (P<0.0001), with a linearly fitted line of y=0.42x+26.4. This relationship was interpreted as subjects with higher summer 25(OH)D3 values having greater reductions in winter 25(OH)D3 concentrations. There were inter-individual differences in Δ25(OH)D3, although the summer and winter 25(OH)D3 concentrations were well-correlated. Since Δ25(OH)D3 was not associated with any of the lifestyle factors, seasonal differences in the 25(OH)D3 concentrations of an individual appeared to reflect her ability to produce 25(OH)D3 photochemically in the skin. Sun bathing would be a less effective means of attaining adequate vitamin D nutritional status in a person with a small seasonal difference in 25(OH)D3, i.e., one with a low 25(OH)D3 level.

  20. Treatment with N- and C-Terminal Peptides of Parathyroid Hormone-Related Protein Partly Compensate the Skeletal Abnormalities in IGF-I Deficient Mice

    PubMed Central

    Portal-Núñez, Sergio; Murillo-Cuesta, Silvia; Lozano, Daniel; Cediel, Rafael; Esbrit, Pedro

    2014-01-01

    Insulin-like growth factor-I (IGF-I) deficiency causes growth delay, and IGF-I has been shown to partially mediate bone anabolism by parathyroid hormone (PTH). PTH-related protein (PTHrP) is abundant in bone, and has osteogenic features by poorly defined mechanisms. We here examined the capacity of PTHrP (1–36) and PTHrP (107–111) (osteostatin) to reverse the skeletal alterations associated with IGF-I deficiency. Igf1-null mice and their wild type littermates were treated with each PTHrP peptide (80 µg/Kg/every other day/2 weeks; 2 males and 4 females for each genotype) or saline vehicle (3 males and 3 females for each genotype). We found that treatment with either PTHrP peptide ameliorated trabecular structure in the femur in both genotypes. However, these peptides were ineffective in normalizing the altered cortical structure at this bone site in Igf1-null mice. An aberrant gene expression of factors associated with osteoblast differentiation and function, namely runx2, osteoprotegerin/receptor activator of NF-κB ligand ratio, Wnt3a, cyclin D1, connexin 43, catalase and Gadd45, as well as in osteocyte sclerostin, was found in the long bones of Igf1-null mice. These mice also displayed a lower amount of trabecular osteoblasts and osteoclasts in the tibial metaphysis than those in wild type mice. These alterations in Igf1-null mice were only partially corrected by each PTHrP peptide treatment. The skeletal expression of Igf2, Igf1 receptor and Irs2 was increased in Igf1-null mice, and this compensatory profile was further improved by treatment with each PTHrP peptide related to ERK1/2 and FoxM1 activation. In vitro, PTHrP (1–36) and osteostatin were effective in promoting bone marrow stromal cell mineralization in normal mice but not in IGF-I-deficient mice. Collectively, these findings indicate that PTHrP (1–36) and osteostatin can exert several osteogenic actions even in the absence of IGF-I in the mouse bone. PMID:24503961

  1. Lead alters parathyroid hormone-related peptide and transforming growth factor-beta1 effects and AP-1 and NF-kappaB signaling in chondrocytes.

    PubMed

    Zuscik, Michael J; Pateder, Dhruv B; Puzas, J Edward; Schwarz, Edward M; Rosier, Randy N; O'Keefe, Regis J

    2002-07-01

    The skeletal system is an important target for lead toxicity. One of the impacts of lead in the skeleton, the inhibition of axial bone development, is likely due to its effect on the normal progression of chondrocyte maturation that is central to the process of endochondral ossification. Since little is known about the effect of lead on chondrocyte function/maturation, its impact on (1) growth factor-induced proliferation, (2) expression of maturation-specific markers type X collagen and BMP-6, and (3) the activity of AP-1 and NF-kappaB was examined in chick growth plate and sternal chondrocyte models. Exposure to lead alone (1-30 microM) resulted in a dose-dependent inhibition of thymidine incorporation in growth plate chondrocytes. Lead also blunted the stimulation of thymidine incorporation by parathyroid hormone-related peptide (PTHrP) and transforming growth factor-beta1 (TGF-beta1), two critical regulators of chondrocyte maturation. Lead (1 and 10 microM), TGF-beta1 (3 ng/ml) and PTHrP (10(-7) M) all significantly inhibited the expression of type X collagen, a marker of chondrocyte terminal differentiation. However, when in combination, lead completely reversed the inhibition of type X collagen by PTHrP and TGF-beta1. The effect of lead on BMP-6. an inducer of terminal differentiation. was also examined. Independently, lead and TGF-beta1 were without effect on BMP-6 expression, but PTHrP significantly suppressed it. Comparatively, lead did not alter PTHrP-mediated suppression of BMP-6, but in combination with TGF-beta1. BMP-6 expression was increased 3-fold. To determine if lead effects on signaling might play a role in facilitating these events, the impact of lead on NF-kappaB and AP-1 signaling was assessed using luciferase reporter constructs in sternal chondrocytes. Lead had no effect on the AP-1 reporter, but it dose-dependently inhibited the NF-kappaB reporter. PTHrP, which signals through AP-1, did not activate the NF-kappaB reporter and did not affect

  2. Treatment with N- and C-terminal peptides of parathyroid hormone-related protein partly compensate the skeletal abnormalities in IGF-I deficient mice.

    PubMed

    Rodríguez-de la Rosa, Lourdes; López-Herradón, Ana; Portal-Núñez, Sergio; Murillo-Cuesta, Silvia; Lozano, Daniel; Cediel, Rafael; Varela-Nieto, Isabel; Esbrit, Pedro

    2014-01-01

    Insulin-like growth factor-I (IGF-I) deficiency causes growth delay, and IGF-I has been shown to partially mediate bone anabolism by parathyroid hormone (PTH). PTH-related protein (PTHrP) is abundant in bone, and has osteogenic features by poorly defined mechanisms. We here examined the capacity of PTHrP (1-36) and PTHrP (107-111) (osteostatin) to reverse the skeletal alterations associated with IGF-I deficiency. Igf1-null mice and their wild type littermates were treated with each PTHrP peptide (80 µg/Kg/every other day/2 weeks; 2 males and 4 females for each genotype) or saline vehicle (3 males and 3 females for each genotype). We found that treatment with either PTHrP peptide ameliorated trabecular structure in the femur in both genotypes. However, these peptides were ineffective in normalizing the altered cortical structure at this bone site in Igf1-null mice. An aberrant gene expression of factors associated with osteoblast differentiation and function, namely runx2, osteoprotegerin/receptor activator of NF-κB ligand ratio, Wnt3a , cyclin D1, connexin 43, catalase and Gadd45, as well as in osteocyte sclerostin, was found in the long bones of Igf1-null mice. These mice also displayed a lower amount of trabecular osteoblasts and osteoclasts in the tibial metaphysis than those in wild type mice. These alterations in Igf1-null mice were only partially corrected by each PTHrP peptide treatment. The skeletal expression of Igf2, Igf1 receptor and Irs2 was increased in Igf1-null mice, and this compensatory profile was further improved by treatment with each PTHrP peptide related to ERK1/2 and FoxM1 activation. In vitro, PTHrP (1-36) and osteostatin were effective in promoting bone marrow stromal cell mineralization in normal mice but not in IGF-I-deficient mice. Collectively, these findings indicate that PTHrP (1-36) and osteostatin can exert several osteogenic actions even in the absence of IGF-I in the mouse bone.

  3. Parathyroid carcinoma in tertiary hyperparathyroidism.

    PubMed

    Kim, Byung Seup; Ryu, Han Suk; Kang, Kyung Ho; Park, Sung Jun

    2016-10-01

    Parathyroid carcinoma is a rare disease of unknown etiology. This study presents a case of parathyroid carcinoma in a patient with tertiary hyperparathyroidism. Despite a successful kidney transplantation, the intact parathyroid hormone (iPTH) level of the patient was elevated consistently and could not be controlled by medical therapy. Due to the development of tertiary hyperparathyroidism with bone pain and osteoporosis, subtotal parathyroidectomy was performed 4 months after the kidney transplantation. Histological evaluation revealed that one of four parathyroid lesions was a parathyroid carcinoma, while the others were diffuse hyperplasia. Postoperative laboratory studies indicated a decreased level of iPTH. A positron emission tomography-computed tomography performed 6 months after the operation revealed no evidence of local recurrence or distant metastasis. PMID:27664600

  4. Green fluorescent protein fused to peptide agonists of two dissimilar G protein-coupled receptors: novel ligands of the bradykinin B2 (rhodopsin family) receptor and parathyroid hormone PTH1 (secretin family) receptor.

    PubMed

    Charest-Morin, Xavier; Fortin, Jean-Philippe; Bawolak, Marie-Thérèse; Lodge, Robert; Marceau, François

    2013-10-01

    We hypothesized that peptide hormone sequences that stimulate and internalize G protein-coupled receptors (GPCRs) could be prolonged with a functional protein cargo. To verify this, we have selected two widely different pairs of peptide hormones and GPCRs that nevertheless share agonist-induced arrestin-mediated internalization. For the parathyroid hormone (PTH) PTH1 receptor (PTH1R) and the bradykinin (BK) B2 receptor (B2R), we have designed fusion proteins of the agonists PTH1-34 and maximakinin (MK, a BK homologue) with the enhanced green fluorescent protein (EGFP), thus producing candidate high molecular weight ligands. According to docking models of each hormone to its receptor, EGFP was fused either at the N-terminus (MK) or C-terminus (PTH1-34) of the ligand; the last construction is also secretable due to inclusion of the preproinsulin signal peptide and has been produced as a conditioned medium. EGFP-MK has been produced as a lysate of transfected cells. Using an enzyme-linked immunosorbent assay (ELISA) for GFP, average concentrations of 1.5 and 1670 nmol/L, respectively, of ligand were found in these preparations. The functional properties and potential of these analogs for imaging receptor-expressing cells were examined. Microscopic and cytofluorometric evidence of specific binding and internalization of both fusion proteins was obtained using recipient HEK 293a cells that expressed the cognate recombinant receptor. Endosomal colocalization studies were conducted (Rab5, Rab7, β-arrestin1). Evidence of agonist signaling was obtained (expression of c-Fos, cyclic AMP responsive element (CRE) reporter gene for PTH1-34-EGFP). The constructs PTH1-34-EGFP and EGFP-MK represent bona fide agonists that support the feasibility of transporting protein cargoes inside cells using GPCRs.

  5. JTT-305, an orally active calcium-sensing receptor antagonist, stimulates transient parathyroid hormone release and bone formation in ovariectomized rats.

    PubMed

    Kimura, Shuichi; Nakagawa, Takashi; Matsuo, Yushi; Ishida, Yuji; Okamoto, Yoshihisa; Hayashi, Mikio

    2011-10-01

    Intermittent administration of parathyroid hormone (PTH) has a potent anabolic effect on bone in humans and animals. Calcium-sensing receptor (CaSR) antagonists stimulate endogenous PTH secretion through CaSR on the surface of parathyroid cells and thereby may be anabolic agents for osteoporosis. JTT-305 is a potent oral short-acting CaSR antagonist and transiently stimulates endogenous PTH secretion. The objective of the present study was to investigate the effects of JTT-305 on PTH secretion and bone in ovariectomized rats. Female rats, immediately after ovariectomy (OVX), were orally administered vehicle or JTT-305 (0.3, 1, or 3 mg/kg) for 12 weeks. The serum PTH concentrations were transiently elevated with increasing doses of JTT-305. In the proximal tibia, JTT-305 prevented OVX-induced decreases in both the cancellous and total bone mineral density (BMD) except for the 0.3mg/kg dose. At the 3mg/kg dose, JTT-305 increased the mineralizing surface and bone formation rate in histomorphometry. The efficacy of JTT-305 at the 3mg/kg dose on the BMD corresponded to that of exogenous rat PTH1-84 injection at doses between 3 and 10 μg/kg. In conclusion, JTT-305 stimulated endogenous transient PTH secretion and bone formation, and consequently prevented bone loss in OVX rats. These results suggest that JTT-305 is orally active and has the potential to be an anabolic agent for the treatment of osteoporosis.

  6. Crystallization of the receptor-binding domain of parathyroid hormone-related protein in complex with a neutralizing monoclonal antibody Fab fragment

    SciTech Connect

    McKinstry, William J.; Polekhina, Galina; Diefenbach-Jagger, Hannelore; Sato, Koh; Onuma, Etsuro; Gillespie, Matthew T.; Martin, Thomas J.; Parker, Michael W.

    2009-04-01

    Parathyroid hormone-related protein (PTHrP) plays an important role in regulating embryonic skeletal development and is abnormally regulated in the pathogenesis of skeletal complications observed with many cancers and osteoporosis. It exerts its action through binding to a G-protein-coupled seven-transmembrane cell-surface receptor (GPCR). Structurally, GPCRs are very difficult to study by X-ray crystallography. In this study, a monoclonal antibody Fab fragment which recognizes the same region of PTHrP as its receptor, PTH1R, was used to aid in the crystallization of PTHrP. The resultant protein complex was crystallized using the hanging-drop vapour-diffusion method with polyethylene glycol as a precipitant. The crystals belonged to the orthorhombic space group P2{sub 1}2{sub 1}2, with unit-cell parameters a = 72.6, b = 96.3, c = 88.5 {angstrom}, and diffracted to 2.0 {angstrom} resolution using synchrotron radiation. The crystal structure will shed light on the nature of the key residues of PTHrP that interact with the antibody and will provide insights into how the antibody is able to discriminate between PTHrP and the related molecule parathyroid homone.

  7. Molecular characterization of an intragenic minisatellite (VNTR) polymorphism in the human parathyroid hormone-related peptide gene in chromosome region 12p12. 1-p11. 2

    SciTech Connect

    Pausova, Z.; Morgan, K.; Fujiwara, M.; Bourdon, J.; Goltzman, D.; Hendy, G.N. )

    1993-07-01

    The human parathyroid hormone-related peptide (hPTHrP) gene in chromosome region 12p12.1-p11.2 plays an important role in mammalian development and specifically in skeletogenesis. The authors have characterized a VNTR polymorphism in the hPTHrP gene that is located in an intron 100-bp downstream of exon VI that encodes a 3[prime] untranslated region. By PCR analysis eight different alleles were identified in a group of 112 unrelated individuals. All eight alleles were sequenced and the repeat unit was identified as the general sequence [G(TA)[sub n]C][sub N], where n = 4 to 11 and N = 3 to 17. This polymorphic sequence-tagged site will be useful for mapping chromosome 12p and will aid in testing for linkage of genetic diseases to the hPTHrP gene. 3 refs., 2 figs.

  8. Induction of Thermal and Mechanical Hypersensitivity by Parathyroid Hormone-related Peptide (PTHrP) Through Upregulation of TRPV1 Function and Trafficking

    PubMed Central

    Mickle, Aaron D.; Shepherd, Andrew J.; Loo, Lipin; Mohapatra, Durga P.

    2016-01-01

    The neurobiological mechanisms underlying chronic pain associated with cancers are not well understood. It has been hypothesized that factors specifically elevated in the tumor microenvironment sensitize adjacent nociceptive afferents. We show that parathyroid hormone-related peptide (PTHrP), which is found at elevated levels in the tumor microenvironment of advanced breast and prostate cancers, is a critical modulator of sensory neurons. Intraplantar injection of PTHrP led to the development of thermal and mechanical hypersensitivity in both male and female mice, which were absent in mice lacking functional transient receptor potential vanilloid-1 (TRPV1). The PTHrP treatment of cultured mouse sensory neurons enhanced action potential firing, and increased TRPV1 activation, which was dependent on protein kinase C (PKC) activity. Parathyroid hormone-related peptide induced robust potentiation of TRPV1 activation and enhancement of neuronal firing at mild acidic pH that is relevant to acidic tumor microenvironment. We also observed an increase in plasma membrane TRPV1 protein levels after exposure to PTHrP, leading to upregulation in the proportion of TRPV1-responsive neurons, which was dependent on the activity of PKC and Src kinases. Furthermore, co-injection of PKC or Src inhibitors attenuated PTHrP-induced thermal but not mechanical hypersensitivity. Altogether, our results suggest that PTHrP and mild acidic conditions could induce constitutive pathological activation of sensory neurons through upregulation of TRPV1 function and trafficking, which could serve as a mechanism for peripheral sensitization of nociceptive afferents in the tumor microenvironment. PMID:25970319

  9. Intermittent administration of human parathyroid hormone (1-34) increases fixation of strontium-doped hydroxyapatite coating titanium implants via electrochemical deposition in ovariectomized rat femur.

    PubMed

    Tao, Zhou-Shan; Zhou, Wan-Shu; Qiang, Zhou; Tu, Kai-kai; Huang, Zheng-Liang; Xu, Hong-Ming; Sun, Tao; Lv, Yang-Xun; Cui, Wei; Yang, Lei

    2016-02-01

    Previous studies have demonstrated the effect of human parathyroid hormone (1-34) (PTH) or strontium-doped hydroxyapatite coating (Sr-HA) on osteoporotic bone implantation. However, reports about effects of PTH plus Sr-HA on bone osseointegration of titanium implants in a state of osteoporosis were limited. This study was designed to investigate the effects of intermittent administration of human parathyroid hormone (1-34) on strontium-doped hydroxyapatite coating (Sr-HA) implant fixation in ovariectomized (OVX) rats. Twelve weeks after bilateral ovariectomy, all animals were randomly divided into four groups including control group, Sr group, PTH group and PTH+Sr group. Forty OVX rats accepted implant insertion in the distal femurs, control group, and PTH group with HA implants and the Sr group and PTH+Sr group with Sr-HA implants. Animals from PTH group and PTH+Sr group then randomly received PTH (60 µg/kg, 3 times a week) until death at 12 weeks. After 12-week healing period, implants from group PTH+Sr revealed improved osseointegration compared with other treatment groups, which is manifested by the exceeding increase of bone area ratio and bone-to-implant contact, the trabecular microarchitecture and the maximal push-out force displayed by tests like histomorphometry, micro-CT, and biomechanics evaluation. These results demonstrated that PTH+ Sr-HA coatings could enhance implant osseointegration in OVX rats, and suggested the feasibility of using this method to improve implant fixation in osteoporotic bone. PMID:26482573

  10. Identification, molecular characterization, and tissue expression of parathyroid hormone-related protein gene (PTHrP) from water buffalo (Bubalus bubalis).

    PubMed

    Liu, J; Qian, L D; Huo, J L; Bi, B L; Li, D L; Wang, S F; Chen, T; Li, L J; Mao, H M; Miao, Y W

    2015-03-27

    Parathyroid hormone-related protein (PTHrP) is involved in the deposition of milk calcium in mammal lactation, but its role in buffalo is unclear. In this study, the full-length coding sequence of the water buffalo PTHrP gene was first isolated using reverse transcription-polymerase chain reaction. The protein was then subjected to molecular characterization using bioinformatic methods, and the tissue expression pattern was further assayed by semi-quantitative reverse-transcription polymerase chain reaction. The water buffalo PTHrP gene contains an open reading frame of 534 base pairs encoding a polypeptide of 177 amino acid residues, a theoretical molecular weight of 20.32 kDa, and an isoelectric point of 10.00. In addition, water buffalo PTHrP was predicted to contain a signal peptide, a typical hydrophobic region with no hydrophobic transmembrane regions, and to exert its function in the cell nucleus. A conserved domain of parathyroid superfamily from amino acids 34-114 was observed in the polypeptide. Sequence comparison and the phylogenetic analysis showed that the sequence of the water buffalo PTHrP protein shared high homology with that of other mammals, particularly cattle and goat. Among the 16 tissues examined, the PTHrP gene was only expressed in adipose tissue, placenta, uterine wall, hypophysis, and mammary gland tissue, but gene expression levels were higher in the uterus wall and adipose tissue. The results of this study suggest that the PTHrP gene plays an important role in the deposition of milk calcium of water buffalo.

  11. Vesicle-Mediated Steroid Hormone Secretion in Drosophila melanogaster.

    PubMed

    Yamanaka, Naoki; Marqués, Guillermo; O'Connor, Michael B

    2015-11-01

    Steroid hormones are a large family of cholesterol derivatives regulating development and physiology in both the animal and plant kingdoms, but little is known concerning mechanisms of their secretion from steroidogenic tissues. Here, we present evidence that in Drosophila, endocrine release of the steroid hormone ecdysone is mediated through a regulated vesicular trafficking mechanism. Inhibition of calcium signaling in the steroidogenic prothoracic gland results in the accumulation of unreleased ecdysone, and the knockdown of calcium-mediated vesicle exocytosis components in the gland caused developmental defects due to deficiency of ecdysone. Accumulation of synaptotagmin-labeled vesicles in the gland is observed when calcium signaling is disrupted, and these vesicles contain an ABC transporter that functions as an ecdysone pump to fill vesicles. We propose that trafficking of steroid hormones out of endocrine cells is not always through a simple diffusion mechanism as presently thought, but instead can involve a regulated vesicle-mediated release process. PMID:26544939

  12. Parathyroids and ultimobranchial bodies in monotremes.

    PubMed

    Haynes, J I

    1999-02-01

    Only scant information is available in the scientific literature on the parathyroids and ultimobranchial bodies in the primitive mammals, the echidna (Tachyglossus aculeatus) and platypus (Ornithorhynchus anatinus). The major aim of this paper is to describe the morphology of the monotreme parathyroid gland and to compare it with parathyroids in mammals and reptiles. The gross anatomy and light microscopic structure of the ultimobranchial body, thymus, and thyroid are also given. Animals were dissected and routine light and electron microscopic techniques used to examine the microscopic morphology. The locations of parathyroid hormone, calcitonin and calcitonin gene-related peptide in tissue sections were identified by immunostaining. Monotremes have one pair of parathyroid glands located in the thorax and they are often associated with thymic tissue but never with the thyroid which is also present in the mediastinum. Ultimobranchial bodies are ventrolateral to the commencement of the trachea. Thymic lobules with Hassall's corpuscles are scattered in the fibrofatty tissue of the mediastinum and the ventral surface of the pericardium. Histologically, principal cells, water-clear cells, and non-secretory cells were identified in the parathyroid glands. Principal cells showed polarity and had microlamellar projections that formed intercellular canaliculi. Non-secretory cells had features similar to those of thymic epithelial reticular cells. Immunostaining of parathyroid hormone showed a diffuse distribution in parathyroid principal cells and none in ultimobranchial bodies. Identification of the ultimobranchial bodies was confirmed by immunostaining. The monotreme parathyroid gland, ultimobranchial bodies and thyroid show reptilian as well as mammalian features.

  13. Amphibian parathyroids: morphological and functional aspects.

    PubMed

    Srivastav, A K; Das, V K; Das, S; Sasayama, Y; Suzuki, N

    1995-10-01

    Amphibians living partially or totally in a terrestrial environment are the first tetrapods to possess parathyroid glands. Purely aquatic amphibians and amphibian larvae lack these endocrine glands. The parathyroids develop at the time of metamorphosis. The parathyroid glands in caecilians consist of a single cell type, that of urodeles may be composed of basal (supporting) cells and suprabasal (chief) cells, and that of anurans of small and large chief cells. Parathyroid glands of caecilians and anurans lack connective tissue, blood vessels, and nerves. The parathyroid cells become activated in response to decreased blood calcium concentration and undergo changes indicating increased parathyroid hormone secretion. Increased blood calcium concentration suppresses secretory activity. Usually, parathyroidectomy elicits hypocalcemia in most amphibians. Such operations have no effect in lower urodeles. Parathyroid hormone administration provokes hypercalcemia in most amphibians. The parathyroids of caecilians have not been studied in detail. The urodeles and anurans exhibit seasonal changes in the parathyroid glands. These changes may be initiated by environmental stimuli such as light, temperature, or alterations in blood calcium levels caused by natural hibernation.

  14. Amphibian parathyroids: morphological and functional aspects.

    PubMed

    Srivastav, A K; Das, V K; Das, S; Sasayama, Y; Suzuki, N

    1995-10-01

    Amphibians living partially or totally in a terrestrial environment are the first tetrapods to possess parathyroid glands. Purely aquatic amphibians and amphibian larvae lack these endocrine glands. The parathyroids develop at the time of metamorphosis. The parathyroid glands in caecilians consist of a single cell type, that of urodeles may be composed of basal (supporting) cells and suprabasal (chief) cells, and that of anurans of small and large chief cells. Parathyroid glands of caecilians and anurans lack connective tissue, blood vessels, and nerves. The parathyroid cells become activated in response to decreased blood calcium concentration and undergo changes indicating increased parathyroid hormone secretion. Increased blood calcium concentration suppresses secretory activity. Usually, parathyroidectomy elicits hypocalcemia in most amphibians. Such operations have no effect in lower urodeles. Parathyroid hormone administration provokes hypercalcemia in most amphibians. The parathyroids of caecilians have not been studied in detail. The urodeles and anurans exhibit seasonal changes in the parathyroid glands. These changes may be initiated by environmental stimuli such as light, temperature, or alterations in blood calcium levels caused by natural hibernation. PMID:8580512

  15. PARATHYROID HORMONE 2 RECEPTOR AND ITS ENDOGENOUS LIGAND TIP39 ARE CONCENTRATED IN ENDOCRINE, VISCEROSENSORY AND AUDITORY BRAIN REGIONS IN MACAQUE AND HUMAN

    PubMed Central

    Bagó, Attila G.; Dimitrov, Eugene; Saunders, Richard; Seress, László; Palkovits, Miklós; Usdin, Ted B.; Dobolyi, Arpád

    2009-01-01

    Parathyroid hormone receptor 2 (PTH2R) and its ligand, tuberoinfundibular peptide of 39 residues (TIP39) constitute a neuromodulator system implicated in endocrine and nociceptive regulations. We now describe the presence and distribution of the PTH2R and TIP39 in the brain of primates using a range of tissues and ages from macaque and human brain. In situ hybridization histochemistry of TIP39 mRNA, studied in young macaque brain, due to its possible decline beyond late postnatal ages, was present only in the thalamic subparafascicular area and the pontine medial paralemniscal nucleus. In contrast in situ hybridization histochemistry in macaque identified high levels of PTH2R expression in the central amygdaloid nucleus, medial preoptic area, hypothalamic paraventricular and periventricular nuclei, medial geniculate, and the pontine tegmentum. PTH2R mRNA was also detected in several human brain areas by RT-PCR. The distribution of PTH2R-immunoreactive fibers in human, determined by immunocytochemistry, was similar to that in rodents including dense fiber networks in the medial preoptic area, hypothalamic paraventricular, periventricular and infundibular (arcuate) nuclei, lateral hypothalamic area, median eminence, thalamic paraventricular nucleus, periaqueductal gray, lateral parabrachial nucleus, nucleus of the solitary tract, sensory trigeminal nuclei, medullary dorsal reticular nucleus, and dorsal horn of the spinal cord. Co-localization suggested that PTH2R fibers are glutamatergic, and that TIP39 may directly influence hypophysiotropic somatostatin containing and indirectly influence corticotropin releasing-hormone containing neurons. The results demonstrate that TIP39 and the PTH2R are expressed in the brain of primates in locations that suggest involvement in regulation of fear, anxiety, reproductive behaviors, release of pituitary hormones, and nociception. PMID:19401215

  16. Duplicated zebrafish co-orthologs of parathyroid hormone-related peptide (PTHrP, Pthlh) play different roles in craniofacial skeletogenesis

    PubMed Central

    Yan, Yi-Lin; Bhattacharya, Poulomi; He, Xin Jun; Ponugoti, Bhaskar; Marquardt, Ben; Layman, Jason; Grunloh, Melissa; Postlethwait, John H.; Rubin, David A.

    2013-01-01

    In mammals, parathyroid hormone-related peptide (PTHrP, alias PTH-like hormone (Pthlh)) acts as a paracrine hormone that regulates the patterning of cartilage, bone, teeth, pancreas, and thymus. Beyond mammals, however, little is known about the molecular genetic mechanisms by which Pthlh regulates early development. To evaluate conserved pathways of craniofacial skeletogenesis, we isolated two Pthlh co-orthologs from the zebrafish (Danio rerio) and investigated their structural, phylogenetic, and syntenic relationships, expression, and function. Results showed that pthlh duplicates originated in the teleost genome duplication. Zebrafish pthlha and pthlhb were maternally expressed and showed overlapping and distinct zygotic expression patterns during skeletal development that mirrored mammalian expression domains. To explore the regulation of duplicated pthlh genes, we studied their expression patterns in mutants and found that both sox9a and sox9b are upstream of pthlha in arch and fin bud cartilages, but only sox9b is upstream of pthlha in the pancreas. Morpholino antisense knockdown showed that pthlha regulates both sox9a and sox9b in the pharyngeal arches but not in the brain or otic vesicles and that pthlhb does not regulate either sox9 gene, which is likely related to its highly degraded nuclear localization signal. Knockdown of pthlha but not pthlhb caused runx2b overexpression in craniofacial cartilages and premature bone mineralization. We conclude that in normal cartilage development, sox9 upregulates pthlh, which downregulates runx2, and that the duplicated nature of all three of these genes in zebrafish creates a network of regulation by different co-orthologs in different tissues. PMID:22761277

  17. Racial differences in the relationship between vitamin D, bone mineral density, and parathyroid hormone in the National Health and Nutrition Examination Survey

    PubMed Central

    Farwell, W. R.; Kermah, D.; Taylor, E. N.

    2011-01-01

    Summary It is unclear whether optimal levels of 25-hydroxyvitamin D (25(OH)D) in whites are the same as in minorities. In adult participants of NHANES, the relationships between 25(OH)D, bone mineral density (BMD), and parathyroid hormone (PTH) differed in blacks as compared to whites and Mexican-Americans, suggesting that optimal 25(OH)D levels for bone and mineral metabolism may differ by race. Introduction Blacks and Hispanics have lower 25-hydroxyvitamin D concentrations than whites. However, it is unclear whether 25(OH)D levels considered “optimal” for bone and mineral metabolism in whites are the same as those in minority populations. Methods We examined the relationships between 25(OH)D and parathyroid hormone in 8,415 adult participants (25% black and 24% Mexican-American) in the National Health and Nutrition Examination Surveys 2003–2004 and 2005–2006; and between 25(OH)D and bone mineral density in 4,206 adult participants (24% black and 24% Mexican-American) in the 2003–2004 sample. Results Blacks and Mexican-Americans had significantly lower 25(OH)D and higher PTH concentrations than whites (P<0.01 for both). BMD significantly decreased (P<0.01) as serum 25(OH)D and calcium intake declined among whites and Mexican-Americans, but not among blacks (P=0.2). The impact of vitamin D deficiency (25 (OH)D≤20 ng/ml) on PTH levels was modified by race/ethnicity (P for interaction, 0.001). Whereas inverse relationships between 25(OH)D and PTH were observed above and below a 25(OH)D level of 20 ng/ml in whites and Mexican-Americans, an inverse association between 25(OH)D and PTH was only observed below this threshold in blacks, with the slope of the relationship being essentially flat (P=0.7) above this cut-point, suggesting that PTH may be maximally suppressed at lower 25(OH)D levels in blacks than in whites or Mexican-Americans. Conclusions The relationships between 25(OH)D, BMD, and PTH may differ by race among US adults. Whether race

  18. Pediatric stress: hormonal mediators and human development.

    PubMed

    Charmandari, Evangelia; Kino, Tomoshige; Souvatzoglou, Emmanuil; Chrousos, George P

    2003-01-01

    Stress activates the central and peripheral components of the stress system, i.e., the hypothalamic-pituitary-adrenal (HPA) axis and the arousal/sympathetic system. The principal effectors of the stress system are corticotropin-releasing hormone (CRH), arginine vasopressin, the proopiomelanocortin-derived peptides alpha-melanocyte-stimulating hormone and beta-endorphin, the glucocorticoids, and the catecholamines norepinephrine and epinephrine. Appropriate responsiveness of the stress system to stressors is a crucial prerequisite for a sense of well-being, adequate performance of tasks and positive social interactions. By contrast, inappropriate responsiveness of the stress system may impair growth and development, and may account for a number of endocrine, metabolic, autoimmune and psychiatric disorders. The development and severity of these conditions primarily depend on the genetic vulnerability of the individual, the exposure to adverse environmental factors and the timing of the stressful event(s), given that prenatal life, infancy, childhood and adolescence are critical periods characterized by increased vulnerability to stressors. The developing brain undergoes rapid growth and is characterized by high turnover of neuronal connections during the prenatal and early postnatal life. These processes and, hence, brain plasticity, slow down during childhood and puberty, and plateau in young adulthood. Hormonal actions in early life, and to a much lesser extent later, can be organizational, i.e., can have effects that last for long periods of time, often for the entire life of the individual. Hormones of the stress system and sex steroids have such effects, which influence the behavior and certain physiologic functions of individuals for life. Exposure of the developing brain to severe and/or prolonged stress may result in hyperactivity/hyperreactivity of the stress system, with resultant amygdala hyperfunction (fear reaction), decreased activity of the hippocampus

  19. Insulin like growth factor-I: a critical mediator of the skeletal response to parathyroid hormone.

    PubMed

    Bikle, Daniel D; Wang, Yongmei

    2012-06-01

    This review focuses on the mechanisms by which PTH stimulates both osteoblast and osteoclast function, emphasizing the critical role that IGF-I plays in these processes. After reviewing the current literature on the skeletal actions of PTH and the modulation of IGF action on bone by the different IGF-binding proteins, the review then examines studies from mouse models in which IGF-I or its receptor have been selectively deleted in different cells of the skeletal system, in particular osteoprogenitors, mature osteoblasts, and osteoclasts. Mice in which IGF-I production has been deleted from all cells are deficient in both bone formation and bone resorption with few osteoblasts or osteoclasts in bone in vivo, reduced osteoblast colony forming units, and an inability of either the osteoblasts or osteoclast precursors to support osteoclastogenesis in vitro. Mice in which the IGF-I receptor is specifically deleted in mature osteoblasts have a mineralization defect in vivo, and bone marrow stromal cells from these mice fail to mineralize in vitro. Mice in which the IGF-I receptor is deleted in osteoprogenitor cells have a marked reduction in osteoblast proliferation and differentiation leading to osteopenia. Finally mice lacking the IGF-I receptor in their osteoclasts have increased bone and decreased osteoclast formation. PTH fails to stimulate bone formation in the mice lacking IGF-I or its receptor in osteoblasts or enhance the signaling between osteoblasts and osteoclasts through RANKL/RANK and Ephrin B2/Eph B4, emphasizing the role IGF-I signaling plays in cell-communication per se and as stimulated by PTH.

  20. Acute metabolic acidosis enhances circulating parathyroid hormone, which contributes to the renal response against acidosis in the rat.

    PubMed Central

    Bichara, M; Mercier, O; Borensztein, P; Paillard, M

    1990-01-01

    Acute PTH administration enhances final urine acidification in the rat. HCl was infused during 3 h in rats to determine the parathyroid and renal responses to acute metabolic acidosis. Serum immunoreactive PTH (iPTH) concentration significantly increased and nephrogenous adenosine 3H,5H-cyclic monophosphate tended to increase during HCl loading in intact and adrenalectomized (ADX) rats despite significant increments in plasma ionized calcium. Strong linear relationships existed between serum iPTH concentration and arterial bicarbonate or proton concentration (P less than 0.0001). Serum iPth concentration and NcAMP remained stable in intact time-control rats and decreased in CaCl2-infused, nonacidotic animals. Urinary acidification was markedly reduced in parathyroidectomized (PTX) as compared with intact rats during both basal and acidosis states; human PTH-(1-34) infusion in PTX rats restored in a dose-dependent manner the ability of the kidney to acidify the urine and excrete net acid. Acidosis-induced increase in urinary net acid excretion was observed in intact, PTX, and ADX, but not in ADX-thyroparathyroidectomized rats. We conclude that (a) acute metabolic acidosis enhances circulating PTH activity, and (b) PTH markedly contributes to the renal response against acute metabolic acidosis by enhancing urinary acidification. PMID:2166755

  1. Hormonally mediated maternal effects, individual strategy and global change.

    PubMed

    Meylan, Sandrine; Miles, Donald B; Clobert, Jean

    2012-06-19

    A challenge to ecologists and evolutionary biologists is predicting organismal responses to the anticipated changes to global ecosystems through climate change. Most evidence suggests that short-term global change may involve increasing occurrences of extreme events, therefore the immediate response of individuals will be determined by physiological capacities and life-history adaptations to cope with extreme environmental conditions. Here, we consider the role of hormones and maternal effects in determining the persistence of species in altered environments. Hormones, specifically steroids, are critical for patterning the behaviour and morphology of parents and their offspring. Hence, steroids have a pervasive influence on multiple aspects of the offspring phenotype over its lifespan. Stress hormones, e.g. glucocorticoids, modulate and perturb phenotypes both early in development and later into adulthood. Females exposed to abiotic stressors during reproduction may alter the phenotypes by manipulation of hormones to the embryos. Thus, hormone-mediated maternal effects, which generate phenotypic plasticity, may be one avenue for coping with global change. Variation in exposure to hormones during development influences both the propensity to disperse, which alters metapopulation dynamics, and population dynamics, by affecting either recruitment to the population or subsequent life-history characteristics of the offspring. We suggest that hormones may be an informative index to the potential for populations to adapt to changing environments.

  2. Thyroid Hormone Mediated Modulation of Energy Expenditure

    PubMed Central

    Vaitkus, Janina A.; Farrar, Jared S.; Celi, Francesco S.

    2015-01-01

    Thyroid hormone (TH) has diverse effects on mitochondria and energy expenditure (EE), generating great interest and research effort into understanding and harnessing these actions for the amelioration and treatment of metabolic disorders, such as obesity and diabetes. Direct effects on ATP utilization are a result of TH’s actions on metabolic cycles and increased cell membrane ion permeability. However, the majority of TH induced EE is thought to be a result of indirect effects, which, in turn, increase capacity for EE. This review discusses the direct actions of TH on EE, and places special emphasis on the indirect actions of TH, which include mitochondrial biogenesis and reduced metabolic efficiency through mitochondrial uncoupling mechanisms. TH analogs and the metabolic actions of T2 are also discussed in the context of targeted modulation of EE. Finally, clinical correlates of TH actions on metabolism are briefly presented. PMID:26193258

  3. Estrogen mediation of hormone responses to exercise.

    PubMed

    Kraemer, Robert R; Francois, Michelle; Castracane, V Daniel

    2012-10-01

    The roles of estrogens extend from the regulation of reproduction to other functions involved in control of metabolism, fluid balance, as well as gastrointestinal, lung, and brain function, with a strong effect on other hormones that subsequently alter the physiology of multiple tissues. As such, alteration of endogenous estrogens across the menstrual cycle, or from oral contraception and estrogen replacement therapy, can affect these tissues. Due to the important effects that estrogens have on different tissues, there are many investigations concerning the effects of a human estrogenic environment on endocrine responses to exercise. The following review will describe the consequences of varying estrogen levels on pituitary, adrenal, gonadal, and endocrine function, followed by discussion of the outcomes of different estrogen levels on endocrine tissues in response to exercise, problems encountered for interpretation of findings, and recommended direction for future research. PMID:22512823

  4. Inhibition of phosphatidylinositide 3-kinase in OK-cells reduces Na/Pi-cotransport but does not interfere with its regulation by parathyroid hormone.

    PubMed

    Pfister, M F; Brunskill, N J; Forgo, J; Stange, G; Biber, J; Murer, H

    1999-08-01

    The importance of phosphatidylinositide 3- kinase(s) [PI 3-kinase(s)] in membrane trafficking processes led us to examine its/their possible role in parathyroid-hormone- (PTH-) induced endocytosis and lysosomal degradation of the type IIa Na/Pi-cotransporter in opossum kidney cells (OK-cells). We used wortmannin, a potent inhibitor of several mammalian PI 3-kinase isoforms, and measured Na/Pi-cotransporter activity and type IIa Na/Pi-cotransporter protein expression; also the induction of a negative dominant subunit (Deltap85) was used to reduce PI 3-kinase activity. Wortmannin and Deltap85 led to a reduction of Na/Pi-cotransport activity but were unable to prevent its inhibition by PTH. Wortmannin led in a dose- and time-dependent manner to a reduction of Na/Pi-cotransport activity and transporter protein expression, and retarded their recovery from PTH-induced inhibition/degradation. The data suggest that a PI 3-kinase "controlled" mechanism is involved in the synthesis (and/or routing) of the apical type IIa Na/Pi-cotransporter in OK-cells. PMID:10398872

  5. Parathyroid hormone PTH(1–34) increases the volume, mineral content, and mechanical properties of regenerated mineralizing tissue after distraction osteogenesis in rabbits

    PubMed Central

    2009-01-01

    Background and purpose Parathyroid hormone (PTH) has attracted considerable interest as a bone anabolic agent. Recently, it has been suggested that PTH can also enhance bone repair after fracture and distraction osteogenesis. We analyzed bone density and strength of the newly regenerated mineralized tissue after intermittent treatment with PTH in rabbits, which undergo Haversian bone remodeling similar to that in humans. Methods 72 New Zealand White rabbits underwent tibial mid-diaphyseal osteotomy and the callus was distracted 1 mm/day for 10 days. The rabbits were divided into 3 groups, which received injections of PTH 25 µg/kg/day for 30 days, saline for 10 days and PTH 25 µg/kg/day for 20 days, or saline for 30 days. At the end of the study, the rabbits were killed and the bone density was evaluated with DEXA. The mechanical bone strength was determined by use of a 3-point bending test. Results In the 2 PTH-treated groups the regenerate callus ultimate load was 33% and 30% higher, absorbed energy was 100% and 65% higher, BMC was 61% and 60% higher, and callus tissue volume was 179% and 197% higher than for the control group. Interpretation We found that treatment with PTH during distraction osteogenesis resulted in substantially higher mineralized tissue volume, mineral content, and bending strength. This suggests that treatment with PTH may benefit new bone formation during distraction osteogenesis and could form a basis for clinical application of this therapy in humans. PMID:19995322

  6. Dynamic modeling of bone metastasis, microenvironment and therapy: Integrating parathyroid hormone (PTH) effect, anti-resorptive and anti-cancer therapy.

    PubMed

    Coelho, Rui Moura; Lemos, João Miranda; Alho, Irina; Valério, Duarte; Ferreira, Arlindo R; Costa, Luís; Vinga, Susana

    2016-02-21

    Bone is a common site for the development of metastasis, as its microenvironment provides the necessary conditions for the growth and proliferation of cancer cells. Several mathematical models to describe the bone remodeling process and how osteoclasts and osteoblasts coupled action ensures bone homeostasis have been proposed and further extended to include the effect of cancer cells. The model proposed here includes the influence of the parathyroid hormone (PTH) as capable of triggering and regulating the bone remodeling cycle. It also considers the secretion of PTH-related protein (PTHrP) by cancer cells, which stimulates the production of receptor activator of nuclear factor kappa-B ligand (RANKL) by osteoblasts that activates osteoclasts, increasing bone resorption and the subsequent release of growth factors entrapped in the bone matrix, which induce tumor growth, giving rise to a self-perpetuating cycle known as the vicious cycle of bone metastases. The model additionally describes how the presence of metastases contributes to the decoupling between bone resorption and formation. Moreover, the effects of anti-cancer and anti-resorptive treatments, through chemotherapy and the administration of bisphosphonates or denosumab, are also included, along with their corresponding pharmacokinetics (PK) and pharmacodynamics (PD). The simulated models, available at http://sels.tecnico.ulisboa.pt/software/, are able to describe bone remodeling cycles, the growth of bone metastases and how treatment can effectively reduce tumor burden on bone and prevent loss of bone strength.

  7. Low peak bone mass and attenuated anabolic response to parathyroid hormone in mice with an osteoblast-specific deletion of connexin43.

    PubMed

    Chung, Dong Jin; Castro, Charlles H M; Watkins, Marcus; Stains, Joseph P; Chung, Min Young; Szejnfeld, Vera Lucia; Willecke, Klaus; Theis, Martin; Civitelli, Roberto

    2006-10-15

    Connexin43 (Cx43) is involved in bone development, but its role in adult bone homeostasis remains unknown. To overcome the postnatal lethality of Cx43 null mutation, we generated mice with selective osteoblast ablation of Cx43, obtained using a Cx43fl allele and a 2.3-kb fragment of the alpha1(I) collagen promoter to drive Cre in osteoblasts (ColCre). Conditionally osteoblast-deleted ColCre;Cx43-/fl mice show no malformations at birth, but develop low peak bone mass and remain osteopenic with age, exhibiting reduced bone formation and defective osteoblast function. By both radiodensitometry and histology, bone mineral content increased rapidly and progressively in adult Cx43+/fl mice after subcutaneous injection of parathyroid hormone (PTH), an effect significantly attenuated in ColCre;Cx43-/fl mice, with Cx43-/fl exhibiting an intermediate response. Attenuation of PTH anabolic action was associated with failure to increase mineral apposition rate in response to PTH in ColCre;Cx43-/fl, despite an increased osteoblast number, suggesting a functional defect in Cx43-deficient bone-forming cells. In conclusion, lack of Cx43 in osteoblasts leads to suboptimal acquisition of peak bone mass, and hinders the bone anabolic effect of PTH. Cx43 represents a potential target for modulation of bone anabolism.

  8. Hypocalcaemia and serum levels of inorganic phosphorus, magnesium parathyroid and calcitonin hormones in the last month of pregnancy in Awassi fat-tail ewes.

    PubMed

    Elias, E; Shainkin-Kestenbaum, R

    1990-01-01

    Serum levels of calcium (Ca), inorganic phosphorus (P), magnesium (Mg), parathyroid (PTH) and calcitonin (CT) hormones of fat-tail Awassi ewes were determined during the last month of pregnancy. The incidence of hypocalcaemia (HCE) was 13.4% of the obstetrical cases examined. Twenty-six (81.3%) of 32 ewes with HCE were 4 yr of age or older. Significant decreases (p less than 0.01) in serum Ca levels from normal values or controls (n = 6; 10.04 +/- 0.22% (w/w)) to pathological values (4.30 +/- 0.35% (w/w)) caused severe clinical manifestations in 75% of affected ewes. This HCE was accompanied by a significant increase in the PTH level (142.6 +/- 9.1 pmol/l in comparison to 99.7 +/- 9.3 pmol/l in controls, p less than 0.05) and significant decrease in serum CT level (98.2 +/- 7.6 pg/ml in comparison to 144.6 +/- 25.7 pg/ml in controls; p less than 0.05). Intravenous administration of Ca borogluconate yielded normal Ca levels which were accompanied by a decrease in serum PTH levels and an increase in CT levels to normal values.

  9. The Parathyroid Hormone Second Receptor PTH2R and its Ligand Tuberoinfundibular Peptide of 39 Residues TIP39 Regulate Intracellular Calcium and Influence Keratinocyte Differentiation.

    PubMed

    Sato, Emi; Muto, Jun; Zhang, Ling-Juan; Adase, Christopher A; Sanford, James A; Takahashi, Toshiya; Nakatsuji, Teruaki; Usdin, Ted B; Gallo, Richard L

    2016-07-01

    Genes related to the parathyroid hormone (PTH) influence cutaneous immune defense and development, but the full functions of the PTH family in cutaneous biology remain incompletely understood. In this study, we examined the expression and potential functions of the PTH second receptor (PTH2R) and its ligand, the tuberoinfundibular peptide of 39 residues (TIP39), in the skin. TIP39 and PTH2R mRNA and protein were detectable in both human and mouse skin, and in cultured keratinocytes and adipocytes. TIP39 was observed in the basal layer of human skin, whereas PTH2R was detected in the spinous to granular layer. The subcellular localization of TIP39 in keratinocytes changed during calcium-induced differentiation and shifted to colocalize with PTH2R at the membrane. The addition of recombinant TIP39 to normal human keratinocytes in culture induced an increase in intercellular calcium and triggered aspects of terminal differentiation including decreased keratin-14 and increased involucrin expression. Consistent with these observations, PTH2R(-/-) mice were observed to have increased epidermal thickness. In summary, identification of TIP39 and its receptor in the epidermis reveals an additional PTH family member that is expressed in the skin and may influence keratinocyte function.

  10. A new human breast cancer cell line, KPL-3C, secretes parathyroid hormone-related protein and produces tumours associated with microcalcifications in nude mice.

    PubMed Central

    Kurebayashi, J.; Kurosumi, M.; Sonoo, H.

    1996-01-01

    Parathyroid hormone-related protein (PTHrP) is the main cause of humoral hypercalcaemia of malignancy (HHM). We recently established a new human breast cancer cell line, designated KPL-3C, from the malignant effusion of a breast cancer patient with HHM. Morphological, cytogenetic and immunohistochemical analyses indicated that the cell line is derived from human breast cancer. The KPL-3C cells stably secrete immunoreactive PTHrP measured by a two-site immunoradiometric assay, possess both oestrogen and progesterone receptors and are tumorigenic in female nude mice. The addition of phorbol-12-myristate-13-acetate to the medium significantly increased PTHrP secretion from the cells. In contrast, hydrocortisone, medroxyprogesterone acetate and 22-oxacalcitriol decreased PTHrP secretion in a dose-dependent manner. Unexpectedly, a number of microcalcifications were observed in the transplanted tumours. Radiographical examination indicated that the microcalcifications in the tumours are very similar to those commonly observed in human breast cancer. These findings suggest that this KPL-3C cell line may be useful for studying the regulatory mechanisms of PTHrP secretion and the mechanisms that lead to the deposition of microcalcifications in breast cancer. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 7 PMID:8688322

  11. Parathyroid hormone-related protein (107-111) improves the bone regeneration potential of gelatin-glutaraldehyde biopolymer-coated hydroxyapatite.

    PubMed

    Lozano, Daniel; Sánchez-Salcedo, Sandra; Portal-Núñez, Sergio; Vila, Mercedes; López-Herradón, Ana; Ardura, Juan Antonio; Mulero, Francisca; Gómez-Barrena, Enrique; Vallet-Regí, María; Esbrit, Pedro

    2014-07-01

    Biopolymer-coated nanocrystalline hydroxyapatite (HA) made as macroporous foams which are degradable and flexible are promising candidates as orthopaedic implants. The C-terminal (107-111) epitope of parathyroid hormone-related protein (PTHrP) exhibits osteogenic properties. The main aim of this study was to evaluate whether PTHrP (107-111) loading into gelatin-glutaraldehyde biopolymer-coated HA (HAGlu) scaffolds would produce an optimal biomaterial for tissue engineering applications. HAGlu scaffolds with and without PTHrP (107-111) were implanted into a cavitary defect performed in both distal tibial metaphysis of adult rats. Animals were sacrificed after 4 weeks for histological, microcomputerized tomography and gene expression analysis of the callus. At this time, bone healing occurred only in the presence of PTHrP (107-111)-containing HAGlu implant, related to an increase in bone volume/tissue volume and trabecular thickness, cortical thickness and gene expression of osteocalcin and vascular cell adhesion molecule 1, but a decreased gene expression of Wnt inhibitors, SOST and dickkopf homolog 1. The autonomous osteogenic effect of the PTHrP (107-111)-loaded HAGlu scaffolds was confirmed in mouse and human osteoblastic cell cultures. Our findings demonstrate the advantage of loading PTHrP (107-111) into degradable HAGlu scaffolds for achieving an optimal biomaterial that is promising for low load bearing clinical applications.

  12. A new immobilization procedure for development of an electrochemical immunosensor for parathyroid hormone detection based on gold electrodes modified with 6-mercaptohexanol and silane.

    PubMed

    Sayıklı Şimşek, Çiğdem; Nur Sonuç Karaboğa, Münteha; Sezgintürk, Mustafa Kemal

    2015-11-01

    Fabrication of a new electrochemical impedance-based biosensor for the analysis of parathyroid hormone (PTH), using self-assembled monolayers (SAMs) of mercaptohexanol and (3-Aminopropyl) triethoxysilane on gold electrodes, was investigated for the first time in the field. Anti-PTH was used as a biorecognition element. To monitor immobilization processes in the biosensor fabrication, cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), and scanning electron microscopy (SEM) techniques were successfully operated. CV and EIS techniques were also used in quantification of PTH. Energy-dispersive X-ray analysis (EDAX) was also applied to identify surface modifications. Fabrication and working parameters of the biosensor were optimized. Moreover, Kramers-Kronig transformations were performed for validation of obtained EIS data in all steps of biosensor fabrication. The linear PTH detection range of the presented biosensor was 10-50 pg/mL PTH. The chrono-impedance technique for real-time monitoring of PTH binding was also implemented. The biosensor has exhibited good repeatability (with a correlation) and reproducibility. Finally, artificial serum samples spiked with known concentrations of PTH were analyzed by the proposed biosensor. To demonstrate the feasibility of the biosensor in practical analysis, real human serum samples and the artificial serum samples were analyzed.

  13. Postnatal establishment of allelic Gαs silencing as a plausible explanation for delayed onset of parathyroid hormone-resistance due to heterozygous Gαs disruption

    PubMed Central

    Turan, Serap; Fernandez-Rebollo, Eduardo; Aydin, Cumhur; Zoto, Teuta; Reyes, Monica; Bounoutas, George; Chen, Min; Weinstein, Lee S.; Erben, Reinhold G.; Marshansky, Vladimir; Bastepe, Murat

    2013-01-01

    Pseudohypoparathyroidism type-Ia (PHP-Ia), characterized by renal proximal tubular resistance to parathyroid hormone (PTH), results from maternal mutations of GNAS that lead to loss of Gαs activity. Gαs expression is paternally silenced in the renal proximal tubule, and this genomic event is critical for the development of PTH-resistance, as patients display impaired hormone action only if the mutation is inherited maternally. The primary clinical finding of PHP-Ia is hypocalcemia, which can lead to various neuromuscular defects including seizures. PHP-Ia patients frequently do not present with hypocalcemia until after infancy, but it has remained uncertain whether PTH-resistance occurs in a delayed fashion. Analyzing reported cases of PHP-Ia with documented GNAS mutations and mice heterozygous for disruption of Gnas, we herein determined that the manifestation of PTH-resistance caused by the maternal loss of Gαs, i.e. hypocalcemia and elevated serum PTH, occurs after early postnatal life. To investigate whether this delay could reflect gradual development of paternal Gαs silencing, we then analyzed renal proximal tubules isolated by laser capture microdissection from mice with either maternal or paternal disruption of Gnas. Our results revealed that, whereas expression of Gαs mRNA in this tissue is predominantly from the maternal Gnas allele at weaning (three-weeks postnatal) and in adulthood, the contributions of the maternal and paternal Gnas alleles to Gαs mRNA expression are equal at postnatal day 3. In contrast, we found that paternal Gαs expression is already markedly repressed in brown adipose tissue at birth. Thus, the mechanisms silencing the paternal Gαs allele in renal proximal tubules are not operational during early postnatal development, and this finding correlates well with the latency of PTH-resistance in patients with PHP-Ia. PMID:23956044

  14. Improvement of calcium balance by Fructus Ligustri Lucidi extract in mature female rats was associated with the induction of serum parathyroid hormone levels.

    PubMed

    Dong, Xiao-Li; Zhao, Ming; Wong, Kwun-Kit; Che, Chun-Tao; Wong, Man-Sau

    2012-07-14

    Fructus Ligustri Lucidi (FLL) is a commonly prescribed herb in many kidney-tonifying Traditional Chinese Medicinal formulae for the treatment of osteoporosis. The present study aimed to identify the active fractions in FLL and to characterise its effects on Ca balance, calciotropic hormone levels as well as bone properties in mature female rats fed diets containing different levels of Ca. In the present study, 4-month-old Sprague-Dawley female rats were treated with either FLL ethanol extract (EE), ethyl acetate-soluble fraction of EE (EAF), water-soluble fraction of EE (WF) or their vehicle for 12 weeks on a medium-Ca diet (MCD, 0·6 % Ca, 0·65 % P). Then, the Sprague-Dawley female rats treated with WF or its vehicle for 12 weeks were fed diets containing different levels of dietary Ca (low-Ca diet (LCD), 0·1 % Ca, 0·65 % P; MCD; high-Ca diet (HCD), 1·2 % Ca, 0·65 % P). The results demonstrated that WF from EE but not EAF exerted a prominent effect on Ca balance by inhibiting urinary and faecal Ca excretion. WF significantly increased Ca balance in rats fed MCD or HCD with an associated increase in serum parathyroid hormone (PTH) levels. WF did not alter bone mineral density or bone mineral content of the tibia in all the rats fed with different levels of dietary Ca. In conclusion, WF was responsible for the positive actions of FLL on Ca absorption and balance. The regulation of Ca balance by WF might involve its action in stimulating PTH production in the mature female rats. PMID:22018100

  15. Parathyroid hormone-related protein and its receptors: nuclear functions and roles in the renal and cardiovascular systems, the placental trophoblasts and the pancreatic islets

    PubMed Central

    Clemens, Thomas L; Cormier, Sarah; Eichinger, Anne; Endlich, Karlhans; Fiaschi-Taesch, Nathalie; Fischer, Evelyne; Friedman, Peter A; Karaplis, Andrew C; Massfelder, Thierry; Rossert, Jérôme; Schlüter, Klaus-Dieter; Silve, Caroline; Stewart, Andrew F; Takane, Karen; Helwig, Jean-Jacques

    2001-01-01

    The cloning of the so-called ‘parathyroid hormone-related protein' (PTHrP) in 1987 was the result of a long quest for the factor which, by mimicking the actions of PTH in bone and kidney, is responsible for the hypercalcemic paraneoplastic syndrome, humoral calcemia of malignancy. PTHrP is distinct from PTH in a number of ways. First, PTHrP is the product of a separate gene. Second, with the exception of a short N-terminal region, the structure of PTHrP is not closely related to that of PTH. Third, in contrast to PTH, PTHrP is a paracrine factor expressed throughout the body. Finally, most of the functions of PTHrP have nothing in common with those of PTH. PTHrP is a poly-hormone which comprises a family of distinct peptide hormones arising from post-translational endoproteolytic cleavage of the initial PTHrP translation products. Mature N-terminal, mid-region and C-terminal secretory forms of PTHrP are thus generated, each of them having their own physiologic functions and probably their own receptors. The type 1 PTHrP receptor, binding both PTH(1-34) and PTHrP(1-36), is the only cloned receptor so far. PTHrP is a PTH-like calciotropic hormone, a myorelaxant, a growth factor and a developmental regulatory molecule. The present review reports recent aspects of PTHrP pharmacology and physiology, including: (a) the identification of new peptides and receptors of the PTH/PTHrP system; (b) the recently discovered nuclear functions of PTHrP and the role of PTHrP as an intracrine regulator of cell growth and cell death; (c) the physiological and developmental actions of PTHrP in the cardiovascular and the renal glomerulo-vascular systems; (d) the role of PTHrP as a regulator of pancreatic beta cell growth and functions, and, (e) the interactions of PTHrP and calcium-sensing receptors for the control of the growth of placental trophoblasts. These new advances have contributed to a better understanding of the pathophysiological role of PTHrP, and will help to identify

  16. Huge Parathyroid Adenoma with Dysphagia Presentation; A Case Report from Southern Iran

    PubMed Central

    Ziaeean, Bizhan; Sohrabi-Nazari, Sahar

    2016-01-01

    Parathyroid adenoma is a benign tumor of the parathyroid glands. The cause of most parathyroid adenomas is unknown. Parathyroid adenoma increases the secretion of parathyroid hormone and results in primary hyperparathyroidism. High amounts of parathyroid hormone in the blood cause the imbalance of calcium, which leads to various complications such as kidney stones, depression, lethargy, nausea, vomiting, abdominal pain, myalgia, bone and joint pain, hoarseness, etc. Oropharyngeal dysphagia is defined as having problem in swallowing due to abnormalities in the structure and function of oropharynx and other related organs. The exact prevalence of dysphagia caused by parathyroid adenoma is unknown, but since this complication can lead to increased mortality and morbidity, its diagnosis is important. It is difficult to distinguish parathyroid malignancies from parathyroid adenoma even after surgery. Therefore, the final diagnosis is possible through surgery and histopathological evaluation. Here, a case of parathyroid adenoma with first presentation of generalized weakness and dysphagia has been reported. PMID:27582595

  17. Huge Parathyroid Adenoma with Dysphagia Presentation; A Case Report from Southern Iran.

    PubMed

    Ziaeean, Bizhan; Sohrabi-Nazari, Sahar

    2016-09-01

    Parathyroid adenoma is a benign tumor of the parathyroid glands. The cause of most parathyroid adenomas is unknown. Parathyroid adenoma increases the secretion of parathyroid hormone and results in primary hyperparathyroidism. High amounts of parathyroid hormone in the blood cause the imbalance of calcium, which leads to various complications such as kidney stones, depression, lethargy, nausea, vomiting, abdominal pain, myalgia, bone and joint pain, hoarseness, etc. Oropharyngeal dysphagia is defined as having problem in swallowing due to abnormalities in the structure and function of oropharynx and other related organs. The exact prevalence of dysphagia caused by parathyroid adenoma is unknown, but since this complication can lead to increased mortality and morbidity, its diagnosis is important. It is difficult to distinguish parathyroid malignancies from parathyroid adenoma even after surgery. Therefore, the final diagnosis is possible through surgery and histopathological evaluation. Here, a case of parathyroid adenoma with first presentation of generalized weakness and dysphagia has been reported. PMID:27582595

  18. Parathyroid disease.

    PubMed

    Wen, Hong Yan; Schumacher, H Ralph; Zhang, Li Yun

    2010-11-01

    Patients with parathyroid disease can have important musculoskeletal problems.Hypoparathyroidism can cause subcutaneous calcifications, tetany, muscle cramps,and paresthesias, but also myopathies and an ankylosing spondylitis-like back disease. Hypoparathyroidism can occur in SLE caused by antiparathyroid antibodies.Patients with hyperparathyroidism can develop bone disease with cysts, erosions,and deformities. They can also develop pseudogout, gout, myopathies, and tendon ruptures.

  19. Foscarnet alters antidiuretic hormone-mediated transport.

    PubMed Central

    Hoch, B S; Shahmehdi, S J; Louis, B M; Lipner, H I

    1995-01-01

    Therapy with foscarnet is associated with acute renal failure. Prior studies have emphasized foscarnet's proximal tubular toxicity, but there have been isolated reports of foscarnet-induced nephrogenic diabetes insipidus. As a phosphate analog, foscarnet is a competitive inhibitor of NaPO4 cotransport. However, foscarnet's effect on antidiuretic hormone (ADH)-induced transport has not been previously investigated. We studied foscarnet's modulation of transport in the toad urinary bladder. Foscarnet at 10 microM to 10 mM did not alter basal water or urea flux. Urea transport induced by a maximal dose of ADH (24 mIU/ml) was inhibited by 0.1 to 5.0 mM foscarnet. In tissues challenged with 0.5 to 1.0 mIU of ADH per ml, 1.0 to 10 mM foscarnet increased water flow but did not alter urea flux. Foscarnet also increased water flow induced by 1.0 to 10 microM forskolin. In tissues pretreated with 10 microM naproxen, foscarnet did not alter water flow induced by 0.5 to 1.0 mIU of ADH per ml or forskolin. These results indicate that foscarnet stimulates water flow induced by 0.5 to 1.0 mIU of ADH per ml at a site proximal to that of the generation of cyclic AMP and inhibits urea flux induced by a maximal dose of ADH at a separate site. In humans, foscarnet nephrotoxicity is likely not limited to the proximal nephron, but extends to the collecting duct. Patients receiving foscarnet should be closely monitored for disorders of urinary concentration. PMID:8540707

  20. Minimally invasive parathyroid surgery

    PubMed Central

    Noureldine, Salem I.; Gooi, Zhen

    2015-01-01

    Traditionally, bilateral cervical exploration for localization of all four parathyroid glands and removal of any that are grossly enlarged has been the standard surgical treatment for primary hyperparathyroidism (PHPT). With the advances in preoperative localization studies and greater public demand for less invasive procedures, novel targeted, minimally invasive techniques to the parathyroid glands have been described and practiced over the past 2 decades. Minimally invasive parathyroidectomy (MIP) can be done either through the standard Kocher incision, a smaller midline incision, with video assistance (purely endoscopic and video-assisted techniques), or through an ectopically placed, extracervical, incision. In current practice, once PHPT is diagnosed, preoperative evaluation using high-resolution radiographic imaging to localize the offending parathyroid gland is essential if MIP is to be considered. The imaging study results suggest where the surgeon should begin the focused procedure and serve as a road map to allow tailoring of an efficient, imaging-guided dissection while eliminating the unnecessary dissection of multiple glands or a bilateral exploration. Intraoperative parathyroid hormone (IOPTH) levels may be measured during the procedure, or a gamma probe used during radioguided parathyroidectomy, to ascertain that the correct gland has been excised and that no other hyperfunctional tissue is present. MIP has many advantages over the traditional bilateral, four-gland exploration. MIP can be performed using local anesthesia, requires less operative time, results in fewer complications, and offers an improved cosmetic result and greater patient satisfaction. Additional advantages of MIP are earlier hospital discharge and decreased overall associated costs. This article aims to address the considerations for accomplishing MIP, including the role of preoperative imaging studies, intraoperative adjuncts, and surgical techniques. PMID:26425454

  1. Parathyroid diseases and animal models.

    PubMed

    Imanishi, Yasuo; Nagata, Yuki; Inaba, Masaaki

    2012-01-01

    CIRCULATING CALCIUM AND PHOSPHATE ARE TIGHTLY REGULATED BY THREE HORMONES: the active form of vitamin D (1,25-dihydroxyvitamin D), fibroblast growth factor (FGF)-23, and parathyroid hormone (PTH). PTH acts to stimulate a rapid increment in serum calcium and has a crucial role in calcium homeostasis. Major target organs of PTH are kidney and bone. The oversecretion of the hormone results in hypercalcemia, caused by increased intestinal calcium absorption, reduced renal calcium clearance, and mobilization of calcium from bone in primary hyperparathyroidism. In chronic kidney disease, secondary hyperparathyroidism of uremia is observed in its early stages, and this finally develops into the autonomous secretion of PTH during maintenance hemodialysis. Receptors in parathyroid cells, such as the calcium-sensing receptor, vitamin D receptor, and FGF receptor (FGFR)-Klotho complex have crucial roles in the regulation of PTH secretion. Genes such as Cyclin D1, RET, MEN1, HRPT2, and CDKN1B have been identified in parathyroid diseases. Genetically engineered animals with these receptors and the associated genes have provided us with valuable information on the patho-physiology of parathyroid diseases. The application of these animal models is significant for the development of new therapies.

  2. Primary hyperparathyroidism due to parathyroid carcinoma.

    PubMed

    Mendoza, V; Hernández, A F; Márquez, M L; Delgadillo, M A; Peña, J; Mercado, M

    1997-01-01

    Most cases of primary hyperparathyroidism are due to either a parathyroid adenoma or to parathyroid hyperplasia. Parathyroid carcinoma is a very rare cause of hyperparathyroidism. Although the diagnosis of parathyroid carcinoma is usually established based on pathological criteria of vascular and capsular invasion, some clinical and biochemical features differentiate it from benign forms of hyperparathyroidism. We report the case of a middle-aged woman with a long standing history of nephrolithiasis, who presented with a palpable neck mass, weight loss, severe hypercalcemia and hypophosphatemia, as well as very high serum levels of intact parathyroid hormone. Surgical neck exploration revealed a large tumor that invaded trachea, esophagus, reccurrent laryngeal nerve, right apical pleura and right carotid artery. Pathological examination confirmed the invasive nature of the tumor. Along with the case report, we review the literature and discuss the diagnostic and therapeutic options of this rare condition.

  3. Successful induction of sclerostin in human-derived fibroblasts by 4 transcription factors and its regulation by parathyroid hormone, hypoxia, and prostaglandin E2.

    PubMed

    Fujiwara, Makoto; Kubota, Takuo; Wang, Wei; Ohata, Yasuhisa; Miura, Kohji; Kitaoka, Taichi; Okuzaki, Daisuke; Namba, Noriyuki; Michigami, Toshimi; Kitabatake, Yasuji; Ozono, Keiichi

    2016-04-01

    Sclerostin, coded by SOST, is a secretory protein that is specifically expressed in osteocytes and suppresses osteogenesis by inhibiting WNT signaling. The regulatory mechanism underlying SOST expression remains unclear mainly due to the absence of an adequate human cell model. Thus, we herein attempted to establish a cell model of human dermal fibroblasts in order to investigate the functions of sclerostin. We selected 20 candidate transcription factors (TFs) that induce SOST expression by analyzing gene expression patterns in the human sarcoma cell line, SaOS-2, between differentiation and maintenance cultures using microarrays. An effective set of TFs to induce SOST expression was sought by their viral transduction into fibroblasts, and a combination of four TFs: ATF3, KLF4, PAX4, and SP7, was identified as the most effective inducer of SOST expression. Quantitative PCR demonstrated that the expression levels of SOST in fibroblasts treated with the 4 TFs were 199- and 1439-fold higher than those of the control after 1-week and 4-week cultures, respectively. The level of sclerostin in the conditioned medium, as determined by ELISA, was 21.2pmol/l 4weeks after the transduction of the 4 TFs. Interestingly, the production of Dickkopf1 (DKK1), another secreted inhibitor of WNT signaling, was also increased by transduction of these 4 TFs. Parathyroid hormone (PTH) significantly suppressed the induced SOST by 38% and sclerostin by 82% that of the vehicle. Hypoxia increased the induced SOST by 62% that of normoxia. Furthermore, prostaglandin E2 (PGE2) increased SOST expression levels to 16-fold those of the vehicle. In conclusion, the efficient induction of SOST expression and sclerostin production was achieved in human dermal fibroblasts by the transduction of ATF3, KLF4, PAX4, and SP7, and the induced SOST and sclerostin were regulated by PTH, hypoxia, and PGE2. This model may contribute to elucidating the regulatory mechanisms underlying SOST expression and advancing

  4. Postprandial metabolic responses of serum calcium, parathyroid hormone and C-telopeptide of type I collagen to three doses of calcium delivered in milk.

    PubMed

    Kruger, Marlena C; von Hurst, Pamela R; Booth, Christine L; Kuhn-Sherlock, Barbara; Todd, Joanne M; Schollum, Linda M

    2014-01-01

    Acute doses of Ca rapidly increase serum Ca and reduce bone resorption concomitant with a reduction in serum parathyroid hormone (PTH) levels. The physiological response to a dose of Ca in milk and to a Ca salt may be different. The present study investigated Ca absorption patterns with increasing levels of fortification in milk, and the response to one dose of a Ca salt. A group of twenty-eight Asian women aged 20-45 years volunteered to attend the laboratory over several weeks. The fasted volunteers were randomised to one of three experimental drinks: 200 ml skimmed milk containing 250, 500 or 1000 mg Ca. A subgroup of seven volunteers also received a calcium gluconate/carbonate salt containing 1000 mg Ca in 200 ml water. Serial blood samples and urine were collected for 5 h from baseline. Different doses of Ca in milk resulted in a graded response in serum corrected Ca, PTH and C-telopeptide of type I collagen (CTx) but not ionised Ca. Serum Ca increased in response to all milk drinks and from 2 to 5 h the blood Ca levels were significantly different for the 250 and 1000 mg doses, as was the integrated response between the loads. The PTH response to the two higher doses was significantly more than following the 250 mg dose. The integrated response for CTx and urinary Ca between all three doses of Ca in milk was significantly different. A dose of Ca salt elicited a more immediate response reaching a plateau faster, and declining faster to baseline. Fortified milk is a safe matrix for delivering larger doses of Ca. PMID:25191614

  5. Local delivery of parathyroid hormone-related protein-derived peptides coated onto a hydroxyapatite-based implant enhances bone regeneration in old and diabetic rats.

    PubMed

    Ardura, Juan A; Portal-Núñez, Sergio; Lozano, Daniel; Gutiérrez-Rojas, Irene; Sánchez-Salcedo, Sandra; López-Herradón, Ana; Mulero, Francisca; Villanueva-Peñacarrillo, María L; Vallet-Regí, María; Esbrit, Pedro

    2016-08-01

    Diabetes mellitus (DM) and aging are associated with bone fragility and increased fracture risk. Both (1-37) N- and (107-111) C-terminal parathyroid hormone-related protein (PTHrP) exhibit osteogenic properties. We here aimed to evaluate and compare the efficacy of either PTHrP (1-37) or PTHrP (107-111) loaded into gelatin-glutaraldehyde-coated hydroxyapatite (HA-Gel) foams to improve bone repair of a transcortical tibial defect in aging rats with or without DM, induced by streptozotocin injection at birth. Diabetic old rats showed bone structural deterioration compared to their age-matched controls. Histological and μ-computerized tomography studies showed incomplete bone repair at 4 weeks after implantation of unloaded Ha-Gel foams in the transcortical tibial defects, mainly in old rats with DM. However, enhanced defect healing, as shown by an increase of bone volume/tissue volume and trabecular and cortical thickness and decreased trabecular separation, occurred in the presence of either PTHrP peptide in the implants in old rats with or without DM. This was accompanied by newly formed bone tissue around the osteointegrated HA-Gel implant and increased gene expression of osteocalcin and vascular endothelial growth factor (bone formation and angiogenic markers, respectively), and decreased expression of Sost gene, a negative regulator of bone formation, in the healing bone area. Our findings suggest that local delivery of PTHrP (1-37) or PTHrP (107-111) from a degradable implant is an attractive strategy to improve bone regeneration in aged and diabetic subjects. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2060-2070, 2016. PMID:27086979

  6. The effects of excipients and particle engineering on the biophysical stability and aerosol performance of parathyroid hormone (1-34) prepared as a dry powder for inhalation.

    PubMed

    Shoyele, Sunday A; Sivadas, Neeraj; Cryan, Sally-Ann

    2011-03-01

    Pulmonary delivery of therapeutic peptides and proteins has many advantages including high relative bioavailability, rapid systemic absorption and onset of action and a non-invasive mode of administration which improves patient compliance. In this study, we investigated the effect of spray-drying (SD) and spray freeze-drying processes on the stability and aerosol performance of parathyroid hormone (PTH) (1-34) microparticles. In this study, the stabilisation effect of trehalose (a non-reducing sugar) and Brij 97 (a non-ionic surfactant) on spray-dried PTH particles was assessed using analytical techniques including circular dichroism (CD), fluorescence spectroscopy, modulated differential scanning calorimetry and an in vitro bioactivity assay. Physical characterisation also included electron microscopy, tap density measurement and laser light diffraction. The aerosol aerodynamic performance of the formulations was assessed using the Andersen cascade impactor. Based on these studies, a formulation for spray freeze-drying was selected and the effects of the two particle engineering techniques on the biophysical stability and aerosol performance of the resulting powders was determined. CD, fluorescence spectroscopy and bioactivity data suggest that trehalose when used alone as a stabilising excipient produces a superior stabilising effect than when used in combination with a non-ionic surfactant. This highlights the utility of CD and fluorescence spectroscopy studies for the prediction of protein bioactivity post-processing. Therefore, a method and formulation suitable for the preparation of PTH as a dry powder was developed based on spray-drying PTH with trehalose as a stabiliser with the bioactivity of SD PTH containing trehalose being equivalent to that of unprocessed PTH.

  7. Long-term effects of intermittent equine parathyroid hormone fragment (ePTH-1-37) administration on bone metabolism in healthy horses.

    PubMed

    Weisrock, Katharina U; Winkelsett, Sarah; Martin-Rosset, William; Forssmann, Wolf-Georg; Parvizi, Nahid; Coenen, Manfred; Vervuert, Ingrid

    2011-11-01

    Intermittent administration of parathyroid hormone (PTH) is an anabolic therapy for osteoporotic conditions in humans. This study evaluated the effects of equine PTH fragment (ePTH-1-37) administration on bone metabolism in 12 healthy horses. Six horses each were treated once daily for 120days with subcutaneous injections of 0.5μg/kg ePTH-1-37 or placebo. Blood was collected to determine ionized calcium (Ca(++)), total Ca (Ca(T)), inorganic phosphorus, serum equine osteocalcin (eOC), carboxy-terminal telopeptide of type I collagen (ICTP), bone-specific alkaline phosphatase, and carboxy-terminal cross-linked telopeptide of type I collagen. Bone mineral density (BMD) was determined with dual X-ray absorptiometry of the metacarpus and calcaneus. Significantly higher blood Ca(++) and plasma Ca(T) concentrations were measured 5h after ePTH-1-37 administration compared to placebo. Higher serum eOC concentrations were found for ePTH-1-37 treatment at days 90 (P<0.05) and 120 (P=0.05). Significantly higher serum ICTP levels were observed with ePTH-1-37 treatment at days 60 and 90. For both study groups, BMD increased significantly in the calcaneus. Long-term use of ePTH-1-37 seemed to have no negative effects on bone metabolism in healthy horses. The absence of undesirable side effects is the premise to ensure safety for further clinical investigations in horses with increased bone resorption processes.

  8. Effects of different dosages of parathyroid hormone-related protein 1-34 on the bone metabolism of the ovariectomized rat model of osteoporosis.

    PubMed

    Xu, Jin; Rong, Haiqin; Ji, Hong; Wang, Dong; Wang, Jie; Zhang, Wenwen; Zhang, Yanling

    2013-09-01

    Intermittent and low-dose parathyroid hormone (PTH) injection to stimulate bone formation has been used in the treatment of osteoporosis. The N-terminal fragment 1-34 of PTH is quite similar in structure and function to N-terminal PTH-related protein (PTHrP). PTH(1-34) and PTHrP also share a coreceptor, the PTH/PTHrP receptor. Therefore, some studies have suggested that PTHrP could effectively stimulate bone formation, similar to PTH. We used an ovariectomized (OVX) rat model of osteoporosis to study the effects of PTHrP(1-34) on bone metabolism by measuring bone mineral density (BMD), bone histomorphometrics, and biomechanical parameters. We found that subcutaneous injection of PTHrP(1-34) (40 or 80 μg/kg body weight every day) in OVX rats increased lumbar and femoral BMD, improved bone biomechanical properties, enhanced bone strength, and promoted bone formation. We selected 40 μg/kg as the preferred therapeutic dose of PTHrP(1-34) and investigated the effects of frequency of treatment (per 1, 2, 3, or 7 days) on bone metabolism in OVX rats. We found that injection of PTHrP(1-34) once per day or every other day significantly improved the BMD and strength of OVX rats. Serum calcium and phosphate levels in all treated rats did not vary significantly from control rats. Based on our results, intermittent low-dose PTHrP(1-34) injection promoted bone formation in OVX rats, suggesting a high potential for therapeutic use in osteoporosis patients.

  9. Parathyroid hormone enhances fluid shear-induced [Ca2+]i signaling in osteoblastic cells through activation of mechanosensitive and voltage-sensitive Ca2+ channels

    NASA Technical Reports Server (NTRS)

    Ryder, K. D.; Duncan, R. L.

    2001-01-01

    Osteoblasts respond to both fluid shear and parathyroid hormone (PTH) with a rapid increase in intracellular calcium concentration ([Ca2+]i). Because both stimuli modulate the kinetics of the mechanosensitive cation channel (MSCC), we postulated PTH would enhance the [Ca2+]i response to fluid shear by increasing the sensitivity of MSCCs. After a 3-minute preflow at 1 dyne/cm2, MC3T3-E1 cells were subjected to various levels of shear and changes in [Ca2+]i were assessed using Fura-2. Pretreatment with 50 nM bovine PTH(1-34) [bPTH(1-34)] significantly enhanced the shear magnitude-dependent increase in [Ca2+]i. Gadolinium (Gd3+), an MSCC blocker, significantly inhibited the mean peak [Ca2+]i response to shear and shear + bPTH(1-34). Nifedipine (Nif), an L-type voltage-sensitive Ca2+ channel (VSCC) blocker, also significantly reduced the [Ca2+]i response to shear + bPTH(1-34), but not to shear alone, suggesting VSCC activation plays an interactive role in the action of these stimuli together. Activation of either the protein kinase C (PKC) or protein kinase A (PKA) pathways with specific agonists indicated that PKC activation did not alter the Ca2+ response to shear, whereas PKA activation significantly increased the [Ca2+]i response to lower magnitudes of shear. bPTH(1-34), which activates both pathways, induced the greatest [Ca2+]i response at each level of shear, suggesting an interaction of these pathways in this response. These data indicate that PTH significantly enhances the [Ca2+]i response to shear primarily via PKA modulation of the MSCC and VSCC.

  10. Loss of Gsα in the Postnatal Skeleton Leads to Low Bone Mass and a Blunted Response to Anabolic Parathyroid Hormone Therapy.

    PubMed

    Sinha, Partha; Aarnisalo, Piia; Chubb, Rhiannon; Poulton, Ingrid J; Guo, Jun; Nachtrab, Gregory; Kimura, Takaharu; Swami, Srilatha; Saeed, Hamid; Chen, Min; Weinstein, Lee S; Schipani, Ernestina; Sims, Natalie A; Kronenberg, Henry M; Wu, Joy Y

    2016-01-22

    Parathyroid hormone (PTH) is an important regulator of osteoblast function and is the only anabolic therapy currently approved for treatment of osteoporosis. The PTH receptor (PTH1R) is a G protein-coupled receptor that signals via multiple G proteins including Gsα. Mice expressing a constitutively active mutant PTH1R exhibited a dramatic increase in trabecular bone that was dependent upon expression of Gsα in the osteoblast lineage. Postnatal removal of Gsα in the osteoblast lineage (P-Gsα(OsxKO) mice) yielded markedly reduced trabecular and cortical bone mass. Treatment with anabolic PTH(1-34) (80 μg/kg/day) for 4 weeks failed to increase trabecular bone volume or cortical thickness in male and female P-Gsα(OsxKO) mice. Surprisingly, in both male and female mice, PTH administration significantly increased osteoblast numbers and bone formation rate in both control and P-Gsα(OsxKO) mice. In mice that express a mutated PTH1R that activates adenylyl cyclase and protein kinase A (PKA) via Gsα but not phospholipase C via Gq/11 (D/D mice), PTH significantly enhanced bone formation, indicating that phospholipase C activation is not required for increased bone turnover in response to PTH. Therefore, although the anabolic effect of intermittent PTH treatment on trabecular bone volume is blunted by deletion of Gsα in osteoblasts, PTH can stimulate osteoblast differentiation and bone formation. Together these findings suggest that alternative signaling pathways beyond Gsα and Gq/11 act downstream of PTH on osteoblast differentiation.

  11. The effects of excipients and particle engineering on the biophysical stability and aerosol performance of parathyroid hormone (1-34) prepared as a dry powder for inhalation.

    PubMed

    Shoyele, Sunday A; Sivadas, Neeraj; Cryan, Sally-Ann

    2011-03-01

    Pulmonary delivery of therapeutic peptides and proteins has many advantages including high relative bioavailability, rapid systemic absorption and onset of action and a non-invasive mode of administration which improves patient compliance. In this study, we investigated the effect of spray-drying (SD) and spray freeze-drying processes on the stability and aerosol performance of parathyroid hormone (PTH) (1-34) microparticles. In this study, the stabilisation effect of trehalose (a non-reducing sugar) and Brij 97 (a non-ionic surfactant) on spray-dried PTH particles was assessed using analytical techniques including circular dichroism (CD), fluorescence spectroscopy, modulated differential scanning calorimetry and an in vitro bioactivity assay. Physical characterisation also included electron microscopy, tap density measurement and laser light diffraction. The aerosol aerodynamic performance of the formulations was assessed using the Andersen cascade impactor. Based on these studies, a formulation for spray freeze-drying was selected and the effects of the two particle engineering techniques on the biophysical stability and aerosol performance of the resulting powders was determined. CD, fluorescence spectroscopy and bioactivity data suggest that trehalose when used alone as a stabilising excipient produces a superior stabilising effect than when used in combination with a non-ionic surfactant. This highlights the utility of CD and fluorescence spectroscopy studies for the prediction of protein bioactivity post-processing. Therefore, a method and formulation suitable for the preparation of PTH as a dry powder was developed based on spray-drying PTH with trehalose as a stabiliser with the bioactivity of SD PTH containing trehalose being equivalent to that of unprocessed PTH. PMID:21271316

  12. Acute changes in serum calcium and parathyroid hormone circulating levels induced by the oral intake of five currently available calcium salts in healthy male volunteers.

    PubMed

    Deroisy, R; Zartarian, M; Meurmans, L; Nelissenne, N; Micheletti, M C; Albert, A; Reginster, J Y

    1997-05-01

    Several calcium supplements are currently available and many of them are marketed without proper comparison of the bioavailability of the actual preparations. The aim of the present trial was to evaluate and compare the acute changes in serum calcium (Ca) and parathyroid hormone (PTH) levels following the oral administration of a vehicle and of five calcium salts currently prescribed in Western Europe. No significant changes in serum Ca or PTH levels were observed after administration of the vehicle. All calcium salts induced significant increases in serum Ca and decreases in serum PTH compared to baseline values. Comparison of the six response curves revealed a significantly greater increase in serum Ca and a greater decrease in serum PTH after each of the calcium salts than observed after the vehicle. However, no statistically significant differences were observed between the different calcium salts for serum Ca increments. The decrease in serum PTH observed after administration of an ossein-hydroxyapatite complex was significantly less important than after the four other calcium salts, even if statistically different than after vehicle. When assessing the area under the curve (AUC) of PTH values, we observed that calcium carbonate and citrate induce a significantly greater decrease in serum PTH than the other calcium salts which are, however, statistically more active than the vehicle. Serum PTH is decreased under the lower limit of the normal range (10 pg/ml), between t60 and t120 for calcium carbonate and citrate and between t60 and t90 for calcium gluconolactate while the mean PTH values remain within the normal range throughout the study with calcium pidolate, the ossein-hydroxyapatite complex and the vehicle. In conclusion, all calcium preparations significantly increase serum calcium and decrease serum parathormone, compared to what is observed after oral intake of a vehicle. However, significant differences in suppression of parathormone are observed

  13. The Role of Parathyroid Hormone-Related Protein (PTHrP) in Osteoblast Response to Microgravity: Mechanistic Implications for Osteoporosis Development.

    PubMed

    Camirand, Anne; Goltzman, David; Gupta, Ajay; Kaouass, Mohammadi; Panda, Dibyendu; Karaplis, Andrew

    2016-01-01

    Prolonged skeletal unloading through bedrest results in bone loss similar to that observed in elderly osteoporotic patients, but with an accelerated timeframe. This rapid effect on weight-bearing bones is also observed in astronauts who can lose up to 2% of their bone mass per month spent in Space. Despite the important implications for Spaceflight travelers and bedridden patients, the exact mechanisms involved in disuse osteoporosis have not been elucidated. Parathyroid hormone-related protein (PTHrP) regulates many physiological processes including skeletal development, and has been proposed as a mechanosensor. To investigate the role of PTHrP in microgravity-induced bone loss, trabecular and calvarial osteoblasts (TOs and COs) from Pthrp +/+ and -/- mice were subjected to actual Spaceflight for 6 days (Foton M3 satellite). Pthrp +/+, +/- and -/- osteoblasts were also exposed to simulated microgravity for periods varying from 6 days to 6 weeks. While COs displayed little change in viability in 0g, viability of all TOs rapidly decreased in inverse proportion to PTHrP expression levels. Furthermore, Pthrp+/+ TOs displayed a sharp viability decline after 2 weeks at 0g. Microarray analysis of Pthrp+/+ TOs after 6 days in simulated 0g revealed expression changes in genes encoding prolactins, apoptosis/survival molecules, bone metabolism and extra-cellular matrix composition proteins, chemokines, insulin-like growth factor family members and Wnt-related signalling molecules. 88% of 0g-induced expression changes in Pthrp+/+ cells overlapped those caused by Pthrp ablation in normal gravity, and pulsatile treatment with PTHrP1-36 not only reversed a large proportion of 0g-induced effects in Pthrp+/+ TOs but maintained viability over 6-week exposure to microgravity. Our results confirm PTHrP efficacy as an anabolic agent to prevent microgravity-induced cell death in TOs. PMID:27463808

  14. [The roles of interleukin-1 alpha, tumor necrosis factor-alpha and parathyroid hormone-related protein in bone resorption of cholesteatoma otitis].

    PubMed

    Kinoshita, K

    1994-08-01

    It is well known that cholesteatoma otitis is characterized by bone destruction, but the mechanisms of this destruction remain to be clarified. Interleukin-1 alpha (IL-1 alpha), tumor necrosis factor-alpha (TNF-alpha) and parathyroid hormone-related protein (PTHrP) were immunohistologically demonstrated in the epithelia of cholesteatoma tissues obtained from patients with cholesteatoma, at ear surgery, in the present study. The staining for IL-1 alpha was marked in epithelial keratinocytes. The existence of PTHrP was demonstrated in the keratinocytes of cholesteatoma epithelium. PTHrP contents in keratinocytes on spinous layers had accumulated to a greater extent than those in basal layers. Compared with the staining of PTHrP in external ear canal epidermis, cholesteatomatous keratinocytes were more strongly stained. Further more, the effects of cholesteatomatous debris on generation of IL-1 alpha and TNF-alpha in cholesteatoma keratinocytes and normal human epidermal keratinocytes (NHEK), derived from chest skin, were examined. Near-confluent medium after seven days incubation of cholesteatomatous keratinocytes and NHEK was discarded and fresh medium was added. Filtrated debris medium, obtained with a milli-pore filter, lipopolysaccharides (LPS) or keratin were added to the incubation culture medium. After 48 hours, the titers of IL-1 alpha and TNF-alpha in the culture medium were measured with enzyme linked immunosorbent assay (ELISA). Debris filtrated medium showed a marked increase in IL-1 alpha, in both cholesteatomatous keratinocytes and NHEK culture, as compared with the effects of LPS, keratin and medium alone.(ABSTRACT TRUNCATED AT 250 WORDS)

  15. Fibroblast growth factor 23 and parathyroid hormone predict extent of aortic valve calcifications in patients with mild to moderate chronic kidney disease

    PubMed Central

    Di Lullo, Luca; Gorini, Antonio; Bellasi, Antonio; Morrone, Luigi F.; Rivera, Rodolfo; Russo, Luigi; Santoboni, Alberto; Russo, Domenico

    2015-01-01

    Background Cardiac valve calcifications are present in dialysis patients and regarded as dependent on a deranged mineral metabolism. Few data are available for patients with chronic kidney disease (CKD) not on dialysis. This study evaluates the potential association between the extent of cardiac valve calcification and levels of intact parathyroid hormone (i-PTH), phosphorus, calcium, 25-OH vitamin D, fibroblast growth factor 23 (FGF-23), Klotho and C-reactive protein (CRP) simultaneously measured in patients with mild to moderate CKD. Methods Consecutive non-hospitalized patients referring to five nephrology units were evaluated. Inclusion criteria were age >18 years, CKD Stages 3–4, and the presence of aortic and/or mitral valve calcification assessed by echocardiography as routinely clinical evaluation. Patients underwent clinical examination and routine biochemistry. Baseline i-PTH, phosphorus, calcium, 25-OH vitamin D, FGF-23, Klotho and CRP were simultaneously ascertained. Results Extent of aortic valve calcification (n = 100 patients) was moderate in 68 patients and mild in the remaining patients. Mitral valve calcification (n = 96 patients) score was 1, 2 and 3 in 61, 34 and 1 patients, respectively. In univariate analysis, no association was found between extent of mitral valve calcification and markers of mineral metabolism and CRP; aortic valve extent of calcification was positively associated with i-PTH (r2 = 0.212; P = 0.03) and FGF-23 (r2 = 0.272; P = 0.01), and negatively with Klotho (r2 = −0.208; P = 0.04). In multivariable analysis, extent of aortic valve calcification was associated with FGF-23 (P = 0.01) and PTH (P = 0.01) levels. Conclusions Extent of aortic valve calcification is associated to FGF-23 and PTH in naïve CKD patients with mild to moderate CKD. Further studies should examine whether FGF-23 assay should be included in routine clinical evaluation of CKD as part of cardiovascular risk stratification. PMID:26613033

  16. Targets for parathyroid hormone in secondary hyperparathyroidism: is a “one-size-fits-all” approach appropriate? A prospective incident cohort study

    PubMed Central

    2014-01-01

    Background Recommendations for secondary hyperparathyroidism (SHPT) consider that a “one-size-fits-all” target enables efficacy of care. In routine clinical practice, SHPT continues to pose diagnosis and treatment challenges. One hypothesis that could explain these difficulties is that dialysis population with SHPT is not homogeneous. Methods EPHEYL is a prospective, multicenter, pharmacoepidemiological study including chronic dialysis patients (≥3 months) with newly SHPT diagnosis, i.e. parathyroid hormone (PTH) ≥500 ng/L for the first time, or initiation of cinacalcet, or parathyroidectomy. Multiple correspondence analysis and ascendant hierarchical clustering on clinico-biological (symptoms, PTH, plasma phosphorus and alkaline phosphatase) and treatment of SHPT (cinacalcet, vitamin D, calcium, or calcium-free calcic phosphate binder) were performed to identify distinct phenotypes. Results 305 patients (261 with incident PTH ≥ 500 ng/L; 44 with cinacalcet initiation) were included. Their mean age was 67 ± 15 years, and 60% were men, 92% on hemodialysis and 8% on peritoneal dialysis. Four subgroups of SHPT patients were identified: 1/ “intermediate” phenotype with hyperphosphatemia without hypocalcemia (n = 113); 2/ younger patients with severe comorbidities, hyperphosphatemia and hypocalcemia, despite SHPT multiple medical treatments, suggesting poor adherence (n = 73); 3/ elderly patients with few cardiovascular comorbidities, controlled phospho-calcium balance, higher PTH, and few treatments (n = 75); 4/ patients who initiated cinacalcet (n = 43). The quality criterion of the model had a cut-off of 14 (>2), suggesting a relevant classification. Conclusion In real life, dialysis patients with newly diagnosed SHPT constitute a very heterogeneous population. A “one-size-fits-all” target approach is probably not appropriate. Therapeutic management needs to be adjusted to the 4 different phenotypes. PMID:25123022

  17. Human renal carcinoma expresses two messages encoding a parathyroid hormone-like peptide: Evidence for the alternative splicing of a single-copy gene

    SciTech Connect

    Thiede, M.A.; Strewler, G.J.; Nissenson, R.A.; Rosenblatt, M.; Rodan, G.A. )

    1988-07-01

    A peptide secreted by tumors associated with the clinical syndrome of humoral hypercalcemia of malignancy was recently purified from human renal carcinoma cell line 786-0. The N-terminal amino acid sequence of this peptide has considerable similarity with those of parathyroid hormone (PTH) and of peptides isolated from human breast and lung carcinoma (cell line BEN). In this study the authors obtained the nucleotide sequence of a 1595-base cDNA complementary to mRNA encoding the PTH-like peptide produced by 786-0 cells. The cDNA contains an open reading frame encoding a leader sequence of 36 amino acids and a 139-residue peptide, in which 8 of the first 13 residues are identical to the N terminus of PTH. Through the first 828 bases the sequence of this cDNA is identical with one recently isolated from a BEN cell cDNA library; however, beginning with base 829 the sequences diverge, shortening the open reading frame by 2 amino acids. Differential RNA blot analysis revealed that 786-0 cells express two major PTH-like peptide mRNAs with different 3{prime} untranslated sequences, one of which hybridizes with the presently described sequence and the other one with that reported for the BEN cell PTH-like peptide cDNA. Primer-extension analysis of 786-0 poly(A){sup +} RNA together with Southern blot analysis of human DNA confirmed the presence of a single-copy gene coding for multiple mRNAs through alternate splicing. In addition, the 3{prime} untranslated sequence of the cDNA described here has significant similarity to the c-myc protooncogene.

  18. Local delivery of parathyroid hormone-related protein-derived peptides coated onto a hydroxyapatite-based implant enhances bone regeneration in old and diabetic rats.

    PubMed

    Ardura, Juan A; Portal-Núñez, Sergio; Lozano, Daniel; Gutiérrez-Rojas, Irene; Sánchez-Salcedo, Sandra; López-Herradón, Ana; Mulero, Francisca; Villanueva-Peñacarrillo, María L; Vallet-Regí, María; Esbrit, Pedro

    2016-08-01

    Diabetes mellitus (DM) and aging are associated with bone fragility and increased fracture risk. Both (1-37) N- and (107-111) C-terminal parathyroid hormone-related protein (PTHrP) exhibit osteogenic properties. We here aimed to evaluate and compare the efficacy of either PTHrP (1-37) or PTHrP (107-111) loaded into gelatin-glutaraldehyde-coated hydroxyapatite (HA-Gel) foams to improve bone repair of a transcortical tibial defect in aging rats with or without DM, induced by streptozotocin injection at birth. Diabetic old rats showed bone structural deterioration compared to their age-matched controls. Histological and μ-computerized tomography studies showed incomplete bone repair at 4 weeks after implantation of unloaded Ha-Gel foams in the transcortical tibial defects, mainly in old rats with DM. However, enhanced defect healing, as shown by an increase of bone volume/tissue volume and trabecular and cortical thickness and decreased trabecular separation, occurred in the presence of either PTHrP peptide in the implants in old rats with or without DM. This was accompanied by newly formed bone tissue around the osteointegrated HA-Gel implant and increased gene expression of osteocalcin and vascular endothelial growth factor (bone formation and angiogenic markers, respectively), and decreased expression of Sost gene, a negative regulator of bone formation, in the healing bone area. Our findings suggest that local delivery of PTHrP (1-37) or PTHrP (107-111) from a degradable implant is an attractive strategy to improve bone regeneration in aged and diabetic subjects. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2060-2070, 2016.

  19. Inhibition of the canonical Wnt pathway by high glucose can be reversed by parathyroid hormone-related protein in osteoblastic cells.

    PubMed

    López-Herradón, Ana; Portal-Núñez, Sergio; García-Martín, Adela; Lozano, Daniel; Pérez-Martínez, Francisco C; Ceña, Valentín; Esbrit, Pedro

    2013-08-01

    Recent in vivo findings suggest that the bone sparing effect of parathyroid hormone-related protein (PTHrP) in diabetic mice might occur at least in part through targeting a suppressed Wnt/β-catenin pathway in osteoblasts. We here aimed to examine the inhibitory action of a high glucose environment on specific components of the canonical Wnt pathway, and the putative compensatory effects of PTHrP, in osteoblastic cell cultures. Mouse osteoblastic MC3T3-E1 cells and primary cultures of fetal mouse calvaria were exposed to normal (5.5 mM) or high (25 mM) D-glucose (HG), with or without PTHrP (1-36) or PTHrP (107-139) for different times. In some experiments, MC3T3-E1 cells were incubated with the Wnt pathway activators Wnt3a and LiCl, or were transfected with plasmids encoding either a mutated β-catenin that cannot be targeted for degradation or a human PTHrP (-36/+139) cDNA, or the corresponding empty plasmid, in the presence or absence of HG. The gene expression of Wnt3a and low density receptor-like proteins (LRP)-5 and 6, as well as β-catenin protein stabilization and β-catenin-dependent transcription activity were evaluated. Oxidative stress status under HG condition was also assessed. The present data demonstrate that HG can target different components of the canonical Wnt pathway, while β-catenin degradation appears to be a key event leading to inhibition of Wnt/β-catenin signaling in mouse osteoblastic cells. Both PTHrP peptides tested were able to counteract this deleterious action of HG. These in vitro findings also provide new clues to understand the underlying mechanisms whereby PTHrP can increase bone formation.

  20. Serum 25-Hydroxyvitamin D and Parathyroid Hormone Levels in Non-Lactating Women with Post-Partum Thyroiditis: The Effect of L-Thyroxine Treatment.

    PubMed

    Krysiak, Robert; Kowalska, Beata; Okopien, Bogusław

    2015-06-01

    Vitamin D deficiency seems to be implicated in the onset and progression of some autoimmune disorders. No previous study has investigated vitamin D homeostasis in post-partum thyroiditis. We compared 25-hydroxyvitamin D and parathyroid hormone (PTH) levels between four groups of non-lactating women who gave birth within 12 months before the beginning of the study: hypothyroid women with post-partum thyroiditis (group A; n = 14), euthyroid females with post-partum thyroiditis (group B; n = 14), women with non-autoimmune hypothyroidism (group C; n = 16) and healthy euthyroid females without thyroid autoimmunity (group D; n = 15). In the second part of the study, groups A and C were treated for 6 months with L-thyroxine. Serum levels of 25-hydroxyvitamin D were lower, while PTH higher in patients with post-partum thyroiditis than in patients without thyroid autoimmunity. They were also lower (25-hydroxyvitamin D) or higher (PTH) in group A than in group B, as well as in group C in comparison with group D. L-thyroxine treatment increased 25-hydroxyvitamin D and reduced PTH levels only in hypothyroid women with post-partum thyroiditis. Baseline levels of 25-hydroxyvitamin D correlated with thyroid antibody titres, thyroid function and circulating PTH levels, while the effect of L-thyroxine on serum levels of this vitamin correlated with the changes in thyroid antibody titres and PTH levels. The results of our study suggest the association of vitamin D status with post-partum thyroiditis and L-thyroxine treatment of this disorder.

  1. Treatment and prevention of chemotherapy-induced alopecia with PTH-CBD, a collagen-targeted parathyroid hormone analog, in a non-depilated mouse model

    PubMed Central

    Katikaneni, Ranjitha; Ponnapakkam, Tulasi; Matsushita, Osamu; Sakon, Joshua; Gensure, Robert

    2014-01-01

    Alopecia is a psychologically devastating complication of chemotherapy for which there is currently no effective therapy. PTH-CBD is a collagen-targeted parathyroid hormone analog that has shown promise as a therapy for alopecia disorders. To compare the efficacy of prophylactic versus therapeutic administration of PTH-CBD in chemotherapy-induced alopecia using a mouse model that mimics the cyclic chemotherapy dosing used clinically. C57BL/6J mice were treated with a single subcutaneous injection of PTH-CBD (320 mcg/kg) or vehicle control before or after hair loss developing from three courses of cyclophosphamide chemotherapy (50–150 mg/kg/week). Mice receiving chemotherapy alone developed hair loss and depigmentation over 6–12 months. Mice pretreated with PTH-CBD did not develop these changes and maintained a normal-appearing coat. Mice treated with PTH-CBD after development of hair loss showed a partial recovery. Observations of hair loss were confirmed quantitatively by gray scale analysis. Histological examination showed that in mice receiving chemotherapy alone, there were small, dystrophic hair follicles mostly in the catagen phase. Mice receiving PTH-CBD before chemotherapy showed a mix of normal-appearing telogen and anagen hair follicles with no evidence of dystrophy. Mice receiving PTH-CBD therapy after chemotherapy showed intermediate histological features. PTH-CBD was effective in both the prevention and the treatment of chemotherapy-induced alopecia in mice, but pretreatment appears to result in a better cosmetic outcome. PTH-CBD shows promise as an agent in the prevention of this complication of chemotherapy and improving the quality of life for cancer patients. PMID:24025564

  2. The Role of Parathyroid Hormone-Related Protein (PTHrP) in Osteoblast Response to Microgravity: Mechanistic Implications for Osteoporosis Development

    PubMed Central

    Camirand, Anne; Goltzman, David; Gupta, Ajay; Kaouass, Mohammadi; Panda, Dibyendu; Karaplis, Andrew

    2016-01-01

    Prolonged skeletal unloading through bedrest results in bone loss similar to that observed in elderly osteoporotic patients, but with an accelerated timeframe. This rapid effect on weight-bearing bones is also observed in astronauts who can lose up to 2% of their bone mass per month spent in Space. Despite the important implications for Spaceflight travelers and bedridden patients, the exact mechanisms involved in disuse osteoporosis have not been elucidated. Parathyroid hormone-related protein (PTHrP) regulates many physiological processes including skeletal development, and has been proposed as a mechanosensor. To investigate the role of PTHrP in microgravity-induced bone loss, trabecular and calvarial osteoblasts (TOs and COs) from Pthrp +/+ and -/- mice were subjected to actual Spaceflight for 6 days (Foton M3 satellite). Pthrp +/+, +/- and -/- osteoblasts were also exposed to simulated microgravity for periods varying from 6 days to 6 weeks. While COs displayed little change in viability in 0g, viability of all TOs rapidly decreased in inverse proportion to PTHrP expression levels. Furthermore, Pthrp+/+ TOs displayed a sharp viability decline after 2 weeks at 0g. Microarray analysis of Pthrp+/+ TOs after 6 days in simulated 0g revealed expression changes in genes encoding prolactins, apoptosis/survival molecules, bone metabolism and extra-cellular matrix composition proteins, chemokines, insulin-like growth factor family members and Wnt-related signalling molecules. 88% of 0g-induced expression changes in Pthrp+/+ cells overlapped those caused by Pthrp ablation in normal gravity, and pulsatile treatment with PTHrP1-36 not only reversed a large proportion of 0g-induced effects in Pthrp+/+ TOs but maintained viability over 6-week exposure to microgravity. Our results confirm PTHrP efficacy as an anabolic agent to prevent microgravity-induced cell death in TOs. PMID:27463808

  3. Programmed administration of parathyroid hormone increases bone formation and reduces bone loss in hindlimb-unloaded ovariectomized rats

    NASA Technical Reports Server (NTRS)

    Turner, R. T.; Evans, G. L.; Cavolina, J. M.; Halloran, B.; Morey-Holton, E.

    1998-01-01

    Gonadal insufficiency and reduced mechanical usage are two important risk factors for osteoporosis. The beneficial effects of PTH therapy to reverse the estrogen deficiency-induced bone loss in the laboratory rat are well known, but the influence of mechanical usage in this response has not been established. In this study, the effects of programed administration of PTH on cancellous bone volume and turnover at the proximal tibial metaphysis were determined in hindlimb-unloaded, ovariectomized (OVX), 3-month-old Sprague-Dawley rats. PTH was administered to weight-bearing and hindlimb-unloaded OVX rats with osmotic pumps programed to deliver 20 microg human PTH (approximately 80 microg/kg x day) during a daily 1-h infusion for 7 days. Compared with sham-operated rats, OVX increased longitudinal and radial bone growth, increased indexes of cancellous bone turnover, and resulted in net resorption of cancellous bone. Hindlimb unloading of OVX rats decreased longitudinal and radial bone growth, decreased osteoblast number, increased osteoclast number, and resulted in a further decrease in cancellous bone volume compared with those in weight-bearing OVX rats. Programed administration of PTH had no effect on either radial or longitudinal bone growth in weight-bearing and hindlimb-unloaded OVX rats. PTH treatment had dramatic effects on selected cancellous bone measurements; PTH maintained cancellous bone volume in OVX weight-bearing rats and greatly reduced cancellous bone loss in OVX hindlimb-unloaded rats. In the latter animals, PTH treatment prevented the hindlimb unloading-induced reduction in trabecular thickness, but the hormone was ineffective in preventing either the increase in osteoclast number or the loss of trabecular plates. Importantly, PTH treatment increased the retention of a baseline flurochrome label, osteoblast number, and bone formation in the proximal tibial metaphysis regardless of the level of mechanical usage. These findings demonstrate that

  4. Human leptin: from an adipocyte hormone to an endocrine mediator.

    PubMed

    Wauters, M; Considine, R V; Van Gaal, L F

    2000-09-01

    Leptin is a mainly adipocyte-secreted protein that was discovered 5 years ago. Most of the research following this discovery focused on the role of leptin in body weight regulation, aiming to illuminate the pathophysiology of human obesity. However, more and more data are emerging that leptin is not only important in the regulation of food intake and energy balance, but that it also has a function as a metabolic and neuroendocrine hormone. It is now clear that it is especially involved in glucose metabolism, as well as in normal sexual maturation and reproduction. Besides this, interactions with the hypothalamic-pituitary-adrenal, thyroid and GH axes and even with haematopoiesis and the immune system have also been described. It has been shown that leptin secretion by the adipocyte is partly regulated by other hormones, such as insulin, cortisol, and sex steroids, mainly testosterone. Also, other hormones like thyroid hormone and GH are possibly involved in leptin synthesis. Leptin itself exerts effects on different endocrine axes, mainly on the hypothalamic-pituitary-gonadal axis and on insulin metabolism, but also on the hypothalamic-pituitary-adrenal, thyroid and GH axes. Leptin may thus be considered a new endocrine mediator, besides its obvious role in body weight regulation.

  5. Calcimimetic and calcilytic drugs: just for parathyroid cells?

    PubMed

    Nemeth, E F

    2004-03-01

    The cell surface calcium receptor (Ca2+ receptor) is a particularly difficult receptor to study because its primary physiological ligand, Ca2+, affects numerous biological processes both within and outside of cells. Because of this, distinguishing effects of extracellular Ca2+ mediated by the Ca2+ receptor from those mediated by other mechanisms is challenging. Certain pharmacological approaches, however, when combined with appropriate experimental designs, can be used to more confidently identify cellular responses regulated by the Ca2+ receptor and select those that might be targeted therapeutically. The Ca2+ receptor on parathyroid cells, because it is the primary mechanism regulating secretion of parathyroid hormone (PTH), is one such target. Calcimimetic compounds, which active this Ca2+ receptor and lower circulating levels of PTH, have been developed for treating hyperparathyroidism. The converse pharmaceutical approach, involving calcilytic compounds that block parathyroid cell Ca2+ receptors and stimulate PTH secretion thereby providing an anabolic therapy for osteoporosis, still awaits clinical validation. Although Ca2+ receptors are expressed throughout the body and in many tissues that are not intimately involved in systemic Ca2+ homeostasis, their physiological and/or pathological significance remains speculative and their value as therapeutic targets is unknown. PMID:15200152

  6. Basal Bone Phenotype and Increased Anabolic Responses to Intermittent Parathyroid Hormone in Healthy Male COX-2 Knockout Mice

    PubMed Central

    Xu, Manshan; Choudhary, Shilpa; Voznesensky, Olga; Gao, Qi; Adams, Douglas; Diaz-Doran, Vilmaris; Wu, Qian; Goltzman, David; Raisz, Lawrence G.; Pilbeam, Carol C.

    2011-01-01

    Cyclooxygenase-2 (COX-2) knockout (KO) mice in inbred strains can have renal dysfunction with secondary hyperparathyroidism (HPTH), making direct effects of COX-2 KO on bone difficult to assess. COX-2 KO mice in an outbred CD-1 background did not have renal dysfunction but still had two-fold elevated PTH compared to wild type (WT) mice. Compared to WT mice, KO mice had increased serum markers of bone turnover, decreased femoral bone mineral density (BMD) and cortical bone thickness, but no differences in trabecular bone volume by μCT or dynamic histomorphometry. Because PTH is a potent inducer of COX-2 and prostaglandin (PG) production, we examined effects of COX-2 KO on bone responses after three weeks of intermittent PTH. Intermittent PTH increased femoral BMD and cortical bone area more in KO mice than in WT mice and increased trabecular bone volume in the distal femur in both WT and KO mice. Although not statistically significant, PTH-stimulated increases in trabecular bone tended to be greater in KO mice than in WT mice. PTH increased serum markers of bone formation and resorption more in KO than in WT mice but increased the ratio of osteoblastic surface to osteoclastic surface only in KO mice. PTH also increased femoral mineral apposition rates and bone formation rates in KO mice more than in WT mice. Acute mRNA responses to PTH of genes that might mediate some anabolic and catabolic effects of PTH tended to be greater in KO than WT mice. We conclude that (1) the basal bone phenotype in male COX-2 KO mice might reflect HPTH, COX-2 deficiency or both, and (2) increased responses to intermittent PTH in COX-2 KO mice, despite the presence of chronic HPTH, suggest that absence of COX-2 increased sensitivity to PTH. It is possible that manipulation of endogenous PGs could have important clinical implications for anabolic therapy with PTH. PMID:20471507

  7. Original Research: Atorvastatin prevents rat cardiomyocyte hypertrophy induced by parathyroid hormone 1-34 associated with the Ras-ERK signaling.

    PubMed

    Liu, Xiaogang; Zou, Chunbo; Yu, Chengyuan; Xie, Rujuan; Sui, Manshu; Mu, Suhong; Li, Li; Zhao, Shilei

    2016-10-01

    We investigated the effects of atorvastatin (Ator) on cardiomyocyte hypertrophy (CMH) induced by rat parathyroid hormone 1-34 (PTH1-34) and Ras-extracellular signal regulated protein kinases 1/2 (ERK1/2) signaling. Rat cardiomyocytes were randomly divided into seven groups: normal controls (NC), PTH1-34 (10(-7) mol/L), Ator (10(-5) mol/L), farnesyl transferase inhibitors-276 (FTI-276, 4 × 10(-5) mol/L), PTH1-34 + Ator, PTH1-34 + FTI-276 and PTH1-34 + Ator + mevalonic acid (MVA, 10(-4) mol/L). After treatment, the hypertrophic responses of cardiomyocytes were assessed by measuring cell diameter, detecting protein synthesis, and single-cell protein content. The concentrations of hypertrophic markers such as atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) were measured by ELISA. Protein expressions of ERK1/2, p-ERK1/2 and Ras were detected by western blotting. The results showed that compared with the PTH1-34 group, cellular diameter, 3H-leucine incorporation, single-cell protein content, ANP and BNP concentration decreased by 12.07 µm, 1622 cpm/well, 84.34 pg, 7.13 ng/L and 20.04 µg/L, respectively, and the expressions of Ras and p-ERK1/2 were downregulated in PTH1-34 + Ator group (P < 0.05). Compared to the PTH1-34 + Ator group, the corresponding hypertrophic responses and hypertrophic markers increased by 4.95 µm, 750 cpm/well, 49.08 pg, 3.12 ng/L and 9.35 µg/L, respectively, and the expressions of Ras and p-ERK1/2 were upregulated in the PTH1-34 + Ator + MVA group (P < 0.05). In conclusion, Ator prevents neonatal rat CMH induced by PTH1-34 and Ras-ERK signaling may be involved in this process.

  8. Original Research: Atorvastatin prevents rat cardiomyocyte hypertrophy induced by parathyroid hormone 1-34 associated with the Ras-ERK signaling.

    PubMed

    Liu, Xiaogang; Zou, Chunbo; Yu, Chengyuan; Xie, Rujuan; Sui, Manshu; Mu, Suhong; Li, Li; Zhao, Shilei

    2016-10-01

    We investigated the effects of atorvastatin (Ator) on cardiomyocyte hypertrophy (CMH) induced by rat parathyroid hormone 1-34 (PTH1-34) and Ras-extracellular signal regulated protein kinases 1/2 (ERK1/2) signaling. Rat cardiomyocytes were randomly divided into seven groups: normal controls (NC), PTH1-34 (10(-7) mol/L), Ator (10(-5) mol/L), farnesyl transferase inhibitors-276 (FTI-276, 4 × 10(-5) mol/L), PTH1-34 + Ator, PTH1-34 + FTI-276 and PTH1-34 + Ator + mevalonic acid (MVA, 10(-4) mol/L). After treatment, the hypertrophic responses of cardiomyocytes were assessed by measuring cell diameter, detecting protein synthesis, and single-cell protein content. The concentrations of hypertrophic markers such as atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) were measured by ELISA. Protein expressions of ERK1/2, p-ERK1/2 and Ras were detected by western blotting. The results showed that compared with the PTH1-34 group, cellular diameter, 3H-leucine incorporation, single-cell protein content, ANP and BNP concentration decreased by 12.07 µm, 1622 cpm/well, 84.34 pg, 7.13 ng/L and 20.04 µg/L, respectively, and the expressions of Ras and p-ERK1/2 were downregulated in PTH1-34 + Ator group (P < 0.05). Compared to the PTH1-34 + Ator group, the corresponding hypertrophic responses and hypertrophic markers increased by 4.95 µm, 750 cpm/well, 49.08 pg, 3.12 ng/L and 9.35 µg/L, respectively, and the expressions of Ras and p-ERK1/2 were upregulated in the PTH1-34 + Ator + MVA group (P < 0.05). In conclusion, Ator prevents neonatal rat CMH induced by PTH1-34 and Ras-ERK signaling may be involved in this process. PMID:27190264

  9. Effects of parathyroid hormone on cortical porosity, non-enzymatic glycation and bone tissue mechanics in rats with type 2 diabetes mellitus.

    PubMed

    Campbell, G M; Tiwari, S; Hofbauer, C; Picke, A-K; Rauner, M; Huber, G; Peña, J A; Damm, T; Barkmann, R; Morlock, M M; Hofbauer, L C; Glüer, C-C

    2016-01-01

    Type 2 diabetes mellitus increases skeletal fragility; however, the contributing mechanisms and the efficacy of bone-forming agents are unclear. We studied diabetes and parathyroid hormone (PTH) treatment effects on cortical porosity (Ct.Po), non-enzymatic glycation (NEG) and bone mechanics in Zucker diabetic fatty (ZDF) rats. Eleven-week old ZDF diabetic (DB) and non-diabetic (ND) rats were given 75μg/kg PTH (1-84) or vehicle 5days per week over 12weeks. The right femora and L4 vertebrae were excised, micro-CT scanned, and tested in 3-point bending and uniaxial compression, respectively. NEG of the samples was determined using fluorescence. Diabetes increased Ct.Po (vertebra (vert): +40.6%, femur (fem): +15.5% vs. ND group, p<0.05) but had no effect on NEG. PTH therapy reduced vertebral NEG in the ND animals only (-73% vs untreated group, p<0.05), and increased femoral NEG in the DB vs. ND groups (+63%, p<0.05). PTH therapy had no effect on Ct.Po. Diabetes negatively affected bone tissue mechanics where reductions in vertebral maximum strain (-22%) and toughness (-42%) were observed in the DB vs. ND group (p<0.05). PTH improved maximum strain in the vertebra of the ND animals (+21%, p<0.05) but did not have an effect in the DB group. PTH increased femoral maximum strain (+21%) and toughness (+28%) in ND and decreased femoral maximum stress (-13%) and toughness (-27%) in the DB animals (treated vs. untreated, p<0.05). Ct.Po correlated negatively with maximum stress (fem: R=-0.35, p<0.05, vert: R=-0.57, p<0.01), maximum strain (fem: R=-0.35, p<0.05, vert: R=-0.43, p<0.05) and toughness (fem: R=-0.34, p<0.05, vert: R=-0.55, p<0.01), and NEG correlated negatively with toughness at the femur (R=-0.34, p<0.05) and maximum strain at the vertebra (R=-0.49, p<0.05). Diabetes increased cortical porosity and reduced bone mechanics, which were not improved with PTH treatment. PTH therapy alone may worsen diabetic bone mechanics through formation of new bone with high AGEs

  10. Parathyroid Hormone-Related Peptide (1-36) Enhances Beta Cell Regeneration and Increases Beta Cell Mass in a Mouse Model of Partial Pancreatectomy

    PubMed Central

    Mozar, Anaïs; Lin, Hugo; Williams, Katoura; Chin, Connie; Li, Rosemary; Kondegowda, Nagesha Guthalu; Stewart, Andrew F.; Garcia-Ocaña, Adolfo; Vasavada, Rupangi Chhaya

    2016-01-01

    Aims/Hypothesis Finding ways to stimulate the regeneration of endogenous pancreatic beta cells is an important goal in the treatment of diabetes. Parathyroid hormone-related protein (PTHrP), the full-length (1–139) and amino-terminal (1–36) peptides, enhance beta cell function, proliferation, and survival. Therefore, we hypothesize that PTHrP(1–36) has the potential to regenerate endogenous beta cells. Methods The partial pancreatectomy (PPx) mouse model of beta cell injury was used to test this hypothesis. Male Balb/c mice underwent either sham-operation or PPx, and were subsequently injected with PTHrP(1–36) (160μg/kg) or vehicle (veh), for 7, 30, or 90 days. The four groups of mice, sham-veh, sham-PTHrP, PPx-veh, and PPx-PTHrP were assessed for PTHrP and receptor expression, and glucose and beta cell homeostasis. Results PTHrP-receptor, but not the ligand, was significantly up-regulated in islets from mice that underwent PPx compared to sham-operated mice. This suggests that exogenous PTHrP could further enhance beta cell regeneration after PPx. PTHrP did not significantly affect body weight, blood glucose, plasma insulin, or insulin sensitivity, in either sham or PPx mice. Glucose tolerance improved in the PPx-PTHrP versus PPx-veh mice only in the early stages of treatment. As hypothesized, there was a significant increase in beta cell proliferation in PPx-PTHrP mice at days 7 and 30; however, this was normalized by day 90, compared to PPx-veh mice. Enhanced beta cell proliferation translated to a marked increase in beta cell mass at day 90, in PPx-PTHrP versus PPx-veh mice. Conclusions PTHrP(1–36) significantly enhances beta cell regeneration through increased beta cell proliferation and beta cell mass after PPx. Future studies will determine the potential of PTHrP to enhance functional beta cell mass in the setting of diabetes. PMID:27391423

  11. Abnormal parathyroid hormone stimulation of 25-hydroxyvitamin D-1 alpha-hydroxylase activity in the hypophosphatemic mouse. Evidence for a generalized defect of vitamin D metabolism.

    PubMed Central

    Nesbitt, T; Drezner, M K; Lobaugh, B

    1986-01-01

    Abnormal regulation of vitamin D metabolism is a feature of X-linked hypophosphatemic rickets in man and of the murine homologue of the disease in the hypophosphatemic (Hyp)-mouse. We previously reported that mutant mice have abnormally low renal 25-hydroxyvitamin D-1 alpha-hydroxylase (1 alpha-hydroxylase) activity for the prevailing degree of hypophosphatemia. To further characterize this defect, we examined whether Hyp-mouse renal 1 alpha-hydroxylase activity responds normally to other stimulatory and inhibitory controls of enzyme function. We studied stimulation by parathyroid hormone (PTH) using: (a) a calcium-deficient (0.02% Ca) diet to raise endogenous PTH; or (b) 24-h continuous infusion of 0.25 IU/h bovine PTH via osmotic minipump. In both cases enzyme activity of identically treated normal mice increased to greater levels than those attained by Hyp-mice. The relative inability of PTH to stimulate 1 alpha-hydroxylase activity is not a function of the hypophosphatemia in the Hyp-mouse since PTH-infused, phosphate-depleted normal mice sustained a level of enzyme activity greater than that of normal and Hyp-mice. In further studies we investigated inhibition of enzyme activity by using: (a) a calcium-loaded (1.2% Ca) diet to suppress endogenous PTH; or (b) 24-h continuous infusion of 0.2 ng/h 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). The 1 alpha-hydroxylase activity of normal and Hyp-mice was significantly reduced to similar absolute levels following maintenance on the calcium-loaded diet. Further, infusion of 1,25(OH)2D3 caused a comparable reduction of 1 alpha-hydroxylase activity in normal, Hyp-, and phosphate-depleted normal mice. These observations indicate that the inhibitory control of 1 alpha-hydroxylase by reduced levels of PTH or increased 1,25(OH)2D3 concentrations is intact in the mutants. However, the inability of PTH and hypophosphatemia to stimulate enzyme activity in a manner analogous to that in normal and phosphate-depleted mice indicates

  12. Parathyroid hormone-related protein (107-139) increases human osteoblastic cell survival by activation of vascular endothelial growth factor receptor-2.

    PubMed

    Alonso, Verónica; de Gortázar, Arancha R; Ardura, Juan A; Andrade-Zapata, Irene; Alvarez-Arroyo, M Victoria; Esbrit, Pedro

    2008-12-01

    Parathyroid hormone-related protein (PTHrP) (107-139), in contrast to the N-terminal fragment PTHrP (1-36), has been shown to interact with the vascular endothelial growth factor (VEGF) system to modulate human osteoblast differentiation. In this study, we evaluated whether this interaction might affect human osteoblastic cell survival. Pre-incubation with PTHrP (107-139) for 1-24 h dose-dependently (0.1-100 nM) inhibited dexamethasone- or etoposide-induced cell death in human osteoblastic MG-63 cells and human osteoblast-like cells from trabecular bone. This effect, but not that elicited by PTHrP (1-36), was abolished by the VEGF receptor (VEGFR)-2 inhibitors SU5614 and SU1498 or VEGFR-2 siRNA transfection in these cells. PTHrP (107-139), but not PTHrP (1-36), at 100 nM, rapidly (within 2 min) increased VEGFR-2 tyrosine-phosphorylation in MG-63 cells; an effect unaffected by several inhibitors of metalloproteinases, neutralizing VEGF(165) or VEGFR-2 antibodies, or the VEGF binding inhibitor CBO-PP1. The latter two antagonists also failed to affect (125)I-[Tyr(116)] PTHrP (107-115) binding to these cells. Consistent with its effect on VEGFR-2 activation, PTHrP (107-139) rapidly induced extracellular signal-regulated kinase (ERK) 1/2 and Akt activaton, and both ERK and phosphatidylinsositol-3 kinase (PI3K) inhibitors abolished its pro-survival effect in human osteoblastic cells. In addition, SU5614 and the latter two types of inhibitors abrogated Runx2 activation by this peptide in MG-63 cells. Transfection with a dominant-negative Runx2 construct abolished the pro-survival effect of PTHrP (107-139), associated with a decrease in Bcl-2/Bax protein ratio. Our findings demonstrate that PTHrP (107-139) interacts with VEGFR-2 to promote human osteoblastic cell survival by a mechanism involving Runx2 activation.

  13. Parathyroid hormone treatment improves the cortical bone microstructure by improving the distribution of type I collagen in postmenopausal women with osteoporosis.

    PubMed

    Ascenzi, Maria-Grazia; Liao, Vivian P; Lee, Brittany M; Billi, Fabrizio; Zhou, Hua; Lindsay, Robert; Cosman, Felicia; Nieves, Jeri; Bilezikian, John P; Dempster, David W

    2012-03-01

    Although an important index, the level of bone mineral density (BMD) does not completely describe fracture risk. Another bone structural parameter, the orientation of type I collagen, is known to add to risk determination, independently of BMD, ex vivo. We investigated the Haversian system of transiliac crest biopsies from postmenopausal women before and after treatment with parathyroid hormone (PTH). We used the birefringent signal of circularly polarized light and its underlying collagen arrangements by confocal and electron microscopy, in conjunction with the degree of calcification by high-resolution micro-X-ray. We found that PTH treatment increased the Haversian system area by 11.92 ± 5.82 mm² to 12.76 ± 4.50 mm² (p = 0.04); decreased bright birefringence from 0.45 ± 0.02 to 0.40 ± 0.01 (scale zero to one, p = 0.0005); increased the average percent area of osteons with alternating birefringence from 48.15% ± 10.27% to 66.33% ± 7.73% (p = 0.034); and nonsignificantly decreased the average percent area of semihomogeneous birefringent osteons (8.36% ± 10.63% versus 5.41% ± 9.13%, p = 0.40) and of birefringent bright osteons (4.14% ± 8.90% versus 2.08% ± 3.36%, p = 0.10). Further, lamellar thickness significantly increased from 3.78 ± 0.11 µm to 4.47 ± 0.14 µm (p = 0.0002) for bright lamellae, and from 3.32 ± 0.12 µm to 3.70 ± 0.12 µm (p = 0.045) for extinct lamellae. This increased lamellar thickness altered the distribution of birefringence and therefore the distribution of collagen orientation in the tissue. With PTH treatment, a higher percent area of osteons at the initial degree of calcification was observed, relative to the intermediate-low degree of calcification (57.16% ± 3.08% versus 32.90% ± 3.69%, p = 0.04), with percentage of alternating osteons at initial stages of calcification increasing from 19.75 ± 1.22 to 80.13 ± 6.47, p = 0.001. In conclusion, PTH treatment increases heterogeneity of collagen orientation, a starting

  14. PLGA microsphere-mediated growth hormone release hormone expression induces intergenerational growth.

    PubMed

    Ren, Xiao-Hui; Zhang, Yong-Liang; Luo, Hu-Ying; Li, Hong-Yi; Liu, Song-Cai; Zhang, Ming-Jun; Ouyang, Song-Ying; Xi, Qian-Yun; Jiang, Qing-Yan

    2009-01-01

    To improve animal growth, growth hormone-releasing hormone (GHRH) expression vectors that maintain constant GHRH expression can be directly injected into muscles. To deliver the GHRH expression vectors, biodegradable microspheres have been used as a sustained release system. Although administering GHRH through microspheres is a common practice, the intergenerational effects of this delivery system are unknown. To investigate the intergenerational effects of polylactic-co-glycolic acid (PLGA) encapsulated plasmid-mediated GHRH supplements, pCMV-Rep-GHRH microspheres were injected into pregnant mice. Growth and expression of GHRH were measured in the offspring. RT-PCR and immunohistochemistry reveal GHRH expression 3-21 days post-injection. The proportion of GH-positive cells in the GHRH treated offspring was 48.2% higher than in the control group (P < 0.01). The GHRH treated offspring were 6.15% (P < 0.05) larger than the control offspring. At day 49 post-injection, IGF-I serum levels were significantly higher in the treatment group than in the control group. This study confirms that intramuscular expression of GHRH mediated by PLGA microspheres significantly enhances intergenerational growth.

  15. [Parathyroid dysfunction and rheumatic manifestations].

    PubMed

    Frey, D P

    2011-11-01

    Parathyroid dysfunction, leading to severe clinical symptoms and radiographic changes, has decreased over the last years due to routine laboratory checks including serum calcium levels. Thus, abnormal calcium levels are detected early in the course of the disease and the underlying cause treated accordingly. Hyperparathyroidism often leads to osteoporosis and low-trauma fractures. When evaluating secondary osteoporosis analysis of calcium, phosphate and intact parathyroid hormone levels are mandatory. Osteitis fibrosa cystica and brown tumors are less frequent findings of hyperparathyroidism. However, in patients with arthritis or bone symptoms, hyperparathyroidism has to be evaluated as a possible reason. Other manifestations of hyperparathyroidism include myopathy, tendon ruptures and unspecific symptoms of the muscles and skeleton. Gout as well as pseudogout may be associated with hyperparathyroidism. Hypoparathyroidism may cause musculoskeletal diseases mimicking ankylosing spondylitis or diffuse idiopathic skeletal hyperostosis. Myopathies are sometimes induced by hypoparathyroidism. An association between systemic lupus erythematosus and hypoparathyroidism seems to exist.

  16. Human Parathyroid Hormone IMMUNOLOGICAL CHARACTERIZATION OF ANTIBODIES AGAINST A GLANDULAR EXTRACT AND THE SYNTHETIC AMINO-TERMINAL FRAGMENTS 1-12 AND 1-34 AND THEIR USE IN THE DETERMINATION OF IMMUNOREACTIVE HORMONE IN HUMAN SERA

    PubMed Central

    Fischer, Jan A.; Binswanger, Ulrich; Dietrich, Felix M.

    1974-01-01

    Antibodies to a urea-trichloroacetic acid extract [hPTH-(TCA)] of human parathyroid tumors and to the synthetic NH2-terminal fragments of human parathyroid hormone hPTH-(1-12) and -(1-34) were developed in goats to characterize immunochemically various PTH preparations and to estimate immunoreactive PTH (iPTH) in human sera. They were quantitated on the basis of their capacity to bind [131I]-hPTH-(1-12), [131I]hPTH-(1-34) or [131I]bovine PTH (bPTH-(1-84)). The quality of the antibodies was assessed by reference to inhibition of their interaction with labeled peptides by synthetic hPTH comprising 34 NH2-terminal amino acid residues or fragments thereof [hPTH-(1-12), -(13-34), -(18-34), -(25-34), -(18-24)] or by the Sephadex G-100-purified full-length peptide hPTH-(1-84) [hPTH-(1-84)G-100]. The synthetic peptides used in this work correspond in their structure to the NH2-terminal amino acid sequence 1-34, as elucidated by Brewer and collaborators (1972. Proc. Natl. Acad. Sci. U. S. A.69: 3583-3588). Inhibition studies were also carried out with bPTH-(1-34) and bPTH-(1-84). Anti-hPTH-(TCA) exhibited specificities directed to determinants in the COOH-terminal and NH2-terminal part of hPTH-(1-84) and exhibited cross-reactivity with bPTH-(1-84). Anti-hPTH-(1-34), on the other hand, showed immunological specificities mainly directed to antigenic determinants located in the COOH-terminal half of hPTH-(1-34). In addition, some reactivity with the NH2-terminal hPTH-(1-12) and with the extractive full-length peptides of human and bovine origin was observed. Antibodies to hPTH-(1-12) cross-reacted with hPTH-(1-34) and -(1-84)G-100. iPTH was radioimmunologically determined in human sera by the following systems: (a) [131I]bPTH-(1-84), anti-hPTH-(TCA) and hPTH-(1-84)G-100 as standard; (b) [131I]hPTH-(1-34), anti-hPTH-(1-34) and hPTH-(1-34) as standard. With system (a), COOH-terminal fragments of hPTH-(1-84) having a molecular weight of approximately 7,000 were detected, and

  17. Growth Hormone-Releasing Hormone and Its Analogues: Significance for MSCs-Mediated Angiogenesis

    PubMed Central

    Tao, Quanwei; Ma, Qunchao; Chen, Huiqiang; Wang, Jian'an

    2016-01-01

    Mesenchymal stromal cells (MSCs) are promising candidates for regenerative medicine because of their multipotency, immune-privilege, and paracrine properties including the potential to promote angiogenesis. Accumulating evidence suggests that the inherent properties of cytoprotection and tissue repair by native MSCs can be enhanced by various preconditioning stimuli implemented prior to cell transplantation. Growth hormone-releasing hormone (GHRH), a stimulator in extrahypothalamus systems including tumors, has attracted great attentions in recent years because GHRH and its agonists could promote angiogenesis in various tissues. GHRH and its agonists are proangiogenic in responsive tissues including tumors, and GHRH antagonists have been tested as antitumor agents through their ability to suppress angiogenesis and cell growth. GHRH-R is expressed by MSCs and evolving work from our laboratory indicates that treatment of MSCs with GHRH agonists prior to cell transplantation markedly enhanced the angiogenic potential and tissue reparative properties of MSCs through a STAT3 signaling pathway. In this review we summarized the possible effects of GHRH analogues on cell growth and development, as well as on the proangiogenic properties of MSCs. We also discussed the relationship between GHRH analogues and MSC-mediated angiogenesis. The analyses provide new insights into molecular pathways of MSCs-based therapies and their augmentation by GHRH analogues. PMID:27774107

  18. Life-threatening intrathyroidal parathyroid adenoma

    PubMed Central

    Dogan, Ugur; Koc, Umit; Mayir, Burhan; Habibi, Mani; Dogan, Berna; Gomceli, Ismail; Bulbuller, Nurullah

    2015-01-01

    Acute primary hyperparathyroidism and parathyroid crisis are characterized by life-threatening hypercalcemia, a rare disorder. A 69-year-old female patient presented at our hospital’s neurology clinic with weakness, nausea, vomiting, depression, and hypercalcemia. Treatment of hypercalcemia resulted in no improvement in neurological symptoms, indicating resistance to treatment. Thyroid ultrasonography and parathyroid scintigraphy revealed hypoechoic nodules in the right lobe, pieces of nodules in the left lobe, and high serum calcium and parathyroid hormone levels. After provision of intensive medical treatment including hydration, diuresis, and bisphosphonate infusion resulted in only minimal decrease in the calcium level, urgent surgical treatment was performed. Frozen biopsy of the right intrathyroidal giant parathyroid adenoma in the right lobe confirmed initial diagnosis of primary hyperparathyroidism. Based on the biopsy findings, right parathyroidectomy and right total and left subtotal thyroidectomy were performed. Histopathologic examination revealed a parathyroid adenoma localized inside large thyroid nodules. Review of the findings resulted in diagnosis of intrathyroidal parathyroid adenoma. Symptoms of hypercalcemia improved rapidly during the postoperative period. PMID:25785164

  19. Mapping the bimolecular interface of the parathyroid hormone (PTH)-PTH1 receptor complex: spatial proximity between Lys(27) (of the hormone principal binding domain) and leu(261) (of the first extracellular loop) of the human PTH1 receptor.

    PubMed

    Greenberg, Z; Bisello, A; Mierke, D F; Rosenblatt, M; Chorev, M

    2000-07-18

    In an effort to characterize the bimolecular interface between parathyroid hormone (PTH) and its human receptor PTH1-Rc (hPTH1-Rc), we previously identified two contact sites in the receptor: one for position 1 and another for position 13 (located at the ends of the principal activation domain) in PTH(1-34). The present study reports a third, novel "contact site" between hPTH1-Rc and Lys(27) of PTH(1-34). Lys(27) is located in the principal binding domain of the hormone (residues 25-34). The photoreactive PTH(1-34) analogue K27 contains a benzophenone (BP) moiety on Lys(27). The analogue binds to stably transfected HEK 293/C-21 cells (which express a high level of recombinant hPTH1-Rc) and stimulates adenylyl cyclase activity with a potency similar to PTH(1-34). In addition, (125)I-K27 cross-links effectively and specifically to the hPTH1-Rc. Enzymatic (Glu-C and Lys-C) and chemical (CNBr and BNPS-skatole) digestions of the photoconjugate between (125)I-K27 and hPTH1-Rc were performed. In addition, photoconjugates involving the bioactive mutants [L261M]- and [R262K]-hPTH1-Rc, transiently expressed in COS-7 cells, were also digested. The data obtained clearly identify L(261) or R(262) of the first extracellular loop of hPTH1-Rc as the contact site for Lys(27) in the hormone. On the basis of (i) the similarity in molecular mass between the CNBr digest of the (125)I-K27-[L261M]hPTH1-Rc conjugate and free (125)I-K27 and (ii) the failure to cross-link (125)I-K27 to a bioactive mutant receptor [L261A]hPTH1-Rc, we conclude that L(261) is the cross-linking site. These results provide the first demonstration of an interaction between the principal binding domain of PTH and the first extracellular loop of hPTH1-Rc. Revealing proximity of Lys(27) (in PTH) to L(261) (in hPTH1-Rc) provides additional insight into the nature of the ligand-receptor bimolecular interface and clearly illustrates that the extracellular loops of the receptor contribute to the specificity of the PTH

  20. Single-sperm typing: determination of genetic distance between the G gamma-globin and parathyroid hormone loci by using the polymerase chain reaction and allele-specific oligomers.

    PubMed Central

    Cui, X F; Li, H H; Goradia, T M; Lange, K; Kazazian, H H; Galas, D; Arnheim, N

    1989-01-01

    The frequency of recombination between the G gamma-globin (HBG2) and parathyroid hormone (PTH) loci on the short arm of human chromosome 11 was estimated by typing greater than 700 single-sperm samples from two males. The sperm-typing technique employed involves the polymerase chain reaction and allele-specific oligonucleotide hybridization. Our maximum likelihood recombination fraction estimate of 0.16 (95%) confidence interval, 0.13-0.19) falls well within previous estimates based on family studies. With current technology and a sample size of 1000 sperm, recombination fractions down to approximately 0.009 can be estimated with statistical reliability; with a sample size of 5000 sperm, this value drops to about 0.004. Reasonable technological improvements could result in the detection of recombination frequencies less than 0.001. PMID:2574460

  1. Alterations of the Wnt/beta-catenin pathway and its target genes for the N- and C-terminal domains of parathyroid hormone-related protein in bone from diabetic mice.

    PubMed

    Portal-Núñez, S; Lozano, D; de Castro, L Fernández; de Gortázar, A R; Nogués, X; Esbrit, P

    2010-07-16

    Type 1 diabetes mellitus (T1D) is associated with bone loss. Given that the Wnt/beta-catenin pathway is a major regulator of bone accrual, we assessed this pathway in mice with streptozotozin-induced T1D. In diabetic mouse long bones, we found alterations favouring the suppression of this pathway by using PCR arrays and beta-catenin immunostaining. Downregulation of sclerostin, an inhibitor of this pathway, also occurred, and related to increased osteocyte apoptosis. Our data show that both N- and C-terminal parathyroid hormone-related peptide fragments might exert osteogenic effects in this setting by targeting several genes of this pathway and increasing beta-catenin in osteoblastic cells.

  2. Parathyroid gland angiography with indocyanine green fluorescence to predict parathyroid function after thyroid surgery

    PubMed Central

    Vidal Fortuny, J.; Belfontali, V.; Sadowski, S. M.; Karenovics, W.; Guigard, S.

    2016-01-01

    Background Postoperative hypoparathyroidism remains the most common complication following thyroidectomy. The aim of this pilot study was to evaluate the use of intraoperative parathyroid gland angiography in predicting normal parathyroid gland function after thyroid surgery. Methods Angiography with the fluorescent dye indocyanine green (ICG) was performed in patients undergoing total thyroidectomy, to visualize vascularization of identified parathyroid glands. Results Some 36 patients underwent ICG angiography during thyroidectomy. All patients received standard calcium and vitamin D supplementation. At least one well vascularized parathyroid gland was demonstrated by ICG angiography in 30 patients. All 30 patients had parathyroid hormone (PTH) levels in the normal range on postoperative day (POD) 1 and 10, and only one patient exhibited asymptomatic hypocalcaemia on POD 1. Mean(s.d.) PTH and calcium levels in these patients were 3·3(1·4) pmol/l and 2·27(0·10) mmol/l respectively on POD 1, and 4·0(1.6) pmol/l and 2·32(0·08) mmol/l on POD 10. Two of the six patients in whom no well vascularized parathyroid gland could be demonstrated developed transient hypoparathyroidism. None of the 36 patients presented symptomatic hypocalcaemia, and none received treatment for hypoparathyroidism. Conclusion PTH levels on POD 1 were normal in all patients who had at least one well vascularized parathyroid gland demonstrated during surgery by ICG angiography, and none required treatment for hypoparathyroidism. PMID:26864909

  3. Effect of angiotensin II type 1 receptor blocker on renal function, arterial blood pressure and parathyroid hormone related protein over expression in cadmium induced nephrotoxicity in adult male rats

    PubMed Central

    Ahmed, Marwa A

    2013-01-01

    Objective: To study the possible effect of angiotensin II type 1 Receptor blocker (AT1 blocker) on renal function, arterial blood pressure and parathyroid hormone related protein over expression in cadmium induced nephrotoxicity in adult male rats. Forty five rats were divided randomly into a control (group I), group II, received cadmium chloride at a dose of 5 mg/kg/day, orally, for nine weeks, group III received telmisartan (TEL) treatment (1 mg/kg/day, orally) one week before cadmium administration and continued for ten weeks. Results: Telmisartan significantly reduced blood urea nitrogen (BUN) and serum creatinine levels which were increased significantly by cadmium. Telmisartan significantly suppressed lipid peroxidation, compensated deficits in the antioxidant defenses (super oxide dismutase (SOD) level and catalase activity), decreased the elevations of nitric oxide (NO) and cadmium ion concentrations in renal tissue observed in Cd-treated rats. Group III had a significant decrease of urinary levels of total protein, N-acetyl-β-d-glucosaminidase (NAG), alkaline phosphatase (ALP) and γ-glutamyl-transpeptidase (GGT) and urinary 8-isoprostanes than those of group II. Telmisartan decreased the systolic blood pressure significantly than those of group II. Histopathological examination revealed that cadmium-induced renal tissue damage was ameliorated by telmisartan treatment. Immunohistochemical analysis revealed that telmisartan significantly decreased the cadmium-induced overexpression of parathyroid hormone receptor 1 (PTHR1) in renal tissue. RT-PCR analysis showed that Cd increased renal expression of PTHrP; however telmisartan could decrease the expression of PTHrP in group III. Conclusion: Blocking AT1 receptors significantly decreases PTHrP over expression and ameliorates renal dysfunction in Cd induced nephrotoxicity. These data suggest that Ang II might contribute to pathophysiology and deleterious effects in cadmium nephrotoxicity. PMID:23750309

  4. Integrating Hormone- and Micromolecule-Mediated Signaling with Plasmodesmal Communication.

    PubMed

    Han, Xiao; Kim, Jae-Yean

    2016-01-01

    Intercellular and supracellular communications through plasmodesmata are involved in vital processes for plant development and physiological responses. Micro- and macromolecules, including hormones, RNA, and proteins, serve as biological information vectors that traffic through the plasmodesmata between cells. Previous studies demonstrated that the plasmodesmata are elaborately regulated, whereby a long queue of multiple signaling molecules forms. However, the mechanism by which these signals are coupled or coordinated in terms of simultaneous transport in a single channel remains a puzzle. In the last few years, several phytohormones that could function as both non-cell-autonomous signals and plasmodesmal regulators have been disclosed. Plasmodesmal regulators such as auxin, salicylic acid, reactive oxygen species, gibberellic acids, chitin, and jasmonic acid could regulate intercellular trafficking by adjusting plasmodesmal permeability. Here, callose, along with β-glucan synthase and β-glucanase, plays a critical role in regulating plasmodesmal permeability. Interestingly, most of the previously identified regulators are capable of diffusing through the plasmodesmata. Given the small sizes of these molecules, the plasmodesmata are prominent intercellular channels that allow diffusion-based movement of those signaling molecules. Obviously, intercellular communication is under the control of a major mechanism, named a feedback loop, at the plasmodesmata, which mediates complicated biological behaviors. Prospective research on the mechanism of coupling micromolecules at the plasmodesmata for developmental signaling and nutrient provision will help us to understand how plants coordinate their development and photosynthetic assimilation, which is important for agriculture.

  5. Female rule in lemurs is ancestral and hormonally mediated

    PubMed Central

    Petty, Joseph M. A.; Drea, Christine M.

    2015-01-01

    Female social dominance (FSD) over males is unusual in mammals, yet characterizes most Malagasy lemurs, which represent almost 30% of all primates. Despite its prevalence in this suborder, both the evolutionary trajectory and proximate mechanism of FSD remain unclear. Potentially associated with FSD is a suite of behavioural, physiological and morphological traits in females that implicates (as a putative mechanism) ‘masculinization’ via androgen exposure; however, relative to conspecific males, female lemurs curiously show little evidence of raised androgen concentrations. By observing mixed‐sex pairs of related Eulemur species, we identified two key study groups ‐‐ one comprised of species expressing FSD and increased female scent marking, the other comprised of species (from a recently evolved clade) showing equal status between the sexes and the more traditional pattern of sexually dimorphic behaviour. Comparing females from these two groups, we show that FSD is associated with more masculine androgen profiles. Based on the widespread prevalence of male‐like features in female lemurs and a current phylogeny, we suggest that relaxation of hormonally mediated FSD emerged only recently and that female masculinization may be the ancestral lemur condition, an idea that could revolutionize our understanding of the ancient socioecology and evolution of primate social systems. PMID:25950904

  6. Thyroid hormone mediates otolith growth and development during flatfish metamorphosis.

    PubMed

    Schreiber, A M; Wang, X; Tan, Y; Sievers, Q; Sievers, B; Lee, M; Burrall, K

    2010-11-01

    Flatfish begin life as bilaterally symmetrical larvae that swim up-right, then abruptly metamorphose into asymmetrically shaped juveniles with lateralized swimming postures. Flatfish metamorphosis is mediated entirely by thyroid hormone (TH). Changes in flatfish swim posture are thought to be regulated via vestibular remodeling, although the influence of TH on teleost inner ear development remains unclear. This study addresses the role of TH on the development of the three otolith end-organs (sacculus, utricle, and lagena) during southern flounder (Paralichthys lethostigma) metamorphosis. Compared with pre-metamorphosis, growth rates of the sacculus and utricle otoliths increase dramatically during metamorphosis in a manner that is uncoupled from general somatic growth. Treatment of P. lethostigma larvae with methimazol (a pharmacological inhibitor of endogenous TH production) inhibits growth of the sacculus and utricle, whereas treatment with TH dramatically accelerates their growth. In contrast with the sacculus and utricle otoliths that begin to form and mineralize during embryogenesis, a non-mineralized lagena otolith is first visible 10-12 days after hatching. The lagena grows during pre- and pro-metamorphosis, then abruptly mineralizes during metamorphic climax. Mineralization of the lagena, but not growth, can be induced with TH treatment, whereas treatment with methimazol completely inhibits lagena mineralization without inhibiting its growth. These findings suggest that during southern flounder metamorphosis TH exerts differential effects on growth and development among the three types of otolith.

  7. Multiple hormone-inducible enhancers as mediators of differential transcription.

    PubMed Central

    Toohey, M G; Morley, K L; Peterson, D O

    1986-01-01

    Sets of genes under a common regulatory control in a given cell type are often differentially transcribed. The possibility that this differential transcription can be modulated by the number or strength of cis-acting regulatory sequences associated with a given gene was tested by using the glucocorticoid-responsive enhancer element associated with the mouse mammary tumor virus promoter. Results indicate that differential levels of hormone-inducible gene expression can be modulated in an additive way by the number of glucocorticoid-responsive enhancers associated with this promoter. Realization of these effects shows little preference for position of the additional elements with respect to the promoter. When sequences that bind the glucocorticoid receptor in vitro with somewhat lower affinity than the enhancer were tested, these additive effects were not detected. The results support that differential transcription of genes subject to a common regulatory control can be mediated, at least in part, by the number or strength of their associated cis-acting regulatory sequences. Images PMID:3025659

  8. Thyroid hormone receptor can modulate retinoic acid-mediated axis formation in frog embryogenesis.

    PubMed Central

    Banker, D E; Eisenman, R N

    1993-01-01

    Thyroid hormone receptor acts as a hormone-dependent transcriptional transactivator and as a transcriptional repressor in the absence of thyroid hormone. Specifically, thyroid hormone receptor can repress retinoic acid-induced gene expression through interactions with retinoic acid receptor. (Retinoic acid is a potent teratogen in the frog Xenopus laevis, acting at early embryonic stages to interfere with the formation of anterior structures. Endogenous retinoic acid is thought to act in normal anterior-posterior axis formation.) We have previously shown that thyroid hormone receptor RNA (alpha isotype) is expressed and polysome-associated during Xenopus embryogenesis preceding thyroid gland maturation and endogenous thyroid hormone production (D. E. Banker, J. Bigler, and R. N. Eisenman, Mol. Cell. Biol. 11:5079-5089, 1991). To determine whether thyroid hormone receptor might influence the effects of retinoic acid in early frog development, we have examined the results of ectopic thyroid hormone receptor expression on retinoic acid teratogenesis. We demonstrate that microinjections of full-length thyroid hormone receptor RNA protect injected embryos from retinoic acid teratogenesis. DNA binding is apparently essential to this protective function, as truncated thyroid hormone receptors, lacking DNA-binding domains but including hormone-binding and dimerization domains, do not protect from retinoic acid. We have shown that microinjections of these dominant-interfering thyroid hormone receptors, as well as anti-thyroid hormone receptor antibodies, increase retinoic acid teratogenesis in injected embryos, presumably by inactivating endogenous thyroid hormone receptor. This finding suggests that endogenous thyroid hormone receptors may act to limit retinoic acid sensitivity. On the other hand, after thyroid hormone treatment, ectopic thyroid hormone receptor mediates teratogenesis that is indistinguishable from the dorsoanterior deficiencies produced in retinoic acid

  9. Parathyroid Carcinoma in a 10 Years Old Female Child.

    PubMed

    Rahman, M M; Karim, S S; Joarder, A I; Mubin, S; Abir, M M; Morshed, M S

    2015-07-01

    Parathyroid carcinoma (PC) is a rare cause of hypercalcaemia in children. Only 7 cases of PC have been reported so far in the world journal. The authors report the 8th case of parathyroid carcinoma in children less than 16 years of age. A 10 year old girl presented with difficulty in walking, dorsiflexion and ulnar deviation of both wrist joints and occasional pain in the central abdomen of about two years duration. Biochemical investigations revealed serum calcium 12.2 mg/dL (normal 9-11 mg/dL), serum alkaline phosphate 4992 U/L (normal 50-136 U/L), PTH (parathyroid hormone) 2217 pg/ml (normal 9-80 pg/ml). Parathyroid scintigraphy localized the lesion in the left parathyroid gland. X-ray showed bilateral coxa vera, genu valgus deformity and multiple stress fractures in both wrist joints. Histopathology confirmed PC with capsular and vascular invasion.

  10. Multiple brown tumours from parathyroid carcinoma.

    PubMed

    Dagang, Daryl Jade Tardo; Gutierrez, Jerico Baliton; Sandoval, Mark Anthony Santiago; Lantion-Ang, Frances Lina

    2016-01-01

    We report a case of a 29-year-old woman who suffered from severe bilateral inguinal pain and left mandibular mass. CT scan showed innumerable expansile osteolytic bone masses on the iliac wings, femur, ribs and vertebral bodies, diffuse skeletal osteopaenia, calyceal lithiasis on the right kidney and a left thyroid mass. Ionised calcium and intact parathyroid hormone (PTH) were elevated. Parathyroid sestamibi scan showed a hyperfunctioning left inferior parathyroid gland. Biopsy of the left mandibular mass was consistent with brown tumour. The patient underwent parathyroidectomy of the enlarged parathyroid gland. Final histopathology, however, revealed parathyroid carcinoma, 4.7 cm in widest dimension, with capsular and vascular space invasion. The patient underwent repeat surgery, specifically, left thyroid lobectomy, isthmectomy and central node dissection. Intact PTH decreased from 681.3 to 74 pg/mL (normal range: 10-65) 24 hours postoperatively. Follow-up at 6 months showed normal serum calcium levels, size reduction of bone lesions and improvement of quality of life. PMID:27358103

  11. Diphtheria Toxin- and GFP-Based Mouse Models of Acquired Hypoparathyroidism and Treatment With a Long-Acting Parathyroid Hormone Analog.

    PubMed

    Bi, Ruiye; Fan, Yi; Lauter, Kelly; Hu, Jing; Watanabe, Tomoyuki; Cradock, Jim; Yuan, Quan; Gardella, Thomas; Mannstadt, Michael

    2016-05-01

    Hypoparathyroidism (HP) arises most commonly from parathyroid (PT) gland damage associated with neck surgery, and is typically treated with oral calcium and active vitamin D. Such treatment effectively increases levels of serum calcium (sCa), but also brings risk of hypercalciuria and renal damage. There is thus considerable interest in using PTH or PTH analogs to treat HP. To facilitate study of this disease and the assessment of new treatment options, we developed two mouse models of acquired HP, and used them to assess efficacy of PTH(1-34) as well as a long-acting PTH analog (LA-PTH) in regulating blood calcium levels. In one model, we used PTHcre-iDTR mice in which the diphtheria toxin (DT) receptor (DTR) is selectively expressed in PT glands, such that systemic DT administration selectively ablates parathyroid cells. For the second model, we generated GFP-PT mice in which green fluorescent protein (GFP) is selectively expressed in PT cells, such that parathyroidectomy (PTX) is facilitated by green fluorescence of the PT glands. In the PTHcre-iDTR mice, DT injection (2 × 5 μg/kg, i.p.) resulted in moderate yet consistent reductions in serum PTH and sCa levels. The more severe hypoparathyroid phenotype was observed in GFP-PT mice following GFP-guided PTX surgery. In each model, a single subcutaneous injection of LA-PTH increased sCa levels more effectively and for a longer duration (>24 hours) than did a 10-fold higher dose of PTH(1-34), without causing excessive urinary calcium excretion. These new mouse models thus faithfully replicate two degrees of acquired HP, moderate and severe, and may be useful for assessing potential new modes of therapy. © 2015 American Society for Bone and Mineral Research. PMID:26678919

  12. Polyclonality of Parathyroid Tumors in Neonatal Severe Hyperparathyroidism.

    PubMed

    Corrado, Kristin R; Andrade, Simone Caixeta; Bellizzi, Justin; D'Souza-Li, Lilia; Arnold, Andrew

    2015-10-01

    Neonatal severe hyperparathyroidism (NSHPT) is a rare disorder characterized by major hypercalcemia, elevated parathyroid hormone levels, and marked enlargement of multiple parathyroid glands, usually associated with germline mutations in the calcium receptor gene CASR. However, little is known about the outgrowth of parathyroid tumors in NSHPT, including whether they represent monoclonal or polyclonal expansions. We sought to examine the clonality of parathyroid tissues resected from a patient with NSHPT and biallelic CASR mutations. DNA from two distinct parathyroid tumors resected from a girl with NSHPT, plus polyclonal/monoclonal control samples, were subjected to analyses of clonality by two independent methods, X-chromosome inactivation analysis at the androgen receptor locus (HUMARA) and BAC array comparative genomic hybridization (CGH). Both parathyroid tumor samples revealed polyclonal patterns by X-inactivation analysis, with polyclonal and monoclonal controls yielding the expected patterns. Similarly, by BAC array CGH, neither parathyroid sample contained monoclonal copy number changes and both appeared identical to the patient-matched polyclonal controls. Our observations provide direct experimental evidence that the markedly enlarged parathyroid tumors in the setting of NSHPT constitute polyclonal, generalized hyperplastic growths rather than monoclonal neoplasms.

  13. Association of the cystatin C/creatinine ratio with the renally cleared hormones parathyroid hormone (PTH) and brain natriuretic peptide (BNP) in primary care patients: a cross-sectional study.

    PubMed

    Risch, Martin; Risch, Lorenz; Purde, Mette-Triin; Renz, Harald; Ambühl, Patrice; Szucs, Thomas; Tomonaga, Yuki

    2016-09-01

    The ratio of cystatin C to creatinine (cysC/crea) is regarded as a marker of glomerular filtration quality and predicts mortality. It has been hypothesized that increased mortality may be mediated by the retention of biologically active substances due to shrinking glomerular pores. The present study investigated whether cysC/crea is independently associated with the levels of two renally cleared hormones, which have been linked to increased mortality. We conducted a multicenter, cross-sectional study with a random selection of general practitioners (GPs) from all GP offices in seven Swiss cantons. Markers of glomerular filtration quality were investigated together with estimated glomerular filtration rate (eGFR), albuminuria and urinary neutrophil gelatinase associated lipocalin (uNGAL) as well as two renally cleared low-molecular-weight protein hormones (i.e. BNP and PTH), Morbidity was assessed with the Charlson Comorbidity Index (CCI). A total of 1000 patients (433 males; mean age 57 ± 17 years) were included. There was a significant univariate association of BNP (r = 0.36, p < 0.001) and PTH (r = 0.18, p < 0.001) with cysC/crea. An adjusted model that accounted for kidney function (eGFR), altered glomerular structure (albuminuria), renal stress (uNGAL), and CCI showed that BNP and PTH were independently associated with cysC/crea as well as with the ratio of cystatin C-based to creatinine-based eGFR. In conclusion, in primary care patients, BNP and PTH are independently associated both with markers of glomerular filtration quality and eGFR regardless of structural kidney damage or renal stress. These findings offer an explanation, how altered glomerular filtration quality could contribute to increased mortality.

  14. Calcitriol-mediated hypercalcemia in a patient with bilateral adrenal non-Hodgkin's B-cell lymphoma case report

    PubMed Central

    Abaroa-Salvatierra, Ana; Shaikh, Bilal; Deshmukh, Mrunalini; Alweis, Richard; Patel, Arti

    2016-01-01

    Calcitriol-mediated hypercalcemia is a frequent manifestation of hematological malignancies. However, there are a few reports of cases presenting with increased angiotensin-converting enzyme (ACE) level, which suggests a possible mechanism similar to that of granulomatous diseases. We present a patient with hypercalcemia, normal parathyroid hormone, and parathyroid hormone-related protein levels but high calcitriol and ACE levels that, after further investigation, was diagnosed with bilateral adrenal non-Hodgkin's B-cell lymphoma. Primary adrenal lymphoma represents only 1% of all non-Hodgkin's lymphomas and is usually asymptomatic but should be considered by clinicians among the malignancies that cause calcitriol-mediated hypercalcemia. PMID:27124160

  15. [Hormone-mediated reactions in the endosalpinx epithelium].

    PubMed

    Glukhovets, B I; Ukhov, Iu I; Lebedev, S S; Plastun, G A; Bulaeva, V P

    1983-07-01

    The epithelium of normal uterine tubes resected in 38 young women of the child-bearing age during the periods of the maximal physiological fluctuations of the ovarian steroid hormones levels has been studied. The correlative dependence between the morphometrical data and the results of quanitative biochemical analysis of the estrogen excretion has been investigated. The morphometric method reliably reflects the hormone-dependent variabilities of the oviduct epithelium and makes it possible to perform an objective morphological evaluation of the ovarian functional activity. The height and specific density of cells in the epithelial layer, portion of the aciliary cells and nuclear volume of the ciliary cells are the most important for diagnosis as compared to the excretory level of the estrogenic hormones. PMID:6625907

  16. Light-Mediated Hormonal Regulation of Plant Growth and Development.

    PubMed

    de Wit, Mieke; Galvão, Vinicius Costa; Fankhauser, Christian

    2016-04-29

    Light is crucial for plant life, and perception of the light environment dictates plant growth, morphology, and developmental changes. Such adjustments in growth and development in response to light conditions are often established through changes in hormone levels and signaling. This review discusses examples of light-regulated processes throughout a plant's life cycle for which it is known how light signals lead to hormonal regulation. Light acts as an important developmental switch in germination, photomorphogenesis, and transition to flowering, and light cues are essential to ensure light capture through architectural changes during phototropism and the shade avoidance response. In describing well-established links between light perception and hormonal changes, we aim to give insight into the mechanisms that enable plants to thrive in variable light environments.

  17. Parathyroid cell resistance to fibroblast growth factor 23 in secondary hyperparathyroidism of chronic kidney disease.

    PubMed

    Galitzer, H; Ben-Dov, I Z; Silver, Justin; Naveh-Many, Tally

    2010-02-01

    Although fibroblast growth factor 23 (FGF23) acting through its receptor Klotho-FGFR1c decreases parathyroid hormone expression, this hormone is increased in chronic kidney disease despite an elevated serum FGF23. We measured possible factors that might contribute to the resistance of parathyroid glands to FGF23 in rats with the dietary adenine-induced model of chronic kidney disease. Quantitative immunohistochemical and reverse transcription-PCR analysis using laser capture microscopy showed that both Klotho and FGFR1 protein and mRNA levels were decreased in histological sections of the parathyroid glands. Recombinant FGF23 failed to decrease serum parathyroid hormone levels or activate the mitogen-activated protein kinase signaling pathway in the glands of rats with advanced experimental chronic kidney disease. In parathyroid gland organ culture, the addition of FGF23 decreased parathyroid hormone secretion and mRNA levels in control animals or rats with early but not advanced chronic kidney disease. Our results show that because of a downregulation of the Klotho-FGFR1c receptor complex, an increase of circulating FGF23 does not decrease parathyroid hormone levels in established chronic kidney disease. This in vivo resistance is sustained in parathyroid organ culture in vitro.

  18. Stages of Parathyroid Cancer

    MedlinePlus

    ... of the head and neck. SPECT scan (single photon emission computed tomography scan) : A procedure that uses ... a recurrence. The parathyroid cancer usually recurs between 2 and 5 years after the first surgery , but ...

  19. Parathyroid Cancer Treatment

    MedlinePlus

    ... of the head and neck. SPECT scan (single photon emission computed tomography scan) : A procedure that uses ... a recurrence. The parathyroid cancer usually recurs between 2 and 5 years after the first surgery , but ...

  20. Combination Therapy with Zoledronic Acid and Parathyroid Hormone Improves Bone Architecture and Strength following a Clinically-Relevant Dose of Stereotactic Radiation Therapy for the Local Treatment of Canine Osteosarcoma in Athymic Rats

    PubMed Central

    Curtis, Ryan C.; Custis, James T.; Ehrhart, Nicole P.; Ehrhart, E. J.; Condon, Keith W.; Gookin, Sara E.; Donahue, Seth W.

    2016-01-01

    Clinical studies using definitive-intent stereotactic radiation therapy (SRT) for the local treatment of canine osteosarcoma (OSA) have shown canine patients achieving similar median survival times as the current standard of care (amputation and adjuvant chemotherapy). Despite this, there remains an unacceptable high risk of pathologic fracture following radiation treatment. Zoledronic acid (ZA) and parathyroid hormone (PTH) are therapeutic candidates for decreasing this fracture risk post-irradiation. Due to differing mechanisms, we hypothesized that the combined treatment with ZA and PTH would significantly improve bone healing more than ZA or PTH treatment alone. Using an orthotopic model of canine osteosarcoma in athymic rats, we evaluated bone healing following clinically-relevant doses of radiation therapy (12 Gy x 3 fractions, 36 Gy total). Groups included 36 Gy SRT only, 36 Gy SRT plus ZA, 36 Gy SRT plus ZA and PTH, 36 Gy SRT plus PTH, and 36 Gy SRT plus localized PTH treatment. Our study showed significant increases in bone volume and increased polar moments of inertia (in the distal femoral metaphysis) 8 weeks after radiation in the combined (ZA/PTH) treatment group as compared to radiation treatment alone. Histomorphometric analysis revealed evidence of active mineralization at the study endpoint as well as successful tumor-cell kill across all treatment groups. This work provides further evidence for the expanding potential indications for ZA and PTH therapy, including post-irradiated bone disease due to osteosarcoma. PMID:27332712

  1. Combination Therapy with Zoledronic Acid and Parathyroid Hormone Improves Bone Architecture and Strength following a Clinically-Relevant Dose of Stereotactic Radiation Therapy for the Local Treatment of Canine Osteosarcoma in Athymic Rats.

    PubMed

    Curtis, Ryan C; Custis, James T; Ehrhart, Nicole P; Ehrhart, E J; Condon, Keith W; Gookin, Sara E; Donahue, Seth W

    2016-01-01

    Clinical studies using definitive-intent stereotactic radiation therapy (SRT) for the local treatment of canine osteosarcoma (OSA) have shown canine patients achieving similar median survival times as the current standard of care (amputation and adjuvant chemotherapy). Despite this, there remains an unacceptable high risk of pathologic fracture following radiation treatment. Zoledronic acid (ZA) and parathyroid hormone (PTH) are therapeutic candidates for decreasing this fracture risk post-irradiation. Due to differing mechanisms, we hypothesized that the combined treatment with ZA and PTH would significantly improve bone healing more than ZA or PTH treatment alone. Using an orthotopic model of canine osteosarcoma in athymic rats, we evaluated bone healing following clinically-relevant doses of radiation therapy (12 Gy x 3 fractions, 36 Gy total). Groups included 36 Gy SRT only, 36 Gy SRT plus ZA, 36 Gy SRT plus ZA and PTH, 36 Gy SRT plus PTH, and 36 Gy SRT plus localized PTH treatment. Our study showed significant increases in bone volume and increased polar moments of inertia (in the distal femoral metaphysis) 8 weeks after radiation in the combined (ZA/PTH) treatment group as compared to radiation treatment alone. Histomorphometric analysis revealed evidence of active mineralization at the study endpoint as well as successful tumor-cell kill across all treatment groups. This work provides further evidence for the expanding potential indications for ZA and PTH therapy, including post-irradiated bone disease due to osteosarcoma. PMID:27332712

  2. Hormone-Mediated Pattern Formation in Seedling of Plants: a Competitive Growth Dynamics Model

    NASA Astrophysics Data System (ADS)

    Kawaguchi, Satoshi; Mimura, Masayasu; Ohya, Tomoyuki; Oikawa, Noriko; Okabe, Hirotaka; Kai, Shoichi

    2001-10-01

    An ecologically relevant pattern formation process mediated by hormonal interactions among growing seedlings is modeled based on the experimental observations on the effects of indole acetic acid, which can act as an inhibitor and activator of root growth depending on its concentration. In the absence of any lateral root with constant hormone-sensitivity, the edge effect phenomenon is obtained depending on the secretion rate of hormone from the main root. Introduction of growth-stage-dependent hormone-sensitivity drastically amplifies the initial randomness, resulting in spatially irregular macroscopic patterns. When the lateral root growth is introduced, periodic patterns are obtained whose periodicity depends on the length of lateral roots. The growth-stage-dependent hormone-sensitivity and the lateral root growth are crucial for macroscopic periodic-pattern formation.

  3. Hormones

    MedlinePlus

    Hormones are your body's chemical messengers. They travel in your bloodstream to tissues or organs. They work ... glands, which are special groups of cells, make hormones. The major endocrine glands are the pituitary, pineal, ...

  4. Treatment Option Overview (Parathyroid Cancer)

    MedlinePlus

    ... not lung cancer. There is no standard staging process for parathyroid cancer. Parathyroid cancer is described as ... Clinical trials are part of the cancer research process. Clinical trials are done to find out if ...

  5. Wild-type and specific mutant androgen receptor mediates transcription via 17β-estradiol in sex hormone-sensitive cancer cells.

    PubMed

    Susa, Takao; Ikaga, Reina; Kajitani, Takashi; Iizuka, Masayoshi; Okinaga, Hiroko; Tamamori-Adachi, Mimi; Okazaki, Tomoki

    2015-07-01

    We previously encountered regulatory processes wherein dihydrotestosterone (DHT) exerted its inhibitory effect on parathyroid hormone-related protein (PTHrP) gene repression through the estrogen receptor (ER)α, but not the androgen receptor (AR), in breast cancer MCF-7 cells. Here, we investigated whether such aberrant ligand-nuclear receptor (NR) interaction is present in prostate cancer LNCaP cells. First, we confirmed that LNCaP cells expressed large amounts of AR at negligible levels of ERα/β or progesterone receptor. Both suppression of PTHrP and activation of prostate-specific antigen genes were observed after independent administration of 17β-estradiol (E2), DHT, or R5020. Consistent with the notion that the LNCaP AR lost its ligand specificity due to a mutation (Thr-Ala877), experiments with siRNA targeting the respective NR revealed that the AR monopolized the role of the mediator of shared hormone-dependent regulation, which was invariably associated with nuclear translocation of this mutant AR. Microarray analysis of gene regulation by DHT, E2, or R5020 disclosed that more than half of the genes downstream of the AR (Thr-Ala877) overlapped in the LNCaP cells. Of particular interest, we realized that the AR (wild-type [wt]) and AR (Thr-Ala877) were equally responsible for the E2-AR interactions. Fluorescence microscopy experiments demonstrated that both EGFP-AR (wt) and EGFP-AR (Thr-Ala877) were exclusively localized within the nucleus after E2 or DHT treatment. Furthermore, reporter assays revealed that some other cancer cells exhibited aberrant E2-AR (wt) signaling similar to that in the LNCaP cells. We herein postulate the presence of entangled interactions between wt AR and E2 in certain hormone-sensitive cancer cells.

  6. The effects of programmed administration of human parathyroid hormone fragment (1-34) on bone histomorphometry and serum chemistry in rats

    NASA Technical Reports Server (NTRS)

    Dobnig, H.; Turner, R. T.

    1997-01-01

    PTH treatment can result in dramatic increases in cancellous bone volume in normal and osteopenic rats. However, this potentially beneficial response is only observed after pulsatile treatment; continuous infusion of PTH leads to hypercalcemia and bone abnormalities. The purpose of these studies was to determine the optimal duration of the PTH pulses. A preliminary study revealed that human PTH-(1-34) (hPTH) is cleared from circulation within 6 h after sc administration of an anabolic dose of the hormone (80 microg/kg). To establish the effects of gradually extending the duration of exposure to hPTH without increasing the daily dose, we programmed implanted Alzet osmotic pumps to deliver the 80 microg/kg x day dose of the hormone during pulses of 1, 2, and 6 h/day, or 40 microg/kg x day continuously. Discontinuous infusion was accomplished by alternate spacing of external tubing with hPTH solution and sesame oil. After 6 days of treatment, we evaluated serum chemistry and bone histomorphometry. As negative and positive controls, groups of rats received pumps that delivered vehicle only and 80 microg/kg x day hPTH by daily sc injection, respectively. Dynamic and static bone histomorphometry revealed that the daily sc injection and 1 h/day infusion dramatically increased osteoblast number and bone formation in the proximal tibial metaphysis, whereas longer infusion resulted in systemic side-effects, including up to a 10% loss in body weight, hypercalcemia, and histological changes in the proximal tibia resembling abnormalities observed in patients with chronic primary hyperparathyroidism, including peritrabecular marrow fibrosis and focal bone resorption. Infusion for as little as 2 h/day resulted in minor weight loss and changes in bone histology that were intermediate between sc and continuous administration. The results demonstrate that the therapeutic interval for hPTH exposure is brief, but that programmed administration of implanted hormone is a feasible

  7. Divergence along the gonadal steroidogenic pathway: Implications for hormone-mediated phenotypic evolution.

    PubMed

    Rosvall, Kimberly A; Bergeon Burns, Christine M; Jayaratna, Sonya P; Ketterson, Ellen D

    2016-08-01

    Across a range of taxa, hormones regulate suites of traits that influence survival and reproductive success; however, the mechanisms by which hormone-mediated traits evolve are still unclear. We hypothesized that phenotypic divergence might follow from differential regulation of genes encoding key steps in hormone biosynthesis and thus the rate of hormone production. We tested this hypothesis in relation to the steroid hormone testosterone by comparing two subspecies of junco (Junco hyemalis) in the wild and in captivity. These subspecies have diverged over the last 10-15kyears in multiple testosterone-mediated traits, including aggression, ornamentation, and body size. We show that variation in gonadal gene expression along the steroid biosynthetic pathway predicts phenotypic divergence within and among subspecies, and that the more androgenized subspecies exhibits a more prolonged time-course of elevated testosterone following exogenous stimulation. Our results point to specific genes that fulfill key conditions for phenotypic evolution because they vary functionally in their expression among individuals and between populations, and they map onto population variation in phenotype in a common garden. Our findings therefore build an important bridge between hormones, genes, and phenotypic evolution. PMID:27206546

  8. R-spondin1 is a novel hormone mediator for mammary stem cell self-renewal

    PubMed Central

    Cai, Cheguo; Yu, Qing Cissy; Jiang, Weimin; Liu, Wei; Song, Wenqian; Yu, Hua; Zhang, Lei; Yang, Ying

    2014-01-01

    Signals from the niche play pivotal roles in regulating adult stem cell self-renewal. Previous studies indicated that the steroid hormones can expand mammary stem cells (MaSCs) in vivo. However, the facilitating local niche factors that directly contribute to the MaSC expansion remain unclear. Here we identify R-spondin1 (Rspo1) as a novel hormonal mediator in the mammary gland. Pregnancy and hormonal treatment up-regulate Rspo1 expression. Rspo1 cooperates with another hormonal mediator, Wnt4, to promote MaSC self-renewal through Wnt/β-catenin signaling. Knockdown of Rspo1 and Wnt4 simultaneously abolishes the stem cell reconstitution ability. In culture, hormonal treatment that stimulates the expression of both Rspo1 and Wnt4 can completely substitute for exogenous Wnt proteins, potently expand MaSCs, and maintain their full development potential in transplantation. Our data unveil the intriguing concept that hormones induce a collaborative local niche environment for stem cells. PMID:25260709

  9. Making sense of hormone-mediated defense networking: from rice to Arabidopsis

    PubMed Central

    De Vleesschauwer, David; Xu, Jing; Höfte, Monica

    2014-01-01

    Phytohormones are not only essential for plant growth and development but also play central roles in triggering the plant immune signaling network. Historically, research aimed at elucidating the defense-associated role of hormones has tended to focus on the use of experimentally tractable dicot plants such as Arabidopsis thaliana. Emerging from these studies is a picture whereby complex crosstalk and induced hormonal changes mold plant health and disease, with outcomes largely dependent on the lifestyle and infection strategy of invading pathogens. However, recent studies in monocot plants are starting to provide additional important insights into the immune-regulatory roles of hormones, often revealing unique complexities. In this review, we address the latest discoveries dealing with hormone-mediated immunity in rice, one of the most important food crops and an excellent model for molecular genetic studies in monocots. Moreover, we highlight interactions between hormone signaling, rice defense and pathogen virulence, and discuss the differences and similarities with findings in Arabidopsis. Finally, we present a model for hormone defense networking in rice and describe how detailed knowledge of hormone crosstalk mechanisms can be used for engineering durable rice disease resistance. PMID:25426127

  10. Hormones as Mediators of Phenotypic and Genetic Integration: an Evolutionary Genetics Approach.

    PubMed

    Cox, Robert M; McGlothlin, Joel W; Bonier, Frances

    2016-08-01

    Evolutionary endocrinology represents a synthesis between comparative endocrinology and evolutionary genetics. This synthesis can be viewed through the breeder's equation, a cornerstone of quantitative genetics that, in its univariate form, states that a population's evolutionary response is the product of the heritability of a trait and selection on that trait (R = h(2)S). Under this framework, evolutionary endocrinologists have begun to quantify the heritability of, and the strength of selection on, a variety of hormonal phenotypes. With specific reference to our work on testosterone and corticosterone in birds and lizards, we review these studies while emphasizing the challenges of applying this framework to hormonal phenotypes that are inherently plastic and mediate adaptive responses to environmental variation. Next, we consider the untapped potential of evolutionary endocrinology as a framework for exploring multivariate versions of the breeder's equation, with emphasis on the role of hormones in structuring phenotypic and genetic correlations. As an extension of the familiar concepts of phenotypic integration and hormonal pleiotropy, we illustrate how the hormonal milieu of an individual acts as a local environment for the expression of genes and phenotypes, thereby influencing the quantitative genetic architecture of multivariate phenotypes. We emphasize that hormones are more than mechanistic links in the translation of genotype to phenotype: by virtue of their pleiotropic effects on gene expression, hormones structure the underlying genetic variances and covariances that determine a population's evolutionary response to selection. PMID:27252188

  11. 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.

    PubMed

    Heishi, M; Tazawa, H; Matsuo, T; Saruta, T; Hanaoka, M; Tsukamoto, Y

    2000-04-01

    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. PMID:10784412

  12. Parathyroid hormone linked to a collagen binding domain (PTH-CBD) promotes hair growth in a mouse model of chemotherapy-induced alopecia in a dose-dependent manner

    PubMed Central

    Katikaneni, Ranjitha; Ponnapakkam, Tulasi; Seymour, Andrew; Sakon, Joshua; Gensure, Robert

    2014-01-01

    Chemotherapy-induced alopecia is a major source of psychological stress in patients undergoing cancer chemotherapy, and can influence treatment decisions. While there is currently no therapy, PTH-CBD, a fusion protein of parathyroid hormone and collagen binding domain, has shown promise in animal models. Objective To determine if there are dose-dependent effects of PTH-CBD on chemotherapy-induced alopecia in a mouse model. Methods C57BL/6J mice were waxed to synchronize hair follicles; treated on day 7 with vehicle or PTH-CBD (100, 320 and 1000 mcg/kg subcutaneous injection); treated on day 9 with vehicle or cyclophosphamide (150 mg/kg i.p.). Mice were photographed every 3–4 days and sacrificed on day 63 for histological analysis. Photographs were quantified by grey scale analysis to assess hair content. Results Mice not receiving chemotherapy showed regrowth of hair 2 weeks following waxing, and normal histology after 2 months. Mice receiving chemotherapy alone showed marked hair loss after chemotherapy, which was sustained for 10 days and was followed by rapid regrowth of a normal coat. Histology revealed rapid cycling dystrophic anagen/catagen follicles. Animals receiving chemotherapy and PTH-CBD showed decreased hair loss and more rapid regrowth of hair than that seen with chemotherapy alone (increased hair growth by grey scale analysis, p<0.05), and the effects were dose dependent. Histologically, hair follicles in animals receiving the highest dose of PTH-CBD were in a quiescent phase, similar to mice which did not receive chemotherapy. Conclusions Single dose subcutaneous administration of PTH-CBD showed dose-dependent effects in minimizing hair loss and speeding recovery from chemotherapy-induced alopecia. PMID:24710191

  13. The parathyroid hormone-related protein is secreted during the osteogenic differentiation of human dental follicle cells and inhibits the alkaline phosphatase activity and the expression of DLX3.

    PubMed

    Klingelhöffer, C; Reck, A; Ettl, T; Morsczeck, C

    2016-08-01

    The dental follicle is involved in tooth eruption and it expresses a great amount of the parathyroid hormone-related protein (PTHrP). PTHrP as an extracellular protein is required for a multitude of different regulations of enchondral bone development and differentiation of bone precursor cells and of the development of craniofacial tissues. The dental follicle contains also precursor cells (DFCs) of the periodontium. Isolated DFCs differentiate into periodontal ligament cells, alveolar osteoblast and cementoblasts. However, the role of PTHrP during the human periodontal development remains elusive. Our study evaluated the influence of PTHrP on the osteogenic differentiation of DFCs under in vitro conditions for the first time. The PTHrP protein was highly secreted after 4days of the induction of the osteogenic differentiation of DFCs with dexamethasone (2160.5pg/ml±345.7SD. in osteogenic differentiation medium vs. 315.7pg/ml±156.2SD. in standard cell culture medium; Student's t Test: p<0.05 (n=3)). We showed that the supplementation of the osteogenic differentiation medium with PTHrP inhibited the alkaline phosphatase activity and the expression of the transcription factor DLX3, but the depletion of PTHrP did not support the differentiation of DFCs. Previous studies have shown that Indian Hedgehog (IHH) induces PTHrP and that PTHrP, in turn, inhibits IHH via a negative feedback loop. We showed that SUFU (Suppressor Of Fused Homolog) was not regulated during the osteogenic differentiation in DFCs. So, neither the hedgehog signaling pathway induced PTHrP nor PTHrP suppressed the hedgehog signaling pathway during the osteogenic differentiation in DFCs. In conclusion, our results suggest that PTHrP regulates independently of the hedgehog signaling pathway the osteogenic differentiated in DFCs. PMID:27368119

  14. Thyroid hormone-mediated autophagy and mitochondrial turnover in NAFLD.

    PubMed

    Sinha, Rohit Anthony; Yen, Paul M

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) is a fast-growing silent epidemic that is present in both developed and developing countries. Initially thought as a benign deposition of lipids in the liver, it now has been shown to be a major risk factor for type II diabetes and one of the leading causes of cirrhosis. Recent findings suggest that dysregulation of mitochondrial homeostasis and autophagy play critical roles in the hepatocyte injury and insulin resistance of NAFLD. Thyroid hormone (TH) is a major stimulator of hepatic autophagy and mitochondrial function. Decreased TH action has been associated with NAFLD in man. In this review, we highlight some of the new discoveries that demonstrate the roles of TH in hepatic mitochondrial homeostasis via mitophagy and their implications for NAFLD. PMID:27437098

  15. Thyroid Hormone Response Element Half-Site Organization and Its Effect on Thyroid Hormone Mediated Transcription

    PubMed Central

    Paquette, Martin A.; Atlas, Ella; Wade, Mike G.; Yauk, Carole L.

    2014-01-01

    Thyroid hormone (TH) exerts its effects by binding to the thyroid hormone receptor (TR), which binds to TH response elements (TREs) to regulate target gene expression. We investigated the relative ability of liganded homodimers TR and retinoid X receptor (RXR), and the heterodimer TR/RXR, to regulate gene expression for the TRE half-site organizations: direct repeat 4 (DR4), inverted repeat 0 (IR0) and everted repeat 6 (ER6). Luciferase reporter assays using a DR4 TRE suggest that both the TR homodimer and TR/RXR heterodimer regulate luciferase expression in the presence of their respective ligands. However, in the presence of the IR0 TRE, transfection with TR/RXR and RXR alone increased luciferase activity and there was no effect of TR alone. The presence of 9-cis-retinoic acid was necessary for luciferase expression, whereas TH treatment alone was insufficient. For the ER6 TRE, transfection with TR/RXR, TR alone and RXR alone (in the presence of their respective ligands) all caused a significant increase in luciferase activity. When both ligands were present, transfection with both TR/RXR caused more activation. Finally, we investigated the efficacy of the TR-antagonist 1–850 in inhibiting transcription by TR or TR/RXR at DR4 and ER6 TREs. We found that 1–850 did not suppress luciferase activation in the presence of TR/RXR for the ER6 TRE, suggesting conformational changes of the ligand binding domain of the TR when bound to different TRE half-site organizations. Collectively, the findings indicate that there are fundamental differences between TRE configurations that affect nuclear receptor interactions with the response element and ability to bind ligands and antagonists. PMID:24971931

  16. Parathyroid hormone induces transcription of collagenase in rat osteoblastic cells by a mechanism using cyclic adenosine 3',5'-monophosphate and requiring protein synthesis

    NASA Technical Reports Server (NTRS)

    Scott, D. K.; Brakenhoff, K. D.; Clohisy, J. C.; Quinn, C. O.; Partridge, N. C.

    1992-01-01

    Collagenase is synthesized and secreted by rat osteoblastic cells in response to PTH. We have previously demonstrated that this effect involves a substantial increase in collagenase mRNA via transcription. Northern blots and nuclear run-on assays were performed to further investigate the induction of collagenase by PTH in the rat osteoblastic cell line UMR 106-01. Detectable amounts of collagenase mRNA were not apparent until 2 h of PTH treatment, showed the greatest abundance at 4 h, and declined to approximately 30% of maximum by 8 h. The changes in the rate of transcription of the collagenase gene in response to PTH paralleled and preceded the changes in the steady state mRNA levels. After an initial lag period of about 1 h, collagenase transcription rates increased from very low levels to a maximal response at 2 h, returning to about 50% of maximum by 10 h. The increased transcriptional rate of the collagenase gene was found to be dependent on the concentration of PTH, with a half-maximal response at approximately 7 x 10(-10) M rat PTH-(1-34) and a maximal effect with a dose of 10(-8) M. The PTH-mediated induction of collagenase transcriptional activity was completely abolished by cycloheximide, while transcription of the beta-actin gene was unaffected by the translation inhibitor. These data suggest that a protein factor(s) is required for PTH-mediated transcriptional induction of collagenase. Since PTH increases intracellular levels of several potential second messengers, agents that mimic these substances were employed to determine which signal transduction pathway is predominant in the PTH-mediated stimulation of collagenase transcription.(ABSTRACT TRUNCATED AT 250 WORDS).

  17. Expression and characterization of a recombinant human parathyroid hormone partial agonist with antagonistic properties: Gly-hPTH(-1-->+84).

    PubMed

    Olstad, O K; Jemtland, R; Loseth, O P; Bringhurst, F R; Gautvik, K M

    1995-01-01

    We have produced and characterized a hPTH analogue with an amino-terminal extension of glycine, Gly-hPTH(-1-->+84) (denoted Gly-hPTH). The hormone analogue was synthesized in E. coli strain BJ5183 transformed with the expression plasmid pKKPTH, extracted from the bacterial pellet and purified by reverse-phase high performance liquid chromatography. Its chemical nature, as determined by amino acid composition analysis, N-terminal amino acid analysis, and mass spectrometry, showed the 9480-Da Gly-hPTH as the predominant species. Because f-Met-Gly-hPTH was the expected form encoded by the plasmid construct, the results indicate that the f-Met residue was efficiently removed from the precurser form. The following functional characteristics of Gly-hPTH were demonstrated. 1) In cells transfected with the human PTH/PTHrP receptor, the receptor binding affinity was reduced threefold compared to the authentic hPTH(1-84) produced by Saccharomyces cerevisiae (apparent Kds: 8.4 and 2.7 nM, respectively). 2) Using the same cells, Gly-hPTH showed 27-fold reduced potency compared to hPTH(1-84) in stimulating intracellular cAMP production (EC50: 32 and 1.2 nM, respectively). 3) Gly-hPTH demonstrated antagonist activity by reducing hPTH-induced cAMP production by 33 +/- 5% (mean +/- SD) when tested at a 1:1 molar ratio. In these studies the recombinant authentic hPTH(1-84) was used as standard for comparisons, and it showed an equal receptor binding affinity and cAMP production as the chemically synthesized peptide [Nle8,18,Tyr34]bovinePTH(1-34)-NH2. PMID:8532584

  18. Effects of a short-term vitamin D(3) and calcium supplementation on blood pressure and parathyroid hormone levels in elderly women.

    PubMed

    Pfeifer, M; Begerow, B; Minne, H W; Nachtigall, D; Hansen, C

    2001-04-01

    Calcium supplementation is effective in reducing blood pressure in various states of hypertension, including pregnancy-induced hypertension and preeclampsia. In addition, calcitropic hormones are associated with blood pressure. The hypothesis is that short-term therapy with calcium and vitamin D(3) may improve blood pressure as well as secondary hyperparathyroidism more effectively than calcium monotherapy. The effects of 8 weeks of supplementation with vitamin D(3) (cholecalciferol) and calcium on blood pressure and biochemical measures of bone metabolism were studied. The sample consisted of 148 women (mean +/- SD age, 74 +/- 1 yr) with a 25-hydroxycholecalciferol (25OHD(3)) level below 50 nmol/L. They received either 1200 mg calcium plus 800 IU vitamin D(3) or 1200 mg calcium/day. We measured intact PTH, 25OHD(3), 1,25-dihydroxyvitamin D(3), blood pressure, and heart rate before and after treatment. Compared with calcium, supplementation with vitamin D(3) and calcium resulted in an increase in serum 25OHD(3) of 72% (P < 0.01), a decrease in serum PTH of 17% (P = 0.04), a decrease in systolic blood pressure (SBP) of 9.3% (P = 0.02), and a decrease in heart rate of 5.4% (P = 0.02). Sixty subjects (81%) in the vitamin D(3) and calcium group compared with 35 (47%) subjects in the calcium group showed a decrease in SBP of 5 mm Hg or more (P = 0.04). No statistically significant difference was observed in the diastolic blood pressures of the calcium-treated and calcium- plus vitamin D(3)-treated groups (P = 0.10). Pearson coefficients of correlation between the change in PTH and the change in SBP were 0.49 (P < 0.01) for the vitamin D(3) plus calcium group and 0.23 (P < 0.01) for the calcium group. A short-term supplementation with vitamin D(3) and calcium is more effective in reducing SBP than calcium alone. Inadequate vitamin D(3) and calcium intake could play a contributory role in the pathogenesis and progression of hypertension and cardiovascular disease in

  19. Molecular mechanisms of hormone-mediated Müllerian duct regression: involvement of beta-catenin.

    PubMed

    Allard, S; Adin, P; Gouédard, L; di Clemente, N; Josso, N; Orgebin-Crist, M C; Picard, J Y; Xavier, F

    2000-08-01

    and cell fate during Müllerian duct regression. To our knowledge, this is the first report that beta-catenin, known for its role in Wnt signaling, may mediate anti-Müllerian hormone action.

  20. Minireview: mechanisms of growth hormone-mediated gene regulation.

    PubMed

    Chia, Dennis J

    2014-07-01

    GH exerts a diverse array of physiological actions that include prominent roles in growth and metabolism, with a major contribution via stimulating IGF-1 synthesis. GH achieves its effects by influencing gene expression profiles, and Igf1 is a key transcriptional target of GH signaling in liver and other tissues. This review examines the mechanisms of GH-mediated gene regulation that begin with signal transduction pathways activated downstream of the GH receptor and continue with chromatin events at target genes and additionally encompasses the topics of negative regulation and cross talk with other cellular inputs. The transcription factor, signal transducer and activator of transcription 5b, is regarded as the major signaling pathway by which GH achieves its physiological effects, including in stimulating Igf1 gene transcription in liver. Recent studies exploring the mechanisms of how activated signal transducer and activator of transcription 5b accomplishes this are highlighted, which begin to characterize epigenetic features at regulatory domains of the Igf1 locus. Further research in this field offers promise to better understand the GH-IGF-1 axis in normal physiology and disease and to identify strategies to manipulate the axis to improve human health.

  1. A Cross-Sectional Association Between Bone Mineral Density and Parathyroid Hormone and Other Biomarkers in Community-Dwelling Young Adults: The CARDIA Study

    PubMed Central

    Polgreen, Lynda E.; Hurley, Daniel L.; Gross, Myron D.; Sidney, Stephen; Jacobs, David R.

    2013-01-01

    Context: Most association studies of bone-related biomarkers (BBMs) with bone mineral density (BMD) have been conducted in postmenopausal women. Objective: We tested whether the following BBMs were cross-sectionally associated with BMD among young adults: serum 1,25-dihydroxyvitamin D (1,25(OH)2D), 25-hydroxyvitamin D (25OHD), PTH, osteocalcin, bone-specific alkaline phosphatase (BAP), and urinary pyridinoline/urinary creatinine. Setting and Participants: We studied 319 individuals (134 women, 149 black, 24–36 years) recruited during 1992 through 1993 in Oakland, California. BMD was assessed with dual-energy x-ray absorptiometry. Linear regression models estimated the association between BMD and each BBM. Results: 1,25(OH)2D was inversely associated with all BMDs. 25OHD was positively, and PTH inversely, associated with lumbar spine, total hip, and whole-body BMD. BAP was inversely associated with left arm, right arm, and whole-body BMD but not with spine or hip BMD. Neither osteocalcin nor urinary pyridinoline/urinary creatinine was associated with BMD. When we placed all BBMs (including 1,25(OH)2D) in one model, the pattern and magnitude of association was similar except for PTH, which was attenuated. The association of BMD and BBMs did not differ significantly by race or sex. Conclusions: In this cross-sectional study of healthy young men and women who had PTH levels considered normal in clinical practice, higher PTH was associated with lower BMD, particularly in weight-bearing sites (ie, spine and hip). The inverse association of 1,25(OH)2D, together with the attenuation of PTH, suggests that the observed association of PTH is mediated by 1,25(OH)2D. BAP was inversely associated with arm BMD. BBMs can be important markers of skeletal activity in young adults, but their clinical role on bone health among this population is yet to be fully determined. PMID:23966240

  2. The Thyroid Hormone Receptor Is a Suppressor of ras-Mediated Transcription, Proliferation, and Transformation

    PubMed Central

    García-Silva, Susana; Aranda, Ana

    2004-01-01

    The thyroid hormone triiodothyronine (T3) has a profound effect on growth, differentiation, and metabolism in higher organisms. Here we demonstrate that T3 inhibits ras-induced proliferation in neuroblastoma cells and blocks induction of cyclin D1 expression by the oncogene. The hormone, at physiological concentrations, strongly antagonizes the transcriptional response mediated by the Ras/mitogen-activated protein kinase/ribosomal-S6 subunit kinase (Rsk) signaling pathway in cells expressing thyroid hormone receptors (TRs). T3 blocks the response to the oncogenic forms of the three ras isoforms (H-, K-, and N-ras) and both TRα and TRβ can mediate this action. The main target for induction of cyclin D1 transcription by oncogenic ras in neuroblastoma cells is a cyclic AMP response element (CRE) located in proximal promoter sequences, and T3 represses the transcriptional activity of b-Zip transcription factors such as CREB (CRE-binding protein) or ATF-2 (activation transcription factor 2) that are direct targets of Rsk2 and bind to this sequence. The hormone also blocks fibroblast transformation by oncogenic ras when TR is expressed. Furthermore, TRs act as suppressors of tumor formation by the oncogene in vivo in nude mice. The TRβ isoform has stronger antitransforming properties than the α isoform and can inhibit tumorigenesis even in hypothyroid mice. These results show the existence of a previously unrecognized transcriptional cross talk between the TRs and the ras oncogene which influences relevant processes such as cell proliferation, transformation, or tumorigenesis. PMID:15314161

  3. Placental Corticotropin-Releasing Hormone Mediates the Association Between Prenatal Social Support and Postpartum Depression

    PubMed Central

    Hahn-Holbrook, Jennifer; Schetter, Christine Dunkel; Arora, Chander; Hobel, Calvin J.

    2013-01-01

    Three decades of research point to both biological and psychological risk factors for postpartum depression, but very little research integrates the two. This study bridged this gap by testing whether prenatal social support predicted depressive symptoms at 8 weeks postpartum in a multiethnic sample of 210 women and whether the stress hormone placental corticotropin-releasing hormone (pCRH), measured at 19, 29, and 37 weeks’ gestation, mediated this relationship. We found that prenatal family support predicted significantly fewer depressive symptoms postpartum and more gradual increases in pCRH from 29 to 37 weeks’ gestation. Furthermore, steeper increases in pCRH during this same period predicted more depressive symptoms postpartum. Finally, these changes in pCRH in late pregnancy mediated the relationship between prenatal family support and postpartum depressive symptoms. These results suggest that social and biological risk factors for postpartum depressive symptoms are intertwined and move us closer to an integrated biopsychosocial understanding of postpartum depression. PMID:23997996

  4. Core binding factor beta (Cbfβ) controls the balance of chondrocyte proliferation and differentiation by upregulating Indian hedgehog (Ihh) expression and inhibiting parathyroid hormone-related protein receptor (PPR) expression in postnatal cartilage and bone formation.

    PubMed

    Tian, Fei; Wu, Mengrui; Deng, Lianfu; Zhu, Guochun; Ma, Junqing; Gao, Bo; Wang, Lin; Li, Yi-Ping; Chen, Wei

    2014-07-01

    Core binding factor beta (Cbfβ) is essential for embryonic bone morphogenesis. Yet the mechanisms by which Cbfβ regulates chondrocyte proliferation and differentiation as well as postnatal cartilage and bone formation remain unclear. Hence, using paired-related homeobox transcription factor 1-Cre (Prx1-Cre) mice, mesenchymal stem cell-specific Cbfβ-deficient (Cbfβ(f/f) Prx1-Cre) mice were generated to study the role of Cbfβ in postnatal cartilage and bone development. These mutant mice survived to adulthood but exhibited severe sternum and limb malformations. Sternum ossification was largely delayed in the Cbfβ(f/f) Prx1-Cre mice and the xiphoid process was noncalcified and enlarged. In newborn and 7-day-old Cbfβ(f/f) Prx1-Cre mice, the resting zone was dramatically elongated, the proliferation zone and hypertrophic zone of the growth plates were drastically shortened and disorganized, and trabecular bone formation was reduced. Moreover, in 1-month-old Cbfβ(f/f) Prx1-Cre mice, the growth plates were severely deformed and trabecular bone was almost absent. In addition, Cbfβ deficiency impaired intramembranous bone formation both in vivo and in vitro. Interestingly, although the expression of Indian hedgehog (Ihh) was largely reduced, the expression of parathyroid hormone-related protein (PTHrP) receptor (PPR) was dramatically increased in the Cbfβ(f/f) Prx1-Cre growth plate, indicating that that Cbfβ deficiency disrupted the Ihh-PTHrP negative regulatory loop. Chromatin immunoprecipitation (ChIP) analysis and promoter luciferase assay demonstrated that the Runx/Cbfβ complex binds putative Runx-binding sites of the Ihh promoter regions, and also the Runx/Cbfβ complex directly upregulates Ihh expression at the transcriptional level. Consistently, the expressions of Ihh target genes, including CyclinD1, Ptc, and Pthlh, were downregulated in Cbfβ-deficient chondrocytes. Taken together, our study reveals not only that Cbfβ is essential for chondrocyte

  5. The history of parathyroid endocrinology

    PubMed Central

    Kalra, Sanjay; Baruah, Manash P.; Sahay, Rakesh; Sawhney, Kanishka

    2013-01-01

    The parathyroid glands are now recognized as being essential for life. Their structure and function is well delineated, and their disease and dysfunction, well characterized. Diagnosis and management of parathyroid disease has improved in the past few decades. The path of parathyroid science, however, has been far from smooth. This paper describes the early history of parathyroid endocrinology. In doing so, it focuses on major events and discoveries, which improved the understanding and practice of our specialty. Contribution in anatomy, physiology, pathology, medicine, surgery and biochemistry are reviewed. PMID:23776911

  6. Fibroblast growth factor 23 and parathyroid hormone after treatment with active vitamin D and sevelamer carbonate in patients with chronic kidney disease stage 3b, a randomized crossover trial

    PubMed Central

    2012-01-01

    Background Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone that is secreted from bone and serum level increases as renal function declines. Higher levels of FGF23 are associated with increased mortality in hemodialysis-patients and in patients with chronic kidney disease (CKD) stage 2-4. The use of active vitamin D and phosphate binders as recommended in international guidelines, may affect the level of FGF23 and thereby clinical outcome. We investigated the effects of a phosphate binder and active vitamin D on the serum levels of intact FGF23 (iFGF23) and intact parathyroid hormone (iPTH) in patients with CKD stage 3b (glomerular filtration rate (GFR) 30–44 ml/min/1.73 m2). Methods Seven women and 14 men were included, mean age 65.6 ± 12.2 years. They were randomized in a 1:1 ratio to receive one of two treatment sequences. Group-1 (the alphacalcidol-sevelamer carbonate group): alphacalcidol 0.25 μg once daily for two weeks followed by sevelamer carbonate 800 mg TID with meals for two weeks after a two-week washout period. Group-2 (the sevelamer carbonate-alphacalcidol group): vice versa. Nineteen patients completed the study. The 25-hydroxyvitamin D level at baseline was 97.6 ± 25.0 nmol/l. Results There were no treatment effects on the iFGF23 and iPTH levels overall. In group-1 the iFGF23 level was higher after treatment with alphacalcidol compared with sevelamer carbonate (mean 105.8 ± 41.6 vs. 79.1 ± 36.5 pg/ml, p = 0.047 (CI: 0.4-52.9), and the iPTH level was lower (median: 26.5, range: 14.6-55.2 vs. median 36.1, range 13.4-106.9 pg/ml, p = 0.011). In group-2 the iFGF23 level increased non-significantly after treatment with sevelamer carbonate and throughout the washout period. Conclusions In this crossover trial with alphacalcidol and sevelamer carbonate in patients with CKD stage 3b, the levels of iFGF23 were not significantly different after the two treatments. However, in the group of patients

  7. Parathyroid hormone-related protein blood test

    MedlinePlus

    ... test is done to find out whether a high blood calcium level is caused by an increase in PTH-related protein. ... may have detectable PTH-related protein values. Normal value ... to your doctor about the meaning of your specific test results.

  8. Are thyroid hormones mediators of incubation temperature-induced phenotypes in birds?

    PubMed Central

    DuRant, S. E.; Carter, A. W.; Denver, R. J.; Hepp, G. R.; Hopkins, W. A.

    2014-01-01

    Incubation temperature influences a suite of traits in avian offspring. However, the mechanisms underlying expression of these phenotypes are unknown. Given the importance of thyroid hormones in orchestrating developmental processes, we hypothesized that they may act as an upstream mechanism mediating the effects of temperature on hatchling phenotypic traits such as growth and thermoregulation. We found that plasma T3, but not T4 concentrations, differed among newly hatched wood ducks (Aix sponsa) from different embryonic incubation temperatures. T4 at hatching correlated with time spent hatching, and T3 correlated with hatchling body condition, tarsus length, time spent hatching and incubation period. In addition, the T3 : T4 ratio differed among incubation temperatures at hatch. Our findings are consistent with the hypothesis that incubation temperature modulates plasma thyroid hormones which in turn influences multiple aspects of duckling phenotype. PMID:24402717

  9. Pathologic Fracture of the Femur in Brown Tumor Induced in Parathyroid Carcinoma: A Case Report

    PubMed Central

    Park, Sang-Hyun; Kwon, Yong-Uk; Park, Jun-Ho

    2016-01-01

    Brown tumor refers to a change of skeletones that develops as a complication of hyperparathyroidism. As osteoclast is activated to stimulate reabsorption and fibrosis of bone, it causes a cystic change of the bone. Parathyroid carcinoma is being reported as a tumor that induces primary hyperparathyroidism. It causes excessive secretion of the parathyroid hormone and increases the blood parathyroid hormone and calcium. Bone deformation due to brown tumor is known to be naturally recovered through the treatment for hyperparathyroidism. However, there is no clearly defined treatment for lesions that can induce pathological fractures developing in lower extremities. We experienced a case where brown tumor developed in the proximal femur of a 57-year-old female patient due to parathyroid carcinoma. In this case, spontaneous fracture occurred without any trauma, and it was cured by performing intramedullary nailing fixation and parathyroidectomy. We report the treatment results along with a literature review. PMID:27777921

  10. Transcription Profiles Reveal Sugar and Hormone Signaling Pathways Mediating Flower Induction in Apple (Malus domestica Borkh.).

    PubMed

    Xing, Li-Bo; Zhang, Dong; Li, You-Mei; Shen, Ya-Wen; Zhao, Cai-Ping; Ma, Juan-Juan; An, Na; Han, Ming-Yu

    2015-10-01

    Flower induction in apple (Malus domestica Borkh.) is regulated by complex gene networks that involve multiple signal pathways to ensure flower bud formation in the next year, but the molecular determinants of apple flower induction are still unknown. In this research, transcriptomic profiles from differentiating buds allowed us to identify genes potentially involved in signaling pathways that mediate the regulatory mechanisms of flower induction. A hypothetical model for this regulatory mechanism was obtained by analysis of the available transcriptomic data, suggesting that sugar-, hormone- and flowering-related genes, as well as those involved in cell-cycle induction, participated in the apple flower induction process. Sugar levels and metabolism-related gene expression profiles revealed that sucrose is the initiation signal in flower induction. Complex hormone regulatory networks involved in cytokinin (CK), abscisic acid (ABA) and gibberellic acid pathways also induce apple flower formation. CK plays a key role in the regulation of cell formation and differentiation, and in affecting flowering-related gene expression levels during these processes. Meanwhile, ABA levels and ABA-related gene expression levels gradually increased, as did those of sugar metabolism-related genes, in developing buds, indicating that ABA signals regulate apple flower induction by participating in the sugar-mediated flowering pathway. Furthermore, changes in sugar and starch deposition levels in buds can be affected by ABA content and the expression of the genes involved in the ABA signaling pathway. Thus, multiple pathways, which are mainly mediated by crosstalk between sugar and hormone signals, regulate the molecular network involved in bud growth and flower induction in apple trees. PMID:26412779

  11. Transcription Profiles Reveal Sugar and Hormone Signaling Pathways Mediating Flower Induction in Apple (Malus domestica Borkh.).

    PubMed

    Xing, Li-Bo; Zhang, Dong; Li, You-Mei; Shen, Ya-Wen; Zhao, Cai-Ping; Ma, Juan-Juan; An, Na; Han, Ming-Yu

    2015-10-01

    Flower induction in apple (Malus domestica Borkh.) is regulated by complex gene networks that involve multiple signal pathways to ensure flower bud formation in the next year, but the molecular determinants of apple flower induction are still unknown. In this research, transcriptomic profiles from differentiating buds allowed us to identify genes potentially involved in signaling pathways that mediate the regulatory mechanisms of flower induction. A hypothetical model for this regulatory mechanism was obtained by analysis of the available transcriptomic data, suggesting that sugar-, hormone- and flowering-related genes, as well as those involved in cell-cycle induction, participated in the apple flower induction process. Sugar levels and metabolism-related gene expression profiles revealed that sucrose is the initiation signal in flower induction. Complex hormone regulatory networks involved in cytokinin (CK), abscisic acid (ABA) and gibberellic acid pathways also induce apple flower formation. CK plays a key role in the regulation of cell formation and differentiation, and in affecting flowering-related gene expression levels during these processes. Meanwhile, ABA levels and ABA-related gene expression levels gradually increased, as did those of sugar metabolism-related genes, in developing buds, indicating that ABA signals regulate apple flower induction by participating in the sugar-mediated flowering pathway. Furthermore, changes in sugar and starch deposition levels in buds can be affected by ABA content and the expression of the genes involved in the ABA signaling pathway. Thus, multiple pathways, which are mainly mediated by crosstalk between sugar and hormone signals, regulate the molecular network involved in bud growth and flower induction in apple trees.

  12. An unusual mediastinal parathyroid carcinoma coproducing PTH and PTHrP: A case report

    PubMed Central

    CAO, CHUANGJIE; DOU, CHENGYUN; CHEN, FUQIN; WANG, YAN; ZHANG, XIAOLI; LAI, HONG

    2016-01-01

    Parathyroid carcinoma (PTCA) is a rare disease, and ectopic PTCA is particularly rare. Parathyroid hormone-related protein (PTHrP) expression in PTCA has not been previously described in the relevant literature to the best of our knowledge. The present study reports a unique case with a mediastinal parathyroid carcinoma producing parathyroid hormone (PTH) and PTHrP. A 53-year-old man presented with hyperparathyroidism symptoms, including fatigue, chest pain, dizziness, muscular soreness, polyuria, night sweats and renal stones. However, neck ultrasound revealed no significantly abnormal thyroid or parathyroid nodules. Tc99m methoxyisobutylisonitrile (Tc99m-MIBI) scintigraphy scanning indicated an ectopic mediastinal parathyroid adenoma. Histopathological examination revealed PTCA, and the tumor tissue was coproducing PTH and PTHrP. The patient underwent successful surgical operation. Serum calcium and PTH levels remained within normal ranges, and there was no tumor recurrence observed at a 3-year follow-up appointment. Although rare, ectopic parathyroid glands may lead to malignant disease. Clinical symptoms, biochemical tests, ultrasound and Tc99m-MIBI scintigraphy scanning may assist with the diagnosis of this disease. Hypersecretion of PTHrP and PTH contributed collaboratively to the pathogenesis of hypercalcemia due to PTCA. Complete surgical resection with microscopically negative margins is the recommended treatment for PTCA and offers the best chance of a cure. PMID:27313750

  13. Parathyroid Lipoadenoma: a Clinicopathological Diagnosis and Possible Trap for the Unaware Pathologist.

    PubMed

    Hyrcza, Martin D; Sargın, Pınar; Mete, Ozgur

    2016-03-01

    The authors present clinicopathological features of parathyroid lipoadenoma in a 48-year-old woman who presented with symptomatic primary hyperparathyroidism manifesting with pathological fractures and osteoporosis. Preoperative sestamibi scan failed to localize the source of her disease. Exploratory surgery identified an enlarged parathyroid gland with abundant fat tissue. The significant drop of intraoperative serum parathyroid hormone after the removal of this gland and postoperative biochemical cure justified the presence of a single gland disease presenting as parathyroid lipoadenoma. From an educational perspective, the presented case emphasizes why the historical approach to parathyroid proliferations by assessing alone the ratio of parenchymal cells to adipocytes is not a reliable method in the diagnostic evaluation of parathyroid disease. While the accurate size and weight of a parathyroid gland are defining parameters of an abnormal gland, intraoperative and postoperative biochemical workup distinguishes uniglandular disease (adenoma) from multiglandular disease (hyperplasia). The authors also provide a brief review of the previously published cases of parathyroid lipoadenomas to highlight their clinicopathological characteristics of relevance to surgical pathologists. PMID:26585863

  14. Epigenetic Methylation of Parathyroid CaR and VDR Promoters in Experimental Secondary Hyperparathyroidism.

    PubMed

    Hofman-Bang, Jacob; Gravesen, Eva; Olgaard, Klaus; Lewin, Ewa

    2012-01-01

    Secondary hyperparathyroidism (s-HPT) in uremia is characterized by decreased expression in the parathyroids of calcium sensing (CaR) and vitamin D receptors (VDR). Parathyroid hormone (PTH) is normalized despite low levels of CaR and VDR after experimental reversal of uremia. The expression of CaR in parathyroid cultures decreases rapidly. Methylation of promoter regions is often detected during epigenetic downregulation of gene expression. Therefore, using an experimental rat model, we examined changes in methylation levels of parathyroid CaR and VDR promoters in vivo and in vitro. Methods. Uremia was induced by 5/6 nephrectomy. Melting temperature profiling of CaR and VDR PCR products after bisulfite treatment of genomic DNA from rat parathyroids was performed. Real-time PCR measured expression of PTH, CaR, VDR, and klotho genes in vitro. Results. Parathyroids from uremic rats had similar low levels of methylation in vivo and in vitro. In culture, a significant downregulation of CaR, VDR, and klotho within two hours of incubation was observed, while housekeeping genes remained stable for 24 hours. Conclusion. In uremic s-HPT and in vitro, no overall changes in methylation levels in the promoter regions of parathyroid CaR and VDR genes were found. Thus, epigenetic methylation of these promoters does not explain decreased parathyroid expression of CaR and VDR genes in uremic s-HPT.

  15. Investigations of receptor-mediated phagocytosis by hormone-induced (imprinted) Tetrahymena pyriformis.

    PubMed

    Kovács, P; Sundermann, C A; Csaba, G

    1996-08-15

    Receptor-mediated endocytosis by Tetrahvmena pyriformis was studied using tetramethylrhodamine isothiocyanate-labeled concanavalin A (TRITC-Con A) with fluorescence and confocal microscopy. In the presence of insulin, or 24 h after insulin pretreatment (hormonal imprinting), the binding and uptake of TRITC-Con A increased when compared to controls, owing to the binding of TRITC-Con A to sugar oligomers of insulin receptors. Mannose inhibited the binding of Con A, thus demonstrating the specificity of binding. Histamine, a phagocytosis-promoting factor in mammals and Tetrahymena, and galactose, did not influence the uptake of TRITC-Con A.

  16. Primary hyperparathyroidism due to an intrathyroidal parathyroid adenoma associated with chronic lymphocytic thyroiditis.

    PubMed

    Cating-Cabral, Monica Therese; Cabungcal, Arsenio Claro; Villafuerte, Cesar Vincent; Añel-Quimpo, Joselynna

    2012-06-08

    This is a case of a 44-year-old woman with an anterior neck mass and hypothyroidism who presented with an incidental finding of an elevated serum calcium level and was found to have primary hyperparathyroidism and osteoporosis. During surgical exploration no parathyroid adenoma was found, although a nodule was palpated within the right thyroid lobe. Examination of the excised right thyroid lobe revealed an intrathyroidal parathyroid adenoma and chronic lymphocytic thyroiditis. After surgery, she did not develop severe hypocalcaemia and this was attributed to preoperative treatment with pamidronate. In the months following surgery, parathyroid hormone remained undetectable.

  17. General Information about Parathyroid Cancer

    MedlinePlus

    ... of the head and neck. SPECT scan (single photon emission computed tomography scan) : A procedure that uses ... a recurrence. The parathyroid cancer usually recurs between 2 and 5 years after the first surgery , but ...

  18. Evaluation of parathyroid autograft growth and function in hemodialysis patients

    SciTech Connect

    Karsenty, G.; Petraglia, A.; Bourdeau, A.; Gambini, D.J.; Moreau, J.F.; Lecharpentier, Y.; Zingraff, J.; Bournerias, F.; Buisson, C.; Dubost, C.

    1986-07-01

    The aim of our study was to evaluate the function and growth of parathyroid tissue autografted into the forearm of hemodialysis patients using several presently available methods. In a dynamic study, the secretory function of autografted tissue was evaluated in seven patients using either zero calcium dialysate or calcium infusion. In an additional prospective study, seven patients had repeated determinations of plasma immunoreactive parathyroid hormone (iPTH) concentration on samples from both forearms, a radionuclide evaluation of autograft function using thallium-201 chloride, and real time ultrasonography. Light microscopy analysis was performed in two patients. The dynamic study demonstrated that induction of hypocalcemia was followed by an increase, and induction of hypercalcemia by a decrease in circulating iPTH in both forearms using three different radioimmunoassays similar to what has been reported for normal parathyroid tissue. A significant gradient (ie, greater than 2.0) of plasma iPTH concentration in samples from both forearms was observed in only three out of the seven patients of the prospective study. Two of these patients disclosed an increased uptake of /sup 201/TI chloride at the site of autografted tissue and had an echographically detectable mass. In both, hyperplastic parathyroid tissue was removed. At present, the remaining third patient does not have other features of recurrent hyperparathyroidism. In conclusion, autotransplanted parathyroid tissue of hemodialysis patients shows an adequate response to physiologic stimuli such as hypo- and hypercalcemia. Dynamic tests, therefore, appear to be a useful tool in the assessment of its function. In addition, radionuclide and echographic studies may be reliable adjuncts in the detection of marked parathyroid autograft hyperplasia.

  19. [Four cases of parathyroid cancer].

    PubMed

    Chew-Wong, A; Herrera, M F; Jiménez, E D; Gamboa-Domínguez, A; Richaud-Patin, Y; Bezaury, P; Reza-A, A; Correa-Rotter, R; Rull, J A

    1998-01-01

    Parathyroid carcinoma is a rare cause of primary hyperparathyroidism with a prevalence ranging between 0.5 and 4%. Because of their aggressiveness, prompt diagnosis and treatment are mandatory. A parathyroid carcinoma was found in four patients (4.5%) of 88 patients who underwent surgical cervical exploration for primary hyperparathyroidism at the Institute Nacional de la Nutrición in a period of seven years. Our paper gives the clinical characteristics, diagnosis, treatment and outcome of the four patients.

  20. Tumour nuclear oestrogen receptor beta 1 correlates inversely with parathyroid tumour weight

    PubMed Central

    Haglund, Felix; Rosin, Gustaf; Nilsson, Inga-Lena; Juhlin, C Christofer; Pernow, Ylva; Norenstedt, Sophie; Dinets, Andrii; Larsson, Catharina; Hartman, Johan; Höög, Anders

    2015-01-01

    Primary hyperparathyroidism (PHPT) is a common endocrinopathy, frequently caused by a parathyroid adenoma, rarely by a parathyroid carcinoma that lacks effective oncological treatment. As the majority of cases are present in postmenopausal women, oestrogen signalling has been implicated in the tumourigenesis. Oestrogen receptor beta 1 (ERB1) and ERB2 have been recently identified in parathyroid adenomas, the former inducing genes coupled to tumour apoptosis. We applied immunohistochemistry and slide digitalisation to quantify nuclear ERB1 and ERB2 in 172 parathyroid adenomas, atypical adenomas and carcinomas, and ten normal parathyroid glands. All the normal parathyroid glands expressed ERB1 and ERB2. The majority of tumours expressed ERB1 (70.6%) at varying intensities, and ERB2 (96.5%) at strong intensities. Parathyroid carcinomas expressed ERB1 in three out of six cases and ERB2 in five out of six cases. The intensity of tumour nuclear ERB1 staining significantly correlated inversely with tumour weight (P=0.011), and patients whose tumours were classified as ERB1-negative had significantly greater tumour weight as well as higher serum calcium (P=0.002) and parathyroid hormone levels (P=0.003). Additionally, tumour nuclear ERB1 was not expressed differentially with respect to sex or age of the patient. Levels of tumour nuclear ERB2 did not correlate with clinical characteristics. In conclusion, decreased ERB1 immunoreactivity is associated with increased tumour weight in parathyroid adenomas. Given the previously reported correlation with tumour-suppressive signalling, selective oestrogen receptor modulation (SERMs) may play a role in the treatment of parathyroid carcinomas. Future studies of SERMs and oestrogen treatment in PHPT should consider tumour weight as a potential factor in pharmacological responsiveness. PMID:25648860

  1. Tumour nuclear oestrogen receptor beta 1 correlates inversely with parathyroid tumour weight.

    PubMed

    Haglund, Felix; Rosin, Gustaf; Nilsson, Inga-Lena; Juhlin, C Christofer; Pernow, Ylva; Norenstedt, Sophie; Dinets, Andrii; Larsson, Catharina; Hartman, Johan; Höög, Anders

    2015-03-01

    Primary hyperparathyroidism (PHPT) is a common endocrinopathy, frequently caused by a parathyroid adenoma, rarely by a parathyroid carcinoma that lacks effective oncological treatment. As the majority of cases are present in postmenopausal women, oestrogen signalling has been implicated in the tumourigenesis. Oestrogen receptor beta 1 (ERB1) and ERB2 have been recently identified in parathyroid adenomas, the former inducing genes coupled to tumour apoptosis. We applied immunohistochemistry and slide digitalisation to quantify nuclear ERB1 and ERB2 in 172 parathyroid adenomas, atypical adenomas and carcinomas, and ten normal parathyroid glands. All the normal parathyroid glands expressed ERB1 and ERB2. The majority of tumours expressed ERB1 (70.6%) at varying intensities, and ERB2 (96.5%) at strong intensities. Parathyroid carcinomas expressed ERB1 in three out of six cases and ERB2 in five out of six cases. The intensity of tumour nuclear ERB1 staining significantly correlated inversely with tumour weight (P=0.011), and patients whose tumours were classified as ERB1-negative had significantly greater tumour weight as well as higher serum calcium (P=0.002) and parathyroid hormone levels (P=0.003). Additionally, tumour nuclear ERB1 was not expressed differentially with respect to sex or age of the patient. Levels of tumour nuclear ERB2 did not correlate with clinical characteristics. In conclusion, decreased ERB1 immunoreactivity is associated with increased tumour weight in parathyroid adenomas. Given the previously reported correlation with tumour-suppressive signalling, selective oestrogen receptor modulation (SERMs) may play a role in the treatment of parathyroid carcinomas. Future studies of SERMs and oestrogen treatment in PHPT should consider tumour weight as a potential factor in pharmacological responsiveness. PMID:25648860

  2. Macrophage/cancer cell interactions mediate hormone resistance by a nuclear receptor derepression pathway.

    PubMed

    Zhu, Ping; Baek, Sung Hee; Bourk, Eliot M; Ohgi, Kenneth A; Garcia-Bassets, Ivan; Sanjo, Hideki; Akira, Shizuo; Kotol, Paul F; Glass, Christopher K; Rosenfeld, Michael G; Rose, David W

    2006-02-10

    Defining the precise molecular strategies that coordinate patterns of transcriptional responses to specific signals is central for understanding normal development and homeostasis as well as the pathogenesis of hormone-dependent cancers. Here we report specific prostate cancer cell/macrophage interactions that mediate a switch in function of selective androgen receptor antagonists/modulators (SARMs) from repression to activation in vivo. This is based on an evolutionarily conserved receptor N-terminal L/HX7LL motif, selectively present in sex steroid receptors, that causes recruitment of TAB2 as a component of an N-CoR corepressor complex. TAB2 acts as a sensor for inflammatory signals by serving as a molecular beacon for recruitment of MEKK1, which in turn mediates dismissal of the N-CoR/HDAC complex and permits derepression of androgen and estrogen receptor target genes. Surprisingly, this conserved sensor strategy may have arisen to mediate reversal of sex steroid-dependent repression of a limited cohort of target genes in response to inflammatory signals, linking inflammatory and nuclear receptor ligand responses to essential reproductive functions.

  3. Nutrient limitation results in juvenile hormone-mediated resorption of previtellogenic ovarian follicles in mosquitoes

    PubMed Central

    Clifton, Mark E.; Noriega, Fernando G.

    2011-01-01

    Juvenile hormone (JH) is a central hormonal regulator of previtellogenic development in female Aedes aegypti mosquitoes. JH levels are low at eclosion and increase during the first day after adult emergence. This initial rise in JH is essential for female reproductive maturation. After previtellogenic maturation is complete, the mosquito enters a ‘state-of-arrest’ during which JH synthesis continues at a slower pace and further ovary development is repressed until a blood meal is taken. By examining the relationships between juvenile hormone, follicular resorption and nutrition in A. aegypti, we were able to define a critical role of JH during the previtellogenic resting stage. The rate of follicular resorption in resting stage mosquitoes is dependent on nutritional quality. Feeding water alone caused the rate of follicular resorption to reach over 20% by day 7 after emergence. Conversely, feeding a 20% sucrose solution caused resorption to remain below 5% during the entire experimental period. Mosquitoes fed 3% sucrose show rates of resorption intermediate between water and 20% sucrose and only reached 10% by day 7 after emergence. Follicular resorption is related to JH levels. Ligated abdomens separated from a source of JH (the corpora allata) showed an increase in resorption comparable to similarly aged starved mosquitoes (16%). Resorption in ligated abdomens was reduced to 6% by application of methoprene. The application of methoprene was also sufficient to prevent resorption in intact mosquitoes starved for 48 hours (14% starved vs. 4% starved with methoprene). Additionally, active caspases were localized to resorbing follicles indicating that an apoptotic cell-death mechanism is responsible for follicular resorption during the previtellogenic resting stage. Taken together, these results indicate that JH mediates reproductive trade-offs in resting stage mosquitoes in response to nutrition. PMID:21708165

  4. Altered Gene Synchrony Suggests a Combined Hormone-Mediated Dysregulated State in Major Depression

    PubMed Central

    Gaiteri, Chris; Guilloux, Jean-Philippe; Lewis, David A.; Sibille, Etienne

    2010-01-01

    Coordinated gene transcript levels across tissues (denoted “gene synchrony”) reflect converging influences of genetic, biochemical and environmental factors; hence they are informative of the biological state of an individual. So could brain gene synchrony also integrate the multiple factors engaged in neuropsychiatric disorders and reveal underlying pathologies? Using bootstrapped Pearson correlation for transcript levels for the same genes across distinct brain areas, we report robust gene transcript synchrony between the amygdala and cingulate cortex in the human postmortem brain of normal control subjects (n = 14; Control/Permutated data, p<0.000001). Coordinated expression was confirmed across distinct prefrontal cortex areas in a separate cohort (n = 19 subjects) and affected different gene sets, potentially reflecting regional network- and function-dependent transcriptional programs. Genewise regional transcript coordination was independent of age-related changes and array technical parameters. Robust shifts in amygdala-cingulate gene synchrony were observed in subjects with major depressive disorder (MDD, denoted here “depression”) (n = 14; MDD/Permutated data, p<0.000001), significantly affecting between 100 and 250 individual genes (10–30% false discovery rate). Biological networks and signal transduction pathways corresponding to the identified gene set suggested putative dysregulated functions for several hormone-type factors previously implicated in depression (insulin, interleukin-1, thyroid hormone, estradiol and glucocorticoids; p<0.01 for association with depression-related networks). In summary, we showed that coordinated gene expression across brain areas may represent a novel molecular probe for brain structure/function that is sensitive to disease condition, suggesting the presence of a distinct and integrated hormone-mediated corticolimbic homeostatic, although maladaptive and pathological, state in major depression. PMID

  5. Hormone stimulation of androgen receptor mediates dynamic changes in DNA methylation patterns at regulatory elements

    PubMed Central

    Dhiman, Vineet K.; Attwood, Kristopher; Campbell, Moray J.; Smiraglia, Dominic J.

    2015-01-01

    DNA methylation is an epigenetic modification that contributes to stable gene silencing by interfering with the ability of transcriptional regulators to bind to DNA. Recent findings have revealed that hormone stimulation of certain nuclear receptors induces rapid, dynamic changes in DNA methylation patterns alongside transcriptional responses at a subset of target loci, over time. However, the ability of androgen receptor (AR) to dynamically regulate gene transcription is relatively under-studied and its role in the regulation of DNA methylation patterns remains to be elucidated. Here we demonstrate in normal prostate cells that hormone stimulated AR activity results in dynamic changes in the transcription rate and DNA methylation patterns at the AR target genes, TIPARP and SGK1. Time-resolved chromatin immunoprecipitation experiments on the SGK1 locus reveals dynamic recruitment of AR and RNA Polymerase II, as well as the recruitment of proteins involved in the DNA demethylation process, TET1 and TDG. Furthermore, the presence of DNA methylation at dynamic regions inhibits protein binding and transcriptional activity of SGK1. These findings establish AR activity as a contributing factor to the dynamic regulation of DNA methylation patterns at target genes in prostate biology and infer further complexity involved in nuclear receptor mediation of transcriptional regulation. PMID:26646795

  6. Root-targeted biotechnology to mediate hormonal signalling and improve crop stress tolerance.

    PubMed

    Ghanem, Michel Edmond; Hichri, Imène; Smigocki, Ann C; Albacete, Alfonso; Fauconnier, Marie-Laure; Diatloff, Eugene; Martinez-Andujar, Cristina; Lutts, Stanley; Dodd, Ian C; Pérez-Alfocea, Francisco

    2011-05-01

    Since plant root systems capture both water and nutrients essential for the formation of crop yield, there has been renewed biotechnological focus on root system improvement. Although water and nutrient uptake can be facilitated by membrane proteins known as aquaporins and nutrient transporters, respectively, there is a little evidence that root-localised overexpression of these proteins improves plant growth or stress tolerance. Recent work suggests that the major classes of phytohormones are involved not only in regulating aquaporin and nutrient transporter expression and activity, but also in sculpting root system architecture. Root-specific expression of plant and bacterial phytohormone-related genes, using either root-specific or root-inducible promoters or grafting non-transformed plants onto constitutive hormone producing rootstocks, has examined the role of root hormone production in mediating crop stress tolerance. Root-specific traits such as root system architecture, sensing of edaphic stress and root-to-shoot communication can be exploited to improve resource (water and nutrients) capture and plant development under resource-limited conditions. Thus, root system engineering provides new opportunities to maintain sustainable crop production under changing environmental conditions.

  7. Hyper-G stress-induced hyperglycemia in rats mediated by glucoregulatory hormones

    NASA Technical Reports Server (NTRS)

    Daligcon, B. C.; Oyama, J.

    1985-01-01

    The present investigation is concerned with possible relations of the hyperglycemic response of rats exposed to hyper-G stress to (1) alterations in blood levels of the glucoregulatory hormones and gluconeogenic substrates, and (2) changes in insulin response on muscle glucose uptake. Male Sprague-Dawley rats weighing 250-300 g were used in the study. The results of the experiments indicate that the initial rapid rise in blood glucose of rats exposed to hyper-G stress is mediated by increases in circulating catecholamines and glucagon, both potent stimulators of hepatic gluconeogenesis. Lactate, derived from epinephrine stimulation of muscle glycogenolysis, appears to be a major precursor for the initial rise in blood glucose. The inhibition of the insulin-stimulated glucose uptake by muscle tissues may be a factor in the observed sustained hyperglycemia.

  8. Hormone-Mediated Intercellular Calcium Signalling in an Insect Salivary Gland Pathways and Mechanisms

    NASA Astrophysics Data System (ADS)

    Zimmermann, Bernhard; Walz, Bernd

    The salivary glands of the blowfly Calliphora vicina are a favourable preparation for investigations into spatio-temporal Ca 2+ dynamics in an intact miniorgan by using Ca 2+-sensitive indicator dyes and digital imaging techniques, including confocal microscopy, in combination with pharmacological approaches. The review summarizes the available data on the spatio-temporal patterns of the hormone-induced and IP 3-mediated Ca 2+ dynamics at both the intracellular and the intercellular level (intra- and intercellular Ca 2+ waves). The underlying signaling mechanisms are addressed, as well as the pathways of intercellular communication responsible for the complex spatio-temporal Ca 2+ dynamics. In addition, we review evidence for the exchange of Ca 2+ between IP 3 sensitive intracellular Ca 2+ stores and mitochondria including a modulatory effect of mitochondrial Ca 2+ uptake on the frequency of IP 3-induced Ca 2+ spiking.

  9. Influence of the parathyroid glands on bone metabolism.

    PubMed

    Malluche, H H; Koszewski, N; Monier-Faugere, M C; Williams, J P; Mawad, H

    2006-08-01

    Bone is a classic target tissue for parathyroid hormone (PTH), whose calciotropic effect is mediated largely via catabolic actions on this tissue. Paradoxically, PTH also exerts anabolic actions, with intermittent injections of PTH or its amino-terminal fragments causing an increase in bone formation and bone mass, actions that form the basis for the use of PTH in the treatment of osteoporosis. Besides vitamin D, PTH is the only other known bone anabolic agent. High-affinity PTH receptors (PTH-1R) have been detected on osteoblasts and osteoclasts (albeit in lower numbers). Bone turnover, which includes activation of osteoclasts and osteoblasts, appears to be best reflected not by absolute concentrations of PTH (which can vary based on the assay and antibody used) but by a balance of circulating full-length PTH-(1-84) and amino-terminally truncated C-PTH fragments. When PTH-(1-84) is predominant, bone turnover is promoted. Among PTH fragments, PTH-(7-84) appears to be the most potent antagonist of PTH-(1-84). The mechanisms involved in these effects are unclear although mediation via unique C-terminal receptors has been suggested. We propose that, within the range of total PTH (100-1000 pg mL(-1)), the ratio of PTH-(1-84)/C-PTH fragment is a valuable tool for diagnosis of bone turnover. Data indicate that at PTH levels < 100-150 pg mL(-1) and > 1000 pg mL(-1), the ratio looses its predictive power. Assay type, patient characteristics (race, underlying renal disease) and treatment attributes (vitamin D, corticosteroids, phosphate binders) have an impact on the PTH ratio, and care should be used in interpreting assay results and making subsequent treatment decisions.

  10. Role and Mechanisms of Actions of Thyroid Hormone on the Skeletal Development.

    PubMed

    Kim, Ha-Young; Mohan, Subburaman

    2013-06-01

    The importance of the thyroid hormone axis in the regulation of skeletal growth and maintenance has been well established from clinical studies involving patients with mutations in proteins that regulate synthesis and/or actions of thyroid hormone. Data from genetic mouse models involving disruption and overexpression of components of the thyroid hormone axis also provide direct support for a key role for thyroid hormone in the regulation of bone metabolism. Thyroid hormone regulates proliferation and/or differentiated actions of multiple cell types in bone including chondrocytes, osteoblasts and osteoclasts. Thyroid hormone effects on the target cells are mediated via ligand-inducible nuclear receptors/transcription factors, thyroid hormone receptor (TR) α and β, of which TRα seems to be critically important in regulating bone cell functions. In terms of mechanisms for thyroid hormone action, studies suggest that thyroid hormone regulates a number of key growth factor signaling pathways including insulin-like growth factor-I, parathyroid hormone related protein, fibroblast growth factor, Indian hedgehog and Wnt to influence skeletal growth. In this review we describe findings from various genetic mouse models and clinical mutations of thyroid hormone signaling related mutations in humans that pertain to the role and mechanism of action of thyroid hormone in the regulation of skeletal growth and maintenance.

  11. Mamun-TKC parathyroid retractor: Parathyroid glands squashed or scooped!

    PubMed

    Mahmud, Syed Mamun

    2015-03-01

    Parathyroid gland by its physiologic and anatomic diversity has interestingly been dealt by multiple specialties, including Urology. Besides primary hyperparathyroidism, urologists in close working relationship with nephrologists, tend to get referrals for tertiary hyperparathyroidism. Data from 1999 to 2012 was retrieved for all parathyroidectomies. Medical record of only cases undergoing parathyroidectomy utilising the instrument Mamun-TKC Parathyroid Retractor were reviewed. It is a metal body surgical instrument resembling Gil Vernet retractor having functional flat metal head attached to solid long handle, designed in two forms; one 'Straight' and other 'Angled' at 30°. During the period, 28 cases of parathyroidectomies were performed. The instrument was used in two cases. It was found to facilitate dissection, retraction and pedicle ligation of parathyroid gland by a-traumatic handling. PMID:25933576

  12. Gonadotrophin-releasing activity of neurohypophysial hormones: II. The pituitary oxytocin receptor mediating gonadotrophin release differs from that of corticotrophs.

    PubMed

    Evans, J J; Catt, K J

    1989-07-01

    Neurohypophysial hormones stimulate gonadotrophin release from dispersed rat anterior pituitary cells in vitro, acting through receptors distinct from those which mediate the secretory response to gonadotrophin-releasing hormone (GnRH). The LH response to oxytocin was not affected by the presence of the phosphodiesterase inhibitor, methyl isobutylxanthine, but was diminished in the absence of extracellular calcium and was progressively increased as the calcium concentration in the medium was raised to normal. In addition, the calcium channel antagonist, nifedipine, suppressed oxytocin-stimulated secretion of LH. It is likely that the mechanisms of LH release induced by GnRH and neurohypophysial hormones are similar, although stimulation of gonadotrophin secretion is mediated by separate receptor systems. Oxytocin was more active than vasopressin in releasing LH, but less active in releasing ACTH. The highly selective oxytocin agonist, [Thr4,Gly7]oxytocin, elicited concentration-dependent secretion of LH but had little effect on corticotrophin secretion. The neurohypophysial hormone antagonist analogues, [d(CH2)5Tyr(Me)2]vasopressin, [d(CH2)5Tyr(Me)2,Orn8]vasotocin and [d(CH2)5D-Tyr(Et)2Val4,Cit8]vasopressin, inhibited the LH response to both oxytocin and vasopressin. However, [d(CH2)5Tyr(Me)2]vasopressin was much less effective in inhibiting the ACTH response to the neurohypophysial hormones, and [d(CH2)5Tyr-(Me)2,Orn8]vasotocin and [d(CH2)5D-Tyr(Et)2,Val4,Cit8]vasopressin exhibited no inhibitory activity against ACTH release. Thus, agonist and antagonist analogues of neurohypophysial hormones display divergent activities with regard to LH and ACTH responses, and the neuropeptide receptor mediating gonadotroph activation is clearly different from that on the corticotroph. Whereas the corticotroph receptor is a vasopressin-type receptor an oxytocin-type receptor is responsible for gonadotrophin release by neurohypophysial hormones.

  13. Recurrent hyperparathyroidism due to proliferation of autotransplanted parathyroid tissue in a multiple endocrine neoplasia type 2A patient

    PubMed Central

    Kim, Bong Kyun; Lee, Jina

    2016-01-01

    About 20%–30% of all cases of multiple endocrine neoplasia type 2A (MEN 2A) is accompanied by primary hyperparathyroidism. These patients undergo parathyroidectomy and, if needed, autotransplantation. In rare cases, autotransplanted parathyroid tissues can cause hypoparathyroidism due to failure of transplantation or hyperparathyroidism due to proliferation of the transplanted tissue. A 68-year-old female with MEN 2A underwent left adrenalectomy for pheochromocytoma 15 years prior to presentation and total thyroidectomy, central and right lateral neck lymph node dissection, and subtotal parathyroidectomy with autotransplantation for medullary thyroid cancer and primary hyperparathyroidism 6 years previous. Recently, a doubtful parathyroid adenoma was detected in the left sternocleidomastoid muscle on ultrasonography and on an additional sestamibi scan. The mass was excised and histologically confirmed as parathyroid adenoma. This is a very rare case, and it suggests that long-term regular monitoring of serum calcium and intact parathyroid hormone levels is necessary after parathyroid autotransplantation. PMID:27617256

  14. Recurrent hyperparathyroidism due to proliferation of autotransplanted parathyroid tissue in a multiple endocrine neoplasia type 2A patient

    PubMed Central

    Kim, Bong Kyun; Lee, Jina

    2016-01-01

    About 20%–30% of all cases of multiple endocrine neoplasia type 2A (MEN 2A) is accompanied by primary hyperparathyroidism. These patients undergo parathyroidectomy and, if needed, autotransplantation. In rare cases, autotransplanted parathyroid tissues can cause hypoparathyroidism due to failure of transplantation or hyperparathyroidism due to proliferation of the transplanted tissue. A 68-year-old female with MEN 2A underwent left adrenalectomy for pheochromocytoma 15 years prior to presentation and total thyroidectomy, central and right lateral neck lymph node dissection, and subtotal parathyroidectomy with autotransplantation for medullary thyroid cancer and primary hyperparathyroidism 6 years previous. Recently, a doubtful parathyroid adenoma was detected in the left sternocleidomastoid muscle on ultrasonography and on an additional sestamibi scan. The mass was excised and histologically confirmed as parathyroid adenoma. This is a very rare case, and it suggests that long-term regular monitoring of serum calcium and intact parathyroid hormone levels is necessary after parathyroid autotransplantation.

  15. Recurrent hyperparathyroidism due to proliferation of autotransplanted parathyroid tissue in a multiple endocrine neoplasia type 2A patient.

    PubMed

    Kim, Bong Kyun; Lee, Jina; Sun, Woo Young

    2016-09-01

    About 20%-30% of all cases of multiple endocrine neoplasia type 2A (MEN 2A) is accompanied by primary hyperparathyroidism. These patients undergo parathyroidectomy and, if needed, autotransplantation. In rare cases, autotransplanted parathyroid tissues can cause hypoparathyroidism due to failure of transplantation or hyperparathyroidism due to proliferation of the transplanted tissue. A 68-year-old female with MEN 2A underwent left adrenalectomy for pheochromocytoma 15 years prior to presentation and total thyroidectomy, central and right lateral neck lymph node dissection, and subtotal parathyroidectomy with autotransplantation for medullary thyroid cancer and primary hyperparathyroidism 6 years previous. Recently, a doubtful parathyroid adenoma was detected in the left sternocleidomastoid muscle on ultrasonography and on an additional sestamibi scan. The mass was excised and histologically confirmed as parathyroid adenoma. This is a very rare case, and it suggests that long-term regular monitoring of serum calcium and intact parathyroid hormone levels is necessary after parathyroid autotransplantation. PMID:27617256

  16. Developmental expression of Manduca shade, the P450 mediating the final step in molting hormone synthesis.

    PubMed

    Rewitz, Kim F; Rybczynski, Robert; Warren, James T; Gilbert, Lawrence I

    2006-03-01

    The ecdysone 20-monooxygenase (E20MO; 20-hydroxylase) is the enzyme that mediates the conversion of ecdysone (E) to the active insect molting hormone, 20-hydroxyecdysone (20E), which coordinates developmental progression. We report the identification and developmental expression of the Halloween gene shade (shd; CYP314A1) that encodes the E20MO in the tobacco hornworm, Manduca sexta. Manduca Shd (MsShd) mediates the conversion of E to 20E when expressed in Drosophila S2 cells. In accord with the central dogma, the data show that Msshd is expressed mainly in the midgut, Malpighian tubules, fat body and epidermis with very low expression in the prothoracic gland and nervous system. Developmental variations in E20MO enzymatic activity are almost perfectly correlated with comparable changes in the gene expression of Msshd in the fat body and midgut during the fifth instar and the beginning of pupal-adult development. The results indicate three successive and overlapping peaks of expression in the fat body, midgut and Malpighian tubules, respectively, during the fifth larval instar. The data suggest that precise tissue-specific transcriptional regulation controls the levels, and thereby the activity, of the Manduca E20MO. PMID:16473459

  17. The Halloween genes code for cytochrome P450 enzymes mediating synthesis of the insect moulting hormone.

    PubMed

    Rewitz, K F; Rybczynski, R; Warren, J T; Gilbert, L I

    2006-12-01

    The developmental events occurring during moulting and metamorphosis of insects are controlled by precisely timed changes in levels of ecdysteroids, the moulting hormones. The final four sequential hydroxylations of steroid precursors into the active ecdysteroid of insects, 20E (20-hydroxyecdysone), are mediated by four cytochrome P450 (P450) enzymes, encoded by genes in the Halloween family. Orthologues of the Drosophila Halloween genes phantom (phm; CYP306A1), disembodied (dib; CYP302A1), shadow (sad; CYP315A1) and shade (shd; CYP314A1) were obtained from the endocrinological model insect, the tobacco hornworm Manduca sexta. Expression of these genes was studied and compared with changes in the ecdysteroid titre that controls transition from the larval to pupal stage. phm, dib and sad, which encode P450s that mediate the final hydroxylations in the biosynthesis of ecdysone, were selectively expressed in the prothoracic gland, the primary source of ecdysone during larval and pupal development. Changes in their expression correlate with the haemolymph ecdysteroid titre during the fifth (final) larval instar. Shd, the 20-hydroxylase, which converts ecdysone into the more active 20E, is expressed in tissues peripheral to the prothoracic glands during the fifth instar. Transcript levels of shd in the fat body and midgut closely parallel the enzyme activity measured in vitro. The results indicate that these Halloween genes are transcriptionally regulated to support the high biosynthetic activity that produces the cyclic ecdysteroid pulses triggering moulting. PMID:17073797

  18. Developmental expression of Manduca shade, the P450 mediating the final step in molting hormone synthesis.

    PubMed

    Rewitz, Kim F; Rybczynski, Robert; Warren, James T; Gilbert, Lawrence I

    2006-03-01

    The ecdysone 20-monooxygenase (E20MO; 20-hydroxylase) is the enzyme that mediates the conversion of ecdysone (E) to the active insect molting hormone, 20-hydroxyecdysone (20E), which coordinates developmental progression. We report the identification and developmental expression of the Halloween gene shade (shd; CYP314A1) that encodes the E20MO in the tobacco hornworm, Manduca sexta. Manduca Shd (MsShd) mediates the conversion of E to 20E when expressed in Drosophila S2 cells. In accord with the central dogma, the data show that Msshd is expressed mainly in the midgut, Malpighian tubules, fat body and epidermis with very low expression in the prothoracic gland and nervous system. Developmental variations in E20MO enzymatic activity are almost perfectly correlated with comparable changes in the gene expression of Msshd in the fat body and midgut during the fifth instar and the beginning of pupal-adult development. The results indicate three successive and overlapping peaks of expression in the fat body, midgut and Malpighian tubules, respectively, during the fifth larval instar. The data suggest that precise tissue-specific transcriptional regulation controls the levels, and thereby the activity, of the Manduca E20MO.

  19. The Halloween genes code for cytochrome P450 enzymes mediating synthesis of the insect moulting hormone.

    PubMed

    Rewitz, K F; Rybczynski, R; Warren, J T; Gilbert, L I

    2006-12-01

    The developmental events occurring during moulting and metamorphosis of insects are controlled by precisely timed changes in levels of ecdysteroids, the moulting hormones. The final four sequential hydroxylations of steroid precursors into the active ecdysteroid of insects, 20E (20-hydroxyecdysone), are mediated by four cytochrome P450 (P450) enzymes, encoded by genes in the Halloween family. Orthologues of the Drosophila Halloween genes phantom (phm; CYP306A1), disembodied (dib; CYP302A1), shadow (sad; CYP315A1) and shade (shd; CYP314A1) were obtained from the endocrinological model insect, the tobacco hornworm Manduca sexta. Expression of these genes was studied and compared with changes in the ecdysteroid titre that controls transition from the larval to pupal stage. phm, dib and sad, which encode P450s that mediate the final hydroxylations in the biosynthesis of ecdysone, were selectively expressed in the prothoracic gland, the primary source of ecdysone during larval and pupal development. Changes in their expression correlate with the haemolymph ecdysteroid titre during the fifth (final) larval instar. Shd, the 20-hydroxylase, which converts ecdysone into the more active 20E, is expressed in tissues peripheral to the prothoracic glands during the fifth instar. Transcript levels of shd in the fat body and midgut closely parallel the enzyme activity measured in vitro. The results indicate that these Halloween genes are transcriptionally regulated to support the high biosynthetic activity that produces the cyclic ecdysteroid pulses triggering moulting.

  20. Cannabinoid CB1 receptor mediates glucocorticoid effects on hormone secretion induced by volume and osmotic changes.

    PubMed

    Ruginsk, S G; Uchoa, E T; Elias, L L K; Antunes-Rodrigues, J

    2012-02-01

    The present study provides the first in vivo evidence that the cannabinoid CB(1) receptor mediates the effects of dexamethasone on hormone release induced by changes in circulating volume and osmolality. Male adult rats were administered with the CB(1) receptor antagonist rimonabant (10 mg/Kg, p.o.), followed or not in 1 hour by dexamethasone (1 mg/Kg, i.p.). Extracellular volume expansion (EVE, 2 mL/100 g of body weight, i.v.) was performed 2 hours after dexamethasone or vehicle treatment using either isotonic (I-EVE, 0.15 mol/L) or hypertonic (H-EVE, 0.30 mol/L) NaCl solution. Five minutes after EVE, animals were decapitated and trunk blood was collected for all plasma measurements. Rimonabant potentiated oxytocin (OT) secretion induced by H-EVE and completely reversed the inhibitory effects of dexamethasone in response to the same stimulus. These data suggest that glucocorticoid modulation of OT release is mediated by the CB(1) receptor. Although dexamethasone did not affect vasopressin (AVP) secretion induced by H-EVE, the administration of rimonabant potentiated AVP release in response to the same stimulus, supporting the hypothesis that the CB(1) receptor regulates AVP secretion independently of glucocorticoid-mediated signalling. Dexamethasone alone did not affect atrial natriuretic peptide (ANP) release stimulated by I-EVE or H-EVE. However, pretreatment with rimonabant potentiated ANP secretion induced by H-EVE, suggesting a possible role for the CB(1) receptor in the control of peripheral factors that modulate cardiovascular function. Rimonabant also reversed the inhibitory effects of dexamethasone on H-EVE-induced corticosterone secretion, reinforcing the hypothesis that the CB(1) receptor may be involved in the negative feedback exerted by glucocorticoids on the activity of the hypothalamic-pituitary-adrenal axis. Collectively, the results of the present study indicate that the CB(1) receptor modulates neurohypophyseal hormone secretion and

  1. Histone Deacetylation Mediates the Rejuvenation of Osteoblastogenesis by the Combination of 25(OH)D3 and Parathyroid Hormone in MSCs from Elders

    PubMed Central

    Zhou, Shuanhu; Geng, Shuo; Glowacki, Julie

    2012-01-01

    Vitamin D metabolites are important effectors of bone and mineral homeostasis. Human bone marrow stromal cells (hMSCs) are targets of 1α,25-dihydroxyvitamin D [1α, 25(OH)2D] action to promote their differentiation to osteoblasts. Osteoblastogenesis is also stimulated by 25-hydroxyvitamin D [25(OH)D], an effect that requires conversion to 1α, 25(OH)2D3 by 25-hydroxyvitamin D3 1α-hydroxylase (CYP27B1). These findings support an autocrine/paracrine role of vitamin D metabolism in osteoblastogenesis of hMSCs. In this study, we assessed whether and by what mechanisms osteoblastogenesis could be rejuvenated with hMSCs from elders. First, knockdown studies with VDR-siRNA showed that both the pro-differentiation and anti-proliferative effects of 1α, 25(OH)2D3 required VDR. Second, 100 nM 25(OH)D3 (p<0.01 vs. control, ANOVA) and 100 nM PTH1-34 (p<0.05) significantly stimulated alkaline phosphatase activity (a measure of osteoblastogenesis), with a synergistic effect when combined (p<0.001). Scriptaid, an inhibitor of histone deacetylase, blocked the effect of 25(OH)D3 and PTH on osteoblastogenesis. Scriptaid alone downregulated VDR in hMSCs. These data demonstrate that histone deacetylation is required for the synergistic effect of 25(OH)D3 and PTH on osteoblastogenesis in hMSCs. Both VDR siRNA and Scriptaid dowregulated VDR mRNA and inhibited osteoblastogenesis. Thus, epigenetic regulation of the VDR may be central to rejuvenating osteoblastogenesis in hMSCs from elders. PMID:22982627

  2. A Case Report of 20 Lung Radiofrequency Ablation Sessions for 50 Lung Metastases from Parathyroid Carcinoma Causing Hyperparathyroidism

    SciTech Connect

    Tochio, Maki Takaki, Haruyuki; Yamakado, Koichiro; Uraki, Junji; Kashima, Masataka; Nakatsuka, Atsuhiro; Takao, Motoshi; Shimamoto, Akira; Tarukawa, Tomohito; Shimpo, Hideto; Takeda, Kan

    2010-06-15

    A 47-year-old man presented with multiple lung metastases from parathyroid carcinoma that caused hyperparathyroidism and refractory hypercalcemia. Lung radiofrequency (RF) ablation was repeated to decrease the serum calcium and parathyroid hormone levels and improve general fatigue. Pulmonary resection was combined for lung hilum metastases. The patient is still alive 4 years after the initial RF session. He has received 20 RF sessions for 50 lung metastases during this period.

  3. Hairy and Groucho mediate the action of juvenile hormone receptor Methoprene-tolerant in gene repression.

    PubMed

    Saha, Tusar T; Shin, Sang Woon; Dou, Wei; Roy, Sourav; Zhao, Bo; Hou, Yuan; Wang, Xue-Li; Zou, Zhen; Girke, Thomas; Raikhel, Alexander S

    2016-02-01

    The arthropod-specific juvenile hormone (JH) controls numerous essential functions. Its involvement in gene activation is known to be mediated by the transcription factor Methoprene-tolerant (Met), which turns on JH-controlled genes by directly binding to E-box-like motifs in their regulatory regions. However, it remains unclear how JH represses genes. We used the Aedes aegypti female mosquito, in which JH is necessary for reproductive maturation, to show that a repressor, Hairy, is required for the gene-repressive action of JH and Met. The RNA interference (RNAi) screen for Met and Hairy in the Aedes female fat body revealed a large cohort of Met- and Hairy-corepressed genes. Analysis of selected genes from this cohort demonstrated that they are repressed by JH, but RNAi of either Met or Hairy renders JH ineffective in repressing these genes in an in vitro fat-body culture assay. Moreover, this JH action was prevented by the addition of the translational inhibitor cycloheximide (CHX) to the culture, indicating the existence of an indirect regulatory hierarchy. The lack of Hairy protein in the CHX-treated tissue was verified using immunoblot analysis, and the upstream regions of Met/Hairy-corepressed genes were shown to contain common binding motifs that interact with Hairy. Groucho (gro) RNAi silencing phenocopied the effect of Hairy RNAi knockdown, indicating that it is involved in the JH/Met/Hairy hierarchy. Finally, the requirement of Hairy and Gro for gene repression was confirmed in a cell transfection assay. Thus, our study has established that Hairy and its cofactor Gro mediate the repressive function of JH and Met. PMID:26744312

  4. Hairy and Groucho mediate the action of juvenile hormone receptor Methoprene-tolerant in gene repression

    PubMed Central

    Saha, Tusar T.; Shin, Sang Woon; Dou, Wei; Roy, Sourav; Zhao, Bo; Hou, Yuan; Wang, Xue-Li; Zou, Zhen; Girke, Thomas; Raikhel, Alexander S.

    2016-01-01

    The arthropod-specific juvenile hormone (JH) controls numerous essential functions. Its involvement in gene activation is known to be mediated by the transcription factor Methoprene-tolerant (Met), which turns on JH-controlled genes by directly binding to E-box–like motifs in their regulatory regions. However, it remains unclear how JH represses genes. We used the Aedes aegypti female mosquito, in which JH is necessary for reproductive maturation, to show that a repressor, Hairy, is required for the gene-repressive action of JH and Met. The RNA interference (RNAi) screen for Met and Hairy in the Aedes female fat body revealed a large cohort of Met- and Hairy-corepressed genes. Analysis of selected genes from this cohort demonstrated that they are repressed by JH, but RNAi of either Met or Hairy renders JH ineffective in repressing these genes in an in vitro fat-body culture assay. Moreover, this JH action was prevented by the addition of the translational inhibitor cycloheximide (CHX) to the culture, indicating the existence of an indirect regulatory hierarchy. The lack of Hairy protein in the CHX-treated tissue was verified using immunoblot analysis, and the upstream regions of Met/Hairy-corepressed genes were shown to contain common binding motifs that interact with Hairy. Groucho (gro) RNAi silencing phenocopied the effect of Hairy RNAi knockdown, indicating that it is involved in the JH/Met/Hairy hierarchy. Finally, the requirement of Hairy and Gro for gene repression was confirmed in a cell transfection assay. Thus, our study has established that Hairy and its cofactor Gro mediate the repressive function of JH and Met. PMID:26744312

  5. Growth hormone STAT5-mediated signaling and its modulation in mice liver during the growth period.

    PubMed

    Martinez, Carolina S; Piazza, Verónica G; Ratner, Laura D; Matos, Marina N; González, Lorena; Rulli, Susana B; Miquet, Johanna G; Sotelo, Ana I

    2013-01-01

    Postnatal growth exhibits two instances of rapid growth in mice: the first is perinatal and independent of growth hormone (GH), the second is peripuberal and GH-dependent. Signal transducer and activator of transcription 5b (STAT5b) is the main GH-signaling mediator and it is related to IGF1 synthesis and somatic growth. The aim of this work was to assess differential STAT5 sensitivity to GH during the growth period in mouse liver of both sexes. Three representative ages were selected: 1-week-old animals, in the GH-independent phase of growth; 2.5-week-old mice, at the onset of the GH-dependent phase of growth; and 9-week-old young adults. GH-signaling mediators were assessed by immunoblotting, quantitative RT-PCR and immunohistochemistry. GH-induced STAT5 phosphorylation is low at one-week and maximal at 2.5-weeks of age when compared to young adults, accompanied by higher protein content at the onset of growth. Suppressor CIS and phosphatase PTP1B exhibit high levels in one-week animals, which gradually decline, while SOCS2 and SOCS3 display higher levels at adulthood. Nuclear phosphorylated STAT5 is low in one-week animals while in 2.5-week animals it is similar to 9-week control; expression of SOCS3, an early response GH-target gene, mimics this pattern. STAT5 coactivators glucocorticoid receptor (GR) and hepatic nuclear factor 1 (HNF1) abundance is higher in adulthood. Therefore, GH-induced STAT5 signaling presents age-dependent activity in liver, with its maximum coinciding with the onset of GH-dependent phase of growth, accompanied by an age-dependent variation of modulating factors. This work contributes to elucidate the molecular mechanisms implicated in GH responsiveness during growth.

  6. Halloween genes encode P450 enzymes that mediate steroid hormone biosynthesis in Drosophila melanogaster.

    PubMed

    Gilbert, Lawrence I

    2004-02-27

    Mutation of members of the Halloween gene family results in embryonic lethality. We have shown that two of these genes code for enzymes responsible for specific steps in the synthesis of ecdysone, a polyhydroxylated sterol that is the precursor of the major molting hormone of all arthropods, 20-hydroxyecdysone. These two mitochondrial P450 enzymes, coded for by disembodied (dib) (CYP302A1) and shadow (sad) (CYP315A1), are the C22 and C2 hydroxylases, respectively, as shown by transfection of the gene into S2 cells and subsequent biochemical analysis. These are the last two enzymes in the ecdysone biosynthetic pathway. A third enzyme, necessary for the critical conversion of ecdysone to 20-hydroxyecdysone, the 20-monooxygenase, is encoded by shade (shd) (CYP314A1). All three enzymes are mitochondrial although shade has motifs suggesting both mitochondrial and microsomal locations. By tagging these enzymes, their subcellular location has been confirmed by confocal microscopy. Shade is present in several tissues as expected while disembodied and shadow are restricted to the ring gland. The paradigm used should allow us to define the enzymes mediating the entire ecdysteroid biosynthetic pathway. PMID:15026169

  7. Behavioral Deficits in Juveniles Mediated by Maternal Stress Hormones in Mice

    PubMed Central

    Maguire, Jamie; Mody, Istvan

    2016-01-01

    Maternal depression has been shown to negatively impact offspring development. Investigation into the impact of maternal depression and offspring behavior has relied on correlative studies in humans. Further investigation into the underlying mechanisms has been hindered by the lack of useful animal models. We previously characterized a mouse model which exhibits depression-like behaviors restricted to the postpartum period and abnormal/fragmented maternal care (Gabrd−/− mice). Here we utilized this unique mouse model to investigate the mechanism(s) through which maternal depression-like behaviors adversely impact offspring development. Cross-fostering experiments reveal increased anxiety-like and depression-like behaviors in mice reared by Gabrd−/− mothers. Wild type and Gabrd−/− mice subjected to unpredictable stress during late pregnancy exhibit decreased pup survival and depression-like behavior in the postpartum period. Exogenous corticosterone treatment in wild type mice during late pregnancy is sufficient to decrease pup survival and induce anxiety-like and depression-like behaviors in the offspring. Further, the abnormal behaviors in juvenile mice reared by Gabrd−/− mice are alleviated by treatment of the mothers with the corticotropin-releasing hormone (CRH) antagonist, Antalarmin. These studies suggest that hyperresponsiveness of the HPA axis is associated with postpartum depression and may mediate the adverse effects of maternal depression on offspring behavior. PMID:26819762

  8. Halloween genes encode P450 enzymes that mediate steroid hormone biosynthesis in Drosophila melanogaster.

    PubMed

    Gilbert, Lawrence I

    2004-02-27

    Mutation of members of the Halloween gene family results in embryonic lethality. We have shown that two of these genes code for enzymes responsible for specific steps in the synthesis of ecdysone, a polyhydroxylated sterol that is the precursor of the major molting hormone of all arthropods, 20-hydroxyecdysone. These two mitochondrial P450 enzymes, coded for by disembodied (dib) (CYP302A1) and shadow (sad) (CYP315A1), are the C22 and C2 hydroxylases, respectively, as shown by transfection of the gene into S2 cells and subsequent biochemical analysis. These are the last two enzymes in the ecdysone biosynthetic pathway. A third enzyme, necessary for the critical conversion of ecdysone to 20-hydroxyecdysone, the 20-monooxygenase, is encoded by shade (shd) (CYP314A1). All three enzymes are mitochondrial although shade has motifs suggesting both mitochondrial and microsomal locations. By tagging these enzymes, their subcellular location has been confirmed by confocal microscopy. Shade is present in several tissues as expected while disembodied and shadow are restricted to the ring gland. The paradigm used should allow us to define the enzymes mediating the entire ecdysteroid biosynthetic pathway.

  9. Effects of a 2X gravity environment on the ultrastructure of the gerbil parathyroid gland

    NASA Technical Reports Server (NTRS)

    Sannes, P. L.; Hayes, T. G.

    1975-01-01

    A number of studies concerning the effects of hypergravity on bone have shown increases in bone mass or bone dimensions. Correlative studies, which could provide clues to the mechanism for such a response, have been lacking. The purpose of the present study was to evaluate the ultrastructure of parathyroid glands of Mongolian gerbils exposed to a continuous 2 X gravity force for 60 d. It was found that the experimental animals had parathyroid glands which had a greater percentage of chief cells in the active stage of their secretory cycle when compared with control animals. This result was interpreted to indicate an increase in parathyroid gland secretory activity and, hence, an increase in parathyroid hormone release. It was suggested that increased parathyroid secretory activity was necessary to maintain serum calcium levels of hypergravity animals within normal limits. Cellular forms resembling water clear cells and highly compact, degenerating cells were described in experimental animals but not in controls. Areas suggestive of cellular dissolution and disorganization were also reported in experimental parathyroids.

  10. Hormonal adaptation to real and simulated microgravity.

    PubMed

    Strollo, F; Strollo, G; More, M; Bollanti, L; Ciarmatori, A; Longo, E; Quintiliani, R; Mambro, A; Mangrossa, N; Ferretti, C

    1998-07-01

    The authors provide an overview of relevant results from endocrine studies in astronauts before, during, and after space flight. The hormonal systems examined are the water-electrolyte regulation, the hypothalamic-pituitary-adrenal axis, the hypothalamic-pituitary gonadal axis, the growth hormone-insulin like growth factor 1-prolactin system, hormones which affect bone turnover, the hypothalamic-pituitary-thyroid axis, and the endocrine pancreas. Hormones studied include renin, aldosterone, vasopressin, atrial natriuretic factor, cortisol, testosterone, lutenizing hormone, prolactin, growth hormone, insulin-like growth factor-1, insulin, glucose, T4, thyroid stimulating hormone, calcitonin, active D3, and parathyroid hormone.

  11. dLKR/SDH regulates hormone-mediated histone arginine methylation and transcription of cell death genes.

    PubMed

    Cakouros, Dimitrios; Mills, Kathryn; Denton, Donna; Paterson, Alicia; Daish, Tasman; Kumar, Sharad

    2008-08-11

    The sequential modifications of histones form the basis of the histone code that translates into either gene activation or repression. Nuclear receptors recruit a cohort of histone-modifying enzymes in response to ligand binding and regulate proliferation, differentiation, and cell death. In Drosophila melanogaster, the steroid hormone ecdysone binds its heterodimeric receptor ecdysone receptor/ultraspiracle to spatiotemporally regulate the transcription of several genes. In this study, we identify a novel cofactor, Drosophila lysine ketoglutarate reductase (dLKR)/saccharopine dehydrogenase (SDH), that is involved in ecdysone-mediated transcription. dLKR/SDH binds histones H3 and H4 and suppresses ecdysone-mediated transcription of cell death genes by inhibiting histone H3R17me2 mediated by the Drosophila arginine methyl transferase CARMER. Our data suggest that the dynamic recruitment of dLKR/SDH to ecdysone-regulated gene promoters controls the timing of hormone-induced gene expression. In the absence of dLKR/SDH, histone methylation occurs prematurely, resulting in enhanced gene activation. Consistent with these observations, the loss of dLKR/SDH in Drosophila enhances hormone-regulated gene expression, affecting the developmental timing of gene activation. PMID:18695041

  12. Constitutive activation of gene expression by thyroid hormone receptor results from reversal of p53-mediated repression.

    PubMed Central

    Qi, J S; Desai-Yajnik, V; Yuan, Y; Samuels, H H

    1997-01-01

    Thyroid hormone receptor (T3R) is a member of the steroid hormone receptor gene family of nuclear hormone receptors. In most cells T3R activates gene expression only in the presence of its ligand, L-triiodothyronine (T3). However, in certain cell types (e.g., GH4C1 cells) expression of T3R leads to hormone-independent constitutive activation. This activation by unliganded T3R occurs with a variety of gene promoters and appears to be independent of the binding of T3R to specific thyroid hormone response elements (TREs). Previous studies indicate that this constitutive activation results from the titration of an inhibitor of transcription. Since the tumor suppresser p53 is capable of repressing a wide variety of gene promoters, we considered the possibility that the inhibitor is p53. Evidence to support this comes from studies indicating that expression of p53 blocks T3R-mediated constitutive activation in GH4C1 cells. In contrast with hormone-independent activation by T3R, p53 had little or no effect on T3-dependent stimulation which requires TREs. In addition, p53 mutants which oligomerize with wild-type p53 and interfere with its function also increase promoter activity. This enhancement is of similar magnitude to but is not additive with the stimulation mediated by unliganded T3R, suggesting that they target the same factor. Since p53 mutants are known to target wild-type p53 in the cell, this suggests that T3R also interacts with p53 in vivo and that endogenous levels of p53 act to suppress promoter activity. Evidence supporting both functional and physical interactions of T3R and p53 in the cell is presented. The DNA binding domain (DBD) of T3R is important in mediating constitutive activation, and the receptor DBD appears to functionally interact with the N terminus of p53 in the cell. In vitro binding studies indicate that the T3R DBD is important for interaction of T3R with p53 and that this interaction is reduced by T3. These findings are consistent with

  13. Parathyroid ultrasonography and bone metabolic profile of patients on dialysis with hyperparathyroidism

    PubMed Central

    Ribeiro, Cláudia; Penido, Maria Goretti Moreira Guimarães; Guimarães, Milena Maria Moreira; Tavares, Marcelo de Sousa; Souza, Bruno das Neves; Leite, Anderson Ferreira; de Deus, Leonardo Martins Caldeira; Machado, Lucas José de Campos

    2016-01-01

    AIM To evaluate the parathyroid ultrasonography and define parameters that can predict poor response to treatment in patients with secondary hyperparathyroidism due to renal failure. METHODS This cohort study evaluated 85 patients with chronic kidney disease stage V with parathyroid hormone levels above 800 pg/mL. All patients underwent ultrasonography of the parathyroids and the following parameters were analyzed: Demographic characteristics (etiology of chronic kidney disease, gender, age, dialysis vintage, vascular access, use of vitamin D), laboratory (calcium, phosphorus, parathyroid hormone, alkaline phosphatase, bone alkaline phosphatase), and the occurrence of bone changes, cardiovascular events and death. The χ2 test were used to compare proportions or the Fisher exact test for small sample frequencies. Student t-test was used to detect differences between the two groups regarding continuous variables. RESULTS Fifty-three patients (66.4%) had parathyroid nodules with higher levels of parathyroid hormone, calcium and phosphorus. Sixteen patients underwent parathyroidectomy and ha