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Sample records for parathyroid hormone vitamin

  1. 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.

  2. 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.

  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. Premenstrual Symptoms in Dysmenorrheic College Students: Prevalence and Relation to Vitamin D and Parathyroid Hormone Levels

    PubMed Central

    Obeidat, Bayan A.; Alchalabi, Haifa A.; Abdul-Razzak, Khalid K.; Al-Farras, Mudhaffar I.

    2012-01-01

    Objectives: To determine the prevalence of premenstrual symptoms (PMS) due to primary dysmenorrhea among a sample of university female students, and to explore possible association with vitamin D and parathyroid (PTH) levels, as well as frequency of consumption of dairy products. Design: A cross-sectional study. Setting: One Jordanian university. Subjects: A total of 177 female students aged between 18 and 24 years who experienced primary dysmenorrhea participated in the study and completed a self administered questionnaire to collect information concerning demographics, menstruation- related information, associated specified premenstrual symptoms, and consumption of dairy products. Plasma 25-hydroxyvitamin vitamin D level and intact parathyroid hormone level were measured. Results: Of the 177 participants 91.5% had two or more symptoms among which fatigue, mood swings, anxiety, abdominal bloating, and depression were the most prevalent symptoms. There was no evident association between presence of symptoms and vitamin D status, PTH level or dairy products consumption. Headaches and social withdrawal were significantly lower in those women who consumed high amounts of dairy products. Conclusion: Premenstrual symptoms are very common in young women with primary dysmenorrhea. PMS has no relation to levels of vitamin D, parathyroid hormone or dairy products consumption. Headache and social withdrawal may be affected by dairy product consumption. PMID:23202842

  5. 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.

  6. 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

  7. [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. PMID:25582993

  8. Vitamin D3 differentially regulates parathyroid hormone/parathyroid hormone-related peptide receptor expression in bone and cartilage

    PubMed Central

    Amizuka, Norio; Kwan, Mei Yee; Goltzman, David; Ozawa, Hidehiro; White, John H.

    1999-01-01

    Transcription of the mouse parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptor (PTHR) gene is controlled by promoters P1 and P2. We performed transcript-specific in situ hybridization and found that P2 is the predominant promoter controlling PTHR gene expression in bone and cartilage. Treatment with 1?,25-dihydroxyvitamin D3 (D3) in vivo specifically downregulated P2-specific transcripts in osteoblasts, but not in chondrocytes, under conditions where it enhanced bone resorption. Treatment of the osteoblastic cell line MC3T3-E1 with D3 in vitro reduced expression of both P2-specific transcripts and PTHR protein. This effect was not blocked by cycloheximide, indicating that D3 inhibits PTHR expression by downregulating transcription of the P2 promoter. A similar inhibitory effect of D3 was not observed in the chondrocytic cell line CFK2. Gene-transfer experiments showed that P2, but not P1, is active in both MC3T3-E1 and CFK2 cells, and that D3 specifically inhibited P2 promoter activity in MC3T3-E1, but not in CFK2 cells. Inhibition of P2 activity by D3 required promoter sequences lying more that 1.6 kb upstream of the P2 transcription start site. Thus, the P2 promoter controls PTHR gene expression in both osteoblasts and chondrocytes. D3 downregulates PTHR gene transcription in a cell-specific manner by inhibiting P2 promoter activity in osteoblasts, but not in chondrocytes. PMID:9927498

  9. 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

  10. Temporal Relationship between Vitamin D Status and Parathyroid Hormone in the United States

    PubMed Central

    Kroll, Martin H.; Bi, Caixia; Garber, Carl C.; Kaufman, Harvey W.; Liu, Dungang; Caston-Balderrama, Anne; Zhang, Ke; Clarke, Nigel; Xie, Minge; Reitz, Richard E.; Suffin, Stephen C.; Holick, Michael F.

    2015-01-01

    Background Interpretation of parathyroid hormone (iPTH) requires knowledge of vitamin D status that is influenced by season. Objective Characterize the temporal relationship between 25-hydroxyvitamin D3 levels [25(OH)D3] and intact iPTH for several seasons, by gender and latitude in the U.S. and relate 25-hydrovitamin D2 [25(OH)D2] levels with PTH levels and total 25(OH)D levels. Method We retrospectively determined population weekly-mean concentrations of unpaired [25(OH)D2 and 25(OH)D3] and iPTH using 3.8 million laboratory results of adults. The 25(OH)D3 and iPTH distributions were normalized and the means fit with a sinusoidal function for both gender and latitudes: North >40, Central 32–40 and South <32 degrees. We analyzed PTH and total 25(OH)D separately in samples with detectable 25(OH)D2 (≥4 ng/mL). Findings Seasonal variation was observed for all genders and latitudes. 25(OH)D3 peaks occurred in September and troughs in March. iPTH levels showed an inverted pattern of peaks and troughs relative to 25(OH)D3, with a delay of 4 weeks. Vitamin D deficiency and insufficiency was common (33% <20 ng/mL; 60% <30 ng/mL) as was elevated iPTH levels (33%>65 pg/mL). The percentage of patients deficient in 25(OH)D3 seasonally varied from 21% to 48% and the percentage with elevated iPTH reciprocally varied from 28% to 38%. Patients with detectable 25(OH)D2 had higher PTH levels and 57% of the samples with a total 25(OH)D > 50 ng/mL had detectable 25(OH)D2. Interpretation 25(OH)D3 and iPTH levels vary in a sinusoidal pattern throughout the year, even in vitamin D2 treated patients; 25(OH)D3, being higher in the summer and lower in the winter months, with iPTH showing the reverse pattern. A large percentage of the tested population showed vitamin D deficiency and secondary hyperparathyroidism. These observations held across three latitudinal regions, both genders, multiple-years, and in the presence or absence of detectable 25(OH)D2, and thus are applicable for patient care. PMID:25738588

  11. 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...

  12. 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.

  13. 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...

  14. Calcium, Parathyroid Hormone, and Vitamin D: Major Determinants of Chronic Pain in Hemodialysis Patients

    PubMed Central

    Haggiag, Isabelle; Os, Pnina; Bernheim, Jacques

    2009-01-01

    Background and objectives: Pain is a frequent complaint of hemodialysis (HD) patients, yet information regarding its causes and frequency is relatively scarce. The aim of this study was to evaluate the frequency and possible causes of chronic pain in patients who are on long-term HD. Design, setting, participants, & measurements: We prospectively enrolled 100 patients who were undergoing maintenance HD for at least 3 mo. Pain was evaluated using the Brief Pain Inventory. Data collected on each participant included age, gender, ethnic origin, body mass index, smoking habits, time on dialysis, type of blood access, comorbidities, and biochemical and hematologic parameters. Results: The average age was 64.5 yr; the average time on dialysis 40.4 mo. Forty-five patients were male. Thirty-one participants were of Arabic origin. Fifty-three patients had diabetes, 36 of whom had diabetic retinopathy. Although 51 patients experienced chronic pain, only 19.6% described the pain as severe. Musculoskeletal pain, neuropathic pain, and headache were the most prevalent forms of pain. The presence of diabetic retinopathy and neuropathy (but not diabetes per se) and levels of intact parathyroid hormone, calcium, and calcitriol (but not 25-hydroxyvitamin D3) differed significantly between those who experienced chronic pain and those who did not. On a logistic regression model, higher serum calcium levels and intact parathyroid hormone levels >250 pg/ml were independently associated with chronic pain, as well as the presence of diabetic retinopathy. Calcitriol had a marginal effect. Conclusions: Disturbed mineral metabolism is strongly associated with chronic pain in long-term HD patients, along with microangiopathy. PMID:19578003

  15. 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 neurodegenerative conditions should be considered in the context of synergistic effects with calcium modulating hormones. PMID:25874538

  16. 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

  17. 1,25(OH)2-vitamin D3 reduces spontaneous and hypocalcemia-stimulated pulsatile component of parathyroid hormone secretion.

    PubMed

    Schmitt, C P; Schaefer, F; Huber, D; Zahn, I; Veldhuis, J D; Ritz, E; Mehls, O

    1998-01-01

    To investigate the effects of 1,25(OH)2-vitamin D3 (1,25(OH)2D3) on pulsatile parathyroid hormone (PTH) release, minute-to-minute intact PTH secretion was examined in nine healthy adults under baseline conditions and during hypocalcemia (sodium citrate clamp) before and after 5 d of oral 1,25(OH)2D3 treatment (1 microgram/d). In addition, acute effects of 1,25(OH)2D3 were examined by a single intravenous bolus of 2 micrograms of 1,25(OH)2D3. Pulsatile and tonic PTH secretion rates were calculated by the multiparameter deconvolution technique. During baseline, 68% of circulating PTH was attributable to tonic, and 32% to pulsatile, secretion. During induction of hypocalcemia, a selective increase in pulsatile secretion (+1100%), mediated by a combined increase in burst frequency and burst mass, was observed. During the subsequent steady-state hypocalcemic period, burst frequency and mass decreased and tonic secretion increased to 3 times the baseline level. Intravenous 1,25(OH)2D3 did not affect the temporal pattern of PTH secretion. In contrast, oral 1,25(OH)2D3 decreased baseline plasma PTH by 30% without a detectable change in Ca2+. This suppression was accounted for mainly by a decrease in PTH burst frequency. During hypocalcemia induction, a significantly lower (30%) increase in burst mass occurred compared with the pretreatment study. During steady-state hypocalcemia, PTH burst mass (-45%) and pulsatile (-50%) and total (-35%) secretion rate were lower than before treatment. In conclusion, acute hypocalcemia selectively increases pulsatile PTH release by stimulating both burst frequency and mass via a Ca2+ rate-sensitive mechanism. Oral 1,25-(OH)2D3 suppresses pulsatile baseline PTH release and reduces the pulsatile secretory capacity of the parathyroids during a hypocalcemic stimulus. PMID:9440087

  18. Arterial Structure and Function in Mild Primary Hyperparathyroidism Is Not Directly Related to Parathyroid Hormone, Calcium, or Vitamin D

    PubMed Central

    Ring, Margareta; Farahnak, Parastou; Gustavsson, Tomas; Nilsson, Inga-Lena; Eriksson, Maria J.; Caidahl, Kenneth

    2012-01-01

    Objective Elevated levels of calcium and parathyroid hormone (PTH), characteristics of primary hyperparathyroidism (PHPT), may be associated with cardiovascular morbidity and mortality in the general population. We evaluated the possible vascular effects of these risk factors in patients with mild PHPT by using standard methods and new imaging techniques. Design A prospective case-control study. Subjects and Methods Forty-eight patients with mild PHPT without any known cardiovascular risk factors were studied at baseline and at one year after parathyroidectomy (PTX) in comparison with 48 healthy age- and gender-matched controls. We measured biochemical variables, augmentation index (AIx), aortic pulse wave velocity (PWVao), radial (IMTrad) and common carotid artery (IMTcca) intima media thicknesses, and the grayscale median (IM-GSM) of the latter. Results No significant differences were observed between PHPT patients and controls at baseline for AIx (28.612.2 vs. 27.712.8%), IMTrad (0.2710.060 vs. 0.2550.053 mm), IMTcca (0.6880.113 vs. 0.6800.135 mm), or IM-GSM (82.317.2 vs. 86.515.3), while PWVao was slightly higher in patients (8.681.50 vs. 8.131.55, p<0.05). Systolic blood pressure (SBP), calcium, and PTH were higher in patients compared with controls, and decreased after PTX, while vitamin D was lower in patients and increased after PTX. While AIx, PWVao, IMTrad, and IMTcca were related to SBP, neither correlated to vitamin D levels. Only PWVao correlated weakly to plasma PTH (r?=?0.29, p<0.01) and ionized calcium (r?=?0.22, p<0.05) but showed no relation when age and SBP were adjusted for. Conclusion We found normal arterial function despite high calcium, PTH, and low vitamin D levels, in patients with mild PHPT without cardiovascular risk factors. The cardiovascular risk associated with low vitamin D and/or high PTH and calcium levels may be explained by their coupling to blood pressure and other risk factors rather than direct effects on arterial structure. PMID:22815708

  19. The Ratio of Parathyroid Hormone to Vitamin D Is a Determinant of Cardiovascular Risk and Insulin Sensitivity in Adolescent Girls

    PubMed Central

    Stanley, Takara; Bredella, Miriam A.; Pierce, Lisa

    2013-01-01

    Abstract Background Vitamin D insufficiency and higher testosterone are common in obese girls and may adversely affect glucose homeostasis and cardiovascular risk. Data are conflicting regarding the impact of parathyroid hormone (PTH) on these factors. Our objective was to determine associations of 25-hydroxyvitamin D (25-OHD), PTH, and testosterone with measures of glucose homeostasis and cardiovascular risk in adolescent girls after controlling for regional adiposity, with the hypothesis that lower 25-OHD, a higher PTH or PTH/25-OHD ratio, and higher testosterone would be associated with lower insulin sensitivity and greater cardiovascular risk. Methods A total of 15 obese girls and 15 matched normal weight controls (1218 years) underwent fasting measurements of 25-OHD, PTH, testosterone, sex hormone-binding globulin (SHBG), high-sensitivity C-reactive protein (hsCRP), oral glucose tolerance testing, and quantification of visceral (VAT) and subcutaneous (SAT) fat by magnetic resonance imaging (MRI). Results There were no associations of 25-OHD with measures of glucose homeostasis or hsCRP. In contrast, PTH and PTH/25-OHD were associated negatively with homeostasis model assessment of insulin resistance (HOMA-IR) and positively with quantitative insulin sensitivity check index (QUICKI) in obese girls but not controls. These associations remained significant after controlling for body mass index standard deviation score (BMI-SDS), but not for VAT. On regression modeling, PTH/25-OHD was positively associated with hsCRP after controlling for BMI-SDS or VAT. Free testosterone positively predicted the corrected insulin response. Conclusions In obese girls, PTH/25-OHD is positively associated with measures of insulin sensitivity and hsCRP. Further studies are needed to investigate the relationship between PTH and glucose homeostasis in obesity. PMID:23130887

  20. Vitamin D Status among Thai School Children and the Association with 1,25-Dihydroxyvitamin D and Parathyroid Hormone Levels

    PubMed Central

    Houghton, Lisa A.; Gray, Andrew R.; Harper, Michelle J.; Winichagoon, Pattanee; Pongcharoen, Tippawan; Gowachirapant, Sueppong; Gibson, Rosalind S.

    2014-01-01

    In several low latitude countries, vitamin D deficiency is emerging as a public health issue. Adequate vitamin D is essential for bone health in rapidly growing children. In the Thai population, little is known about serum 25-hydroxyvitamin D [25(OH)D] status of infants and children. Moreover, the association between 25(OH)D and the biological active form of 1,25-dihydroxyvitamin D [1,25(OH)]2D is not clear. The specific aims of this study were to characterize circulating serum 25(OH)D, 1,25(OH)2D and their determinants including parathyroid hormone (PTH), age, sex, height and body mass index (BMI) in 529 school-aged Thai children aged 6–14 y. Adjusted linear regression analysis was performed to examine the impact of age and BMI, and its interaction with sex, on serum 25(OH)D concentrations and 1,25(OH)2D concentrations. Serum 25(OH)D, 1,25(OH)2D and PTH concentrations (geometric mean ± geometric SD) were 72.7±1.2 nmol/L, 199.1±1.3 pmol/L and 35.0±1.5 ng/L, respectively. Only 4% (21 of 529) participants had a serum 25(OH)D level below 50 nmol/L. There was statistically significant evidence for an interaction between sex and age with regard to 25(OH)D concentrations. Specifically, 25(OH)D concentrations were 19% higher in males. Moreover, females experienced a statistically significant 4% decline in serum 25(OH)D levels for each increasing year of age (P = 0.001); no decline was seen in male participants with increasing age (P = 0.93). When BMI, age, sex, height and serum 25(OH)D were individually regressed on 1,25(OH)2D, height and sex were associated with 1,25(OH)2D with females exhibiting statistically significantly higher serum 1,25(OH)2D levels compared with males (P<0.001). Serum 1,25(OH)2D among our sample of children exhibiting fairly sufficient vitamin D status were higher than previous reports suggesting an adaptive mechanism to maximize calcium absorption. PMID:25111832

  1. Relationships among vitamin D levels, parathyroid hormone, and calcium absorption in young adolescents

    Technology Transfer Automated Retrieval System (TEKTRAN)

    BACKGROUND: Evidence suggests that vitamin D status in adults, as assessed by serum 25-hydroxyvitamin D (25-OHD), is positively associated with calcium absorption fraction and inversely associated with serum PTH. Few comparable pediatric data exist. OBJECTIVES: The objective of this study was to ev...

  2. Role of 1,25-Dihydroxy Vitamin D3 and Parathyroid Hormone in Urinary Calcium Excretion in Calcium Stone Formers

    PubMed Central

    Kim, Won Tae; Kim, Yong-June; Yun, Seok Joong; Shin, Kyung-Sub; Choi, Young Deuk; Kim, Wun-Jae

    2014-01-01

    Purpose To find out the possible role of 1,25(OH)2 vitamin D3 [1,25(OH)2D3] and parathyroid hormone (PTH) as intrinsic factors in urinary calcium stone formers (SFs), we investigated their relationship with serum and urinary biochemical parameters. Materials and Methods A total of 326 calcium SFs (male: 204, female: 122) were enrolled and underwent outpatient metabolic evaluations including 1,25(OH)2D3 and PTH as well as serum and 24-hour urinary biochemical parameters. As control, 163 age- and sex-matched (2:1) individuals (non-SFs) who have never urinary stone episode were included. Results 1,25(OH)2D3 level was positively correlated with urinary calcium excretion (r=0.347, p<0.001). The hypercalciuric group and recurrent SFs had higher serum 1,25(OH)2D3 levels than the normocalciuric group (p<0.001) and first SFs (p=0.050). In the adjusted multiple linear regression analysis, serum 1,25(OH)2D3 level (β=0.259, p<0.001) and serum PTH level (β=-0.160, p<0.001) were significantly correlated with urinary calcium excretion. The patients in highest tertile of 1,25(OH)2D3 had a more than 3.1 fold risk of hypercalciuria than those in the lowest tertile (odds ratio=3.14, 95% confidence interval: 1.431-6.888, p=0.004). No correlation was observed between PTH and 1,25(OH)2D3 (R=0.005, p=0.929) in calcium SFs, while a negative correlation was found in controls (R=-0.269, p=0.001). Conclusion 1,25(OH)2D3 was closely correlated with urinary calcium excretion, and high 1,25(OH)2D3 levels were detected in the hypercalciuric group and in recurrent SFs. However, 1,25(OH)2D3 was not correlated with PTH in calcium SFs. These findings suggest that 1,25(OH)2D3 might be important intrinsic factor for altered calcium regulation in SFs. PMID:25048492

  3. 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.

  4. 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.

  5. Vitamin D-fortified milk achieves the targeted serum 25-hydroxyvitamin D concentration without affecting that of parathyroid hormone in New Zealand toddlers.

    PubMed

    Houghton, Lisa A; Gray, Andrew R; Szymlek-Gay, Ewa A; Heath, Anne-Louise M; Ferguson, Elaine L

    2011-10-01

    For young children, the level of vitamin D required to ensure that most achieve targeted serum 25-hydroxyvitamin D [25(OH)D] ≥50 nmol/L has not been studied. We aimed to investigate the effect of vitamin D-fortified milk on serum 25(OH)D and parathyroid hormone (PTH) concentrations and to examine the dose-response relationship between vitamin D intake from study milks and serum 25(OH)D concentrations in healthy toddlers aged 12-20 mo living in Dunedin, New Zealand (latitude 46°S). Data from a 20-wk, partially blinded, randomized trial that investigated the effect of providing red meat or fortified toddler milk on the iron, zinc, iodine, and vitamin D status in young New Zealand children (n = 181; mean age 17 mo) were used. Adherence to the intervention was assessed by 7-d weighed diaries at wk 2, 7, 11, 15, and 19. Serum 25(OH)D concentration was measured at baseline and wk 20. Mean vitamin D intake provided by fortified milk was 3.7 μg/d (range, 0-10.4 μg/d). After 20 wk, serum 25(OH)D concentrations but not PTH were significantly different in the milk groups. The prevalence of having a serum 25(OH)D <50 nmol/L remained relatively unchanged at 43% in the meat group, whereas it significantly decreased to between 11 and 15% in those consuming fortified study milk. In New Zealand, vitamin D intake in young children is minimal. Our findings indicate that habitual consumption of vitamin D-fortified milk providing a mean intake of nearly 4 μg/d was effective in achieving adequate year-round serum 25(OH)D for most children. PMID:21832027

  6. [Comparative study of parathyroid function by serum parathyroid hormone, total adenosine cyclic monophosphate in the urine and its nephrogenic fraction].

    PubMed

    Ivanov, I; Milkov, V

    1988-01-01

    The immune heterogeneity of the parathyroid hormone and the possibility of its peripheral activation by 1.25 (OH)2 vitamin D3 hinders the precise evaluation of the functional state of parathyroid glands by direct determination of the hormone in the serum and also the creation of a suppressive test similar to the suppressive tests applied in the study of other hormones. A study was carried out which proves that the indirect examination of the parathyroid function by determining the cyclic adenosine monophosphate in urine and its nephrogenic fraction (i.e. by the effects of the active parathyroid hormone) is of greater importance for clinical practice than the direct determination of the parathyroid hormone in peripheral blood. This is the method of choice in the diagnosis of the subclinical variant of primary normocalcemic hyperparathyroidism. PMID:2850656

  7. 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 ?-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'. PMID:25446885

  8. 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....

  9. 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....

  10. 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....

  11. 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....

  12. 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....

  13. 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

  14. Immunocytochemical localization of parathyroid hormone in bovine parathyroid glands and human parathyroid adenomas.

    PubMed Central

    Futrell, J. M.; Roth, S. I.; Su, S. P.; Habener, J. F.; Segre, G. V.; Potts, J. T.

    1979-01-01

    Light and electron microscopic localization of parathyroid hormone (PTH) in human and bovine parathyroid tissue has been achieved using an indirect peroxidase labeled antibody method. Granular deposition of the reaction product was found throughout the chief cell cytoplasm. There was no nuclear staining. At the ultrastructural level, parathyroid hormone localized by this method appeared to be largely confined to the secretory granules in the cytoplasm of cells. Mitochondria and nuclei were free of reaction product. Aggregated sacs of granular endoplasmic reticulum were minimally reactive, and Golgi apparatuses did not show reaction product. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 PMID:371413

  15. Xeno-Klotho Inhibits Parathyroid Hormone Signaling.

    PubMed

    Takenaka, Tsuneo; Inoue, Tsutomu; Miyazaki, Takashi; Hayashi, Matsuhiko; Suzuki, Hiromichi

    2016-02-01

    Although fibroblast growth factor (FGF) 23 was recently identified as a phosphatonin that influences vitamin D metabolism, the underlying signaling mechanisms remain unclear. FGF23 elevates the renal levels of membrane-associated klotho as well as soluble klotho. Klotho is expressed on distal tubules. Upon enzymatic cleavage, soluble klotho is released into the renal interstitial space and then into the systemic circulation. The expression of 25-hydroxyvitamin D3 1α-hydroxylase (1-OH) on proximal tubular cells is controlled by parathyroid hormone (PTH). Klotho binds to various membrane proteins to alter their function. Here, the interaction between the PTH receptor and klotho was studied using various approaches, including immunoprecipitation, in vitro cell culture, and in vivo animal experiments. Immunoprecipitation studies demonstrate, for the first time, that recombinant human klotho protein interacts with human PTH receptors to inhibit the binding of human PTH. Furthermore, when applied to human proximal tubular cells, recombinant human klotho suppresses PTH-stimulated generation of inositol trisphosphate in vitro. Moreover, PTH-induced increase of cyclic AMP secretion and 1α,25-dihydroxyvitamin D3 (1,25VD) was attenuated by recombinant human klotho in vivo. In addition, recombinant human klotho inhibits the expression of 1-OH by PTH both in vitro and in vivo. These results suggest that free klotho mediates the FGF23-induced inhibition of 1,25VD synthesis. © 2015 American Society for Bone and Mineral Research. PMID:26287968

  16. Parathyroid hormone (PTH) blood test

    MedlinePlus

    ... side of the thyroid gland. PTH controls calcium, phosphorus, and vitamin D levels in the blood. It ... You have a high calcium level or low phosphorus level in your blood. You have severe osteoporosis ...

  17. 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

  18. 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

  19. 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.

  20. Parathyroid hormone action in calcium transport in the distal nephron.

    PubMed

    Lau, K; Bourdeau, J E

    1995-01-01

    Urinary calcium excretion is regulated homeostatically. Regulation is achieved, in part, by the action of parathyroid hormone on Ca2+ absorption in the distal nephron. Parathyroid hormone increases Ca2+ absorption in the cortical portion of the thick ascending limb of Henle's loop in all species studied, in the murine distal convoluted tubule, and in the rabbit connecting tubule. All of these sites contain parathyroid hormone-stimulated adenylate cyclase. Both cellular and paracellular pathways of Ca2+ absorption are regulated by parathyroid hormone in the cortical portion of the thick ascending limb of Henle's loop. In both distal convoluted and connecting tubule cells, parathyroid hormone regulates transcellular Ca2+ absorption by controlling the insertion and open probability of luminal plasmalemmal Ca2+ ion channels. These channels are stimulated and inhibited by L-type calcium channel agonists and antagonists, respectively, but differ from similar channels in excitable cells in that membrane depolarization does not activate them. Parathyroid hormone also increases the driving force for diffusional Ca2+ ion entry from the luminal fluid into the cytosol by increasing the intracellular negative electrical potential (at least in murine distal convoluted tubule cells) by increasing the chloride ion conductance of the basolateral cell membrane. The effects of parathyroid hormone on the other components of cellular Ca2+ transport, via both protein kinases A and C and their interactions, remain to be examined. PMID:7743158

  1. Parathyroid hormone and parathyroid hormone type-1 receptor accelerate myocyte differentiation

    PubMed Central

    Kimura, Shigemi; Yoshioka, Kowasi

    2014-01-01

    The ZHTc6-MyoD embryonic stem cell line expresses the myogenic transcriptional factor MyoD under the control of a tetracycline-inducible promoter. Following induction, most of the ZHTc6-MyoD cells differentiate to myotubes. However, a small fraction does not differentiate, instead forming colonies that retain the potential for myocyte differentiation. In our current study, we found that parathyroid hormone type 1 receptor (PTH1R) expression in colony-forming cells at 13 days after differentiation was higher than that in the undifferentiated ZHTc6-MyoD cells. We also found that PTH1R expression was required for myocyte differentiation, and that parathyroid hormone accelerated the differentiation. Our analysis of human and mouse skeletal muscle tissues showed that most cells expressing PTH1R also expressed Pax7 and CD34, which are biomarkers of satellite cells. Furthermore, we found that parathyroid hormone treatment significantly improved muscle weakness in dystrophin-deficient mdx mice. This is the first report indicating that PTH1R and PTH accelerate myocyte differentiation. PMID:24919035

  2. 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.

  3. Parathyroid Carcinoma: Current Understanding and New Insights into Gene Expression and Intraoperative Parathyroid Hormone Kinetics

    PubMed Central

    Abdelgadir Adam, Mohamed; Untch, Brian R.

    2010-01-01

    Parathyroid carcinoma is an indolent but ultimately life-threatening malignancy. Due to the lack of definitive diagnostic markers and overlapping clinical features of benign primary hyperparathyroidism (PHPT), this disease is often misdiagnosed as parathyroid adenoma. Therefore, a high index of suspicion preoperatively and early intraoperative recognition with en bloc surgical resection are crucial for favorable outcome. Owing to the rarity of the disease, little is known about the molecular pathogenesis of parathyroid carcinoma. Here, we review the literature to present current understanding of the disease and provide new information on gene expression and use of intraoperative parathyroid hormone (PTH) monitoring in the surgical management of this rare malignancy. Specifically, using microarray transcriptome analysis of an unequivocal case of parathyroid carcinoma and a biopsy from the same patient's normal parathyroid gland, we identify APP, CDH1, KCNJ16, and UCHL1 as differentially expressed genes in parathyroid carcinoma. Further, using case records from four cases of unequivocal parathyroid carcinoma, we compared intraoperative PTH kinetics of these patients to 475 patients with benign PHPT, and show that intraoperative PTH monitoring is accurate in predicting postoperative normocalcemia in initial en bloc operations for parathyroid carcinoma. PMID:20051478

  4. Therapy of Hypoparathyroidism by Replacement with Parathyroid Hormone

    PubMed Central

    2014-01-01

    Hypoparathyroidism (HypoPT) is a state of hypocalcemia due to inappropriate low levels of parathyroid hormone (PTH). HypoPT is normally treated by calcium supplements and activated vitamin D analogues. Although plasma calcium is normalized in response to conventional therapy, quality of life (QoL) seems impaired and patients are at increased risk of renal complications. A number of studies have suggested subcutaneous injections with PTH as an alternative therapy. By replacement with the missing hormone, urinary calcium may be lowered and QoL may improve. PTH replacement therapy (PTH-RT) possesses, nevertheless, a number of challenges. If PTH is injected only once a day, fluctuations in calcium levels may occur resulting in hypercalcemia in the hours following an injection. Twice-a-day injections seem to cause less fluctuation in plasma calcium but do stimulate bone turnover to above normal. Most recently, continuous delivery of PTH by pump has appeared as a feasible alternative to injections. Plasma calcium levels do not fluctuate, urinary calcium is lowered, and bone turnover is only stimulated modestly (into the normal range). Further studies are needed to assess the long-term effects. If beneficial, it seems likely that standard treatment of HypoPT in the future will change into replacement therapy with the missing hormone. PMID:25101193

  5. Parathyroid-hormone-related protein in sarcoidosis.

    PubMed Central

    Zeimer, H. J.; Greenaway, T. M.; Slavin, J.; Hards, D. K.; Zhou, H.; Doery, J. C.; Hunter, A. N.; Duffield, A.; Martin, T. J.; Grill, V.

    1998-01-01

    Parathyroid-hormone-related protein (PTHrP) is the main mediator of the humoral hypercalcemia of malignancy. It is also detected in many normal adult and fetal tissues. Altered calcium metabolism occurs in sarcoidosis, and two cases of sarcoidosis with hypercalcemia and elevated plasma PTHrP are described. An archival study of 20 lymph node biopsies with the pathological diagnosis of sarcoidosis was performed. Immunohistochemistry using a polyclonal antiserum to human PTHrP and in situ hybridization using a riboprobe to human PTHrP were performed on the lymph node biopsies. Immunohistochemistry for PTHrP was also performed on the biopsies from the two cases with elevated plasma levels. Immunohistochemical analysis detected PTHrP in macrophages within granulomata in 17 of the 20 (85%) biopsies. In situ hybridization detected a positive signal for messenger RNA in the granulomata of 11 of 19 (58%) biopsies. PTHrP immunoreactivity and PTHrP gene expression are present in sarcoid granulomata. PTHrP may contribute to the hypercalcemia of sarcoidosis. Images Figure 1 PMID:9422518

  6. Parathyroid Hormone Applications in the Craniofacial Skeleton

    PubMed Central

    Chan, H.L.; McCauley, L.K.

    2013-01-01

    Parathyroid hormone (PTH) is known for its ability to ‘build’ bone, with research in this area centered on its use as an osteoporosis therapeutic. Recent interest has developed regarding its potential for regenerative applications such as fracture healing and osseous defects of the oral cavity. Many years of investigation using murine gene-targeted models substantiate a role for signaling at the PTH/PTH-related protein (PTHrP) receptor (PPR) in intramembranous bone formation in the craniofacial region as well as in tooth development. Pre-clinical studies clearly support a positive role of intermittent PTH administration in craniofacial bones and in fracture healing and implant integration. A few human clinical studies have shown favorable responses with teriparatide (the biologically active fragment of PTH) administration. Favorable outcomes have emerged with teriparatide administration in patients with osteonecrosis of the jaw (ONJ). New delivery strategies are in development to optimize targeted application of PTH and to help maximize local approaches. The promising host-modulating potential of PTH requires more information to further its effectiveness for craniofacial regeneration and osseous wound-healing, including a better delineation of cellular targets, temporal effects of PTH action, and improved approaches for local/targeted delivery of PTH. PMID:23071071

  7. 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.

  8. 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.

  9. Parathyroid hormone in sodium-dependent hypertension

    SciTech Connect

    Doris, P.A.; Harvey, S.; Pang, P.K.T.

    1987-09-14

    Plasma parathyroid hormone (pPTH) levels have been assessed in three separate radioimmunoassay systems in samples from Wistar-Kyoto rats. The animals were subjected to one of three dietary regimens throughout the study period: Group 1 animals consumed normal rat chow and drank tap water; Group 2 animals consumed normal rat chow and tap water was replaced with 0.05% saline solution; Group 3 animals consumed normal rat chow to which 2.5% CaCO/sub 3/ had been added and also drank 0.5% saline solution. Three assay systems were used to measure pPTH levels from trunk blood samples obtained by guillotine decapitation. One assay used an antiserum directed toward the vasoactive N terminal fragment 1-34 and produced pPTH measurements of 0.74 +/- 0.05 ng/ml in Gp 1 animals, 1.04 +/- 0.07 ng/ml in Gp 2 animals and 1.12 +/- 0.08 ng/ml in Gp 3 animals. This pattern was consistent with that obtained by another antiserum which had been raised against the intact 1-84 PTH molecule and produced values of 0.25 +/- 0.03 ng/ml in Gp 1 animals, 0.55 +/- 0.07 ng/ml in Gp 2 animals and 0.74 +/- 0.04 ng/ml in Gp 3 animals. Antiserum raised against the C-terminal did not show any difference in pPTH across groups. The authors conclude that saline consumption may increase some portions of circulating PTH. 26 references, 2 tables.

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

    PubMed

    Metz, S A; Baylink, D J; Hughes, M R; Haussler, M R; Robertson, R P

    1977-11-17

    To investigate the role of vitamin D metabolites in the pathogenesis of pseudohypoparathyroidism, we studied an elderly man with a unique variant of the disease, which was characterized by hypocalcemia, elevated serum parathyroid hormone (513 +/- 13 pg per milliliter, mean +/- S.E.M., normal, less than 450) but normal renal responses (phosphate and cyclic AMP) to exogenous parathyroid extract. Treatment with parathyroid extract did not produce a calcemic effect, suggesting an isolated skeletal hyporesponsiveness to parathyroid hormone. Although 25-hydroxyvitamin D levels were not reduced, levels of 1,25-dihydroxycholecalciferol were extremely low (0.52 ng per deciliter; normal 3.3 +/- 0.06, S.D.). Treatment with 1,25-dihydroxycholecalciferol (1 microgram by mouth per day for four days) increased circulating levels to normal (4.60 ng per deciliter) and restored to normal the calcemic response to parathyroid (change in calcium 3.0 mg per deciliter). These data suggest that 1,25-dihydroxycholecalciferol deficiency may explain the skeletal resistance, but not the renal resistance, often present in classic pseudohypoparathyroidism. PMID:198661

  11. Sarcoidosis-related hypercalcaemia due to production of parathyroid hormone-related peptide.

    PubMed

    van Raalte, Daniel H; Goorden, Susan M; Kemper, Evelien A; Brosens, Lodewijk A A; ten Kate, Reinier W

    2015-01-01

    Hypercalcaemia is frequently observed in patients with sarcoidosis. This is classically attributed to ectopic production of 1,25 dihydroxy vitamin D by sarcoid granulomas. We present a case of sarcoidosis-related hypercalcaemia with normal vitamin D levels. In this patient, production of parathyroid hormone-related peptide (PTHrp) was the cause for sarcoidosis-induced hypercalcaemia. As such, plasma PTHrp levels were increased and bone marrow granulomas stained positively for PTHrp expression. Medium-dose prednisolone treatment improved symptoms of sarcoidosis and normalised serum calcium, and PTHrp concentrations. Thus, production of PTHrp may be the cause for hypercalcaemia in some patients with sarcoidosis. PMID:26160550

  12. Human parathyroid hormone: amino-acid sequence of the amino-terminal residues 1-34.

    PubMed

    Brewer, H B; Fairwell, T; Ronan, R; Sizemore, G W; Arnaud, C D

    1972-12-01

    Human parathyroid hormone has been isolated in highly purified form from human parathyroid adenomas. The primary sequence of the amino-terminal 34 residues of the human hormone was obtained by automated degradation with a Beckman Sequencer. The phenylthiohydantoin amino acids were identified by gas chromatography and mass spectrometry. The first 34 residues of human parathyroid hormone differ from the bovine hormone by six residues, and from the porcine hormone by five residues. The amino-terminal residue is serine, similar to the porcine parathyroid hormone; bovine parathyroid hormone contains an amino-terminal alanine. Human parathyroid hormone contains two methionine residues, similar to the bovine species, whereas porcine parathyroid hormone contains a single methionine residue. Amino-acid residues in the first 34 that are unique to the human sequence include an asparagine at position 16, glutamine at position 22, lysine at position 28, and a leucine at position 30. PMID:4509319

  13. [Role of parathyroid hormone in Klotho-FGF23 system].

    PubMed

    Kimura, Takaaki; Shiizaki, Kazuhiro; Kuro-O, Makoto

    2016-06-01

    Klotho was originally identified as an anti-aging gene that accelerated aging when disrupted and extended life span when overexpressed in mice. The Klotho gene encodes a single-pass transmembrane protein and is expressed in the kidney and parathyroid gland. Klotho protein functions as an obligate subunit of the receptor for fibroblast growth factor 23(FGF23). FGF23 is a hormone secreted from osteocytes and osteoblasts and acts on renal tubular cells to promote phosphate excretion into the urine and suppress synthesis of active form of vitamin D(1,25-dihydroxyvitamin D3;1,25(OH)2D3). Decreased Klotho expression due to the kidney damage including CKD might increase the circulating level of FGF23 and trigger disturbed mineral-bone metabolism, leading to CKD-MBD. Characteristic features of CKD-MBD including hyperphosphatemia, hypocalcemia, and decreased serum 1,25(OH)2D3 can be explained by(mal)adaptation of the Klotho-FGF23 system, which also contributes to the pathophysiology of secondary hyperparathyroidism(SHPT). In addition to its function as a receptor for FGF23, the extracellular domain of Klotho is secreted by ectodomain shedding and functions as a humoral factor that regulates multiple ion channels and transporters. Thus, Klotho has emerged as a key regulator of mineral metabolism in health and disease. PMID:27230841

  14. Effect of phorbol myristate acetate on secretion of parathyroid hormone

    SciTech Connect

    Morrissey, J.J. )

    1988-01-01

    The influence of phorbol myristate acetate (PMA), an activator of protein kinase c, on the secretion of parathyroid hormone from collagenase-dispersed bovine parathyroid cells was tested. The cells were incubated at low or high concentrations of calcium in the medium, and the hormone secreted into the medium was measured by a radioimmunoassay that recognizes both intact and C-terminal fragments of hormone. A stimulatory effect of PMA at high calcium, seen at PMA concentrations as low as 1.6 nM, did not occur with a biologically inactive 4{alpha}-isomer of phorbol ester, and was independent of changes in cellular adenosine 3{prime},5{prime}-cyclic monophosphate levels. Examination of {sup 32}P-labeled phosphoproteins by two-dimensional gel electrophoresis revealed acidic proteins of {approximately}20,000 and 100,000 Da that were phosphorylated at low and high calcium + 1.6 {mu}M PMA but not at high calcium alone. The protein kinase c activity associated with the membrane fraction of parathyroid cells significantly decreased 40% when the cells were incubated at high vs. low calcium. The data suggest that calcium may regulate parathyroid hormone secretion through changes in protein kinase c activity of the membrane fraction of the cell and protein phosphorylation.

  15. Parathyroid Disorders

    MedlinePlus

    ... the neck. Though their names are similar, the thyroid and parathyroid glands are completely different. The parathyroid glands make parathyroid hormone (PTH), which helps your body keep the right balance of calcium and phosphorous. If your parathyroid glands make too ...

  16. 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 initiating therapy with sevelamer carbonate the iFGF23 levels seemed to increase while this response was mitigated in the group of patients given alphacalcidol followed by sevelamer carbonate. This may have therapeutic implications on choice of first line therapy. The number of patients is small and this conclusion is in part based on subgroup analysis. It is therefore important that these results are confirmed in larger studies. Trial registration Trial Registration Number: European Clinical Trial Database (EudraCT) 2010-020415-36 and Clinical Trials.gov NCT01231438 PMID:22742720

  17. Cellular changes following direct vitamin D injection into the uraemia-induced hyperplastic parathyroid gland

    PubMed Central

    Shiizaki, Kazuhiro; Hatamura, Ikuji; Negi, Shigeo; Nakazawa, Eiko; Tozawa, Ryoko; Izawa, Sayoko; Akizawa, Tadao; Kusano, Eiji

    2008-01-01

    Background. Hyperplasia of the parathyroid gland (PTG) is associated not only with excessive secretion of parathyroid hormone (PTH) but also with changes in the parathyroid cell (PTC) characteristics (i.e. hyperproliferative activity and low contents of vitamin D and calcium-sensing receptors). The control of PTG hyperplasia is most important in the management of secondary hyperparathyroidism (SHPT), because the advanced stage of hyperplasia is considered irreversible. For the better control of the PTH level in dialysis patients with such advanced SHPT, percutaneous vitamin D injection therapy (PDIT) under ultrasonographic guidance was developed and various cellular changes caused by this treatment were also investigated using an animal model. Methods. The PTGs of Sprague–Dawley rats, which had been 5/6-nephrectomized and fed a high-phosphate diet, were treated with the direct injections of vitamin D agents, and cellular effects focusing the above-mentioned characters were investigated. Results. An adequacy of the direct injection technique into the rats’ PTGs and the successful effects of this treatment in various biochemical parameters were confirmed. Such characteristics of advanced SHPT were simultaneously improved; in particular, it was confirmed that this treatment may be effective in controlling PTG hyperplasia by, at least in part, apoptosis-induced cell death. Conclusions. A locally high level of vitamin D strongly may suppress PTH secretion and regress hyperplasia, which is involved in the induction of apoptosis in PTCs, based on the simultaneous improvements of cellular characters of advanced SHPT. The PTH control introduced by this treatment successfully ameliorated osteitis fibrosa (high bone turnover rate). PMID:25983973

  18. Interspecies comparison of renal cortical receptors for parathyroid hormone and parathyroid hormone-related protein

    SciTech Connect

    Orloff, J.J.; Goumas, D.; Wu, T.L.; Stewart, A.F. )

    1991-03-01

    Parathyroid hormone (PTH) and PTH-related proteins (PTHrP) interact with a common receptor in rat bone cells and in canine renal membranes with similar affinity, but PTHrP are substantially less potent than PTH in stimulating adenylate cyclase in canine renal membranes; in contrast, PTH and PTHrP are equipotent in stimulating adenylate cyclase in rat bone cells. This discrepancy has been largely viewed as reflecting differences in the relative efficiency of signal transduction of PTHrP between bone and kidney assay systems. To test the alternative (but not mutually exclusive) hypothesis that these differences could reflect interspecies differences in PTH receptors, we have characterized the bioactivity of amino-terminal PTHrP and PTH in rat and human renal cortical membranes (RCM) and compared them to results we previously reported in canine RCM. The stability of PTH and PTHrP peptides under binding and adenylate cyclase assay conditions was greater than 80% for each species. Competitive inhibition of ({sup 125}I)(Tyr36)hPTHrP-(1-36)NH{sub 2} binding to rat RCM by bPTH-(1-34) and (Tyr36)hPTHrP-(1-36)NH{sub 2} yielded nearly identical binding dissociation constants (3.7 and 3.6 nM, respectively), and binding to human RCM demonstrated slightly greater potency for PTHrP (0.5 nM) than for PTH (0.9 nM). Similarly, adenylate cyclase stimulating activity was equivalent for the two peptides in rat RCM, but PTHrP was twofold more potent than PTH in human RCM. Covalent photoaffinity labeling of protease-protected rat RCM yielded an apparent 80 kD receptor protein, and cross-linking of human RCM labeled an 85 kD receptor, indistinguishable in size from the canine renal PTH receptor. We conclude that rat, canine, and human renal cortical PTH receptors exhibit species specificity.

  19. Parathyroid hormone induces adipocyte lipolysis via PKA-mediated phosphorylation of hormone-sensitive lipase.

    PubMed

    Larsson, Sara; Jones, Helena A; Göransson, Olga; Degerman, Eva; Holm, Cecilia

    2016-03-01

    Parathyroid hormone (PTH) is secreted from the parathyroid glands in response to low plasma calcium levels. Besides its classical actions on bone and kidney, PTH may have other important effects, including metabolic effects, as suggested for instance by increased prevalence of insulin resistance and type 2 diabetes in patients with primary hyperparathyroidism. Moreover, secondary hyperparathyroidism may contribute to the metabolic derangements that characterize states of vitamin D deficiency. PTH has been shown to induce adipose tissue lipolysis, but the details of the lipolytic action of PTH have not been described. Here we used primary mouse adipocytes to show that intact PTH (1-84) as well as the N-terminal fragment (1-37) acutely stimulated lipolysis in a dose-dependent manner, whereas the C-terminal fragment (38-84) was without lipolytic effect. The lipolytic action of PTH was paralleled by phosphorylation of known protein kinase A (PKA) substrates, i.e. hormone-sensitive lipase (HSL) and perilipin. The phosphorylation of HSL in response to PTH occurred at the known PKA sites S563 and S660, but not at the non-PKA site S565. PTH-induced lipolysis, as well as phosphorylation of HSL at S563 and S660, was blocked by both the PKA-inhibitor H89 and the adenylate cyclase inhibitor MDL-12330A, whereas inhibitors of extracellular-regulated kinase (ERK), protein kinase B (PKB), AMP-activated protein kinase (AMPK) and Ca(2+)/calmodulin-dependent protein kinase (CaMK) had little or no effect. Inhibition of phosphodiesterase 4 (PDE4) strongly potentiated the lipolytic action of PTH, whereas inhibition of PDE3 had no effect. Our results show that the lipolytic action of PTH is mediated by the PKA signaling pathway with no or minor contribution of other signaling pathways and, furthermore, that the lipolytic action of PTH is limited by simultaneous activation of PDE4. Knowledge of the signaling pathways involved in the lipolytic action of PTH is important for our understanding of how metabolic derangements develop in states of hyperparathyroidism, including vitamin D deficiency. PMID:26724218

  20. Co-secretion of parathyroid hormone and parathyroid-hormone-related protein via a regulated pathway in human parathyroid adenoma cells.

    PubMed Central

    Matsushita, H.; Usui, M.; Hara, M.; Shishiba, Y.; Nakazawa, H.; Honda, K.; Torigoe, K.; Kohno, K.; Kurimoto, M.

    1997-01-01

    Parathyroid-hormone-related protein (PTHrP) is widely expressed not only in malignant tumors but also in both epithelial and nonepithelial cells of normal tissues. Secreted PTHrP is suspected to act as a paracrine or autocrine regulator. However, little is known about its secretory pathway. To cast light on this question, we studied the intracytoplasmic distribution of parathyroid hormone (PTH) and PTHrP immunohistochemically and immunoelectron microscopically in 10 surgically resected parathyroid adenomas. Double immunostaining was performed using anti-PTH antibody and a newly established anti-PTHrP antibody to reveal the relationship between their two distributions. Additional examination by cell immunoblot assay was performed to determine whether both PTH and PTHrP are secreted simultaneously. Both PTH and PTHrP were actually secreted from individual parathyroid cells simultaneously on cell immunoblot assay. Immunohistochemically, there were two different types of adenoma cells, i.e., one positive only for PTH and the other positive for both PTH and PTHrP. PTH was distributed linearly or fine granularly along the cytoplasmic membrane, whereas PTHrP was distributed diffusely or coarse granularly in the cytoplasm. The intracytoplasmic distributions of PTH and PTHrP often overlapped. Immunoelectron microscopical examination demonstrated that PTHrP co-localized with PTH in the same secretory granules. The results clearly demonstrated that PTHrP can be co-secreted with PTH via a regulated pathway using secretory granules. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:9060824

  1. 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.

  2. 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

  3. Age-related increases in parathyroid hormone may be antecedent to both osteoporosis and dementia

    PubMed Central

    Braverman, Eric R; Chen, Thomas JH; Chen, Amanda LC; Arcuri, Vanessa; Kerner, Mallory M; Bajaj, Anish; Carbajal, Javier; Braverman, Dasha; Downs, B William; Blum, Kenneth

    2009-01-01

    Background Numerous studies have reported that age-induced increased parathyroid hormone plasma levels are associated with cognitive decline and dementia. Little is known about the correlation that may exist between neurological processing speed, cognition and bone density in cases of hyperparathyroidism. Thus, we decided to determine if parathyroid hormone levels correlate to processing speed and/or bone density. Methods The recruited subjects that met the inclusion criteria (n = 92, age-matched, age 18-90 years, mean = 58.85, SD = 15.47) were evaluated for plasma parathyroid hormone levels and these levels were statistically correlated with event-related P300 potentials. Groups were compared for age, bone density and P300 latency. One-tailed tests were used to ascertain the statistical significance of the correlations. The study groups were categorized and analyzed for differences of parathyroid hormone levels: parathyroid hormone levels <30 (n = 30, mean = 22.7 ± 5.6 SD) and PTH levels >30 (n = 62, mean = 62.4 ± 28.3 SD, p ≤ 02). Results Patients with parathyroid hormone levels <30 showed statistically significantly less P300 latency (P300 = 332.7 ± 4.8 SE) relative to those with parathyroid hormone levels >30, which demonstrated greater P300 latency (P300 = 345.7 ± 3.6 SE, p = .02). Participants with parathyroid hormone values <30 (n = 26) were found to have statistically significantly higher bone density (M = -1.25 ± .31 SE) than those with parathyroid hormone values >30 (n = 48, M = -1.85 ± .19 SE, p = .04). Conclusion Our findings of a statistically lower bone density and prolonged P300 in patients with high parathyroid hormone levels may suggest that increased parathyroid hormone levels coupled with prolonged P300 latency may become putative biological markers of both dementia and osteoporosis and warrant intensive investigation. PMID:19825157

  4. 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 fractions had turnover times in the plasma of a uremic patient more than 100 times greater than the active form, remained elevated even in the presence of post-parathyroidectomy hypoparathyroidism in this patient and were presumed to be biologically inactive. The ratio of biologically inactive fragments to the active form was greater in secondary hyperparathyroidism. The evidence presented favors a glandular origin for the fragments. Comparison of hormonal assays with the two antisera reveals a striking advantage in the preoperative diagnosis of primary hyperparathyroidism with antiserum 273 that is due to the enhanced sensitivity occasioned by its detection of a biologically inactive as well as the biologically active hormonal form. Images PMID:4719672

  5. Three-phase model harmonizes estimates of the maximal suppression of parathyroid hormone by 25-hydroxyvitamin D in persons 65 y of age and older

    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 two-phase regression approach used, ...

  6. 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...

  7. 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.

  8. The induction of C/EBP? contributes to vitamin D inhibition of ADAM17 expression and parathyroid hyperplasia in kidney disease

    PubMed Central

    Arcidiacono, Maria Vittoria; Yang, Jing; Fernandez, Elvira; Dusso, Adriana

    2015-01-01

    Background In secondary hyperparathyroidism (SHPT), enhanced parathyroid levels of transforming growth factor-? (TGF?) increase EGF receptor (EGFR) activation causing parathyroid hyperplasia, high parathyroid hormone (PTH) and also reductions in vitamin D receptor (VDR) that limit vitamin D suppression of SHPT. Since anti-EGFR therapy is not an option in human SHPT, we evaluated ADAM17 as a therapeutic target to suppress parathyroid hyperplasia because ADAM17 is required to release mature TGF?, the most potent EGFR-activating ligand. Methods Computer analysis of the ADAM17 promoter identified TGF? and C/EBP? as potential regulators of the ADAM17 gene. Their regulation of ADAM17 expression, TGF?/EGFR-driven growth and parathyroid gland (PTG) enlargement were assessed in promoterreporter assays in A431 cells and corroborated in rat and human SHPT, using erlotinib as anti-EGFR therapy to suppress TGF? signals, active vitamin D to induce C/EBP? or the combination. Results While TGF? induced ADAM17-promoter activity by 2.2-fold exacerbating TGF?/EGFR-driven growth, ectopic C/EBP? expression completely prevented this vicious synergy. Accordingly, in advanced human SHPT, parathyroid ADAM17 levels correlated directly with TGF? and inversely with C/EBP?. Furthermore, combined erlotinib + calcitriol treatment suppressed TGF?/EGFR-cell growth and PTG enlargement more potently than erlotinib in part through calcitriol induction of C/EBP? to inhibit ADAM17-promoter activity, mRNA and protein. Importantly, in rat SHPT, the correction of vitamin D deficiency effectively reversed the resistance to paricalcitol induction of C/EBP? to suppress ADAM17 expression and PTG enlargement, reducing PTH by 50%. Conclusion In SHPT, correction of vitamin D and calcitriol deficiency induces parathyroid C/EBP? to efficaciously attenuate the severe ADAM17/TGF? synergy, which drives PTG enlargement and high PTH. PMID:25294851

  9. 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

  10. Influence of parathyroid hormone on bone cell ultrastructure

    SciTech Connect

    Matthews, J.L.; Talmage, R.V.

    1981-05-01

    A study in rats demonstrated that morphologic changes in the bone osteocytes and osteoblasts are produced following parathyroid hormone (PTH) injection into thyroparathyroidectomized animals. It further showed that similar changes occur in normal rats as the result of extended fasting. The most significant morphologic alterations involved surface microvilli and blebs as determined by scanning electron microscopy. Transmission electron microscopy studies showed alterations in the cisternae of the rough endoplasmic reticulum. Additionally, cell shape varied markedly from the control cuboidal morphology. These morphologic changes occurred during peak periods of plasma calcium change and returned to control morphology as plasma calcium levels normalized. The study supports the concept that osteocytes and lining cells on the surface of bone play a role in maintenance of plasma calcium concentrations. (JMT)

  11. NHERF1 mutations and responsiveness of renal parathyroid hormone.

    PubMed

    Karim, Zoubida; Gérard, Bénédicte; Bakouh, Naziha; Alili, Rohia; Leroy, Christine; Beck, Laurent; Silve, Caroline; Planelles, Gabrielle; Urena-Torres, Pablo; Grandchamp, Bernard; Friedlander, Gérard; Prié, Dominique

    2008-09-11

    Impaired renal phosphate reabsorption, as measured by dividing the tubular maximal reabsorption of phosphate by the glomerular filtration rate (TmP/GFR), increases the risks of nephrolithiasis and bone demineralization. Data from animal models suggest that sodium-hydrogen exchanger regulatory factor 1 (NHERF1) controls renal phosphate transport. We sequenced the NHERF1 gene in 158 patients, 94 of whom had either nephrolithiasis or bone demineralization. We identified three distinct mutations in seven patients with a low TmP/GFR value. No patients with normal TmP/GFR values had mutations. The mutants expressed in cultured renal cells increased the generation of cyclic AMP (cAMP) by parathyroid hormone (PTH) and inhibited phosphate transport. These NHERF1 mutations suggest a previously unrecognized cause of renal phosphate loss in humans. PMID:18784102

  12. Responsiveness of mouse calvaria to parathyroid hormone after explant cryopreservation: 45Ca release in vitro

    SciTech Connect

    Wezeman, F.H.; Dungan, D.D.

    1986-08-01

    Newborn mouse calvaria prelabeled with /sup 45/Ca and cryopreserved at -196 degrees C in serum-free medium containing dimethylsulfoxide were compared to unpreserved explants for response to parathyroid hormone during subsequent culture. After short-term cryopreservation followed by rapid thawing, the viable explants continued to release /sup 45/Ca to the culture medium but additions of parathyroid hormone to the medium did not cause increased bone resorption. The data suggest that cryopreservation and thawing impairs mechanisms responsible for parathyroid hormone action on bone cells.

  13. 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. PMID:23060860

  14. Effects of parathyroid hormone on bone of thyroparathyroidectomized rats: an ultrastructural and enzymatic study.

    PubMed

    Weisbrode, S E; Capen, C C; Nagode, L A

    1974-06-01

    Osteoblasts and osteocytes in adult thyroparathyroidectomized (T(x)PT(x)) rats fed a low calcium vitamin D-free diet and given parathyroid (PTH) had ultrastructural evidence of increased activity compared to controls. Osteoblasts in PTH-treated rats had prominent rough endoplasmic reticulum and Golgi apparatuses and large mitochondria. The plasma membranes were extensively convoluted and associated with initial loci of mineralization in osteoid. Osteocytes contained increased rough endoplasmic reticulum, well-developed Golgi apparatuses and large mitochondria. Lacunar walls were roughened, but osteocytic osteolysis was not observed. Osteoclasts were encountered more frequently in PTH-treated rats, but their ultrastructural features were similar to those of controls. Osteoblasts and osteocytes in controls appeared to be inactive cells lining quiescent mineral surfaces. Parathyroid hormone treatment increased serum calcium levels and urinary hydroxyproline excretion, indicating enhanced resorption of bone mineral and matrix. Bone alkaline phosphatase and calcium-adenosine triphosphatase activities were elevated after PTH treatment and may be related to increased calcium transport by bone cells. These findings were interpreted to suggest that PTH mobilizes bone mineral by osteoclasis and increases metabolic activity of the osteocyte-osteoblast pump. PMID:4275712

  15. Expression of parathyroid hormone-related protein and the parathyroid hormone/parathyroid hormone-related protein receptor in rat thymic epithelial cells

    PubMed Central

    FUNK, JANET L.; JONES, GERAINT V.; BOTHAM, CATHERINE A.; MORGAN, GEOFFREY; WOODING, PETER; KENDALL, MARION D.

    1999-01-01

    Thymic epithelial cells are an important source of cytokines and other regulatory peptides which guide thymocyte proliferation and maturation. Parathyroid hormone-related protein (PTHrP), a cytokine-like peptide, has been reported to affect the proliferation of lymphocytes in vitro. The studies presented here were undertaken to test the hypotheses that PTHrP is produced locally within the thymus where it could influence thymocyte maturation and, more specifically, that thymic epithelial cells (TEC) could be the intrathymic source of PTHrP expression. To this end, immunohistochemical studies were performed to localise PTHrP and the PTH/PTHrP receptor within the adult rat thymus. Antibodies directed against 2 different PTHrP epitopes, PTHrP(1–34) and PTHrP(34–53), demonstrated prominent specific PTHrP immunoreactivity in both subcapsular and medullary TEC. In addition, faint but specific staining for PTHrP was seen in the cortex, interdigitating between cortical lymphocytes while sparing epithelial-free subcapsular areas, thus suggesting that cortical TEC could also be a source of PTHrP immunoreactivity. In contrast, PTH/PTHrP receptor immunoreactivity was only seen in medullary and occasional septal TEC; no evidence of cortical or lymphocytic PTH/PTHrP receptor immunoreactivity was detected. Immunohistochemical studies of cultured cytokeratin-positive rat TEC confirmed the results of these in situ studies as cultured TEC were immunoreactive both for PTHrP and the PTH/PTHrP receptor. Thus these results demonstrate that PTHrP is produced by the epithelial cells of the mature rat thymus. This suggests that PTHrP, a peptide with known cytokine, growth factor and neuroendocrine actions, could exert important intrathymic effects mediated by direct interactions with TEC, or indirect effects on PTH/PTHrP receptor-negative thymocytes. PMID:10337958

  16. Parathyroid Hormone, Cognitive Function and Dementia: A Systematic Review

    PubMed Central

    Lourida, Ilianna; Thompson-Coon, Jo; Dickens, Chris M.; Soni, Maya; Kuźma, Elżbieta; Kos, Katarina; Llewellyn, David J.

    2015-01-01

    Background Metabolic factors are increasingly recognized to play an important role in the pathogenesis of Alzheimer’s disease and dementia. Abnormal parathyroid hormone (PTH) levels play a role in neuronal calcium dysregulation, hypoperfusion and disrupted neuronal signaling. Some studies support a significant link between PTH levels and dementia whereas others do not. Methods We conducted a systematic review through January 2014 to evaluate the association between PTH and parathyroid conditions, cognitive function and dementia. Eleven electronic databases and citation indexes were searched including Medline, Embase and the Cochrane Library. Hand searches of selected journals, reference lists of primary studies and reviews were also conducted along with websites of key organizations. Two reviewers independently screened titles and abstracts of identified studies. Data extraction and study quality were performed by one and checked by a second reviewer using predefined criteria. A narrative synthesis was performed due to the heterogeneity of included studies. Results The twenty-seven studies identified were of low and moderate quality, and challenging to synthesize due to inadequate reporting. Findings from six observational studies were mixed but suggest a link between higher serum PTH levels and increased odds of poor cognition or dementia. Two case-control studies of hypoparathyroidism provide limited evidence for a link with poorer cognitive function. Thirteen pre-post surgery studies for primary hyperparathyroidism show mixed evidence for improvements in memory though limited agreement in other cognitive domains. There was some degree of cognitive impairment and improvement postoperatively in observational studies of secondary hyperparathyroidism but no evident pattern of associations with specific cognitive domains. Conclusions Mixed evidence offers weak support for a link between PTH, cognition and dementia due to the paucity of high quality research in this area. PMID:26010883

  17. 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

  18. 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

  19. Parathyroid hormone gene with bone phenotypes in Chinese.

    PubMed

    Zhou, Xiao-Gang; Liu, Yao-Zhong; Li, Miao-Xin; Jian, Wei-Xia; Lei, Shu-Feng; Qin, Yue-Juan; Zhou, Qi; Deng, Hong-Wen

    2003-08-01

    Osteoporosis is a common disorder afflicting old people. The parathyroid hormone (PTH) gene is involved in bone remodeling and calcium homeostasis, and has been considered as an important candidate gene for osteoporosis. In this study, we simultaneously tested linkage and/or association of PTH gene with bone mineral density (BMD) and bone mineral content (BMC), two important risk factors for osteoporosis. A sample of 1263 subjects from 402 Chinese nuclear families was used. The families are composed of both parents and at least one healthy daughter aged from 20 to 45 years. All the subjects were genotyped at the polymorphic BstBI site inside the intron 2 of the PTH gene (a nucleotide substitution of G to A at the position +3244). BMD and BMC were measured at the lumbar spine and the hip region via dual-energy X-ray absorptiometry (DXA). Using QTDT (quantitative trait transmission disequilibrium test), we did not find significant results for association or linkage between the PTH gene and BMD or BMC variation at the spine or hip. Our data do not support the PTH gene as a quantitative trait locus (QTL) underlying the bone phenotypic variation in the Chinese population. PMID:12893275

  20. 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.

  1. Sustained cyclic AMP production by parathyroid hormone receptor endocytosis

    PubMed Central

    Ferrandon, Sébastien; Feinstein, Timothy N; Castro, Marian; Wang, Bin; Bouley, Richard; Potts, John T; Gardella, Thomas J; Vilardaga, Jean-Pierre

    2011-01-01

    Cell signaling mediated by the G protein-coupled parathyroid hormone receptor type 1 (PTHR) is fundamental to bone and kidney physiology. It has been unclear how the two ligand systems—PTH, endocrine and homeostatic, and PTH-related peptide (PTHrP), paracrine—can effectively operate with only one receptor and trigger different durations of the cAMP responses. Here we analyze the ligand response by measuring the kinetics of activation and deactivation for each individual reaction step along the PTHR signaling cascade. We found that during the time frame of G protein coupling and cAMP production, PTHrP1–36 action was restricted to the cell surface, whereas PTH1–34 had moved to internalized compartments where it remained associated with the PTHR and Gαs, potentially as a persistent and active ternary complex. Such marked differences suggest a mechanism by which PTH and PTHrP induce differential responses, and these results indicate that the central tenet that cAMP production originates exclusively at the cell membrane must be revised. PMID:19701185

  2. Monoclonal antibodies to bovine parathyroid hormone: production and characterization.

    PubMed

    Vieira, J G; Federico, P; Matsueda, G; Neer, R M

    1988-01-01

    1. This paper describes the production and characterization of monoclonal antibodies against bovine parathyroid hormone (bPTH)-(1-84). 2. Spleen cells from A/J mice successfully immunized with bPTH-(1-84) were fused with SP2/O myeloma cells using PEG 4000 as fusogen. The screening method employed microtiter plates coated with sheep antimouse IgG and the presence of specific monoclonal antibodies was demonstrated by the binding of 125I-bPTH-(1-84). 3. A detailed study of the specificity of the three viable monoclonals with highest affinity showed that two (6FH6 and 6CD4) were amino-terminal specific and the other (5BG9) carboxyl-terminal specific. The two amino-terminal monoclonal antibodies appear to recognize the same antigenic site. 4. The monoclonal antibodies produced are potentially useful reagents for the development of new methods for the measurement of PTH in biological fluids, studies on the interaction of PTH with its receptor, as well as localization of PTH producing cells. PMID:3248228

  3. Angiogenesis inhibitor attenuates parathyroid hormone-induced anabolic effect.

    PubMed

    Rhee, Yumie; Park, So Young; Kim, Yoo Mee; Lee, Sihoon; Lim, Sung-Kil

    2009-01-01

    In vivo osteogenic responses to anabolic stimuli are expected to be accompanied by angiogenesis as well as in the process of remodeling of bone. Consequently, angiogenesis might play an important role in mediating bone forming stimulating effect of parathyroid hormone (PTH). To investigate this relationship, we used actively growing young Sprague-Dawley rats and CKD-732, one of the angiogenesis inhibitor (AI) to reveal the relationship of angiogenesis in the effect of PTH. The groups were divided as (1) vehicle [VEH group], (2) PTH(1-84) [PTH group], (3) AI alone [AI group], (4) PTH(1-84)+AI concomitance [PTH-AI group] and were treated for 6 weeks. The bone mineral density (BMD) of PTH group was higher than VEH group and the gain of bone mass was attenuated in PTH-AI group. The maximal failure load in PTH group was higher than VEH group, but it was definitely attenuated by concurrent use of AI. Moreover, the toughness showed similar significant deterioration in PTH-AI group. General bone turnover was also significantly decreased in PTH-AI group as shown by the absence of increase in osteocalcin and beta-crosslaps and by decrease in metaphyseal length. The BMD or the biomechanic data of AI only group were similar to the VEH group, suggesting the minimal effect of AI itself on the normal modeling phase of the growing rats. In conclusion, the angiogenesis seemed to contribute to completing the anabolic effect of PTH especially for bone strength. PMID:18457934

  4. 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

  5. Vitamin D hormone: a multitude of actions potentially influencing the physical function decline in older persons.

    PubMed

    Cesari, Matteo; Incalzi, Raffaele Antonelli; Zamboni, Valentina; Pahor, Marco

    2011-04-01

    Vitamin D, a secosteroid (pro)-hormone, has been traditionally considered as a key regulator of bone metabolism, and calcium and phosphorous homeostasis through a negative feedback with the parathyroid hormone. However, during the last 20 years, the role played by vitamin D has been largely revised by recognizing its pleiotropic action on a wide spectrum of systems, apparatuses and tissues. Thus, vitamin D has growingly been involved as a primary determinant of biological modifications and specific clinical conditions. The effect of vitamin D on skeletal muscle and related outcomes (including physical function decline and disability) is surely one of the most relevant to study in the context of global aging. In the present review, the subclinical and clinical consequences of vitamin D deficiency/insufficiency, extremely frequent conditions in older age, are described. Special focus is given to skeletal muscle and physical function. Limitations of available scientific evidence on the topic are also discussed. PMID:21134097

  6. 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. PMID:25851690

  7. The combined effect of parathyroid hormone and bone graft on implant fixation

    PubMed Central

    Daugaard, H.; Elmengaard, B.; Andreassen, T. T.; Baas, J.; Bechtold, J. E.; Søballe, K.

    2013-01-01

    Impaction allograft is an established method of securing initial stability of an implant in arthroplasty. Subsequent bone integration can be prolonged, and the volume of allograft may not be maintained. Intermittent administration of parathyroid hormone has an anabolic effect on bone and may therefore improve integration of an implant. Using a canine implant model we tested the hypothesis that administration of parathyroid hormone may improve osseo-integration of implants surrounded by bone graft. In 20 dogs a cylindrical porous-coated titanium alloy implant was inserted into normal cancellous bone in the proximal humerus and surrounded by a circumferential gap of 2.5 mm. Morsellised allograft was impacted around the implant. Half of the animals were given daily injections of human parathyroid hormone (1-34) 5 μg/kg for four weeks and half received control injections. The two groups were compared by mechanical testing and histomorphometry. We observed a significant increase in new bone formation within the bone graft in the parathyroid hormone group. There were no significant differences in the volume of allograft, bone-implant contact or in the mechanical parameters. These findings suggest that parathyroid hormone improves new bone formation in impacted morsellised allograft around an implant and retains the graft volume without significant resorption. Fixation of the implant was neither improved nor compromised at the final follow-up of four weeks. PMID:21196558

  8. 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

  9. Parathyroid adenoma

    MedlinePlus

    ... bones) Complications from surgery include: Damage to a nerve that controls your voice Damage to the parathyroid glands, which causes hypoparathyroidism (lack of enough parathyroid hormone) and low calcium levels

  10. Supplementation with 1000 IU vitamin D/d leads to parathyroid hormone suppression, but not increased fractional calcium absorption, in 4-8-y-old children: A double-blind randomized controlled trial

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The effects of vitamin D supplementation in healthy prepubertal children on physiologic outcomes have not been investigated. The objective was to evaluate the effects of supplementation with 1000 IU vitamin D(3)/d on calcium absorption. In a double-blind, placebo-controlled trial, we randomly assign...

  11. Direct in vitro evidence of the suppressive effect of cinacalcet HCl on parathyroid hormone secretion in human parathyroid cells with pathologically reduced calcium-sensing receptor levels.

    PubMed

    Kawata, Takehisa; Imanishi, Yasuo; Kobayashi, Keisuke; Onoda, Naoyoshi; Okuno, Senji; Takemoto, Yoshiaki; Komo, Takeshi; Tahara, Hideki; Wada, Michihito; Nagano, Nobuo; Ishimura, Eiji; Miki, Takami; Ishikawa, Tetsuro; Inaba, Masaaki; Nishizawa, Yoshiki

    2006-01-01

    Clinical studies have been performed to determine the effect of cinacalcet HCl (cinacalcet), an allosteric modulator of the calcium-sensing receptor (CaR), on primary hyperparathyroidism (PHPT) and secondary hyperparathyroidism of uremia (SHPT). However, no in vitro studies on human parathyroid cells have been reported to date. In this study, the inhibitory effect of cinacalcet on PTH secretion was analyzed in primary cultured parathyroid cells obtained from patients. The investigation involved three PHPT and three SHPT patients subjected to therapeutic parathyroidectomy. Notably, all SHPT patients were resistant to intravenous vitamin D analogue therapy. Removed parathyroid tumors were used for immunohistochemistry and parathyroid cell primary culture. Immunohistochemical analyses revealed diminished expression of CaR and vitamin D receptor (VDR) in all parathyroid tumors. PTH secretion from cultured parathyroid cells of PHPT and SHPT patients was suppressed by extracellular Ca2+ and cinacalcet in a dose-dependent manner. Rates of suppression of PTH secretion in PHPT and SHPT by cinacalcet (1000 nmol/l) were 61% +/- 21% and 61% +/- 19%, respectively. Cinacalcet demonstrates significant potency in the suppression of PTH secretion in primary cultured human parathyroid cells in vitro, despite reduced levels of the target protein, CaR. Data from this in vitro analysis support the clinical application of cinacalcet in PHPT and SHPT therapy. PMID:16816924

  12. Calcium mobilization from fish scales is mediated by parathyroid hormone related protein via the parathyroid hormone type 1 receptor.

    PubMed

    Rotllant, J; Redruello, B; Guerreiro, P M; Fernandes, H; Canario, A V M; Power, D M

    2005-12-15

    The scales of bony fish represent a significant reservoir of calcium but little is known about their contribution, as well as of bone, to calcium balance and how calcium deposition and mobilization are regulated in calcified tissues. In the present study we report the action of parathyroid hormone-related protein (PTHrP) on calcium mobilization from sea bream (Sparus auratus) scales in an in vitro bioassay. Ligand binding studies of piscine 125I-(1-35(tyr))PTHrP to the membrane fraction of isolated sea bream scales revealed the existence of a single PTH receptor (PTHR) type. RT-PCR of fish scale cDNA using specific primers for two receptor types found in teleosts, PTH1R, and PTH3R, showed expression only of PTH1R. The signalling mechanisms mediating binding of the N-terminal amino acid region of PTHrP were investigated. A synthetic peptide (10(-8) M) based on the N-terminal 1-34 amino acid residues of Fugu rubripes PTHrP strongly stimulated cAMP synthesis and [3H]myo-inositol incorporation in sea bream scales. However, peptides (10(-8) M) with N-terminal deletions, such as (2-34), (3-34) and (7-34)PTHrP, were defective in stimulating cAMP production but stimulated [3H]myo-inositol incorporation. (1-34)PTHrP induced significant osteoclastic activity in scale tissue as indicated by its stimulation of tartrate-resistant acid phosphatase. In contrast, (7-34)PTHrP failed to stimulate the activity of this enzyme. This activity could also be abolished by the adenylyl cyclase inhibitor SQ-22536, but not by the phospholipase C inhibitor U-73122. The results of the study indicate that one mechanism through which N-terminal (1-34)PTHrP stimulates osteoclastic activity of sea bream scales, is through PTH1R and via the cAMP/AC intracellular signalling pathway. It appears, therefore, that fish scales can act as calcium stores and that (1-34)PTHrP regulates calcium mobilization from them; it remains to be established if this mechanism contributes to calcium homeostasis in vivo. PMID:16181689

  13. Influence of Sodium and Parathyroid Hormone on Calcium Release from Intestinal Mucosal Cells

    PubMed Central

    Birge, Stanley J.; Switzer, Sandra C.; Leonard, David R.

    1974-01-01

    The uptake and release of 45Ca from the intestinal mucosal epithelium were investigated under a variety of conditions. The initial rate of uptake characterized a calcium pool with a half-time of saturation of less than 2 min. The entry of 45Ca into this pool was inhibited by NaCN and ethacrynic acid and was stimulated by the removal of Cl- from the incubation. The initial rate of 45Ca release was also inhibited by NaCN and removal of Na+ from the incubation. Parathyroid hormone administration enhanced the release of 45Ca from cells prepared from parathyroid-ectomized animals. These observations suggest that calcium transport across the brush border and basallateral membranes are identifiable components of the kinetics of 45Ca uptake and release and that parathyroid hormone stimulates a sodium-dependent mechanism of calcium transport across the basal-lateral membranes. PMID:4852449

  14. Parathyroid hormone secretion by multiple distinct cell populations, a time dynamic mathematical model

    PubMed Central

    Pruett, William A.; Hester, Robert L.

    2014-01-01

    Abstract The acute response of parathyroid hormone to perturbations in serum ionized calcium ([Ca2+]) is physiologically complex, and poorly understood. The literature provides numerous observations of quantitative and qualitative descriptions of parathyroid hormone (PTH) dynamics. We present a physiologically based mathematical model of PTH secretion constructed from mechanisms suggested in the literature, and validated against complex [Ca2+] clamping protocols from human data. The model is based on two assumptions. The first is that secretion is a fraction of cellular reserves, with the fraction being determined by the kinetics of [Ca2+] with its receptor. The second is that there are multiple distinct populations of parathyroid cells, with different secretory parameters. The steady state and transient PTH secretion responses of the model are in agreement with human experimental PTH responses to different hypocalcemia and hypercalcemia stimuli. This mathematical model suggests that a population of secreting cells is responsible for the PTH secretory dynamics observed experimentally. PMID:24744900

  15. Serum parathyroid hormone-related protein concentration in a dog with a thymoma and persistent hypercalcemia.

    PubMed Central

    Foley, P; Shaw, D; Runyon, C; McConkey, S; Ikede, B

    2000-01-01

    A thymoma was tentatively diagnosed by radiographic and cytologic examination in a dog with hypercalcemia and elevated serum parathyroid hormone-related protein (PTHrP) concentration. Following surgical excision, the diagnosis of thymoma was confirmed via histopathologic examination, the hypercalcemia resolved, and the PTHrP concentration decreased to below detectable limits. Images Figure 1. Figure 2. PMID:11126493

  16. Preoperative Localization and Intraoperative Parathyroid Hormone Assay in Korean Patients with Primary Hyperparathyroidism

    PubMed Central

    Cho, Eirie; Chang, Jung Mi; Yoon, Seok Young; Lee, Gil Tae; Ku, Yun Hyi; Kim, Hong Il; Lee, Myung-Chul; Lee, Guk Haeng

    2014-01-01

    Background The intraoperative parathyroid hormone (IOPTH) assay is widely used in patients with primary hyperparathyroidism (PHPT). We investigated the usefulness of the IOPTH assay in Korean patients with PHPT. Methods We retrospectively reviewed the data of 33 patients with PHPT who underwent parathyroidectomy. Neck ultrasonography (US) and 99mTc-sestamibi scintigraphy (MIBI scan) were performed preoperatively and IOPTH assays were conducted. Results The sensitivity of neck US and MIBI scans were 91% and 94%, respectively. A 50% decrease in parathyroid hormone (PTH) levels 10 minutes after excision of the parathyroid gland was obtained in 91% (30/33) of patients and operative success was achieved in 97% (32/33) of patients. The IOPTH assay was 91% true-positive, 3% true-negative, 0% false-positive, and 6% false-negative. The overall accuracy of the IOPTH assay was 94%. In five cases with discordant neck US and MIBI scan results, a sufficient decrease in IOPTH levels helped the surgeon confirm the complete excision of the parathyroid gland with no additional neck exploration. Conclusion The IOPTH assay is an accurate tool for localizing hyperfunctioning parathyroid glands and is helpful for evaluating cases with discordant neck US and MIBI scan results. PMID:25325266

  17. Impact of calcium and vitamin D insufficiencies on serum parathyroid hormone and bone mineral density: analysis of the 4th & 5th Korean National Health and Nutrition Examination Survey

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The relative contributions of calcium and vitamin D to calcium metabolism and bone mineral density (BMD) have been examined previously, but not in a population with very low calcium intake. To determine the relative importance of dietary calcium intake and serum 25-hydroxyvitamin D [25(OH)D] concent...

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

    PubMed

    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

    2014-04-01

    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

  19. 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

  20. Vitamin D, steroid hormones, and autoimmunity.

    PubMed

    Cutolo, Maurizio; Paolino, Sabrina; Sulli, Alberto; Smith, Vanessa; Pizzorni, Carmen; Seriolo, Bruno

    2014-05-01

    The endogenous serum metabolite of vitamin D (calcitriol, 1,25(OH)2 D3 ) is considered a true steroid hormone (D hormone), and like glucocorticoids (GCs) and gonadal hormones, may exert several immunomodulatory activities. Serum vitamin D deficiency (25(OH) D), and therefore reduced 1,25(OH)2 D3 availability, is considered a risk factor for several chronic/inflammatory or autoimmune conditions, including infectious diseases, type 1 diabetes, multiple sclerosis, and especially autoimmune rheumatic diseases (ARD). In ARD in particular, 1,25(OH)2 D3 regulates both innate and adaptive immunity, potentiating the innate response (antimicrobial activity) but reducing adaptive immunity (antigen presentation, T and B cell activities). Regarding a possible synergism between vitamin D and GCs, several studies show that 1,25(OH)2 D3 has significant additive effects on dexamethasone-mediated inhibition of human lymphocyte and monocyte proliferation. Conversely, vitamin D deficiency seems to play a role in increasing autoantibody production by B cells, and seasonal vitamin D declines may trigger flares in ARD, as recently shown. Finally, 1,25(OH)2 D3 seems to reduce aromatase activity and limit the negative effects related to increased peripheral estrogen metabolism (cell proliferation, B cell overactivity). PMID:24739090

  1. 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

  2. The relationship between total mass and blood supply of parathyroid glands and their secretion of parathyroid hormone in hemodialysis patients with secondary hyperparathyroidism.

    PubMed

    Ahmadi, Farrokhlagha; Aghajanzadeh, Pegah; Yazdi, Hadi Rokni; Maziar, Sima; Gatmiri, Sayad Mansour

    2016-01-01

    Characteristics of parathyroid glands usually determined by ultrasonography such as its total weight or volume might be a good indicator for the induction or suppression of parathyroid hormone (PTH) secretion from these glands. In the present study, we investigated the relationship between the volume and blood supply grade of the parathyroid glands, and its PTH secretion. Study subjects included 52 consecutive patients with the secondary hyperparathyroidism undergoing maintenance hemodialysis therapy referred to dialysis wards of the Imam Khomeini and Amiralam University Hospitals in Tehran. Serum intact PTH (i-PTH) was measured by an ELISA assay. The parathyroid glands characteristics were identified by ultrasonography that was performed simultaneously with blood collection. Parathyroid blood flows were evaluated by power-Doppler color imaging. There was no significant correlation between the total mass of the glands and serum concentration of i-PTH. No significant correlations were also observed between both total central and peripheral parathyroid glands blood flow and serum i-PTH level. Dialysis duration and serum alkaline phosphatase were significantly correlated in a positive manner with i-PTH level. Furthermore, serum level of i-PTH was not correlated with the total signals of glands blood flow in a multivariable linear regression analysis. Serum secreted i-PTH level might not be predictable by a total mass of parathyroid glands as well as their blood supply. PMID:26997379

  3. Intraoperative Parathyroid Hormone Monitoring Corroborates the Success of Parathyroidectomy in Children

    PubMed Central

    Çelik, Ahmet; Divarcı, Emre; Dökümcü, Zafer; Ergün, Orkan; Özen, Samim; Gökşen, Damla; Darcan, Şükran; Ertan, Yeşim

    2014-01-01

    Ob­jec­ti­ve: To assess the efficacy of intraoperative parathyroid hormone (PTH) monitoring in evaluating the outcome of parathyroidectomy in pediatric patients. Methods: Intraoperative PTH monitoring during parathyroidectomy was performed in five children (3M, 2F); three had parathyroid adenomas (single gland disease) and two had primary hyperplasia. One patient had undergone two previous surgical interventions to remove the parathyroid glands, but the PTH levels had remained high with persistence of symptoms. Immunoradiometric analysis was used for PTH measurements. Preoperative PTH values were obtained to monitor the baseline levels. Serum samples were collected 20 minutes after removal of the adenoma/parathyroid gland(s) and PTH levels were compared with preoperative values. Specimens were also confirmed by frozen sectional examination. Results: Mean age of the patients was 11 years (range: 3 months-16 years). Mean preoperative PTH values were 633.3±579 pg/mL (range: 143-1300 pg/mL). Intraoperative values decreased to 18.7±5.5 pg/mL (range: 8-27 pg/mL) following removal of the gland(s). Normal calcium levels were achieved with adequate management following surgery. One patient (with multiple surgeries and found to have an ectopic parathyroid gland) had hungry bone syndrome after the operation and was treated successfully. There were no major complications. All patients maintained normal calcium/phosphorus levels in the follow-up period, ranging from 2 to 5 years. Conclusion: An ectopic parathyroid gland or another undetected adenoma can be overlooked during surgery. Owing to the short life of the hormone, intraoperative PTH monitoring to determine PTH clearance proved to be a feasible marker for adequacy and safety of surgery and “cure”. PMID:25241609

  4. THE VITAMIN D HORMONE: A MULTITUDE OF ACTIONS POTENTIALLY INFLUENCING THE PHYSICAL FUNCTION DECLINE IN OLDER PERSONS

    PubMed Central

    Cesari, Matteo; Incalzi, Raffaele Antonelli; Zamboni, Valentina; Pahor, Marco

    2015-01-01

    Vitamin D, a secosteroid (pro)-hormone, has been traditionally considered as a key regulator of bone metabolism, and calcium and phosphorous homeostasis through a negative feedback with the parathyroid hormone. However, during the last twenty years, the role played by vitamin D has been largely revised by recognizing it a pleiotropic action on a wide spectrum of systems, apparati, and tissues. Thus, vitamin D has growingly been involved as a primary determinant of biological modifications and specific clinical conditions. The effect of vitamin D on skeletal muscle and related outcomes (including physical function decline and disability) is surely one of the most relevant to study in the context of global aging. In the present review, the subclinical and clinical consequences of vitamin D deficiency/insufficiency, extremely frequent conditions in older age, are described. Special focus is given to skeletal muscle and physical function. Limitations of available scientific evidence on the topic are also discussed. PMID:21134097

  5. Developmental cues for bone formation from parathyroid hormone and parathyroid hormone-related protein in an ex vivo organotypic culture system of embryonic chick femora.

    PubMed

    Smith, Emma L; Kanczler, Janos M; Roberts, Carol A; Oreffo, Richard O C

    2012-12-01

    Enhancement and application of our understanding of skeletal developmental biology is critical to developing tissue engineering approaches to bone repair. We propose that use of the developing embryonic femur as a model to further understand skeletogenesis, and the effects of key differentiation agents, will aid our understanding of the developing bone niche and inform bone reparation. We have used a three-dimensional organotypic culture system of embryonic chick femora to investigate the effects of two key skeletal differentiation agents, parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP), on bone and cartilage development, using a combination of microcomputed tomography and histological analysis to assess tissue formation and structure, and cellular behavior. Stimulation of embryonic day 11 (E11) organotypic femur cultures with PTH and PTHrP initiated osteogenesis. Bone formation was enhanced, with increased collagen I and STRO-1 expression, and cartilage was reduced, with decreased chondrocyte proliferation, collagen II expression, and glycosaminoglycan levels. This study demonstrates the successful use of organotypic chick femur cultures as a model for bone development, evidenced by the ability of exogenous bioactive molecules to differentially modulate bone and cartilage formation. The organotypic model outlined provides a tool for analyzing key temporal stages of bone and cartilage development, providing a paradigm for translation of bone development to improve scaffolds and skeletal stem cell treatments for skeletal regenerative medicine. PMID:22690868

  6. 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

  7. The Utility of Intraoperative Bilateral Internal Jugular Venous Sampling With Rapid Parathyroid Hormone Testing

    PubMed Central

    Ito, Fumito; Sippel, Rebecca; Lederman, Julie; Chen, Herbert

    2007-01-01

    Objective: To determine the utility of routine perioperative bilateral internal jugular venous sampling of parathyroid hormone (BIJ PTH) for localization during parathyroid surgery. Summary Background Data: Venous sampling for PTH is a useful tool for parathyroid localization in patients undergoing reoperative surgery for hyperparathyroidism (HPT). With the development of intraoperative rapid PTH (ioPTH) testing, internal jugular PTH sampling with ioPTH testing to guide operative localization has been shown to be possible in select, difficult cases. However, the value of BIJ PTH for patients with HPT is unclear. Methods: Between May 2004 and February 2006, 216 consecutive patients underwent neck exploration for HPT by one surgeon. Of these, 168 patients had BIJ PTH. Internal jugular venous blood was drawn from both left and right sides and analyzed for PTH using a rapid PTH assay. BIJ PTH levels were defined as lateralizing if >5% differences were observed between the right and left internal jugular vein samples. Results: Of the 168 patients, 120 (71.4%) had a single parathyroid adenoma, 15 (8.9%) had double adenoma, and 33 (19.6%) had hyperplasia. The cure rate after parathyroidectomy was 98.2%. There were no complications related to BIJ PTH sampling. Sensitivity and positive predictive value of BIJ PTH for primary hyperparathyroidism were 80% and 71%, respectively. BIJ PTH was diagnostic in 95 cases (62.9%) in primary HPT. BIJ PTH successfully localized an abnormal gland in 26 of 45 (57.8%) in patients with negative sestamibi scanning. BIJ PTH was especially helpful in 18 of 168 (10.7%) cases when intraoperative peripheral parathyroid hormone did not fall by 50% and BIJ PTH successfully localized the hyperfunctioning glands. Conclusions: In patients with HPT, BIJ PTH is safe and effective, providing additional localization information in the majority of cases. BIJ PTH is particularly useful in the setting of negative sestamibi scanning and in complex multigland disease cases. PMID:17522522

  8. Small Molecule Inhibited Parathyroid Hormone Mediated cAMP Response by N-Terminal Peptide Binding.

    PubMed

    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

  9. 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.

  10. 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

  11. Primary hyperparathyroidism from a probable ectopic parathyroid adenoma with severe skeletal disease and vitamin D deficiency

    PubMed Central

    Garingarao, Carlo Jan P; Paz-Pacheco, Elizabeth; Jimeno, Cecilia A

    2014-01-01

    Primary hyperparathyroidism (PHPT) may lead to skeletal deformities, fractures and renal failure in symptomatic patients if untreated. We present a case of a 30-year-old woman presented with muscle weakness, weight loss, hypercalcaemia and a pathological fracture, eventually with rapidly progressive musculoskeletal disease. Subsequent biochemical, radiographic and scintigraphy findings were consistent with PHPT from an ectopic mediastinal adenoma, and concomitant vitamin D deficiency. The severe hypercalcaemia was adequately temporised with hydration, forced diuresis and intravenous bisphosphonates. Removal of the adenoma by video-assisted thoracoscopic surgery was contemplated; however, consent was withdrawn precluding histological confirmation. A review of literature shows the changing profiles of patients with PHPT, the uncommon occurrence of parathyroid adenomas in ectopic locations and possible association between severity of PHPT and vitamin D status. PMID:24632909

  12. 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. PMID:25935225

  13. Measurement of serum parathyroid hormone, with particular reference to some infants with hypocalcaemia

    PubMed Central

    Fairney, Angela; Jackson, Doreen; Clayton, Barbara E.

    1973-01-01

    Parathyroid hormone (PTH) in serum has been determined by a double antibody radioimmunoassay which is suitable for use in infants. The concentration in normal infants rose after birth from a mean level of 97 pg/ml in cord blood to 217 pg/ml at 6 days of age. It remained at this level in the older infants and children. In a group of infants with hypocalcaemia and many complicating factors, the PTH concentration was significantly lower than normal. All but one of the affected infants maintained a normal serum calcium without treatment 1 year after the episode of hypocalcaemia. It is suggested that prolonged immaturity of parathyroid function may contribute significantly to the aetiology of hypocalcaemia and may be related to immaturity of the mechanisms responsible for converting glandular PTH to secreted PTH. PMID:4712771

  14. 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.

  15. 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.

  16. Changes in calcium phosphate on bone surfaces and in lining cells after the administration of parathyroid hormone or calcitonin

    SciTech Connect

    Norimatsu, H.; Yamamoto, T.; Ozawa, H.; Talmage, R.V.

    1982-04-01

    Small doses of parathyroid hormone and calcitonin were injected into thyroparathyroidectomized newborn rats to investigate the histological and chemical changes in bone surfaces and in mitochondrial granules of bone lining cells. Nondecalcified tissue specimens were observed under transmission electron microscope, electron probe X-ray microanalyzer, and microdiffraction after freeze substitution preparation of tibia shafts. Amorphous calcium phosphate, which appears as clusters and globules by this freeze substitution preparation, appears on the bone surfaces in a short time after the administration of a small dose of calcitonin. The Ca:PO4 ratio in the mitochondria of bone lining cells rises slightly with a small dose of parathyroid hormone and is reduced with a small dose of calcitonin. These data support the postulate that both parathyroid hormone and calcitonin act directly on bone lining cells in the process of influencing calcium concentrations of blood and temporarily storing calcium at bone surfaces.

  17. 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.

  18. Two-site immunoradiometric intact parathyroid hormone assay versus C-terminal parathyroid hormone in predicting osteodystrophic bone lesions in predialysis chronic renal failure.

    PubMed

    Coen, G; Mazzaferro, S; Ballanti, P; Bonucci, E; Cinotti, G A; Fondi, G; Manni, M; Pasquali, M; Perruzza, I; Sardella, D

    1993-07-01

    Intact parathyroid hormone (iPTH) radioimmunoassay represents an important advancement in the measurement of serum PTH levels, permitting the evaluation of the actual rate of secretion of the parathyroid glands. The aim of the study was to compare the value of intact and C-terminal PTH measurements in predicting the osteodystrophic bone lesion in predialysis patients with chronic renal failure (CRF). We have studied 37 subjects with CRF who were receiving conservative treatment. In each subject a transiliac bone biopsy for histomorphometric examination was performed in addition to the assay of serum intact and C-terminal PTH, osteocalcin, and alkaline phosphatase. Serum C-terminal and intact PTH levels were closely correlated, both showing a high degree of correlation with serum osteocalcin. Similar degrees of correlation were observed between the two PTH assays and the histologic parameters osteoblastic surface (ObS/BS) and osteoclastic surface (OcS/BS). The evaluation of specificity and sensitivity of the two PTH assays in selecting patients with normal or pathologic histomorphometric parameters gave an equivalent number of false positive and negative cases. Based on discriminant analysis of histomorphometric parameters, intact PTH shows a higher discriminant power when compared with C-terminal PTH assay for the parameters OcS/BS and eroded surface (ES/BS), but without practical clinical value. In conclusion, in analogy to the short lived N-terminal PTH fragment assay, prediction of elementary hyperparathyroid bone lesions in predialysis CRF is not improved by the use of intact PTH as compared to the more traditional C-terminal assay. PMID:8320484

  19. Levels of parathyroid hormone and calcitonin in serum among atomic bomb survivors

    SciTech Connect

    Fujiwara, Saeko; Yokoyama, Naokata; Sasaki, Hideo; Kodama, Kazunori; Sposto, R.; Shimaoka, Katsutaro; Shiraki, Mastaka

    1994-01-01

    To examines the potential causes of increased levels of calcium in serum with increasing dose of atomic bomb radiation, which was obtained from the previous preliminary analysis, levels of parathyroid hormone (PTH) and calcitonin in serum were examined among 1459 subjects in Hiroshima and Nagasaki. A significant effect of radiation on levels of calcium, PTH and calcitonin in serum was found, even after patients with hyperparathyroidism were excluded. The level of calcium in serum increased with radiation dose; this can be explained partly by the increase in the level of PTH with radiation dose. However, the dose effect on calcium remained even after adjustment for PTH, calcitonin and confounding factors such as renal function, serum albumin level and medication. Parathyroid hormone increased initially by 6.8% per gray, but the dose response leveled off after about 1 Gy. The level of calcitonin increased with radiation dose, probably in part due to feedback mechanisms stimulated by the increase in calcium. However, after adjustment for the level of calcium, the increase in the level of calcitonin with dose was still found. Although the etiological mechanisms of the effect of radiation on serum levels of calcium, PTH and calcitonin are unclear, radiation exposure may affect secretion of PTH and calcitonin and regulation of calcium a long time after atomic bomb exposure. 21 refs., 3 figs., 6 tabs.

  20. Effect of propranolol and metoprolol on parathyroid hormone and calcitonin secretions in uraemic patients.

    PubMed Central

    Coevoet, B; Desplan, C; Sebert, J L; Makdassi, R; Andrejak, M; Gheerbrant, J D; Tolani, M; Calmette, C; Moukhtar, M S; Fournier, A

    1980-01-01

    Nine uraemic patients not being treated by dialysis received intravenous propranolol 1 microgram/kg/min for 85 minutes after a priming dose of 1 mg. Fifteen days later, six of them received intravenous metoprolol 1.2 microgram/kg/min after a priming dose of 1.2 mg. Plasma concentrations of parathyroid hormone (PTH) and calcitonin fell significantly after propranolol but not after metoprolol, whereas no change in plasma concentrations of ionised calcium and phosphate occurred with either drug. Heart rate fell similarly with both drugs. The fact that propranolol acutely suppressed PTH and calcitonin secretion in uraemic patients indicates that further studies are warranted to assess the long-term effects of the drug on the secretion of these hormones and on renal osteodystrophy. The contrast between the responses to propranolol and metoprolol supports the concept that PTH and calcitonin secretion is modulated through specific beta 2-receptors. PMID:7388535

  1. Extremely high parathyroid hormone concentrations associated with pityriasis rubra pilaris and monoclonal gammopathy of unknown significance: a clinical dilemma.

    PubMed

    Tanriover, Mine Durusu; Portakal, Oytun; Hapa, Asli; Tekinel, Yasemin; Dagdelen, Selcuk; Buyukasik, Yahya; Arici, Mustafa

    2012-11-01

    We present a case with extremely high parathyroid hormone (PTH) concentrations in the order of hundred thousands accompanied by dermatological and hematological diseases. After several diagnostic interventions, no malignancy could be demonstrated except monoclonal gammopathy of unknown significance. The dermatological findings were taken to be manifestations of the hematological disease. Since the first serum intact PTH concentration of the patient was found to be higher than 2500 pg/ml, dilution study was performed and found to be 215,977 pg/ml. The high concentration of serum PTH was taken to be falsely high due to assay interference. This concentration was checked from three different paths; a test for linear dilution was performed, the test was repeated with another method and the sample was treated to remove or inhibit interfering substances. The results were compatible with endogenous antibody interference, presumed to be a result of monoclonal gammopathy. The extremely high PTH concentrations were not only due to assay interference, but also secondary hyperparathyroidism, which was evident by the decrease in PTH concentrations with calcium and vitamin D treatments. PMID:22906636

  2. 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

  3. Cinacalcet Effectively Reduces Parathyroid Hormone Secretion and Gland Volume Regardless of Pretreatment Gland Size in Patients with Secondary Hyperparathyroidism

    PubMed Central

    Komaba, Hirotaka; Nakanishi, Shohei; Fujimori, Akira; Tanaka, Motoko; Shin, Jeongsoo; Shibuya, Koji; Nishioka, Masato; Hasegawa, Hirohito; Kurosawa, Takeshi

    2010-01-01

    Background and objectives: Cinacalcet is effective in reducing serum parathyroid hormone (PTH) in patients with secondary hyperparathyroidism. However, it has not been proven whether parathyroid gland size predicts response to therapy and whether cinacalcet is capable of inducing a reduction in parathyroid volume. Design, setting, participants, & measurements: This 52-week, multicenter, open-label study enrolled hemodialysis patients with moderate to severe secondary hyperparathyroidism (intact PTH >300 pg/ml). Doses of cinacalcet were adjusted between 25 and 100 mg to achieve intact PTH <180 pg/ml. Ultrasonography was performed to measure the parathyroid gland size at baseline, week 26, and week 52. Findings were also compared with those of historical controls. Results: Of the 81 subjects enrolled, 56 had parathyroid glands smaller than 500 mm3 (group S) and 25 had at least one enlarged gland larger than 500 mm3 (group L). Treatment with cinacalcet effectively decreased intact PTH by 55% from baseline in group S and by 58% in group L. A slightly greater proportion of patients in group S versus group L achieved an intact PTH <180 pg/ml (46 versus 32%) and a >30% reduction from baseline (88 versus 78%), but this was not statistically significant. Cinacalcet therapy also resulted in a significant reduction in parathyroid gland volume regardless of pretreatment size, which was in sharp contrast to historical controls (n = 87) where parathyroid gland volume progressively increased with traditional therapy alone. Conclusions: Cinacalcet effectively decreases serum PTH levels and concomitantly reduces parathyroid gland volume, even in patients with marked parathyroid hyperplasia. PMID:20798251

  4. 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 PTHrP in osteogenic cells compensates by increasing bone accrual. PMID:23716486

  5. 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 Parathyroid Hormone; TOP) has been designed to assess the bone-building and fracture-reducing potential of the drug, and over 2600 postmenopausal women with osteoporosis who have not received previous drug therapy for osteoporosis have been enrolled. Treatment will be completed in September 2003, but more than 75% of patients enrolled in the TOP study have chosen to enrol in an Open Label Extension Study (OLES), which allows for a total treatment period of up to 24 months. NPS Pharmaceuticals has signed an agreement with Bio-Imaging Technologies, which will provide all image handling and analysis for this trial. In September 2002, NPS Pharmaceuticals announced that it has met its patient enrolment target (n > 150) for its POWER (PTH for Osteoporotic Women on Estrogen Replacement) study; a 24-month phase III trial initiated in Europe in November 2001. In this trial, women with osteoporosis receive SC injections of ALX 111 or placebo, in combination with their existing hormone replacement therapies, to test the bone building potential of the drug. In addition to the POWER study, a clinical trial sponsored by the National Institutes of Health (NIH) is being conducted to evaluate the potential of ALX 111 to build bone in combination with another osteoporosis medication. The 'PaTH' study (PTH/alendronate) is designed to assess the effect of various combinations and sequential uses of ALX 111 and Merck's Fosamax, a drug for slowing the loss of bone due to osteoporosis. The PaTH study, initiated in May 2000 and scheduled to conclude in September 2003, involved 238 patients with postmenopausal osteoporosis. It is thought that alendronic acid and ALX 111, when administered in combination, may act in an additive manner to treat osteoporosis because they act in different ways; alendronic acid acts to inhibit resorption and ALX 111 speeds up bone formation and resorption, with a net increase in formation. Results of this study are still being analysed but preliminary results appear to be positive. The effect of ALX 111 on bone cell cultures underare still being analysed but preliminary results appear to be positive. The effect of ALX 111 on bone cell cultures under conditions of microgravity was tested in orbit on the Space Shuttle Columbia, which was launched on 16 January 2003 but did not survive re-entry. This study was one in a series of studies known as 'OSTEO' and had been prepared by researchers from NPS Pharmaceuticals using Millenium Biologix' OSTEO Mini-Lab System. Under space flight conditions, astronauts experience a loss in bone density at a rate up to ten times faster than that of earth-bound patients with osteoporosis, and it was hoped that this study would indicate the mechanism of action of ALX 111 at cellular and genetic levels. The results of these studies were represented by the samples of human bone cells, which were lost during the re-entry tragedy. PMID:12848587

  6. Relationship between parathyroid calcium-sensing receptor expression and potency of the calcimimetic, cinacalcet, in suppressing parathyroid hormone secretion in an in vivo murine model of primary hyperparathyroidism.

    PubMed

    Kawata, Takehisa; Imanishi, Yasuo; Kobayashi, Keisuke; Kenko, Takao; Wada, Michihito; Ishimura, Eiji; Miki, Takami; Nagano, Nobuo; Inaba, Masaaki; Arnold, Andrew; Nishizawa, Yoshiki

    2005-10-01

    Cinacalcet HCl, an allosteric modulator of the calcium-sensing receptor (CaR), has recently been approved for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis, due to its suppressive effect on parathyroid hormone (PTH) secretion. Although cinacalcet's effects in patients with primary and secondary hyperparathyroidism have been reported, the crucial relationship between the effect of calcimimetics and CaR expression on the parathyroid glands requires better understanding. To investigate its suppressive effect on PTH secretion in primary hyperparathyroidism, in which hypercalcemia may already have stimulated considerable CaR activity, we investigated the effect of cinacalcet HCl on PTH-cyclin D1 transgenic mice (PC2 mice), a model of primary hyperparathyroidism with hypo-expression of CaR on their parathyroid glands. A single administration of 30 mg/kg body weight (BW) of cinacalcet HCl significantly suppressed serum calcium (Ca) levels 2 h after administration in 65- to 85-week-old PC2 mice with chronic biochemical hyperparathyroidism. The percentage reduction in serum PTH was significantly correlated with CaR hypo-expression in the parathyroid glands. In older PC2 mice (93-99 weeks old) with advanced hyperparathyroidism, serum Ca and PTH levels were not suppressed by 30 mg cinacalcet HCl/kg. However, serum Ca and PTH levels were significantly suppressed by 100 mg/kg of cinacalcet HCl, suggesting that higher doses of this compound could overcome severe hyperparathyroidism. To conclude, cinacalcet HCl demonstrated potency in a murine model of primary hyperparathyroidism in spite of any presumed endogenous CaR activation by hypercalcemia and hypo-expression of CaR in the parathyroid glands. PMID:16189180

  7. 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. PMID:22754549

  8. Evidence that protease inhibitors reduce the degradation of parathyroid hormone and calcitonin injected subcutaneously.

    PubMed Central

    Parsons, J. A.; Rafferty, B.; Stevenson, R. W.; Zanelli, J. M.

    1979-01-01

    1 Agents known to delay absorption from a subcutaneous site were tested in chicks for their ability to prolong the hypercalcaemic response to parathyroid hormone (PTH). 2 Polyvinylpyrrolidone was found to enhance the response but gelatine greatly reduced the 2 h hypercalcaemia. 3 The reduction by gelatine was reversed when the protease inhibitor aprotinin was added to the injection vehicle, and hypercalcaemia then persisted for more than 8 h. 4 Of other protease inhibitors studied, epsilon-aminocaproic acid was also found to enhance the hypercalcaemic response to subcutaneous PTH and its fragments but, unlike aprotinin, it was ineffective in the presence of gelatine. 5 By radioimmunoassay and bioassay respectively, it was confirmed that aprotinin raised circulating levels of PTH and also of another peptide hormone, calcitonin, injected subcutaneously. 6 Addition of calcium to the solutions injected subcutaneously abolished the hypercalcaemic response to PTH while injection of calcium and PTH simultaneously but at separate sites left the response unaltered. 7 The two protease inhibitors, epsilon-aminocaproic acid and aprotinin, each restored the response to subcutaneous PTH despite the presence of calcium at the injection site. 8 It was concluded that protease inhibitors injected subcutaneously with PTH and calcitonin in the chick reduced the rate of degradation of these hormones and that the proteases responsible for hormone degradation at the subcutaneous injection site may be released or activated by calcium ions. PMID:313228

  9. 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

  10. Treatment study of distal femur for parathyroid hormone (1-34) and β-tricalcium phosphate on bone formation in critical size defects in rats.

    PubMed

    Tao, Zhou-Shan; Qiang, Zhou; Tu, Kai-kai; Huang, Zheng-liang; Xu, Hong-ming; Sun, Tao; Lv, Yang-Xun; Cui, Wei; Yang, Lei

    2015-10-01

    The objective of this study was to evaluate local bone formation following systemic administration of parathyroid hormone (1-34), a surgically implanted synthetic β-tricalcium phosphate bone biomaterial serving as a matrix to support new bone formation. Twelve weeks after bilateral ovariectomy, all rats underwent bone defect in the distal femurs, and β-tricalcium phosphate was implanted into critical sized defects. After defect operation, all animals were randomly divided into four groups and received following subcutaneous injections until death at four and eight weeks: sham rats (group ST); sham rats + parathyroid hormone, 30 µg/kg, three times a week (group SPT); OVX rats (group OT); and OVX rats + parathyroid hormone (group OPT). The distal femurs of rats were harvested for evaluation. The treatment group demonstrating the highest levels of new bone formation was the defects treated with parathyroid hormone as assessed by micro-computed tomography, biomechanical strength, and histological analysis for sham rats. Furthermore, parathyroid hormone showed a stronger effect on accelerating the degradation of β-tricalcium phosphate. Osteoporosis can limit the function of parathyroid hormone and/or β-tricalcium phosphate. The results from our study demonstrate that combination of parathyroid hormone and β-tricalcium phosphate brings better effect to bone tissue repair in non-osteoporosis and/or osteoporosis status. PMID:26116022

  11. Parathyroid hormone and its receptor gene polymorphisms: implications in osteoporosis and in fracture healing.

    PubMed

    Noordin, Shahryar; Glowacki, Julie

    2016-01-01

    Parathyroid glands secrete parathyroid hormone (PTH) which plays multiple roles in calcium homeostasis and in bone remodeling. Secretion of PTH is regulated by extracellular calcium levels and other humoral factors including 1α,25(OH)2D3. PTH regulates gene expression and induces biological effects directly and indirectly. The human gene encoding PTH is located on chromosome 11. In this review, we study the diverse PTH along with its receptor gene polymorphisms and their association with osteoporosis and fracture healing. Genetic factors are associated with osteoporosis by influencing bone mineral density (BMD), bone turnover, calcium homeostasis, and susceptibility to osteoporotic fractures. Polymorphisms in genes encoding PTH may contribute to genetic regulation of BMD and thus susceptibility to fracture risk. PTH stimulates the proliferation of osteoprogenitor cells, production of alkaline phosphatise, and bone matrix proteins that contribute to hard callus formation and increases strength at the site of fractured bone. During remodeling, PTH promotes osteoclastogenesis restoring the original shape, structure, and mechanical strength of the bone. Some PTH polymorphisms have shown an association with fracture risk. Further research is needed to elucidate the relative importance of PTH genetics and the mechanisms of genetic contributions to gene-gene interactions in the pathogenesis of osteoporosis and in fracture healing. PMID:26194148

  12. Suppression of Parathyroid Hormone in a Patient with Severe Magnesium Depletion

    PubMed Central

    Fernandez, Isaac; Kochar, Tina

    2016-01-01

    Hypomagnesemia is often associated with coexisting electrolyte abnormalities like hypokalemia and hypocalcemia. Hypocalcemia has been shown to be secondary to hypoparathyroidism induced by hypomagnesemia. Here, we discuss a case of a patient with severe hypomagnesemia and associated hypocalcemia. A 38-year-old lady was admitted to the hospital for weakness of lower extremities and an eventual fall. The exam was significant for decreased motor strength and some paresthesias. The laboratory data was significant for hypomagnesemia, hypokalemia, and low parathyroid level in the face of hypocalcemia. After replacing magnesium, the parathyroid hormone levels normalized and led to eventual correction of calcium levels without any additional calcium replacement therapy. There was complete symptom resolution with correction of electrolyte abnormalities. This case highlights the importance of looking for all associated abnormalities in a patient with hypomagnesemia and starting the replacement therapy by first replacing the magnesium and then the others as needed. Replacing the magnesium alone may correct the hypoparathyroidism and eliminate the need for calcium replacement. PMID:27190662

  13. Parathyroid-specific epidermal growth factor-receptor inactivation prevents uremia-induced parathyroid hyperplasia in mice

    PubMed Central

    Arcidiacono, Maria Vittoria; Yang, Jing; Fernandez, Elvira; Dusso, Adriana

    2015-01-01

    Background In chronic kidney disease (CKD), parathyroid hyperplasia contributes to high serum parathyroid hormone (PTH) and also to an impaired suppression of secondary hyperparathyroidism by calcium, vitamin D and fibroblast growth factor 23 (FGF23). In rats, systemic inhibition of epidermal growth factor receptor (EGFR) activation markedly attenuated uremia-induced parathyroid hyperplasia and vitamin D receptor (VDR) loss, hence restoring the response to vitamin D. Therefore, we propose that parathyroid-specific EGFR inactivation should prevent CKD-induced parathyroid hyperplasia. Methods A dominant-negative human EGFR mutant, which forms non-functional heterodimers with full-length endogenous EGFR, was successfully targeted to the parathyroid glands (PTGs) of FVB/N mice, using the 5? regulatory sequence of the PTH promoter. The parathyroid phenotype and serum chemistries of wild-type (WT) and transgenic mice were examined after 14 weeks of either sham operation or 75% renal mass reduction (NX). Results Both genotypes had similar morphology and body weight, and NX-induction enhanced similarly serum blood urea nitrogen compared with sham-operated controls. However, despite similar serum calcium, phosphate and FGF23 levels in NX mice of both genotypes, parathyroid EGFR inactivation sufficed to completely prevent the marked increases in PTG enlargement, serum PTH and in parathyroid levels of transforming growth factor-?, a powerful EGFR-activator, and the VDR reductions observed in WT mice. Conclusion In CKD, parathyroid EGFR activation is essential for parathyroid hyperplasia and VDR loss, rendering this transgenic mouse a unique tool to scrutinize the pathogenesis of parathyroid and multiple organ dysfunction of CKD progression unrelated to parathyroid hyperplasia. PMID:25324357

  14. 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.

  15. 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

    2016-01-01

    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

  16. 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

  17. Actin-Sorting Nexin 27 (SNX27)-Retromer Complex Mediates Rapid Parathyroid Hormone Receptor Recycling.

    PubMed

    McGarvey, Jennifer C; Xiao, Kunhong; Bowman, Shanna L; Mamonova, Tatyana; Zhang, Qiangmin; Bisello, Alessandro; Sneddon, W Bruce; Ardura, Juan A; Jean-Alphonse, Frederic; Vilardaga, Jean-Pierre; Puthenveedu, Manojkumar A; Friedman, Peter A

    2016-05-20

    The G protein-coupled parathyroid hormone receptor (PTHR) regulates mineral-ion homeostasis and bone remodeling. Upon parathyroid hormone (PTH) stimulation, the PTHR internalizes into early endosomes and subsequently traffics to the retromer complex, a sorting platform on early endosomes that promotes recycling of surface receptors. The C terminus of the PTHR contains a type I PDZ ligand that binds PDZ domain-containing proteins. Mass spectrometry identified sorting nexin 27 (SNX27) in isolated endosomes as a PTHR binding partner. PTH treatment enriched endosomal PTHR. SNX27 contains a PDZ domain and serves as a cargo selector for the retromer complex. VPS26, VPS29, and VPS35 retromer subunits were isolated with PTHR in endosomes from cells stimulated with PTH. Molecular dynamics and protein binding studies establish that PTHR and SNX27 interactions depend on the PDZ recognition motif in PTHR and the PDZ domain of SNX27. Depletion of either SNX27 or VPS35 or actin depolymerization decreased the rate of PTHR recycling following agonist stimulation. Mutating the PDZ ligand of PTHR abolished the interaction with SNX27 but did not affect the overall rate of recycling, suggesting that PTHR may directly engage the retromer complex. Coimmunoprecipitation and overlay experiments show that both intact and mutated PTHR bind retromer through the VPS26 protomer and sequentially assemble a ternary complex with PTHR and SNX27. SNX27-independent recycling may involve N-ethylmaleimide-sensitive factor, which binds both PDZ intact and mutant PTHRs. We conclude that PTHR recycles rapidly through at least two pathways, one involving the ASRT complex of actin, SNX27, and retromer and another possibly involving N-ethylmaleimide-sensitive factor. PMID:27008860

  18. 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.

  19. RAGE supports parathyroid hormone-induced gains in femoral trabecular bone

    PubMed Central

    Philip, Binu K.; Childress, Paul J.; Robling, Alexander G.; Heller, Aaron; Nawroth, Peter P.; Bierhaus, Angelika

    2010-01-01

    Parathyroid hormone (PTH) restores bone mass to the osteopenic skeleton, but significant questions remain as to the underlying mechanisms. The receptor for advanced glycation end products (RAGE) is a multiligand receptor of the immunoglobulin superfamily; however, recent studies indicate a role in bone physiology. We investigated the significance of RAGE to hormone-induced increases in bone by treating 10-wk-old female Rage-knockout (KO) and wild-type (WT) mice with human PTH-(1–34) at 30 μg·kg−1·day−1 or vehicle control, 7 days/wk, for 7 wk. PTH produced equivalent relative gains in bone mineral density (BMD) and bone mineral content (BMC) throughout the skeleton in both genotypes. PTH-mediated relative increases in cortical area of the midshaft femur were not compromised in the null mice. However, the hormone-induced gain in femoral cancellous bone was significantly attenuated in Rage-KO mice. The loss of RAGE impaired PTH-mediated increases in femoral cancellous bone volume, connectivity density, and trabecular number but did not impact increases in trabecular thickness or decreases in trabecular spacing. Disabling RAGE reduced femoral expression of bone formation genes, but their relative PTH-responsiveness was not impaired. Neutralizing RAGE did not attenuate vertebral cancellous bone response to hormone. Rage-null mice exhibited an attenuated accrual rate of bone mass, with the exception of the spine, and an enhanced accrual rate of fat mass. We conclude that RAGE is necessary for key aspects of the skeleton's response to anabolic PTH. Specifically, RAGE is required for hormone-mediated improvement of femoral trabecular architecture but not intrinsically necessary for increasing cortical thickness. PMID:20028966

  20. Parathyroid cancer

    PubMed Central

    McClenaghan, Fiona

    2015-01-01

    Parathyroid carcinoma is an exceedingly rare endocrine malignancy first described in 1933. It accounts for between 0.5% and 5% of all cases of primary hyperparathyroidism. Parathyroid carcinoma is unusual among endocrine malignancies, being more hormonally active than its benign counterpart. Parathyroid carcinoma poses a diagnostic challenge both clinically and histologically due to the lack of features which can definitively distinguish malignant from benign disease early in its clinical course. Here, we describe the clinical features of the disease, and present the current opinion on optimal management. Further, we analyse the most recent histological advances made to aid in the diagnosis and management of this rare, but potentially devastating, disease. PMID:26312219

  1. 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.

  2. FGF23 Fails to Inhibit Uremic Parathyroid Glands

    PubMed Central

    Canalejo, Rocío; Canalejo, Antonio; Martinez-Moreno, Julio Manuel; Rodriguez-Ortiz, M. Encarnacion; Estepa, Jose C.; Mendoza, Francisco Javier; Munoz-Castaneda, Juan Rafael; Shalhoub, Victoria; Rodriguez, Mariano

    2010-01-01

    Fibroblast growth factor 23 (FGF23) modulates mineral metabolism by promoting phosphaturia and decreasing the production of 1,25-dihydroxyvitamin D3. FGF23 decreases parathyroid hormone (PTH) mRNA and secretion, but despite a marked elevation in FGF23 in uremia, PTH production increases. Here, we investigated the effect of FGF23 on parathyroid function in normal and uremic hyperplastic parathyroid glands in rats. In normal parathyroid glands, FGF23 decreased PTH production, increased expression of both the parathyroid calcium-sensing receptor and the vitamin D receptor, and reduced cell proliferation. Furthermore, FGF23 induced phosphorylation of extracellular signal–regulated kinase 1/2, which mediates the action of FGF23. In contrast, in hyperplastic parathyroid glands, FGF23 did not reduce PTH production, did not affect expression of the calcium-sensing receptor or vitamin D receptor, and did not affect cell proliferation. In addition, FGF23 failed to activate the extracellular signal–regulated kinase 1/2–mitogen-activated protein kinase pathway in hyperplastic parathyroid glands. We observed very low expression of the FGF23 receptor 1 and the co-receptor Klotho in uremic hyperplastic parathyroid glands, which may explain the lack of response to FGF23 in this tissue. In conclusion, in hyperparathyroidism secondary to renal failure, the parathyroid cells resist the inhibitory effects of FGF23, perhaps as a result of the low expression of FGF23 receptor 1 and Klotho in this condition. PMID:20431039

  3. 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.

  4. Regional myocardial blood flow distribution during intracoronary infusion of parathyroid hormone

    SciTech Connect

    Crass, M.F. III; Lust, R.M.

    1986-03-01

    Although low doses of the biologically-active fragment of parathyroid hormone PTH-(1-34), have been shown to produce potent dilation of the coronary circulation specific regional and transmural (endo/epi) myocardial blood flow (MBF) responses to the hormone have not been described. Anesthetized open-chest mongrel dogs were instrumented to quantitate coronary blood flow and other cardiodynamic parameters. PTH-(1-34) was infused into the left circumflex artery (.008 nmol kg/sup -1/ min/sup -1/). Using the reference withdrawal method, radionuclide-labeled microspheres were injected before (basal flow), during (8 min after new steady-state flow), and after (restoration of basal flow) a 20 min infusion of PTH-(1-34). MFB increased from 76 +- 1.9 to 152 +- 3.5 ml min/sup -1/ 100 g/sup -1/ (P < .001) during PTH-(1-34) infusion. No differences in endo/epi flow ratio or regional coronary blood flow within the left ventricle were detected. Thus, in anesthetized dogs, the increase in MBF observed secondary to the PTH-(1-34)-induced decrease in coronary resistance appeared to be uniform transmurally and regionally, and is probably not the result of a shunting or steal phenomenon.

  5. 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.

  6. 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.

  7. HUMAN INTERVENTIONS TO CHARACTERIZE NOVEL RELATIONSHIPS BETWEEN THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM AND PARATHYROID HORMONE

    PubMed Central

    Brown, Jenifer M.; Williams, Jonathan S.; Luther, James M.; Garg, Rajesh; Garza, Amanda E.; Pojoga, Luminita H.; Ruan, Daniel T.; Williams, Gordon H.; Adler, Gail K.; Vaidya, Anand

    2014-01-01

    Observational studies in primary hyperaldosteronism (PA) suggest a positive relationship between aldosterone and parathyroid hormone (PTH); however, interventions to better characterize the physiologic relationship between the renin-angiotensin-aldosterone system (RAAS) and PTH are needed. We evaluated the effect of individual RAAS components on PTH using 4 interventions in humans without PA. PTH was measured before and after: Study 1) low-dose angiotensin II [AngII] infusion (1 ng/kg/min) and captopril administration (25 mg × 1); Study 2) high-dose AngII infusion (3 ng/kg/min); Study 3) blinded crossover randomization to aldosterone infusion (0.7 µg/kg/hr) and vehicle; and Study 4) blinded randomization to spironolactone (50mg/daily) or placebo for 6 weeks. Infusion of AngII at 1 ng/kg/min acutely increased aldosterone (+148%) and PTH (+10.3%), while AngII at 3 ng/kg/min induced larger incremental changes in aldosterone (+241%) and PTH (+36%) (P<0.01). Captopril acutely decreased aldosterone (−12%) and PTH (−9.7%) (P<0.01). In contrast, aldosterone infusion robustly raised serum aldosterone (+892%) without modifying PTH. However, spironolactone therapy over 6 weeks modestly lowered PTH when compared to placebo (P<0.05). In vitro studies revealed the presence of AngII type I and mineralocorticoid receptor mRNA and protein expression in normal and adenomatous human parathyroid tissues. We observed novel pleiotropic relationships between RAAS components and the regulation of PTH in individuals without PA: the acute modulation of PTH by the RAAS appears to be mediated by AngII, whereas the long-term influence of the RAAS on PTH may involve aldosterone. Future studies to evaluate the impact of RAAS inhibitors in treating PTH-mediated disorders are warranted. PMID:24191286

  8. Hypercalcemia and parathyroid hormone-related peptide expression in a dog with thyroid carcinoma and histiocytic sarcoma.

    PubMed

    Scruggs, Jennifer L; Nobrega-Lee, Michelle; Fry, Michael M; Applegate, Rory

    2015-06-01

    A 9.5-year-old, male castrated Walker Hound was presented for evaluation of progressive weakness, anorexia, and weight loss. Imaging revealed multiple abdominal and thoracic masses and ascites; fine-needle aspirates of mesenteric and splenic masses confirmed malignancy, most likely histiocytic sarcoma. Laboratory analyses revealed increased ionized calcium and parathyroid hormone-related peptide (PTH-rP) concentrations, and concurrent low-normal parathyroid hormone concentration, consistent with humoral hypercalcemia of malignancy. Necropsy was performed after euthanasia. The dog had disseminated histiocytic sarcoma, including sarcomatosis, as well as bilateral thyroid carcinoma. PTH-rP immunostaining was positive in the thyroid carcinoma but negative in the histiocytic neoplasm. These results suggest that thyroid carcinoma-associated hypercalcemia can be caused by tumor secretion of PTH-rP. PMID:25707928

  9. Humoral hypercalcemia due to gastric carcinoma secreting parathyroid hormone-related protein during chemotherapy: a case report.

    PubMed

    Iino, Chikara; Shimoyama, Tadashi; Akemoto, Yui; Igarashi, Takasato; Aihara, Tomoyuki; Ishii, Kentaro; Sakamoto, Juichi; Tono, Hiroshi; Fukuda, Shinsaku

    2016-04-01

    Humoral hypercalcemia due to a gastric carcinoma-secreting parathyroid hormone-related protein (PTHrP) is a rare disease associated with poor prognosis. A 61-year-old male with gastric cancer who had been receiving chemotherapy showed serum hypercalcemia and an elevated level of serum PTHrP with a suppressed intact parathyroid hormone level. Computed tomography revealed stable disease 4 weeks prior, and the laboratory examination revealed no adverse effects 2 weeks prior. The biopsy at the time of diagnosis was immunohistochemically positive for PTHrP later. Despite intensive care, the patient died of multiorgan failure on the 14th day after admission. In case of undifferentiated gastric cancer, the possibility of humoral hypercalcemia of malignancy caused by gastric cancer should be considered even when the patient is receiving chemotherapy. PMID:26972102

  10. 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

  11. 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; Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan 430079

    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 asymmetry.

  12. Parathyroid carcinoma.

    PubMed

    Butt, Waqas Tariq; Azim, Asad; Abbas, Ansab; Gauhar, Tooba Mahmud; Afzal, Ameer; Azim, Khawaja Muhammad

    2012-09-01

    Parathyroid carcinoma is a rare endocrine malignancy accounting for less than 1% of all cases of hyperparathyroidism. We present a case of a middle-aged woman who was undiagnosed for 3 years before presenting with renal stones and advanced musculoskeletal disease. Investigations revealed primary hyperparathyroidism. Focused cervical exploration and left inferior parathyroidectomy was carried out based on the pre-operative localization studies. Parathyroid carcinoma was diagnosed on histopathology postoperatively. Subsequent en bloc resection was not performed and the patient is being monitored with serial parathyroid hormone levels which have not shown any increase in 6 months of follow-up. Only two previous cases of parathyroid carcinoma have been reported from Pakistan. PMID:22980615

  13. 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.

  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. Serum Parathyroid Hormone Concentrations and Clinical Outcomes in ESRD: A Call for Targeted Clinical Trials.

    PubMed

    Zand, Ladan; Kumar, Rajiv

    2016-05-01

    Secondary hyperparathyroidism almost universally accompanies end-stage renal disease (ESRD). In some, but not all studies, elevated serum parathyroid hormone (PTH) concentrations are associated with increased fracture rates, cardiovascular disease, and mortality in ESRD. The serum concentration of PTH required for optimal bone health and reduced cardiovascular risk in such patients remains elusive. Recent clinical trials have failed to show substantial changes in morbidity and mortality following reductions of elevated serum PTH concentrations. In this review, we will assess some of the difficulties in evaluating elevated serum PTH concentrations, and their association with skeletal fractures and mortality in ESRD patients. We are of the opinion that in the context of ESRD, elevated PTH concentrations occur in conjunction with other comorbid conditions such as diabetes mellitus, malnutrition, hypertension, volume excess, preexisting heart disease, all of which have prevented establishing a precise association between elevated serum PTH concentrations and global or skeletal outcomes. Age, gender, and racial variability among groups make interpretation exceptionally difficult. Analysis of prevalent ESRD populations with secondary hyperparathyroidism should take all these factors into account. We suggest that future clinical trials which examine the usefulness of reductions in serum PTH concentrations be conducted in age, sex, and racially balanced groups, without or with minimal coexisting confounding disease. Furthermore, trials in such populations should have as their primary outcome a reduction in fractures rather than an alteration in mortality. PMID:26676210

  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. Effects of Nigella sativa and human parathyroid hormone on bone mass and strength in diabetic rats.

    PubMed

    Altan, Mehmet Fatih

    2007-06-01

    Osteoporosis is a major complication in patients with diabetes mellitus (DM), particularly in those with insulin dependency. Recently, many therapeutic effects of Nigella sativa L. (NS) extracts have been exhibited such as anti-inflammatory, antitumor, and antidiabetic with clinical and experimental studies. Mechanical strength in the femur and vertebrae increases with human parathyroid hormone (hPTH) treatment. The aim of the present study was to test the hypothesis that combined treatment with NS and hPTH is more effective than treatment with NS or hPTH alone in improving bone mass, connectivity, and biomechanical behavior using the finite element method (FEM) in insulin-dependent diabetic rats. In the mechanical analysis, five rat bones (control, diabetic diabetic NS treated, diabetic hPTH treated, and diabetic NS + hPTH treated) have been studied for bending analysis using the finite element analysis program ANSYS. Combined treatment of NS and hPTH was more effective on bone histomorphometry and mechanical strength than treatment with NS or hPTH alone for streptozotocin-induced diabetic osteopenia, which notably decreased bone volume. PMID:17709912

  18. Association between Parathyroid Hormone Levels and Inflammatory Markers among US Adults

    PubMed Central

    Cheng, Shih-Ping; Liu, Chien-Liang; Liu, Tsang-Pai; Hsu, Yi-Chiung; Lee, Jie-Jen

    2014-01-01

    Background and Aims. High levels of parathyroid hormone (PTH) appear to be associated with an increased mortality. Previous studies concerning the relationship of inflammatory markers with hyperparathyroidism have yielded inconsistent results. This study investigated whether serum PTH concentrations were independently associated with several inflammatory markers among the US adults. Materials and Methods. Using data from the National Health and Nutrition Examination Survey, we examined the relation between serum PTH and C-reactive protein (CRP), red cell distribution width (RDW), and platelet-to-lymphocyte ratio (PLR) levels with weighted linear regression. Additionally, we examined the relation with increased modified Glasgow Prognostic Score (mGPS) by using weighted logistic regression. Results. CRP, RDW, and PLR values increased with increasing serum PTH concentration. After extensively adjusting for covariates, CRP and RDW increased linearly and across PTH categories (all P < 0.001), while PLR marginally increased (P = 0.190 and P = 0.095 using PTH as a categorical and continuous variable, resp.). The odds ratio of increased mGPS was 1.11 and 1.31 across PTH categories and with increasing PTH levels continuously. Conclusion. These nationally representative data indicate that serum PTH levels are independently associated with several inflammatory markers in the US population. The casual relationship between PTH levels and inflammation remains to be elucidated. PMID:24782595

  19. Canine renal parathyroid hormone receptor is a glycoprotein: characterization and partial purification

    SciTech Connect

    Karpf, D.B.; Arnaud, C.D.; King, K.; Bambino, T.; Winer, J.; Nyiredy, K.; Nissenson, R.A.

    1987-12-01

    Covalent labeling of the canine renal parathyroid hormone receptor with (/sup 125/I)bPTH(1-34) reveals several major binding components that display characteristic consistent with a physiologically relevant adenylate cyclase linked receptor. Through the use of the specific glycosidases neuraminidase and endoglycosidase F and affinity chromatography on lectin-agarose gels, we show here that the receptor is a glycoprotein that contains several complex N-linked carbohydrate chains consisting of terminal sialic acid and penultimate galactose in a ..beta..1,4 linkage to N-acetyl-D-glucosamine. No high mannose chains or O-linked glycans appear to be present. The peptide molecular weight of the deglycosylated labeled receptor is 62,000 (or 58,000 if the mass of bPTH(1-34) is excluded). The binding of (/sup 125/I)bPTH(1-34) to the receptor is inhibited in a dose-dependent fashion by wheat-germ agglutinin, but not by either succinylated wheat-germ agglutinin or Ricinus communis lectin, suggesting that terminal sialic acid may be involved in agonist binding. A combination of lectin affinity chromatography and immunoaffinity chromatography affords a 200-fold purification of the covalently labeled receptor.

  20. 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.

  1. 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

  2. Role of Parathyroid Hormone-Related Protein Signaling in Chronic Pancreatitis

    PubMed Central

    Falzon, Miriam; Bhatia, Vandanajay

    2015-01-01

    Chronic pancreatitis (CP), a progressive inflammatory disease where acini are destroyed and replaced by fibrous tissue, increases the risk for pancreatic cancer. Risk factors include alcohol, smoking, and obesity. The effects of these risk factors are exacerbated in patients with mutations in genes that predispose to CP. The different environmental and genetic factors produce the same clinical phenotype; once CP develops, disease course is the same regardless of etiology. Critical questions still need to be answered to understand what modifies predisposition to develop CP in persons exposed to risk factors. We postulate that risk factors modulate endogenous pathways, with parathyroid hormone-related protein (PTHrP) signaling being one such pathway. In support, PTHrP levels are elevated in mice treated with alcohol, and in mouse models of cerulein- and pancreatic duct ligation-induced CP. Disrupting the Pthrp gene in acinar cells exerts protective effects (decreased edema, histological damage, amylase and cytokine release, and fibrosis) in these CP models. PTHrP levels are elevated in human CP. Currently, CP care lacks specific pharmacological interventions. Targeting PTHrP signaling may present a novel therapeutic strategy that inhibits pancreatic inflammation and fibrosis, especially since the risk of developing pancreatic cancer is strongly associated with duration of chronic inflammation. PMID:26095761

  3. 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

    2015-01-01

    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. 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

  4. The parathyroid hormone, its fragments and analogues--potent bone-builders for treating osteoporosis.

    PubMed

    Whitfield, J; Morley, P; Willick, G

    2000-06-01

    As populations age a rising number of men and women, but especially women during the first decade after menopause, become victims of a severe, accelerated loss of bone with crippling fractures known as osteoporosis. This often results in costly, prolonged hospitalisation and perhaps indirectly, death. Osteoporosis in women is caused by the menopausal oestrogen decline, which removes several key restraints on the generation, longevity and activity of bone-resorbing osteoclasts. Although there are many antiresorptive drugs on or coming onto the market (calcitonin, bisphosphonates, oestrogen and SERMS) that can slow or stop further bone loss, there are none that can restore lost bone mechanical strength by directly stimulating osteoblast activity and bone growth. However, there is a family of potent bone-building peptides, namely the 84 amino acid parathyroid hormone (PTH). Its 31 to 38 amino acid N-terminal fragments are currently in or about to enter clinical trials. We can predict that these peptides will be effective therapeutics for osteoporosis especially when supplemented with bisphosphonates or SERMs to protect the new bone from osteoclasts. These peptides should also accelerate the healing of fractures in persons of all ages and restore lost bone mass and mechanical strength to astronauts following their return to earth after long voyages in space. PMID:11060744

  5. Immunoassays for parathyroid hormone 1-84 in the diagnosis of hyperparathyroidism.

    PubMed

    Nussbaum, S R; Potts, J T

    1991-10-01

    The two most frequent causes for hypercalcemia are primary hyperparathyroidism and hypercalcemia associated with malignancy. Elevated or inappropriately high PTH serum levels are the hallmark of hyperparathyroidism. Sensitive immunometric assays for the secreted, biologically active, intact parathyroid hormone molecule, PTH-(1-84), employ two populations of region-specific antibodies, take advantage of saturation kinetics rather than competitive binding, and have many technical advantages over conventional radioimmunoassay. Approximately 90% of patients with primary hyperparathyroidism have elevated serum levels of PTH-(1-84) by immunometric assay; the remainder have inappropriately elevated values of PTH for the serum calcium concentration. Clinical correlation studies comparing measurements of PTH using antisera that recognize the carboxyl, midregion, or amino terminus of PTH with PTH levels determined by immunometric assays demonstrate elevated values in equivalent numbers of hyperparathyroid individuals. Immunometric assays for PTH-(1-84) have their greatest value in separating patients with hyperparathyroidism from those with hypercalcemia of malignancy. In earlier studies using region-specific antisera, there was virtually always an overlap of serum PTH levels in hyperparathyroidism and hypercalcemia associated with malignancy. In contrast, analysis of results using PTH-(1-84) immunometric assays in several hundred reported patients shows a complete separation of PTH values. Clinical judgment, combined with measurement of PTH in the setting of hypercalcemia, can lead to the diagnosis of hyperparathyroidism with confidence in essentially all patients. PMID:1722383

  6. Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease.

    PubMed

    Isakova, Tamara; Wahl, Patricia; Vargas, Gabriela S; Gutiérrez, Orlando M; Scialla, Julia; Xie, Huiliang; Appleby, Dina; Nessel, Lisa; Bellovich, Keith; Chen, Jing; Hamm, Lee; Gadegbeku, Crystal; Horwitz, Edward; Townsend, Raymond R; Anderson, Cheryl A M; Lash, James P; Hsu, Chi-Yuan; Leonard, Mary B; Wolf, Myles

    2011-06-01

    Fibroblast growth factor 23 (FGF23) regulates phosphorus metabolism and is a strong predictor of mortality in dialysis patients. FGF23 is thought to be an early biomarker of disordered phosphorus metabolism in the initial stages of chronic kidney disease (CKD). We measured FGF23 in baseline samples from 3879 patients in the Chronic Renal Insufficiency Cohort study, which is a diverse cohort of patients with CKD stage 2-4. Mean serum phosphate and median parathyroid hormone (PTH) levels were in the normal range, but median FGF23 was markedly greater than in healthy populations, and increased significantly with decreasing estimated glomerular filtration rate (eGFR). High levels of FGF23, defined as being above 100 RU/ml, were more common than secondary hyperparathyroidism and hyperphosphatemia in all strata of eGFR. The threshold of eGFR at which the slope of FGF23 increased was significantly higher than the corresponding threshold for PTH based on non-overlapping 95% confidence intervals. Thus, increased FGF23 is a common manifestation of CKD that develops earlier than increased phosphate or PTH. Hence, FGF23 measurements may be a sensitive early biomarker of disordered phosphorus metabolism in patients with CKD and normal serum phosphate levels. PMID:21389978

  7. T Lymphocytes Amplify the Anabolic Activity of Parathyroid Hormone Through Wnt10b Signaling

    PubMed Central

    Terauchi, Masakazu; Li, Jau-Yi; Bedi, Brahmchetna; Baek, Ki-Hyun; Tawfeek, Hesham; Galley, Sarah; Gilbert, Linda; Nanes, Mark S.; Zayzafoon, Majd; Guldberg, Robert; Lamar, David L.; Singer, Meredith A.; Lane, Timothy F.; Kronenberg, Henry M.; Weitzmann, M. Neale; Pacifici, Roberto

    2009-01-01

    Summary Intermittent administration of parathyroid hormone (iPTH) is used to treat osteoporosis as it improves bone architecture and strength, but the underlying cellular and molecular mechanisms are unclear. Here we show that iPTH increases the production of Wnt10b by bone marrow CD8+ T cells, and induces these lymphocytes to activate canonical Wnt-signaling in pre-osteoblasts. Accordingly, in responses to iPTH, T cell null mice display diminished Wnt signaling in pre-osteoblasts and blunted osteoblastic commitment, proliferation, differentiation and lifespan which result in decreased trabecular bone anabolism and no increase in strength. Demonstrating the specific role of lymphocytic Wnt10b, iPTH has no anabolic activity in mice lacking T cell produced Wnt10b. Therefore, T cell mediated activation of Wnt signaling in osteoblastic cells plays a key permissive role in the mechanism by which iPTH increases bone strength, suggesting that T cell osteoblast cross-talk pathways may provide pharmacological targets for bone anabolism. PMID:19723499

  8. 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

  9. [Design and activity verification of human parathyroid hormone (1-34) mutant protein].

    PubMed

    Qiu, Shuang; Jiang, Yue-Shui; Li, Zhi-Qin; Lei, Jian-Yong; Chen, Yun; Jin, Jian

    2012-07-01

    Through protein-protein BLAST of homologous sequences in different species in NCBI database and preliminary simulating molecular docking and molecular dynamics by computer software discovery studio 3.1, three amino acids R25K26K27 of natural human parathyroid hormone (1-34) with Q25E26L27 were mutated and the biological activity of the mutant peptide was evaluated. Result showed that: root mean superposition deviation RMSD value between PTH (1-34)-(RKK-QEL) and PTH (1-34) peptide main chain was 2.509 3, indicating that the differences between the two main chain structural conformation was relatively small; the interaction energy between PTH (1-34)-(RKK-QEL) and its receptor protein PTH1R had been enhanced by 7.5% compared to nature PTH (1-34), from -554.083 kcal x mol(-1) to -599.253 kcal x mol(-1); the number of hydrogen bonds was increased from 32 to 38; PTH (1-34)-(RKK-QEL) can significantly stimulate the RANKL gene expression (P < 0.01) while inhibiting the OPG gene expression (P < 0.01) in UAMS-32P cells; in the co-culture system of UAMS-32P cells and mouse primary femur bone marrow cells, PTH (1-34)-(RKK-QEL) stimulated the formation of osteoclasts (P < 0.01) and had a higher biological activity than PTH (1-34) standard reagents. PMID:22993856

  10. 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 intermittent administration of parathyroid hormone and noise-like whole-body vibration. Indentation modulus was 46% higher in groups treated with noise-like whole-body vibration and 43% higher in groups treated with both intermittent administration of parathyroid hormone and noise-like whole-body vibration, and hardness was 31% higher in groups treated with both intermittent administration of parathyroid hormone and noise-like whole-body vibration compared with the control group. There was no interaction between the two treatments for both structure and mechanical indexes. The main effects of intermittent administration of parathyroid hormone and noise-like whole-body vibration on bone repair included increased bone formation and enhanced mechanical function of regenerated bone, respectively. The combined treatment resulted in further regeneration of bone with high indentation modulus and hardness, suggesting the therapeutic potential of the combined use of noise-like whole-body vibration and intermittent administration of parathyroid hormone for enhancing osteoporotic bone healing. PMID:26586525

  11. 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

  12. Circulating parathyroid hormone activity: familial hypocalciuric hypercalcemia versus typical primary hyperparathyroidism.

    PubMed

    Marx, S J; Spiegel, A M; Brown, E M; Windeck, R; Gardner, D G; Downs, R W; Attie, M; Aurbach, G D

    1978-12-01

    Three indices of circulating parathyroid hormone (PTH) activity were compared between two groups: the first a group of 23 patients from three large kindreds with autosomal dominant hypercalcemia without hypercalciuria [familial hypocalciuric hypercalcemia (FHH)] and the second a group of 64 patients with typical primary hyperparathyroidism (1HPT) manifesting comparable hypercalcemia. The group with 1HPT differed from normal with respect to plasma PTH 1HPT concentration (normal, less 0.2 ng/ml), urinary cAMP excretion per 100 ml glomerular filtrate (U cAMP/GF) (normal, 2.3 x/divided by 0.6 nmol/100 ml glomerular filtrate; mean, x/divided 1 SD), and renal tubular maximum of phosphate transport corrected for glomerular filtration rate (TMP/GFR; normal, 3.4 +/- 0.4 mg/dl; mean, +/- 1 SD). The group with 1HPT also diverged significantly from the group with FHH for all three indices: for PTH, 0.37 x/divided by .48 vs. 0.25 x/divided .46 (P less than 0.05); for UcAMP/GF, 4.3 x/divided by .53 vs. 2.6 x/divided .60 (P less than 0.0005); and for TMP/GFR, 2.0 +/- 0.6 vs. 2.6 +/- 0.7 (P less than 0.01). The between-group differences for all three indices were also significant after adjustment for their variation with serum calcium. However, only the difference in TMP/GFR remained significant after adjustment for covariance attributable to serum calcium concentration, age, and creatinine clearance. The group with FHH differed from normal for TMP/GFR but not for UcAMP/GF. However, analysis of changes in UcAMP/GF and serum calcium concentration around the time of parathyroidectomy in three patients with FHH suggested that the parathyroid glands contributed to the abnormalities of mineral homeostasis in at least one. It was concluded that higher serum concentrations of PTH do not account for the lower renal clearance of calcium and magnesium in FHH calcium concentration, the group with FHH showed indices suggesting lower circulating PTH activity than the group with 1HPT. PMID:233692

  13. 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. PMID:25395280

  14. A 10-Year Experience in Intraoperative Parathyroid Hormone Measurements for Primary Hyperparathyroidism: A Prospective Study of 91 Previous Unexplored Patients

    PubMed Central

    Neves, M. C.; Ohe, M. N.; Rosano, M.; Abrahão, M.; Cervantes, O.; Lazaretti-Castro, M.; Vieira, J. G. H.; Kunii, I. S.; Santos, R. O.

    2012-01-01

    Introduction. Primary hyperparathyroidism (PHP) is characteristically determined by high levels of calcium and high or inappropriate levels of parathyroid hormone (PTH). Technological advances have dramatically changed the surgical technique over the years once intraoperative parathyroid hormone (IOPTH) assay had allowed for focused approaches. Objective. To evaluate our 10-year experience in employing a rapid intraoperative PTH assay for PHP. Methods. A prospective cohort of 91 PHP-operated patients in a tertiary institution in São Paulo, Brazil, from June 2000 to April 2011. Results. We had 85 (93.4%) successful parathyroidectomies, 6 (6.6%) failed parathyroidectomies in 91 previous unexplored patients, and 5 (100%) successful remedial surgeries. The IOPTH was true-positive in 88.5%, true-negative in 7.3%, false-positive in 2.1%, and false-negative in 2.1% of the procedures. IOPTH was able to obviate additional exploration or to ask for additional exploration in 92 (95.8%) procedures. Conclusion. The IOPTH revealed to be an important technological adjunct in the current parathyroid surgery for PHP. PMID:22523718

  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 examples of this are still unknown. This review will focus on what is known about PTH-mediated cell signaling, and discuss the established or putative PTH-regulated pattern of gene expression in osteoblastic cells following treatment with catabolic (high) or anabolic (low) concentrations of the hormone.

  16. The Association of 25 Hydroxyvitamin D and Parathyroid Hormone with Metabolic Syndrome in Two Ethnic Groups in South Africa

    PubMed Central

    George, Jaya A.; Norris, Shane A.; van Deventer, Hendrik Emmanuel; Crowther, Nigel J.

    2013-01-01

    Introduction Though inconsistent, a number of studies have shown an association between vitamin D (25(OH)D) status, parathyroid hormone (PTH) and the metabolic syndrome (Met S). These have largely been carried out in Caucasians or black subjects living in high income countries. There no data on the relationship of 25(OH)D and PTH status with Met S in populations resident in Africa. The aims of this study were to evaluate if there was an association of 25(OH)D or PTH with Met S in non-Caucasian populations in South Africa, and whether these molecules explained ethnic differences in the prevalence of Met S and its individual components. Methods We measured anthropometry, serum 25(OH)D and PTH levels and the components of Met S, plus related metabolic variables, in 374 African and 350 Asian Indian healthy adults from the greater Johannesburg metropolitan area. Results Met S was diagnosed in 29% of the African and 46% of the Asian Indian subjects (p<0.0001). Subjects with Met S had higher PTH than those without Met S, (p<0.0001), whilst 25(OH)D levels were not significantly different (p = 0.50). In multivariate analysis, 25(OH)D was not associated with any components of the Met S however PTH was shown to be positively associated with systolic (p = 0.018) and diastolic (p = 0.005) blood pressures and waist circumference (p<0.0001) and negatively associated with HOMA (p = 0.0008) levels. Logistic regression analysis showed that Asian Indian ethnicity (OR 2.24; 95% CIs 1.57, 3.18; p<0.0001) and raised PTH (OR 2.48; 95% CIs 1.01, 6.08; p = 0.04; adjusted for 25(OH)D) produced an increased risk of Met S but 25(OH)D did not (OR 1.25; 95% CI 0.67, 2.24; p = 0.48). Conclusions Plasma PTH but not 25(OH)D is an independent predictor of the Met S in African and Asian Indians in South Africa. PMID:23596520

  17. Heparin-insensitive calcium release from intracellular stores triggered by the recombinant human parathyroid hormone receptor.

    PubMed Central

    Seuwen, K; Boddeke, H G

    1995-01-01

    1. In the present study we have characterized the parathyroid hormone (PTH)-induced calcium signalling in 293 cells stably transfected with the human PTH receptor cDNA. In these cells, human PTH-1(1-38) strongly stimulates adenosine 3':5'-cyclic monophosphate (cyclic AMP) formation (EC50 = 0.39 nM) but fails to activate phosphoinositide (PI) turnover. The latter pathway is strongly activated, however, by carbachol (CCh) acting through endogenous M3-muscarinic receptors. 2. Despite the lack of detectable inositol phosphate (IP) formation, hPTH-(1-38) elicited calcium transients (EC50 = 11.2 nM) which were comparable to the signals evoked by CCh. These signals are independent of cyclic AMP generation as cyclic AMP elevating agents did not mimic or modify the PTH response. 3. The PTH-stimulated calcium signal still occurred in calcium-free medium but was absent in cells pretreated with thapsigargin, an inhibitor of the calcium pump of the endoplasmic reticulum (ER). hPTH-(1-38) did not accelerate Mn(2+)-influx through the plasma membrane. These data indicate that PTH releases calcium from intracellular stores. 4. Using heparin, an inhibitor of the IP3-activated calcium release channel of the ER, we tested whether the formation of a low amount of IP3, escaping detection by our biochemical assay, might be the origin of the PTH-induced calcium response. However, intracellular infusion of heparin through patch pipettes in voltage clamp experiments failed to block hPTH-(1-38)-induced calcium signals, whereas it abolished the CCh response.(ABSTRACT TRUNCATED AT 250 WORDS) Images Figure 1 PMID:7599930

  18. 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.

  19. 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.

  20. 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.

  1. Parathyroid hormone and arterial dysfunction in the Multi-Ethnic Study of Atherosclerosis

    PubMed Central

    Bosworth, Cortney; Sachs, Michael C.; Duprez, Daniel; Hoofnagle, Andrew N.; Ix, Joachim H.; Jacobs, David R.; Peralta, Carmen A.; Siscovick, David S.; Kestenbaum, Bryan; de Boer, Ian H.

    2013-01-01

    Objective High circulating concentrations of parathyroid hormone (PTH) have been associated with increased risks of hypertension, left ventricular hypertrophy, congestive heart failure, and cardiovascular mortality. Impaired arterial function is a potential mechanism for these associations. We tested whether serum PTH concentration is associated with measures of arterial function. Design Cross-sectional study. Participants 6,545 persons without clinical cardiovascular disease participating in the community-based Multi-Ethnic Study of Atherosclerosis. Measurements Brachial artery flow-mediated dilation as well as aortic pulse pressure and arterial pulse parameters derived from Windkessel modeling of the radial pressure waveform. Results Higher serum PTH concentration was associated with lower brachial artery flow-mediated dilation (mean difference −0.09% per 10 pg/mL PTH), higher aortic pulse pressure (0.53 mmHg per 10 pg/mL), and reduced Windkessel capacitive index C1 (large artery elasticity, −0.12 ml/mmHg X 10 per 10 pg/mL), adjusting for potential confounding variables (all p-values ≤ 0.001). These relationships were independent of serum calcium concentration, serum 25-hydroxyvitamin D concentration, and estimated glomerular filtration rate and were consistent across relevant participant subgroups. Associations of PTH with aortic pulse pressure and capacitive index C1 were attenuated after adjustment for blood pressure. Serum PTH concentration was not associated with the oscillatory index C2 (small artery elasticity). Conclusions Higher serum PTH concentration was associated with impaired endothelial function, increased aortic pulse pressure, and decreased capacitive index C1 in a large, diverse, community-based population. These relationships may help explain previously observed associations of elevated PTH with cardiovascular disease. PMID:23402353

  2. Minimally invasive parathyroidectomy with or without intraoperative parathyroid hormone for primary hyperparathyroidism

    PubMed Central

    Kim, Hyun Gu; Kim, Woo Young; Woo, Sang Uk; Lee, Jae Bok

    2015-01-01

    Purpose The improvement of intraoperative parathyroid hormone (IOPTH) assay and localization studies has enabled a minimally invasive parathyroidectomy (MIP) in primary hyperparathyroidism (pHPT). The aim of this study is to analyze the demographics, clinical presentations, and surgical outcomes of the pHPT patients who received surgical management with versus without IOPTH. Methods Analysis of a database was performed on 53 patients who underwent parathyroidectomy for pHPT from 2004 to 2013. Preoperative localization was done by both sestamibi scan and ultrasonography. We divided the patients into two groups (without IOPTH versus with IOPTH) and analyzed the surgical outcomes statistically between two groups. Results The concordance rate of Technetium 99m sestamibi scan and ultrasonography was 73.6% and 90.6%, respectively. The overall cure rate of group 1 (without IOPTH) was 94.9% and that of group 2 (with IOPTH) was 100%. The decline of PTH at postoperative 5 minutes and 10 minutes was 75.2% ± 14.9% and 84.9% ± 8.6% in cured patients. On the other hand, that of noncured patients at 5 minutes and 10 minutes was 17.2% ± 9.7% and 8.2% ± 2.2%. There was a significant difference in the drop rate of IOPTH between cured and persistent patients (P < 0.01). Pathological examination showed adenoma in 41 of 53 patients (77.4%) and hyperplasia in 10 of 53 patients (18.9%). Conclusion Even though the localization studies were successful, IOPTH monitoring is essential to avoid a surgical failure in MIP. PMID:26366379

  3. Renal adenylate cyclase assay for biologically active parathyroid hormone: clinical utility and physiological significance.

    PubMed

    Auf'mkolk, B; Hesch, R D

    1986-01-01

    The stimulation of cyclic AMP production by human renal cortical membranes in the presence of the GTP analogue 5'-guanylimidodiphosphate and a calcium chelator represents a homologous assay system for the evaluation of biologically active parathyroid hormone (bioPTH) in human serum. Bioactive PTH was raised above normal (normal range: undetectable to 4.6 pmol human PTH(1-34) per 1) in 13/17 (76%) patients with primary hyperparathyroidism, in 5/6 (83%) patients with surgically proven hyperparathyroidism secondary to chronic renal failure, in 4/5 (80%) patients with hyperparathyroidism secondary to hypocalcaemia, in all three patients with pseudohypoparathyroidism, in 5/17 (29%) patients with osteoporosis and in 1/9 (11%) patients with renal stones and/or hypercalciuria. Bioactive PTH correlated positively with immunoreactive PTH (iPTH) measured with a radioimmunoassay predominantly recognizing the middle- and carboxyl-terminal region of the PTH molecule (r = 0.503, P less than 0.001). A positive correlation (r = 0.572, P less than 0.05) was found between values of serum calcium and bioPTH in the group with primary hyperparathyroidism. Immunoreactive PTH did not correlate significantly with calcium in this group. In the other patients except those who had chronic renal failure, a negative correlation between serum calcium and both bioPTH and iPTH was observed (P less than 0.01). When alkaline phosphatase was compared with bioPTH in all patients, the correlation was positive (r = 0.390, P less than 0.01); no significant correlation existed between iPTH and alkaline phosphatase in the patients studied.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:3944539

  4. Parathyroid hormone-related protein (pthrp) is a gravisensor for lung and bone.

    NASA Astrophysics Data System (ADS)

    Torday, J.

    Parathyroid Hormone-related Protein (PTHrP) and its receptor represent a stretch- sensitive paracrine signaling mechanism (Torday, 1999) that may sense gravity. PTHrP has been shown to be essential for the development and homeostatic regulation of lung (Rubin et al, 2000) and bone (Kronenberg et al, 1994). Since both lung and bone structure and function are affected by microgravity, we hypothesized that microgravity down-regulates PTHrP signaling. To test this hypothesis, we suspended lung and bone cells in the microgravity environment of a rotating wall vessel apparatus, which simulates microgravity, for up to 72 hours. During the first 6-8 hours, PTHrP expression fell precipitously, decreasing by 80-90%; during the subsequent 64-66 hours, PTHrP expression remained at this newly established level. PTHrP production decreased from 5 pmol/ml/3hours to undetectable levels in culture medium from microgravity-exposed cells. The cells were then put back in culture 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 SLS-2, provided courtesy of the Biospecimen Facility, Ames Research Center, NASA, as a result of a peer-reviewed proposal). Analysis of PTHrP expression by femurs and tibias from these animals (n=5) revealed that PTHrP expression was 60% lower than in bones from ground-based rats. Interestingly, there were no differences in PTHrP exp ression by parietal bones, 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.

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

    PubMed

    Torday, J S

    2003-01-01

    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 x 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 x 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 24 hours, 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. PMID:15000128

  6. Low Dose Parathyroid Hormone Maintains Normal Bone Formation in Adult Male Rats During Rapid Weight Loss

    PubMed Central

    Turner, Russell T.; Iwaniec, Urszula T.

    2011-01-01

    A persistent negative energy balance results in bone loss. It is not clear whether the bone loss associated with chronic negative energy balance can be prevented. The objective of this study was to assess the efficacy of intermittent low dose parathyroid hormone (PTH) treatment in maintaining normal bone formation during severe energy restriction. Six-month-old male Fisher 344 rats were divided into 4 treatment groups: (1) baseline, (2) ad libitum (ad lib)-fed control, (3) energy-restricted (to consume 40% ad lib caloric intake), or (4) energy-restricted + low dose (1 μg/kg/d) PTH. Severe energy restriction for 14 days decreased body weight and serum leptin levels. Compared to ad lib-fed controls, energy-restricted rats had lower cancellous bone formation, higher osteoclast perimeter/bone perimeter and higher bone marrow adiposity in the proximal tibial metaphysis. Also, the energy-restricted rats had a lower periosteal bone formation rate at the tibia-fibula synostosis. Administration of PTH to energy-restricted rats had no effect on weight loss or osteoclast perimeter/bone perimeter. In contrast, energy-restricted rats treated with PTH had higher rates of cancellous and cortical bone formation compared to energy-restricted rats, and did not differ from the ad lib-fed control animals. Furthermore, PTH treatment maintained normal bone marrow adiposity. In conclusion, rapid weight loss in adult male rats was accompanied by decreased bone formation and increased bone marrow adiposity and these changes were prevented by low dose PTH treatment. Taken together, the results suggest that the energy cost of bone formation in adult rats is low and PTH therapy is effective in preventing the reduced bone formation associated with rapid weight loss. PMID:21215827

  7. 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

  8. Recombinant human parathyroid hormone 1-34: pharmacokinetics, tissue distribution and excretion in rats.

    TOXLINE Toxicology Bibliographic Information

    Hu Z; Niu H; Yang X; Li H; Sang G; Li B

    2006-07-24

    The objective of this work was to characterize the preclinical pharmacokinetics, tissue distribution, and excretion profiles of recombinant human parathyroid hormone (1-34) [rhPTH (1-34)] in healthy rats. Pharmacokinetic properties of (125)I-rhPTH (1-34) were examined after a single subcutaneous (s.c.) and intravenous (i.v.) bolus injection, respectively. Tissue distribution and urinary, fecal, and biliary excretion patterns of (125)I-rhPTH (1-34) were also investigated following a single s.c. injection. Our results suggested that rhPTH (1-34) was rapidly distributed and cleared in a bi-exponential manner after a single i.v. bolus injection. Following a single s.c. administration, rhPTH (1-34) exhibited rapid and considerable absorption and declined in a mono-exponential manner, with the absolute bioavailability and elimination half-life of 65% and 3.4-4.1h, respectively. The TCA-precipitated radioactivity was widely distributed and rapidly diminished in most tissues/organs. Approximately 91% and 2% of the total radioactivity was recovered in urine and feces by 72h postdosing, respectively; whereas 6% excreted into bile up to 24h postdosing. These findings indicated high absolute bioavailability, rapid absorption and disposition of rhPTH (1-34) following a single s.c. administration in healthy rats. The accumulation of rhPTH (1-34) in tissues/organs examined appeared to be low. The major elimination route was urinary excretion.

  9. 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, Mos; 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 (?-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 calcium concentrations and ?-adrenergic agonists modify PTH levels by two different and independent mechanisms. On the other hand, it appears that the magnitude of change of the PTH levels to either stimulus is partially modulated by exposure to the other. PMID:96135

  10. Interleukin-6 enhances hypercalcemia and bone resorption mediated by parathyroid hormone-related protein in vivo.

    PubMed Central

    de la Mata, J; Uy, H L; Guise, T A; Story, B; Boyce, B F; Mundy, G R; Roodman, G D

    1995-01-01

    Tumors frequently induce the multifunctional cytokine IL-6, which has been linked to several paraneoplastic syndromes, most notably cachexia. IL-6 stimulates osteoclast formation, causes mild hypercalcemia, and is produced by bone cells in vitro upon exposure to systemic hormones. Since IL-6 is produced together with parathyroid hormone-related protein (PTH-rP) in some patients with cancer, we tested the hypothesis that production of IL-6 potentiates the effects of PTH-rP on Ca2+ homeostasis and osteoclastic bone resorption and examined potential mechanisms for these interactions in vivo. Chinese hamster ovarian (CHO) cells stably transfected with cDNAs for IL-6 (CHO/IL-6) and PTH-rP sense (CHO/PTH-rP) or antisense (CHO/PTH-rP AS) were inoculated intramuscularly into nude mice. Experimental groups included CHO/IL-6 plus CHO/PTH-rP; CHO/IL-6 plus CHO/PTH-rP AS; CHO/IL-6 alone; and CHO/PTH-rP alone. Blood ionized Ca2+ was measured on days 0, 7, 10, 12, and 13. Three different developmental stages in the osteoclast lineage were examined at day 13: the early multipotential precursor, granulocyte macrophage colony-forming units (CFU-GM); more mature mononuclear osteoclast precursors, assessed by their capacity to form tartrate-resistant acid phosphatase-positive multinucleated cells in marrow cultures; and mature osteoclasts, assessed by histomorphometry. IL-6 increased CFU-GM but not bone resorption or Ca2+. In contrast, PTH-rP induced hypercalcemia and bone resorption and increased multinucleated osteoclasts and more mature precursors cells, but not CFU-GM. However, mice treated with both IL-6 and PTH-rP had very marked hypercalcemia and osteoclastosis as well as an increase in the number of both CFU-GM and mature osteoclast precursors. These data demonstrate that IL-6 enhances PTH-rP-mediated hypercalcemia and bone resorption, most likely by increasing the pool of early osteoclast precursors that in turn can differentiate to mature osteoclasts. We conclude that IL-6 stimulatory effects on osteoclast precursors may enhance the effects of other bone resorption factors that act at later stages in the osteoclast lineage. Images PMID:7769125

  11. 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.; Department of Medicine, University of California, Los Angeles; Department of Bioengineering, University of California, Los Angeles ; 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, FoxO1 and ATF4, were also elevated in the untreated, control Ldlr{sup −/−}PON1{sup tg} mice, suggesting enhancement of cellular protection against oxidants. These findings suggest that PON1 restores responsiveness to PTH through effects on oxidant stress, PTH receptor expression, and/or Wnt signaling.

  12. Accentuated Osteoclastic Response to Parathyroid Hormone Undermines Bone Mass Acquisition in Osteonectin-null Mice

    PubMed Central

    do Reis, Luciene Machado; Kessler, Catherine B.; Adams, Douglas J.; Lorenzo, Joseph; Jorgetti, Vanda; Delany, Anne M.

    2008-01-01

    Matricellular proteins play a unique role in the skeleton as regulators of bone remodeling, and the matricellular protein osteonectin (SPARC, BM-40) is the most abundant non-collagenous protein in bone. In the absence of osteonectin, mice develop progressive low turnover osteopenia, particularly affecting trabecular bone. Polymorphisms in a regulatory region of the osteonectin gene are associated with bone mass in a subset of idiopathic osteoporosis patients, and these polymorphisms likely regulate osteonectin expression. Thus it is important to determine how osteonectin gene dosage affects skeletal function. Moreover, intermittent administration of parathyroid hormone (PTH) (1-34) is the only anabolic therapy approved for the treatment of osteoporosis, and it is critical to understand how modulators of bone remodeling, such as osteonectin, affect skeletal response to anabolic agents. In this study, 10 week old female wild type, osteonectin-haploinsufficient, and osteonectin-null mice (C57Bl/6 genetic background) were given 80 μg/kg body weight/day PTH(1-34) for 4 weeks. Osteonectin gene dosage had a profound effect on bone microarchitecture. The connectivity density of trabecular bone in osteonectin-haploinsufficient mice was substantially decreased compared with that of wild type mice, suggesting compromised mechanical properties. Whereas mice of each genotype had a similar osteoblastic response to PTH treatment, the osteoclastic response was accentuated in osteonectin-haploinsufficient and osteonectin-null mice. Eroded surface and osteoclast number were significantly higher in PTH-treated osteonectin-null mice, as was endosteal area. In vitro studies confirmed that PTH induced the formation of more osteoclast-like cells in marrow from osteonectin-null mice compared with wild type. PTH treated osteonectin-null bone marrow cells expressed more RANKL mRNA compared with wild type. However, the ratio of RANKL:OPG mRNA was somewhat lower in PTH treated osteonectin-null cultures. Increased expression of RANKL in response to PTH could contribute to the accentuated osteoclastic response in osteonectin-/- mice, but other mechanisms are also likely to be involved. The molecular mechanisms by which PTH elicits bone anabolic vs. bone catabolic effects remain poorly understood. Our results imply that osteonectin levels may play a role in modulating the balance of bone formation and resorption in response to PTH. PMID:18499553

  13. Effects of Age on Parathyroid Hormone Signaling in Human Marrow Stromal Cells

    PubMed Central

    Zhou, Shuanhu; Bueno, Ericka M.; Kim, Sung Won; Amato, Ilaria; Shen, Longxiang; Hahne, Jochen; Bleiberg, Ilan; Morley, Paul; Glowacki, Julie

    2011-01-01

    Summary Human bone marrow stromal cells (hMSCs) have the potential to differentiate into osteoblasts; there are age-related decreases in their proliferation and differentiation to osteoblasts. Parathyroid hormone (PTH), when applied intermittently in vivo, has osteoanabolic effects in a variety of systems. In this study, we compared PTH signaling and osteoanabolic effects in hMSCs from young and old subjects. There were age-related decreases in expression of PTH/PTHrP receptor type 1 (PTHR1) gene (p=0.049, n=19) and in PTH activation of CREB (p=0.029, n=7) and PTH stabilization of β-catenin (p=0.018, n=7). Three human PTH peptides, PTH1–34, PTH1-31C (Ostabolin-C, Leu27, Cyclo[Glu22-Lys26]-hPTH1–31), and PTH1–84 (10 nM) stimulated osteoblast differentiation with hMSCs. Treatment with PTH1–34 resulted in a significant 67% increase in alkaline phosphatase (ALP) activity in hMSCs obtained from younger subjects (<50-year-old, n=5), compared with an 18% increase in hMSCs from elders (>55-year-old, n=7). Both knockdown of CREB and treatment with a PKA inhibitor H-89 blocked PTH stimulation of osteoblast differentiation in hMSCs from young subjects. The PTH peptides significantly stimulated proliferation of hMSCs. Treatment with PTH1–34 resulted in an average of twice as many cells in cultures of hMSCs from young subjects (n=4), but had no effect with hMSCs from elders (n=7). Upregulation of PTHR1 by 24-hour pre-treatment with 100 nM dexamethasone rescued PTH stimulation of proliferation in hMSCS from elders. In conclusion, age-related intrinsic alterations in signaling responses to osteoanabolic agents like PTH may contribute to cellular and tissue aging of the human skeleton. PMID:21518242

  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. PMID:27142453

  15. Update on the efficacy, safety, and adherence to treatment of full length parathyroid hormone, PTH (1-84), in the treatment of postmenopausal osteoporosis

    PubMed Central

    Pietrogrande, Luca

    2010-01-01

    Full length (1-84) parathyroid hormone (PTH) was introduced in Europe as a treatment for postmenopausal osteoporosis in 2006. The efficacy of PTH (1-84) in the prevention of vertebral fractures is very high, and is similar to that of teriparatide. Its action in the prevention of femoral fractures has yet to be fully demonstrated, but the incidence of such fractures in trials was very low, and a decrease in nonvertebral fractures was seen in high-risk patients. The effect on bone mineral density (BMD) was clearly demonstrated in the spine and also in the hip. The effects on BMD were evident and increased progressively with treatment until 36 months. After its discontinuation there was a clear decrease in BMD if no antiresorptive treatment was initiated. Increases in bone volumetric density and bone volume in trabecular sites were also reported. Moreover, a bone volume increase was detected in cortical sites. Hypercalcemia and hypercalciuria are frequent consequences of PTH treatment, but rarely have clinical effects and are usually well controlled by reducing calcium and vitamin D supplementation. PMID:21072288

  16. 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

  17. 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...

  18. Associations between Sympathetic Activity, Plasma Concentrations of Renin, Aldosterone, and Parathyroid Hormone, and the Degree of Intractability of Blood Pressure Control in Hemodialysis Patients

    PubMed Central

    Hong, Zoong-Rock; Yang, Jong-Oh; Lee, Eun-Young; Ahn, Jae-Ouk; Hong, Sae-Yong

    2007-01-01

    This study was designed to examine how such factors as hemodialysis parameters, body mass index, renin and aldosterone concentrations, sympathetic nervous activity, and parathyroid hormone concentrations are associated with the control of hypertension in hemodialysis patients. Hemodialysis patients (n=114) were grouped into four categories. Group 1 had normal BP without antihypertensive medication. Group 2 needed one antihypertensive drug, Group 3 needed combination of two or three categories of antihypertensive drugs without minoxidil. Group 4 needed more than three categories of antihypertensive drugs including minoxidil. Parathyroid hormone, ?2-microglobulin, renin and aldosterone, epinephrine, norepinephrine, and hemodialysis parameters were measured. The fractional clearance of urea as Kt/V urea was significantly lower in Group 3 and Group 4 than in Group 2 (p<0.01). Concentrations of parathyroid hormone were significantly higher in Group 4 than the other groups (p<0.01). Pre-hemodialysis norepinephrine concentrations were significantly higher in Group 4 than the other groups (p<0.05). Traditional factors associated with hypertension did not seem to be relevant to the degree of hypertension in hemodialysis patients in the present study. In conclusion, poor Kt/V urea, elevated parathyroid hormone concentrations, and elevated concentrations of plasma norepinephrine seemed to be the factors that might be associated with control of hypertension in hemodialysis patients. PMID:17728496

  19. Inhibition of parathyroid hormone release by maitotoxin, a calcium channel activator

    SciTech Connect

    Fitzpatrick, L.A.; Yasumoto, T.; Aurbach, G.D.

    1989-01-01

    Maitotoxin, a toxin derived from a marine dinoflagellate, is a potent activator of voltage-sensitive calcium channels. To further test the hypothesis that inhibition of PTH secretion by calcium is mediated via a calcium channel we studied the effect of maitotoxin on dispersed bovine parathyroid cells. Maitotoxin inhibited PTH release in a dose-dependent fashion, and inhibition was maximal at 1 ng/ml. Chelation of extracellular calcium by EGTA blocked the inhibition of PTH by maitotoxin. Maitotoxin enhanced the effects of the dihydropyridine calcium channel agonist (+)202-791 and increased the rate of radiocalcium uptake in parathyroid cells. Pertussis toxin, which ADP-ribosylates and inactivates a guanine nucleotide regulatory protein that interacts with calcium channels in the parathyroid cell, did not affect the inhibition of PTH secretion by maitotoxin. Maitotoxin, by its action on calcium channels allows entry of extracellular calcium and inhibits PTH release. Our results suggest that calcium channels are involved in the release of PTH. Inhibition of PTH release by maitotoxin is not sensitive to pertussis toxin, suggesting that maitotoxin may act distal to the site interacting with a guanine nucleotide regulatory protein, or maitotoxin could interact with other ions or second messengers to inhibit PTH release.

  20. About the Parathyroid Glands

    MedlinePlus

    ... the kidneys, increasing your chances of having a kidney stone. In fact, everyone with a fracture that isn’ ... of major trauma and everyone who has a kidney stone should have blood calcium and parathyroid hormone measured. ...

  1. [Parathyroid Hormone-related Peptide (PTHrP) Producing Lung Cancer Presenting Hypercalcemia; Report of a Case].

    PubMed

    Okagawa, Takehiko; Hiramatsu, Yoshinori

    2015-03-01

    An 82-year-old man was admitted to our hospital with hemoptysis and weight loss. Chest computed tomography(CT) showed a 90 mm mass with cavity formation in the right lower lobe adjacent to chest wall. Laboratory data revealed hypercalcemia and elevation of parathyroid hormone-related protein C (PTHrP). He was diagnosed as squamous cell carcinoma of lung by transbronchial lung biopsy (TBLB) [cT3aN1M0]. Nausea and anorexia due to hypercalcemia became worse and a right middle and lower lobectomy was performed because of difficult control of symptoms by medicine and worsening of his general condition. His symptoms were improved immediately after surgery. PMID:25743561

  2. Treatment for chemotherapy-induced alopecia in mice using parathyroid hormone agonists and antagonists linked to a collagen binding domain

    PubMed Central

    Katikaneni, Ranjitha; Ponnapakkam, Tulasi; Suda, Hirofumi; Miyata, Shigeru; Sakon, Joshua; Matsushita, Osamu; Gensure, Robert C.

    2013-01-01

    Parathyroid hormone (PTH) agonists and antagonists have been shown to improve hair growth after chemotherapy; however, rapid clearance and systemic side-effects complicate their usage. To facilitate delivery and retention to skin, we fused PTH agonists and antagonists to the collagen binding domain (CBD) of Clostridium histolyticum collagenase. in-vitro studies showed that the agonist fusion protein, PTH-CBD, bound collagen and activated the PTH/parathyroid hormone-related peptide receptor in SaOS-2 cells. The antagonist fusion proteins, PTH(7–33)-CBD and PTH([−1]–33)-CBD, also bound collagen and antagonized PTH(1–34) effect in SaOS-2 cells; however, PTH(7–33)-CBD had lower intrinsic activity. Distribution studies confirmed uptake of PTH-CBD to the skin at 1 and 12 hr after subcutaneous injection. We assessed in vivo efficacy of PTH-CBD and PTH(7–33)-CBD in C57BL/6J mice. Animals were depilated to synchronize the hair follicles; treated on Day 7 with agonist, antagonist, or vehicle; treated on Day 9 with cyclophosphamide (150 mg/kg i.p.) or vehicle; and sacrificed on Day 39. Normal mice (no chemo and no treatment) showed rapid regrowth of hair and normal histology. Chemo + Vehicle mice showed reduced hair regrowth and decreased pigmentation; histology revealed reduced number and dystrophic anagen/catagen follicles. Chemo + Antagonist mice were grossly and histologically indistinguishable from Chemo + Vehicle mice. Chemo + Agonist mice showed more rapid regrowth and repigmentation of hair; histologically, there was a normal number of hair follicles, most of which were in the anagen phase. Overall, the agonist PTH-CBD had prominent effects in reducing chemotherapy-induced damage of hair follicles and may show promise as a therapy for chemotherapy-induced alopecia. PMID:22130912

  3. Induction of thermal and mechanical hypersensitivity by parathyroid hormone-related peptide through upregulation of TRPV1 function and trafficking.

    PubMed

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

    2015-09-01

    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

  4. Impact of race on intraoperative parathyroid hormone kinetics: an analysis of 910 patients undergoing parathyroidectomy for primary hyperparathyroidism.

    PubMed

    Cisco, Robin M; Kuo, Jennifer H; Ogawa, Lauren; Scholten, Anouk; Tsinberg, Michael; Duh, Quan-Yang; Clark, Orlo H; Gosnell, Jessica E; Shen, Wen T

    2012-11-01

    HYPOTHESIS African American patients exhibit different intraoperative parathyroid hormone (IOPTH) profiles than non-African American patients. DESIGN Retrospective review. SETTING University medical center. PATIENTS Nine hundred ten patients who underwent parathyroidectomy for primary hyperparathyroidism between July 2005 and August 2010. INTERVENTIONS All patients underwent preoperative imaging with ultrasonography and sestamibi; operative exploration; and IOPTH measurement at 2 points preexcision and 5 and 10 minutes postexcision. MAIN OUTCOME MEASURES Preexcision and postexcision IOPTH measurements. RESULTS Of the 910 patients, 734 self-reported their race as white (81%); 91, Latino/other (10%); 56, Asian (6%); and 28, African American (3%). African American patients had significantly higher initial preexcision IOPTH levels compared with white patients (348 vs 202 pg/mL; P = .048) and significantly higher 5-minute postexcision IOPTH levels (151 vs 80 pg/mL; P = .01). The 10-minute postexcision IOPTH levels were similar between the 2 groups (52 vs 50 pg/mL). A similar percentage of white and African American patients had a 50% drop in IOPTH level at 10 minutes postexcision. No differences in IOPTH kinetics were observed in the other racial groups examined. CONCLUSIONS African American patients with primary hyperparathyroidism exhibit significantly higher preincision and 5-minute postexcision IOPTH values when compared with white patients. The 10-minute postexcision IOPTH values did not differ between races. The altered IOPTH kinetics identified in African American patients may reflect the severity of biochemical disease but may also be related to genetically predetermined differences in parathyroid hormone metabolism. PMID:22801754

  5. Treatment for chemotherapy-induced alopecia in mice using parathyroid hormone agonists and antagonists linked to a collagen binding domain.

    PubMed

    Katikaneni, Ranjitha; Ponnapakkam, Tulasi; Suda, Hirofumi; Miyata, Shigeru; Sakon, Joshua; Matsushita, Osamu; Gensure, Robert C

    2012-09-01

    Parathyroid hormone (PTH) agonists and antagonists have been shown to improve hair growth after chemotherapy; however, rapid clearance and systemic side-effects complicate their usage. To facilitate delivery and retention to skin, we fused PTH agonists and antagonists to the collagen binding domain (CBD) of Clostridium histolyticum collagenase. in-vitro studies showed that the agonist fusion protein, PTH-CBD, bound collagen and activated the PTH/parathyroid hormone-related peptide receptor in SaOS-2 cells. The antagonist fusion proteins, PTH(7-33)-CBD and PTH([-1]-33)-CBD, also bound collagen and antagonized PTH(1-34) effect in SaOS-2 cells; however, PTH(7-33)-CBD had lower intrinsic activity. Distribution studies confirmed uptake of PTH-CBD to the skin at 1 and 12 hr after subcutaneous injection. We assessed in vivo efficacy of PTH-CBD and PTH(7-33)-CBD in C57BL/6J mice. Animals were depilated to synchronize the hair follicles; treated on Day 7 with agonist, antagonist, or vehicle; treated on Day 9 with cyclophosphamide (150 mg/kg i.p.) or vehicle; and sacrificed on Day 39. Normal mice (no chemo and no treatment) showed rapid regrowth of hair and normal histology. Chemo+Vehicle mice showed reduced hair regrowth and decreased pigmentation; histology revealed reduced number and dystrophic anagen/catagen follicles. Chemo+Antagonist mice were grossly and histologically indistinguishable from Chemo+Vehicle mice. Chemo+Agonist mice showed more rapid regrowth and repigmentation of hair; histologically, there was a normal number of hair follicles, most of which were in the anagen phase. Overall, the agonist PTH-CBD had prominent effects in reducing chemotherapy-induced damage of hair follicles and may show promise as a therapy for chemotherapy-induced alopecia. PMID:22130912

  6. Treatment for chemotherapy-induced alopecia in mice using parathyroid hormone agonists and antagonists linked to a collagen binding domain.

    TOXLINE Toxicology Bibliographic Information

    Katikaneni R; Ponnapakkam T; Suda H; Miyata S; Sakon J; Matsushita O; Gensure RC

    2012-09-01

    Parathyroid hormone (PTH) agonists and antagonists have been shown to improve hair growth after chemotherapy; however, rapid clearance and systemic side-effects complicate their usage. To facilitate delivery and retention to skin, we fused PTH agonists and antagonists to the collagen binding domain (CBD) of Clostridium histolyticum collagenase. in-vitro studies showed that the agonist fusion protein, PTH-CBD, bound collagen and activated the PTH/parathyroid hormone-related peptide receptor in SaOS-2 cells. The antagonist fusion proteins, PTH(7-33)-CBD and PTH([-1]-33)-CBD, also bound collagen and antagonized PTH(1-34) effect in SaOS-2 cells; however, PTH(7-33)-CBD had lower intrinsic activity. Distribution studies confirmed uptake of PTH-CBD to the skin at 1 and 12 hr after subcutaneous injection. We assessed in vivo efficacy of PTH-CBD and PTH(7-33)-CBD in C57BL/6J mice. Animals were depilated to synchronize the hair follicles; treated on Day 7 with agonist, antagonist, or vehicle; treated on Day 9 with cyclophosphamide (150 mg/kg i.p.) or vehicle; and sacrificed on Day 39. Normal mice (no chemo and no treatment) showed rapid regrowth of hair and normal histology. Chemo+Vehicle mice showed reduced hair regrowth and decreased pigmentation; histology revealed reduced number and dystrophic anagen/catagen follicles. Chemo+Antagonist mice were grossly and histologically indistinguishable from Chemo+Vehicle mice. Chemo+Agonist mice showed more rapid regrowth and repigmentation of hair; histologically, there was a normal number of hair follicles, most of which were in the anagen phase. Overall, the agonist PTH-CBD had prominent effects in reducing chemotherapy-induced damage of hair follicles and may show promise as a therapy for chemotherapy-induced alopecia.

  7. Abundant expression of parathyroid hormone-related protein in primary rat aortic smooth muscle cells accompanies serum-induced proliferation.

    PubMed Central

    Hongo, T; Kupfer, J; Enomoto, H; Sharifi, B; Giannella-Neto, D; Forrester, J S; Singer, F R; Goltzman, D; Hendy, G N; Pirola, C

    1991-01-01

    Parathyroid hormone-related protein (PTHrP), which is responsible for producing hypercalcemia in patients with humoral hypercalcemia of malignancy, has recently been identified in several normal tissues. Because PTHrP, like parathyroid hormone (PTH), is known to exhibit vasodilatory properties, we investigated the expression and regulation of PTHrP mRNA in cultured rat aortic smooth muscle cells (SMC). We report here that PTHrP mRNA is expressed in SMC and is markedly induced by serum in a time- and concentration-dependent fashion. Addition of 10% fetal calf serum to serum-deprived, confluent cells, resulted in a marked induction of PTHrP mRNA by 2 h with a peak at 4-6 h. PTHrP was detected in SMC by immunocytochemistry and radioimmunoassay of conditioned medium, and was shown to be up-regulated within 24 h after the addition of serum. The serum induction of PTHrP mRNA was blocked by actinomycin D and by cycloheximide indicating the need for protein synthesis to evoke the serum effect on PTHrP gene transcription. In addition, treatment with dexamethasone, which has been previously shown to reduce the constitutive expression of PTHrP in human cancer cells, also blunted the serum induction of PTHrP mRNA in SMC. Treatment of quiescent cells with the serum mitogens platelet-derived growth factor or insulin-like growth factor-I had no effect on PTHrP, whereas the vasoactive peptides endothelin, norepinephrine and thrombin stimulated PTHrP expression. Exogenous addition of recombinant PTHrP-(1-141) had no significant effect on SMC DNA synthesis as measured by [3H]thymidine incorporation. In summary, the abundance of PTHrP mRNA and the characteristics of its regulation in SMC suggest a major role for PTHrP as a local modulator in vascular smooth muscle. Images PMID:1752945

  8. CYP2D6, GST-M1 and GST-T1 enzymes: expression in parathyroid gland and association with the parathyroid hormone concentration during early renal replacement therapy

    PubMed Central

    Yan, Feng-Xiang; Langub, M Chris; Ihnen, Mark A; Hornung, Carlton; Juronen, Erkki; Rayens, Mary K; Cai, Wei-Min; Wedlund, Peter J; Fanti, Paolo

    2003-01-01

    Aims The purpose of this research was to characterize CYP2D6, GST-M1 and GST-T1 enzyme expression in human parathyroid tissue, and to determine whether or not there is any association between deficiencies in these enzymes and serum parathyroid hormone concentrations in patients with end-stage renal disease. Methods Surgical human parathyroid tissue was obtained and evaluated by immunohistochemistry for cellular localization of CYP2D6, GST-M1 and GST-T1 and colocalization of CYP2D6 with parathyroid hormone. Blood samples were collected from 328 Caucasian patients with end-stage renal disease for genetic testing of CYP2D6*3, *4, *5, *6, *7 and GST-M1*0 and GST-T1*0 alleles. Clinical chemistry data and serum intact parathyroid hormone (iPTH) concentrations were obtained from patient medical records. In 277 of the patients, the same laboratory performed all clinical tests. Results CYP2D6, GST-M1 and GST-T1 were present in human parathyroid tissue. CYP2D6 was colocalized with parathyroid hormone in parathyroid chief cells. Within the end-stage renal disease population, a nonfunctional CYP2D6 genotype was present in 18.2%[95% confidence interval (CI) 8.0, 28.4] of patients in the 1st iPTH concentration quintile (iPTH < 64 pg mL−1), in 0% (95% CI 0, 7.5) of those in the 2nd quintile, in 1.8% (95% CI 0, 9.3) of those in the 3rd quintile, in 9.1% (95% CI 1.5, 16.7) of those in the 4th quintile, and in 16.7% (95% CI 6.8, 26.5) of those in the 5th quintile (iPTH > 347 pg mL−1) (P = 0.001). Out of 12 CYP2D6-deficient females, seven were in the 1st iPTH concentration quintile and the remaining five were in the 5th quintile. Patients deficient in the GST-M1 and GST-T1 enzymes displayed a far more uniform frequency distribution relative to serum iPTH concentrations. Conclusions The presence of CYP2D6, GST-M1 and GST-T1 in parathyroid cells was observed. An association is reported between a lack of CYP2D6 and iPTH concentrations in newly diagnosed end-stage renal disease patients. Gender and concomitant deficiency in GST-M1 and/or GST-T1 appear to define this association further. It remains to be established whether these associations reflect a cause-effect relationship between deficient expression of metabolizing enzymes and severity of secondary manifestation of renal failure. PMID:12848777

  9. Parathyroid cell proliferation in normal and chronic renal failure rats. The effects of calcium, phosphate, and vitamin D.

    PubMed Central

    Naveh-Many, T; Rahamimov, R; Livni, N; Silver, J

    1995-01-01

    Secondary hyperparathyroidism is characterized by an increase in parathyroid (PT) cell number, and parathyroid hormone (PTH) synthesis and secretion. It is still unknown as to what stimuli regulate PT cell proliferation and how they do this. We have studied rats with dietary-induced secondary hyper- and hypoparathyroidism, rats given 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and rats after 5/6 nephrectomy for the presence of PT cell proliferation and apoptosis. PT cell proliferation has been measured by staining for proliferating cell nuclear antigen (PCNA) and apoptosis by in situ detection of nuclear DNA fragmentation and correlated with serum biochemistry and PTH mRNA levels. A low calcium diet led to increased levels of PTH mRNA and a 10-fold increase in PT cell proliferation. A low phosphate diet led to decreased levels of PTH mRNA and the complete absence of PT cell proliferation. 1,25 (OH)2D3 (25 pmol/d x 3) led to a decrease in PTH mRNA levels and unlike the hypophosphatemic rats there was no decrease in cell proliferation. There were no cells undergoing apoptosis in any of the experimental conditions. The secondary hyperparathyroidism of 5/6 nephrectomized rats was characterized by an increase in PTH mRNA levels and PT cell proliferation which were both markedly decreased by a low phosphate diet. The number of PCNA positive cells was increased by a high phosphate diet. Therefore hypocalcemia, hyperphosphatemia and uremia lead to PT cell proliferation, and hypophosphatemia completely abolishes this effect. Injected 1,25 (OH)2D3 had no effect. These findings emphasize the importance of a normal phosphate and calcium in the prevention of PT cell hyperplasia. Images PMID:7560070

  10. 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

  11. Serum concentrations of 25-hydroxyvitamin D and its association with bone mineral density and serum parathyroid hormone levels during winter in urban males from Guiyang, Southwest China.

    PubMed

    Zhang, Qiao; Shi, Lixin; Peng, Nianchun; Xu, Shujing; Zhang, Miao; Zhang, Song; Li, Hong; Zhuang, Huijun; Gong, Mingxian; Wu, Danrong; Wang, Rui

    2016-03-01

    Serum vitamin D (25-hydroxyvitamin D (25OHD)) may influence serum parathyroid hormone (PTH) levels and bone mineral density (BMD). In the present study, we assessed serum 25OHD concentration and its association with PTH and BMD in urban males from Guiyang (N26.57°), the capital city of Guizhou province, Southwest China. We recruited 634 males aged >20 years from the Guiyang Health Measures Survey, and stratified them into three groups according to age: young (20-39 years), middle aged (40-59 years) and older (60-79 years). We measured serum concentrations of 25OHD, PTH levels and BMD of the lumbar spine (L1-L4), femoral neck and total hip. In addition, we also explored the relationship between 25OHD and lifestyle, socio-economic characteristics and medical history by applying covariance analysis and locally weighted regression plots. The results showed that serum 25OHD was 75 nmol/l in 12·6 % of the subjects. Higher level of serum PTH was detected in relation to lower concentrations of serum 25OHD up to 50 nmol/l. A negative correlation between serum 25OHD and PTH concentrations was observed (r -0·207, P=0·003). Mean concentration of serum PTH increased gradually and plateaued while concentrations of serum 25OHD decreased to 50 nmol/l. Gradual increase in serum PTH was observed as 25OHD concentration was <25 nmol/l (P=0·004). BMD values at all sites were greater in the higher serum 25OHD concentration group. This study shows that low concentrations of serum 25OHD were common in males, and bone health was likely to be improved when serum 25OHD values were between 30 and 50 nmol/l. PMID:26843386

  12. The G protein α-subunit variant XLαs promotes Gq/11-dependent signaling and mediates the renal actions of parathyroid hormone in vivo*

    PubMed Central

    He, Qing; Zhu, Yan; Corbin, Braden A.; Plagge, Antonius; Bastepe, Murat

    2015-01-01

    GNAS, which encodes the stimulatory G protein α subunit (Gαs), also encodes a large variant of Gαs termed XLαs, and alterations in XLαs abundance or activity are implicated in various human disorders. Although XLαs, like Gαs, stimulates generation of the second messenger cAMP, evidence suggests that XLαs and Gαs have opposing effects in vivo. We investigated the role of XLαs in mediating signaling by parathyroid hormone (PTH), which activates a GPCR that stimulates both Gαs and Gαq/11 in renal proximal tubules to maintain phosphate and vitamin D homeostasis. At postnatal day 2 (P2), XLαs-knockout (XLKO) mice exhibited hyperphosphatemia, hypocalcemia, and increased serum concentrations of PTH and 1,25-dihydroxyvitamin D, indicative of compromised PTH responsiveness. The ability of PTH to reduce serum phosphate concentrations was impaired and the abundance of the sodium-phosphate cotransporter Npt2a in renal brush-border membranes was reduced in XLKO mice, whereas PTH-induced cAMP excretion in the urine was modestly increased. Basal and PTH-stimulated production of inositol trisphosphate (IP3), which is the second messenger produced by Gαq/11 signaling, were repressed in renal proximal tubules from XLKO mice. Crossing of XLKO mice with mice overexpressing XLαs specifically in renal proximal tubules rescued the phenotype of the XLKO mice. Overexpression of XLαs in HEK 293 cells enhanced Gq/11-dependent signaling in unstimulated cells and in cells stimulated with PTH or thrombin, which is a Gq/11-coupled receptor. Together, our findings suggest that XLαs enhances Gq/11 signaling to mediate the renal actions of PTH during early postnatal development. PMID:26307011

  13. An Extrarenal Role for Parathyroid Hormone in the Disposal of Acute Acid Loads in Rats and Dogs

    PubMed Central

    Fraley, Donald S.; Adler, Sheldon

    1979-01-01

    Acid infusion studies were performed in nephrectomized rats and dogs with either intact parathyroid glands (intact) or after thyroparathyroidectomy (thyroparathyroidectomized [TPTX]) to determine the role of parathyroid hormone (PTH) in extrarenal disposal and buffering of acutely administered acid. 29 intact rats given 5 mM/kg HCl and 6 intact dogs given 7 mM/kg HCl developed severe metabolic acidosis but all survived. However, each of 12 TPTX rats and 4 TPTX dogs given the same acid loads died. Intact rats and dogs buffered 39 and 50% of administered acid extracellularly, respectively, whereas extracellular buffering of administered acid was 97 and 78% in TPTX rats and dogs, respectively. 17 TPTX rats and 6 TPTX dogs given synthetic PTH 2 h before acid infusion survived. The blood bicarbonate and extracellular buffering in these animals, measured 2 h after acid infusion, was similar to intact animals. Changes in liver, heart, and skeletal muscle pH determined from [14C]5,5-dimethyl-2,4 oxazolidinedione distribution seemed insufficient to account for the increased cell buffering of PTH-replaced animals. Indeed, muscle pH in TPTX dogs given PTH and acid was only 0.06 pH units lower than in control dogs given no acid, suggesting that another tissue, presumably bone, was the target for PTH-mediated increased cell buffering. This conclusion was supported by the observation that PTH did not alter the pH of intact rat diaphragms in vitro. These results indicate that PTH is necessary for the optimal buffering of large, acute acid loads presumably by increasing bone buffering. PMID:36406

  14. The Relationship Between Parathyroid Hormone and 25-Hydroxyvitamin D During and After Pregnancy.

    PubMed

    Kramer, Caroline K; Ye, Chang; Hanley, Anthony J; Connelly, Philip W; Sermer, Mathew; Zinman, Bernard; Retnakaran, Ravi

    2016-04-01

    We evaluated the effects of supplementation with DHEA (in elderly men and women) and testosterone (in elderly men) on postprandial or iv insulin suppression of lipolysis. We found no effect of these hormones on systemic lipolysis. PMID:26895390

  15. [How to slow down parathyroid hormone (PTH) secretion without the risk of inducing an adynamic bone disease].

    PubMed

    Torres, Pablo Ureña; Canaud, Bernard

    2005-12-01

    Medical treatment for secondary hyperparathyroidism (HPTH-II) consists in correcting: hypocalcemia by providing a supply of calcium salts, vitamin D or its derivatives; hyperphosphatemia by a suitable diet and by using gastrointestinal phosphate-binders; metabolic acidosis by providing sodium bicarbonate. Very recently, this treatment armamentarium was expanded by the advent of a new therapeutic agent called a calcimimetic (cinacalcet HCL). Cinacalcet increases the calcium sensitivity of the calcium receptor (CaR) of parathyroid cells and thereby induces a rapid and sustained decrease in PTH secretion. When treatment with medical inhibitors proves to be ineffective or involves risks due to an increase in the calcium-phosphorus ion product and the occurrence or worsening of cardiovascular calcifications, it is then necessary to resort to surgical reduction of PTH production by surgical parathyroidectomy (PTX). The very high efficacy of medical inhibitory treatment of HPTH-II logically poses the problem of excessive inhibition of the secretion of PTH and its corollary, the increased risk of adynamic osteopathy. The primary purpose of this article is to provide the reader with an updated review of these problems consisting, on the one hand, of inhibiting PTH secretion and, on the other, of maintaining a sufficient level of bone remodeling to prevent any possible repercussions on other organs. PMID:17373205

  16. The release of parathyroid hormone and the exocytosis of a proteoglycan are modulated by extracellular Ca2+ in a similar manner.

    PubMed Central

    Muresan, Z; MacGregor, R R

    1994-01-01

    Secretion of parathyroid hormone (PTH) is regulated in part by a classical "stimulus-secretion" pathway responsive to catecholamines. The primary physiological modulator of PTH exocytosis in parathyroid cells, however, is extracellular free Ca2+. Ca(2+)-modulated PTH release exhibits several characteristics suggestive of constitutive secretion. The aim of this work was to obtain further information about the possible intracellular origins of Ca(2+)-modulated exocytosis in parathyroid cells. Freshly dissociated bovine parathyroid cells labeled with [35S]sulfate synthesized a soluble chondroitin/dermatan sulfate proteoglycan (M(r) approximately 90-150 K) that was secreted into the medium. The export of [35S]sulfated proteoglycan satisfied several criteria that generally define constitutive release: 1) export is detected in the medium shortly (7-15 min) after a 5-min pulse, 2) there is minimal intracellular storage after equilibrium labeling (because of combined processes of rapid release and intracellular degradation), and 3) there is insensitivity to stimulation with isoproterenol, a known secretagogue in parathyroid cells. Nevertheless, the increase in extracellular Ca2+ from 0.5 to 2.0 mM reduced the export of the [35S]sulfated proteoglycan from 60% of total labeled to 30%. In addition, a secreted pool of immunoreactive PTH and [35S]sulfated proteoglycan was modulated by external Ca2+ to the same degree and sensitivity, although isoproterenol was more effective in stimulating the release of PTH than that of proteoglycan. Together, our experimental results show that in the parathyroid cell extracellular Ca2+ modulates negatively the export of both PTH and proteoglycan, a putative marker for constitutive secretion. We further suggest that a portion of newly synthesized PTH also enters this pathway, whereas another portion proceeds to an isoproterenol-releasable compartment from which the proteoglycan is largely excluded. Images PMID:7812042

  17. 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.

  18. A rare case of double parathyroid lipoadenoma with hyperparathyroidism.

    PubMed

    Ogrin, Cristina

    2013-11-01

    A rare case of double lipoadenomas of parathyroid glands with hyperparathyroidism is described. A 56-year-old woman was referred for management of diabetes. Work up revealed: serum Calcium (Ca) =11.9 mg/dl, glomerular filtration rate (GFR) = 103 ml/min/m2, parathyroid hormone (PTH) = 60 pg/ml, Phosphorus = 3.0 mg/dl, 25 hydroxy vitamin D (25 OH D) =16.5 ng/ml, 24 h urine Calcium =179 mg/day. Parathyroid sestamibi scan showed increased activity in the left thyroid and right thyroid lobe. Single photon emission computed tomography demonstrated uptake in inferior left and right thyroid lobes. Her serum calcium following successful bilateral parathyroidectomy was 9.3 mg/dl. Pathology showed double parathyroid lipoadenomas. After surgery, her serum Calcium and PTH normalized to 9.8 mg/dl and 32 pg/ml respectively. Lipoadenoma has been described as a very rare lesion of the parathyroid gland and is most commonly non-functional. PubMed search failed to reveal any case of hyperparathyroidism due to double parathyroid lipoadenomas. PMID:24157966

  19. A Transgenic Mouse Model for Studying the Role of the Parathyroid Hormone-Related Protein System in Renal Injury

    PubMed Central

    Bosch, Ricardo J.; Ortega, Arantxa; Izquierdo, Adriana; Arribas, Ignacio; Bover, Jordi; Esbrit, Pedro

    2011-01-01

    Parathyroid hormone- (PTH-) related protein (PTHrP) and its receptor, the PTH1 receptor (PTH1R), are widely expressed in the kidney, where PTHrP exerts a modulatory action on renal function. PTHrP is known to be upregulated in several experimental nephropathies such as acute renal failure (ARF), obstructive nephropathy (ON) as well as diabetic nephropathy (DN). In this paper, we will discuss the functional consequences of chronic PTHrP overexpression in the damaged kidney using a transgenic mouse strain overexpressing PTHrP in the renal proximal tubule. In both ARF and ON, PTHrP displays proinflammatory and profibrogenic actions including the induction of epithelia to mesenquima transition. Moreover, PTHrP participates in the mechanisms of renal hypertrophy as well as proteinuria in experimental DN. Angiotensin II (Ang II), a critical factor in the progression of renal injury, appears to be, at least in part, responsible for endogenous PTHrP upregulation in these pathophysiological settings. These findings provide novel insights into the well-known protective effects of Ang II antagonists in renal diseases, paving the way for new therapeutic approaches. PMID:21052497

  20. Zfp521 Is a Target Gene and Key Effector of Parathyroid Hormone-Related Peptide Signaling in Growth Plate Chondrocytes

    PubMed Central

    Correa, Diego; Hesse, Eric; Seriwatanachai, Dutmanee; Kiviranta, Riku; Saito, Hiroaki; Yamana, Kei; Neff, Lynn; Atfi, Azeddine; Coillard, Lucie; Sitara, Despina; Maeda, Yukiko; Warming, Soren; Jenkins, Nancy A.; Copeland, Neal G.; Horne, William C.; Lanske, Beate; Baron, Roland

    2010-01-01

    Summary In the growth plate, the interplay between Parathyroid Hormone-Related Peptide (PTHrP) and Indian Hedgehog (Ihh) signaling tightly regulates chondrocyte proliferation and differentiation during longitudinal bone growth. We found that PTHrP increases the expression of Zfp521, a zinc finger transcriptional co-regulator, in pre-hypertrophic chondrocytes. Mice with chondrocyte-targeted deletion of Zfp521 resembled PTHrP-/- and chondrocyte-specific PTHR1-/- mice, with decreased chondrocyte proliferation, early hypertrophic transition and reduced growth plate thickness. Deleting Zfp521 increased expression of Runx2 and Runx2 target genes, and decreased cyclin D1 and Bcl-2 expression while increasing caspase-3 activation and apoptosis. Zfp521 associated with Runx2 in chondrocytes, antagonizing its activity via an HDAC4-dependent mechanism. PTHrP failed to up-regulate cyclin D1 and to antagonize Runx2, Ihh and Collagen X expression when Zfp521 was absent. Thus, Zfp521 is an important PTHrP target gene that regulates growth plate chondrocyte proliferation and differentiation. PMID:20951345

  1. Multiple biomarker strategy based on parathyroid hormone and natriuretic peptides testing for improved prognosis of chronic heart failure.

    PubMed

    Gruson, Damien; Ahn, Sylvie A; Rousseau, Michel F

    2015-02-01

    Biomarkers offer new perspectives for a more personalized management of patients with heart failure (HF). Hyperparathyroidism is common in HF patients and parathyroid hormone (PTH) testing might provide added value for the prognostication of HF patients. Our objectives were therefore to determine the efficiency of multiple biomarker strategy based on PTH and natriuretic peptides measurement for the risk stratification of patients with HF. Circulating concentrations of bioactive PTH 1-84 and natriuretic peptides, B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP), were measured with automated immunoassays in 45 healthy individuals and 137 HF patients with reduced left ventricular ejection fraction. Circulating levels of PTH 1-84 and natriuretic peptides were significantly increased in HF patients in comparison to HF patients. Over a long-term follow-up, baseline PTH 1-84 levels were related to the risk of cardiovascular death. Furthermore, in multiple biomarker approach, PTH measurement was additive to BNP and NT-proBNP testing for the cardiovascular risk assessment of HF patients. In conclusion, the combination of PTH 1-84 and natriuretic peptides testing improves the prognostication of HF patients and might allowed more personalized approach for risk stratification and treatment selection in HF patients. PMID:25572303

  2. Bone-specific alkaline phosphatase concentrations are less variable than those of parathyroid hormone in stable hemodialysis patients

    PubMed Central

    Sardiwal, Sunita; Gardham, Clare; Coleman, Adrian E; Stevens, Paul E; Delaney, Michael P; Lamb, Edmund J

    2012-01-01

    Abnormalities of bone mineral metabolism and vascular calcification are prevalent in patients with kidney failure. Clinical management is based on biochemical targets, in particular parathyroid hormone (PTH) concentrations, but this has many limitations including high biological variation. A possible alternative is bone-specific alkaline phosphatase (ALP); therefore, we evaluated the biological variation of this marker in patients undergoing hemodialysis. Bone ALP was measured in non-fasting serum samples taken twice a week over a 6-week period in 22 stable hemodialysis patients and 12 healthy volunteers. The within-individual coefficients of variance were calculated and used to derive the critical difference required to be certain that an observed change was significant. The coefficient of variance for bone ALP was significantly higher in hemodialysis patients compared to healthy individuals. Seven samples were required to estimate the homeostatic set point of bone ALP, within 10%, in a hemodialysis patient. The concentration of serial bone ALP measurements would need to change by 36% between any two measurements before it can be considered a significant change. Since the biological variation of bone ALP is less than half that reported for PTH, our study provides further support for the use of bone ALP as an alternative marker of bone mineral metabolism in the setting of chronic kidney disease–mineral and bone disorder. PMID:22456600

  3. Pharmacokinetics in rats of a long-acting human parathyroid hormone-collagen binding domain peptide construct.

    PubMed

    Stratford, Robert; Vu, Christopher; Sakon, Joshua; Katikaneni, Ranjitha; Gensure, Robert; Ponnapakkam, Tulasi

    2014-02-01

    The pharmacokinetics of a hybrid peptide consisting of the N-terminal biologically active region of human parathyroid hormone (PTH) linked to a collagen-binding domain (CBD) were evaluated in female Sprague-Dawley rats. The peptide, PTH-CBD, consists of the first 33 amino acids of PTH linked as an extension of the amino acid chain to the CBD peptide derived from ColH collagenase of Clostridium histolyticum. Serum concentrations arising from single dose administration by the subcutaneous and intravenous routes were compared with those measured following route-specific mole equivalent doses of PTH(1-34). Population-based modeling demonstrated similar systemic absorption kinetics and bioavailability for both peptides. Exposure to PTH-CBD was sixfold higher because of a systemic clearance of approximately 20% relative to PTH(1-34); however, these kinetics were consistent with more than 95% of a dose being eliminated from serum within 24 h. Results obtained support continued investigation of PTH-CBD as a bone-targeted anabolic agent for the treatment of postmenopausal osteoporosis. PMID:24399637

  4. Combined application of high resolution and tandem mass spectrometers to characterize methionine oxidation in a parathyroid hormone formulation.

    PubMed

    Pan, Changkang; Valente, Joseph J; LoBrutto, Rosario; Pickett, Jennifer S; Motto, Michael

    2010-03-01

    Identification and monitoring of degradation products is a critical aspect of drug product stability programs. This process can present unique challenges when working with complex biopharmaceutical formulations that do not readily lend themselves to straightforward HPLC analysis. The therapeutic 34 amino acid parathyroid hormone fragment (PTH1-34) contains methionine (Met) residues at positions 8 and 18. Oxidation of these Met residues results in reduced biological activity and thus efficacy of the potential drug product. Here, we present an effective approach for the identification of PTH1-34 oxidation products in a drug product formulation in which the stability indicating method used non-MS compatible HPLC conditions to separate excipients, drug substance and degradation products. High resolution and tandem mass spectrometers were used in conjunction with cyanogen bromide (CNBr) mediated digestion to accurately identify the oxidation products observed in an alternative MS compatible HPLC method used for drug substance analysis. All anticipated CNBr digested peptide fragments, including both oxidized and nonoxidized peptide fragments, were positively identified using TOF MS without the need for additional enzymatic digestion. Once identified, the oxidation products generated were injected onto the original non-MS compatible HPLC drug product stability indicating method and the respective retention times were confirmed. This allowed the oxidative stability of different formulations to be effectively monitored during the solid state stability program and during variant selection. PMID:19711445

  5. Calcium Dependent Ligand Binding and G-protein Signaling of Family B GPCR Parathyroid Hormone 1 Receptor Purified in Nanodiscs

    PubMed Central

    Mitra, Nivedita; Liu, Yuting; Liu, Jian; Serebryany, Eugene; Mooney, Victoria; DeVree, Brian T.; Sunahara, Roger K.; Yan, Elsa C. Y.

    2014-01-01

    GPCRs mediate intracellular signaling upon external stimuli, making them ideal drug targets. However, little is known about their activation mechanisms due to the difficulty in purification. Here, we introduce a method to purify GPCRs in nanodiscs, which incorporates GPCRs into lipid bilayers immediately after membrane solubilization, followed by single-step purification. Using this approach, we purified a family B GPCR, parathyroid hormone 1 receptor (PTH1R), which regulates calcium and phosphate homeostasis and is a drug target for osteoporosis. We demonstrated that the purified PTH1R in nanodiscs can bind to PTH(1-34) and activate G protein. We also observed that Ca2+ is a weak agonist of PTH1R and Ca2+ in millimolar concentration can switch PTH(1-34) from an inverse agonist to an agonist. Hence, our results show that nanodiscs are a viable vehicle for GPCR purification, enabling studies of GPCRs under precise experimental conditions without interference from other cellular or membrane components. PMID:23237450

  6. Parathyroid Hormone Levels May Predict Nonalcoholic Steatohepatitis in Morbidly Obese Patients

    PubMed Central

    Ghoghaei, Morteza; Taghdiri, Foad; Khajeh, Elias; Azmoudeh Ardalan, Farid; Sedaghat, Mojtaba; Hosseini Shirvani, Sepideh; Zarei, Shadi; Toolabi, Karamollah

    2015-01-01

    Background: Obesity as a worldwide health problem is associated with nonalcoholic steatohepatitis (NASH). Since severe liver injury may be present in asymptomatic obese patients and a definite diagnosis of nonalcoholic steatohepatitis can only be made after an invasive procedure of liver biopsy, there is a need for noninvasive methods to predict the probability of NASH. Objectives: To investigate the role of vitamin D endocrine system in predicting the probability of presence of NASH in asymptomatic morbidly obese candidates of bariatric surgery. Patients and Methods: From December 09 to March 11, every patient undergoing bariatric surgery had a liver biopsy. Nonalcoholic steatohepatitis was diagnosed using the Lee’s criteria, the baseline labs obtained and the association between laboratory data and presence of NASH assessed. Results: Forty-six patients (34 women, aged 36.5 ± 10.6 years) were analyzed. The mean levels of liver enzymes were significantly higher in the group with NASH (P value < 0.01). In an unadjusted logistic model, PTH was the only variable in vitamin D endocrine system which was significantly associated with NASH (odds ratio (OR): 1.04, 95%CI: 1.01 - 1.07). After adjustment for possible confounding factors, age (OR: 1.22, 95%CI: 1.00 - 1.50) and PTH (OR: 1.08, 95%CI: 1.01 - 1.16) were predictive factors for NASH (P value < 0.05). Conclusions: Elevated serum PTH level was the predictive factor for NASH in morbidly obese patients. Also, we reported elevated serum liver enzymes, high serum PTH levels and older age as predictors of NASH in patients seeking obesity surgical treatments. PMID:26300934

  7. Parathyroid Hormone-Related Peptide-Linked Hypercalcemia in a Melanoma Patient Treated With Ipilimumab: Hormone Source and Clinical and Metabolic Correlates.

    PubMed

    Mills, Teresa Anne; Orloff, Marlana; Domingo-Vidal, Marina; Cotzia, Paolo; Birbe, Ruth C; Draganova-Tacheva, Rossitza; Martinez Cantarin, Maria P; Tuluc, Madalina; Martinez-Outschoorn, Ubaldo

    2015-12-01

    A patient diagnosed with metastatic melanoma developed the paraneoplastic syndrome of humoral hypercalcemia of malignancy and cachexia after receiving ipilumumab. The cause of the hypercalcemia was thought to be secondary to parathyroid hormone-related peptide (PTHrP) as plasma levels were found to be elevated. The patient underwent two tumor biopsies: at diagnosis (when calcium levels were normal) and upon development of hypercalcemia and cachexia. PTHrP expression was higher in melanoma cells when hypercalcemia had occurred than prior to its onset. Metabolic characterization of melanoma cells revealed that, with development of hypercalcemia, there was high expression of monocarboxylate transporter 1 (MCT1), which is the main importer of lactate and ketone bodies into cells. MCT1 is associated with high mitochondrial metabolism. Beta-galactosidase (β-GAL), a marker of senescence, had reduced expression in melanoma cells upon development of hypercalcemia compared to pre-hypercalcemia. In conclusion, PTHrP expression in melanoma is associated with cachexia, increased cancer cell lactate and ketone body import, high mitochondrial metabolism, and reduced senescence. Further studies are required to determine if PTHrP regulates cachexia, lactate and ketone body import, mitochondrial metabolism, and senescence in cancer cells. PMID:26615135

  8. Effect of glucocorticoid-, parathyroid- and thyroid hormones excess on human iliac crest bone matrix insulin-like growth factor (IGF)-I in patients with osteoporosis.

    PubMed

    Pepene, C E; Seck, T; Diel, I; Minne, H W; Ziegler, R; Pfeilschifter, J

    2010-05-01

    Insulin-like growth factor-I (IGF-I) is a well documented bone-active growth factor. Clinical studies reported that circulating hormones may affect serum IGF-I levels, with potential consequences on bone remodeling. However, no data on bone matrix concentrations of IGF-I in subjects with endocrine dysfunction is available in humans. Bone mineral density and cancellous bone matrix IGF-I levels were assessed in iliac crest biopsies from 38 patients with low bone mass related to glucocorticoid- (n=10), parathyroid- (n=14) or thyroid (n=14) hormones excess. Results were compared to those of sex- and age-matched patients with primary osteoporosis. Bone matrix extraction was performed based on a guanidine-chlorhidric acid/ethylendiamine-tetraacetic acid method. Long-term glucocorticoid therapy (> or =24 months) led to significantly lower cancellous bone matrix IGF-I levels in comparison to age-matched controls (p=0.03). Although higher trabecular bone IGF-I levels were seen in hyperparathyroid subjects, the difference was not significant in comparison to controls (p=0.24). Likewise, no difference was noticed in cancellous bone matrix IGF-I concentrations between subjects with low bone mass and sub-clinical or overt thyrotoxicosis and euthyroid controls. Neither parathyroid hormone (PTH) nor thyroxin (T (4)) concentrations were associated with bone matrix IGF-I levels. To conclude, our study documented that in vivo long-term corticotherapy is associated with low trabecular human bone matrix IGF-I. In contrast, no influence of increased circulating parathyroid- or thyroid hormones levels on human iliac crest skeletal IGF-I concentrations was observed. PMID:19998242

  9. Parathyroid hormone attenuates radiation-induced increases in collagen crosslink ratio at periosteal surfaces of mouse tibia.

    PubMed

    Oest, Megan E; Gong, Bo; Esmonde-White, Karen; Mann, Kenneth A; Zimmerman, Nicholas D; Damron, Timothy A; Morris, Michael D

    2016-05-01

    As part of our ongoing efforts to understand underlying mechanisms contributing to radiation-associated bone fragility and to identify possible treatments, we evaluated the longitudinal effects of parathyroid hormone (PTH) treatment on bone quality in a murine model of limited field irradiation. We hypothesized PTH would mitigate radiation-induced changes in the chemical composition and structure of bone, as measured by microscope-based Raman spectroscopy. We further hypothesized that collagen crosslinking would be especially responsive to PTH treatment. Raman spectroscopy was performed on retrieved tibiae (6-7/group/time point) to quantify metrics associated with bone quality, including: mineral-to-matrix ratio, carbonate-to-phosphate ratio, mineral crystallinity, collagen crosslink (trivalent:divalent) ratio, and the mineral and matrix depolarization ratios. Irradiation disrupted the molecular structure and orientation of bone collagen, as evidenced by a higher collagen crosslink ratio and lower matrix depolarization ratio (vs. non-irradiated control bones), persisting until 12weeks post-irradiation. Radiation transiently affected the mineral phase, as evidenced by increased mineral crystallinity and mineral-to-matrix ratio at 4weeks compared to controls. Radiation decreased bone mineral depolarization ratios through 12weeks, indicating increased mineral alignment. PTH treatment partially attenuated radiation-induced increases in collagen crosslink ratio, but did not restore collagen or mineral alignment. These post-radiation matrix changes are consistent with our previous studies of radiation damage to bone, and suggest that the initial radiation damage to bone matrix has extensive effects on the quality of tissue deposited thereafter. In addition to maintaining bone quality, preventing initial radiation damage to the bone matrix (i.e. crosslink ratio, matrix orientation) may be critical to preventing late-onset fragility fractures. PMID:26960578

  10. Enhanced Bone Morphogenetic Protein-2-Induced Ectopic and Orthotopic Bone Formation by Intermittent Parathyroid Hormone (1–34) Administration

    PubMed Central

    Kempen, Diederik H.R.; Hefferan, Theresa E.; Creemers, Laura B.; Heijink, Andras; Maran, Avudaiappan; Dhert, Wouter J.A.; Yaszemski, Michael J.

    2010-01-01

    Bone morphogenetic proteins (BMPs) play a central role in local bone regeneration strategies, whereas the anabolic features of parathyroid hormone (PTH) are particularly appealing for the systemic treatment of generalized bone loss. The aim of the current study was to investigate whether local BMP-2-induced bone regeneration could be enhanced by systemic administration of PTH (1–34). Empty or BMP-2-loaded poly(lactic-co glycolic acid)/poly(propylene fumarate)/gelatin composites were implanted subcutaneously and in femoral defects in rats (n = 9). For the orthotopic site, empty defects were also tested. Each of the conditions was investigated in combination with daily administered subcutaneous PTH (1–34) injections in the neck. After 8 weeks of implantation, bone mineral density (BMD) and bone volume were analyzed using microcomputed tomography and histology. Ectopic bone formation and almost complete healing of the femoral defect were only seen in rats that received BMP-2-loaded composites. Additional treatment of the rats with PTH (1–34) resulted in significantly (p < 0.05) enhanced BMD and bone volume in the BMP-2 composites at both implantation sites. Despite its effect on BMD in the humerus and vertebra, PTH (1–34) treatment had no significant effect on BMD and bone volume in the empty femoral defects and the ectopically or orthotopically implanted empty composites. Histological analysis showed that the newly formed bone had a normal woven and trabecular appearance. Overall, this study suggests that intermittent administration of a low PTH dose alone has limited potential to enhance local bone regeneration in a critical-sized defect in rats. However, when combined with local BMP-2-releasing scaffolds, PTH administration significantly enhanced osteogenesis in both ectopic and orthotopic sites. PMID:20666615

  11. 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

  12. Bone-Invasive Oral Squamous Cell Carcinoma in Cats: Pathology and Expression of Parathyroid Hormone-Related Protein

    PubMed Central

    Martin, C. K.; Tannehill-Gregg, S. H.; Wolfe, T. D.; Rosol, T. J.

    2014-01-01

    Feline oral squamous cell carcinoma (OSCC) is the most common oral tumor in cats. There is no effective treatment, and the average duration of survival after diagnosis is only 2 months. Feline OSCC is frequently associated with osteolysis; however, the mechanisms responsible are unknown. The objective of this study was to characterize the epidemiology and pathology of bone-invasive OSCC in cats and to determine the expression of select bone resorption agonists. In sum, 451 cases of feline OSCC were evaluated. There was no sex or breed predisposition, although there were more intact cats in the OSCC group compared to the control group. Gingiva was the most common site, followed by the sublingual region and tongue. Cats with lingual OSCC were younger (mean, 11.9 years) compared to cats with gingival OSCC (mean, 13.6 years). In addition to osteolysis, there was periosteal new bone formation, osseous metaplasia of tumor stroma, and direct apposition of OSCC to fragments of bone, suggestive of bone-binding behavior. Eighty-two cases were selected for immunohistochemical detection of parathyroid hormone-related protein (PTHrP). Specimens with osteolysis had increased PTHrP expression and nuclear localization, compared to OSCC without osteolysis. Thirty-eight biopsies of OSCC with osteolysis were evaluated for tumor necrosis factor α expression, and only 4 biopsies had such expression in a small proportion of tumor cells. Increased tumor expression of PTHrP and increased localization of PTHrP to the nucleus were associated with osteolysis and may play an important role in bone resorption and tumor invasion in cats with OSCC. PMID:20940448

  13. Bone-invasive oral squamous cell carcinoma in cats: pathology and expression of parathyroid hormone-related protein.

    PubMed

    Martin, C K; Tannehill-Gregg, S H; Wolfe, T D; Rosol, T J

    2011-01-01

    Feline oral squamous cell carcinoma (OSCC) is the most common oral tumor in cats. There is no effective treatment, and the average duration of survival after diagnosis is only 2 months. Feline OSCC is frequently associated with osteolysis; however, the mechanisms responsible are unknown. The objective of this study was to characterize the epidemiology and pathology of bone-invasive OSCC in cats and to determine the expression of select bone resorption agonists. In sum, 451 cases of feline OSCC were evaluated. There was no sex or breed predisposition, although there were more intact cats in the OSCC group compared to the control group. Gingiva was the most common site, followed by the sublingual region and tongue. Cats with lingual OSCC were younger (mean, 11.9 years) compared to cats with gingival OSCC (mean, 13.6 years). In addition to osteolysis, there was periosteal new bone formation, osseous metaplasia of tumor stroma, and direct apposition of OSCC to fragments of bone, suggestive of bone-binding behavior. Eighty-two cases were selected for immunohistochemical detection of parathyroid hormone-related protein (PTHrP). Specimens with osteolysis had increased PTHrP expression and nuclear localization, compared to OSCC without osteolysis. Thirty-eight biopsies of OSCC with osteolysis were evaluated for tumor necrosis factor α expression, and only 4 biopsies had such expression in a small proportion of tumor cells. Increased tumor expression of PTHrP and increased localization of PTHrP to the nucleus were associated with osteolysis and may play an important role in bone resorption and tumor invasion in cats with OSCC. PMID:20940448

  14. 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.

  15. Endotoxin increases parathyroid hormone-related protein mRNA levels in mouse spleen. Mediation by tumor necrosis factor.

    PubMed Central

    Funk, J L; Krul, E J; Moser, A H; Shigenaga, J K; Strewler, G J; Grunfeld, C; Feingold, K R

    1993-01-01

    Parathyroid hormone-related protein (PTHrP) causes hypercalcemia in malignancy. However, the role and regulation of PTHrP in normal physiology is just beginning to be explored. PTHrP is found in the spleen and has several other features common to cytokines. Since endotoxin (LPS) causes many of its effects indirectly by inducing cytokines, studies were undertaken to determine whether LPS might also induce splenic PTHrP expression. LPS (100 ng/mouse) increased splenic PTHrP mRNA levels 3.6-fold in C3H/OuJ mice. This effect was maximal at 2 h and returned to baseline by 4 h. PTHrP peptide levels also increased 3.3-fold in splenic extracts in response to LPS (1 microgram/mouse). Murine TNF-alpha and human IL-1 beta, cytokines that mediate many of the effects of LPS, also increased splenic PTHrP mRNA levels. LPS-resistant C3H/HeJ mice, which produce minimal amounts of TNF and IL-1 in response to LPS, were resistant to LPS induction of splenic PTHrP mRNA, while TNF-alpha and IL-1 beta readily increased PTHrP mRNA levels in C3H/HeJ mice. Anti-TNF antibody blocked LPS induction of splenic PTHrP mRNA in C3H/OuJ mice by 68%, indicating that TNF is a mediator of the LPS induction of PTHrP levels. In contrast, an IL-1 receptor antagonist (IL-1ra) was ineffective. The increase in PTHrP in the spleen during the immune response suggests that PTHrP may play an important role in immune modulation, perhaps by mediating changes in lymphocyte proliferation and/or function. Images PMID:8227368

  16. 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

  17. The Effect of Bovine Parathyroid Hormone Withdrawal on MC3T3-E1 Cell Proliferation and Phosphorus Metabolism

    PubMed Central

    Li, Sijia; Cui, Tongxia; Li, Zhonghe; Zhang, Bin; Li, Zhuo; Wu, Jianxiong; Liang, Xinling; Lin, Zheng; Shi, Wei

    2015-01-01

    Hypocalcemia and hypophosphatemia are common complications after parathyroidectomy (PTX). Sudden removal of high circulating levels of parathyroid hormone (PTH) causes decreased osteoclastic resorption resulting in a decreased bone remodeling space. These phenomena are likely due to an increased influx of calcium and phosphorus into bone. However, there are currently no data to support this hypothesis. In this study, we found that PTX significantly reduced levels of PTH, calcium and phosphate. Compared with preoperative levels, after 1 year, postoperative PTH, calcium and phosphate levels were 295.6 ± 173.7 pg/mL (P < 0.05), 86.62 ± 15.98 mg/dL (P < 0.05) and 5.56 ± 2.03 mg/dL (P < 0.05), respectively. We investigated continuous bovine PTH administration as well as withdrawal of bovine PTH stimulation in the mouse osteoblast precursor cell line MC3T3-E1. MC3T3-E1 cells were cultured with continuous bovine PTH treatment for 20 days or with transient bovine PTH treatment for 10 days. High doses of continuous bovine PTH exposure strongly reduced cell proliferation, alkaline phosphatase activity and the number of mineralized calcium nodules. However, withdrawal of bovine PTH (100 ng/mL) significantly increased the number of mineralized calcium nodules and caused a rapid decline in calcium and phosphorus content of culture medium. In conclusion, continuous exposure to bovine PTH inhibited osteoblast differentiation and reduced the formation of mineralized nodules. However, this inhibition was removed and mineralized nodule formation resumed with withdrawal of bovine PTH. According to the results of our clinical examinations and in vitro experiments, we hypothesize that the sudden removal of high levels of PTH may cause an increased influx of calcium and phosphorus into bone after PTX. PMID:25775025

  18. The effect of bovine parathyroid hormone withdrawal on MC3T3-E1 cell proliferation and phosphorus metabolism.

    PubMed

    Liu, Shuangxin; Zhu, Weiping; Li, Sijia; Cui, Tongxia; Li, Zhonghe; Zhang, Bin; Li, Zhuo; Wu, Jianxiong; Liang, Xinling; Lin, Zheng; Shi, Wei

    2015-01-01

    Hypocalcemia and hypophosphatemia are common complications after parathyroidectomy (PTX). Sudden removal of high circulating levels of parathyroid hormone (PTH) causes decreased osteoclastic resorption resulting in a decreased bone remodeling space. These phenomena are likely due to an increased influx of calcium and phosphorus into bone. However, there are currently no data to support this hypothesis. In this study, we found that PTX significantly reduced levels of PTH, calcium and phosphate. Compared with preoperative levels, after 1 year, postoperative PTH, calcium and phosphate levels were 295.6 ± 173.7 pg/mL (P < 0.05), 86.62 ± 15.98 mg/dL (P < 0.05) and 5.56 ± 2.03 mg/dL (P < 0.05), respectively. We investigated continuous bovine PTH administration as well as withdrawal of bovine PTH stimulation in the mouse osteoblast precursor cell line MC3T3-E1. MC3T3-E1 cells were cultured with continuous bovine PTH treatment for 20 days or with transient bovine PTH treatment for 10 days. High doses of continuous bovine PTH exposure strongly reduced cell proliferation, alkaline phosphatase activity and the number of mineralized calcium nodules. However, withdrawal of bovine PTH (100 ng/mL) significantly increased the number of mineralized calcium nodules and caused a rapid decline in calcium and phosphorus content of culture medium. In conclusion, continuous exposure to bovine PTH inhibited osteoblast differentiation and reduced the formation of mineralized nodules. However, this inhibition was removed and mineralized nodule formation resumed with withdrawal of bovine PTH. According to the results of our clinical examinations and in vitro experiments, we hypothesize that the sudden removal of high levels of PTH may cause an increased influx of calcium and phosphorus into bone after PTX. PMID:25775025

  19. Disruption of β-catenin binding to parathyroid hormone (PTH) receptor inhibits PTH-stimulated ERK1/2 activation.

    PubMed

    Yang, Yanmei; Wang, Bin

    2015-08-14

    The type I parathyroid hormone receptor (PTH1R) mediates PTH and PTH-related protein (PTHrP) actions on extracellular mineral ion homeostasis and bone remodeling. These effects depend in part on the activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2). Sequences located within or at the carboxyl-terminus of PTH1R control its activation and trafficking. β-catenin regulates PTH1R signaling and promotes chondrocyte hypertrophy through binding to the intracellular carboxyl-terminal region of the receptor. How the interaction of PTH1R with β-catenin affects PTH-stimulated ERK1/2 is unknown. In the present study, human embryonic kidney 293 (HEK293) cells, which do not express the PTH1R, were used to investigate whether the disruption of β-catenin binding to PTH1R affects PTH-stimulated ERK1/2 activation. We demonstrated that β-catenin interacted with wild-type PTH1R but this interaction was markedly reduced with mutant PTH1R (L584A/L585A). PTH stimulated less cAMP formation and increased more intracellular calcium in HEK293 cells transfected with wild-type PTH1R compared with mutant PTH1R, indicating β-catenin switches PTH1R signaling from Gαs activation to Gαq signaling. In addition, ERK1/2 activation in HEK293 cells transfected with PTH1R exhibited time and concentration dependence. PTH-stimulated ERK1/2 activation was mostly mediated through Gαq/PLC signaling pathway. Importantly, transfection of mutant PTH1R decreased PTH-induced ERK1/2 activation by inhibiting Gαq-mediated signaling. This study shows for the first time that the interference of β-catenin binding to PTH1R inhibits PTH-stimulated ERK1/2 phosphorylation. PMID:26047699

  20. Low parathyroid hormone status induced by high dialysate calcium is an independent risk factor for cardiovascular death in hemodialysis patients.

    PubMed

    Merle, Emilie; Roth, Hubert; London, Grard M; Jean, Guillaume; Hannedouche, Thierry; Bouchet, Jean-Louis; Dreke, Tilman; Fouque, Denis; Daugas, Eric

    2016-03-01

    Here we studied a possible association between low parathyroid hormone (PTH) status and mortality in incident patients undergoing hemodialysis . A total of 1983 patients were included at baseline and prospectively followed for 24months. Patients were classified according to their Kidney Disease: Improving Global Outcomes PTH status at baseline and at 12 months, and mortality evaluated at 12 to 24 months using adjusted Cox analysis. Factors potentially involved in PTH status variability between baseline and 12months were analyzed. A decrease in serum PTH from normal or high to low values between baseline and 12months was associated with significantly increased cardiovascular mortality at 12 to 24 months (hazard ratio, 2.03; 95% confidence interval, 1.22-3.36). For patients with high or normal baseline PTH levels, the main independent factor at 6 months for a decrease to low PTH levels at 12months was high dialysate calcium (1.75 mmol/L), whereas prescription of non-calcium-based phosphate binders was associated with a lower risk of PTH decrease. Inthe high cardiovascular (CV) mortality risk subgroup of patients who acquired a low PTH status at 12 months, the main independent factor at 12 months associated with significant 12- to 24-month CV mortality was high dialysate calcium (odds ratio, 5.44; 95% CI, 2.52-11.75). Thus, patients with a serum PTH decrease to low values after 1year of hemodialysis treatment are at high risk of short-term CV death. High dialysate calcium was an important contributor to PTH oversuppression, and continued use was associated with increased CV mortality. PMID:26880460

  1. Fibroblast growth factor 23, but not parathyroid hormone, is associated with urinary phosphate regulation in patients on peritoneal dialysis.

    PubMed

    Yamada, Shunsuke; Tsuruya, Kazuhiko; Tokumoto, Masanori; Yoshida, Hisako; Hasegawa, Shoko; Tanaka, Shigeru; Eriguchi, Masahiro; Nakano, Toshiaki; Masutani, Kosuke; Ooboshi, Hiroaki; Kitazono, Takanari

    2015-02-01

    Fibroblast growth factor (FGF) 23 plays an important role in regulation of renal phosphate excretion in patients with chronic kidney disease. However, it remains undetermined whether FGF23 is closely linked to renal phosphate handling in patients with low glomerular filtration rate (GFR). The present cross-sectional study included 52 outpatients undergoing peritoneal dialysis with urine volume ≥ 100 mL/day. The primary outcome was level of urinary phosphate excretion, and the secondary outcomes were tubular maximal reabsorption of phosphate normalized to GFR (TmP/GFR), an index of the renal threshold for phosphate excretion, and level of peritoneal phosphate excretion. Variates of interest were serum FGF23 and parathyroid hormone (PTH) levels. The median and interquartile range of serum FGF23 level, TmP/GFR, and total urinary and peritoneal phosphate excretion were 5610 (1493-11 430) ng/mL, 1.30 (0.44-1.86) mg/dL, 117 (40-234) mg/day, and 208 (156-250) mg/day, respectively. Multivariate linear regression analysis revealed that serum FGF23 level was significantly (P < 0.05) associated with TmP/GFR negatively and significantly (P < 0.05) associated with urinary phosphate excretion positively, even after adjusting for confounders. In contrast, none of the three outcome variates was associated with serum PTH level. Neither serum FGF23 nor PTH level was associated with peritoneal phosphate excretion. The present study indicates that FGF23, but not PTH, is involved in urinary phosphate regulation, even in patients on peritoneal dialysis with residual renal function. PMID:25195562

  2. Mitogen-activated protein kinase phosphatase 1 regulates bone mass, osteoblast gene expression, and responsiveness to parathyroid hormone

    PubMed Central

    Mahalingam, Chandrika D; Datta, Tanuka; Patil, Rashmi V; Kreider, Jaclynn; Bonfil, R Daniel; Kirkwood, Keith L; Goldstein, Steven A; Abou-Samra, Abdul B; Datta, Nabanita S

    2013-01-01

    Parathyroid hormone (PTH) signaling via PTH 1 receptor (PTH1R) involves mitogen-activated protein kinase (MAPK) pathways. MAPK phosphatase 1 (MKP1) dephosphorylates and inactivates MAPKs in osteoblasts, the bone-forming cells. We previously showed that PTH1R activation in differentiated osteoblasts upregulates MKP1 and downregulates pERK1/2MAPK and cyclin D1. In this study, we evaluated the skeletal phenotype of Mkp1 knockout (KO) mice and the effects of PTH in vivo and in vitro. Microcomputed tomography analysis of proximal tibiae and distal femora from 12-week-old Mkp1 KO female mice revealed osteopenic phenotype with significant reduction (846%) in bone parameters compared with wild-type (WT) controls. Histomorphometric analysis showed decreased trabecular bone area in KO females. Levels of serum osteocalcin (OCN) were lower and serum tartrate-resistant acid phosphatase 5b (TRAP5b) was higher in KO animals. Treatment of neonatal mice with hPTH (134) for 3 weeks showed attenuated anabolic responses in the distal femora of KO mice compared with WT mice. Primary osteoblasts derived from KO mice displayed delayed differentiation determined by alkaline phosphatase activity, and reduced expressions of Ocn and Runx2 genes associated with osteoblast maturation and function. Cells from KO females exhibited attenuated PTH response in mineralized nodule formation in vitro. Remarkably, this observation was correlated with decreased PTH response of matrix Gla protein expression. Expressions of pERK1/2 and cyclin D1 were inhibited dramatically by PTH in differentiated osteoblasts from WT mice but much less in osteoblasts from Mkp1 KO mice. In conclusion, MKP1 is important for bone homeostasis, osteoblast differentiation and skeletal responsiveness to PTH. PMID:21852324

  3. Covalent labeling of a high-affinity, guanyl nucleotide sensitive parathyroid hormone receptor in canine renal cortex

    SciTech Connect

    Nissenson, R.A.; Karpf, D.; Bambino, T.; Winer, J.; Canga, M.; Nyiredy, K.; Arnaud, C.D.

    1987-04-07

    Putative parathyroid hormone (PTH) receptors in canine renal membranes were affinity labeled with /sup 125/I-bPTH(1-34) using the heterobifunctional cross-linking reagent N-hydroxysuccinimidyl 4-azido-benzoate. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed the presence of a major 85,000 molecular weight (M/sub r/) PTH binding component, the labeling of which was inhibited by nanomolar concentrations of unlabeled PTH and by micromolar concentrations of 5'-guanylyl imidodiphosphate (Gpp-(NH)p). Labeling was not influenced by the unrelated peptides insulin and arginine vasopressin. Minor PTH binding components of M/sub r/ 55,000 and 130,000 were also seen, and labeling of these was likewise sensitive to unlabeled PTH and to Gpp(NH)p. Omission of protease inhibitors during the isolation of plasma membranes resulted in the loss of the M/sub r/ 85,000 PTH binding species and the appearance of an M/sub r/ 70,000 form. Several minor PTH binding components also were observed. Equilibrium binding studies showed that such membranes had an affinity for PTH indistinguishable from that in membranes isolated with protease inhibitors and displaying a major M/sub r/ 85,000 PTH binding species. The authors conclude that the major form of the adenylate cyclase coupled PTH receptor in canine renal membranes is an M/sub r/ 85,000 protein. An endogenous enzyme, probably a lysosomal cathepsin, can cleave this form to produce an M/sub r/ 70,000 receptor that retains full functional activity with respect to high-affinity, guanyl nucleotide sensitive PTH binding. The ability to covalently label the PTH receptor in high yield represents a major step toward the structural characterization of this important detector molecule.

  4. 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.

  5. Enhanced expression of parathyroid hormone-related protein in prostate cancer as compared with benign prostatic hyperplasia.

    PubMed

    Asadi, F; Farraj, M; Sharifi, R; Malakouti, S; Antar, S; Kukreja, S

    1996-12-01

    Parathyroid hormone-related protein (PTHrP) has been shown to be the primary factor responsible for humoral hypercalcemia of malignancy. Recently PTHrP has been shown to be an early-response gene that may be involved in cellular proliferation or differentiation. In addition, PTHrP has been implicated in the pathogenesis of bone metastases. Bone metastases are a significant complication in patients with prostate cancer. We compared the expression of PTHrP by immunohistochemical staining using a monoclonal antibody directed against epitope between amino acids [53-64] in benign prostatic hyperplasia (BPH) with that in various stages of prostate cancer. Tissue sections were obtained on formalin-fixed paraffin-embedded blocks from BPH, well-differentiated prostate cancer, poorly differentiated prostate cancer, lymph node metastases (n = 15 each), and normal prostate (n = 2). In the normal prostate tissue there was no staining observed. In BPH, 13 of 15 tissue samples were positive for PTHrP immunoreactivity. An average of 33% of the cells stained positive with 1+ intensity. All samples from prostate cancer stained positive for PTHrP. In the samples from well-differentiated prostate cancer, an average of 87% of cells stained positive for PTHrP, whereas 100% of cells were positive in poorly differentiated and metastatic tumors. The intensity of staining was 3+ in well-differentiated tumors and 4+ in poorly differentiated tumors. Therefore, the expression of PTHrP is enhanced in prostate cancer as compared with BPH and is greater in poorly differentiated carcinoma as compared with the well-differentiated tumors. The role of PTHrP in the pathogenesis of prostate cancer deserves further study. PMID:8958305

  6. Parathyroid hormone promotes the disassembly of cytoskeletal actin and myosin in cultured osteoblastic cells: Mediation by cyclic AMP

    SciTech Connect

    Egan, J.J.; Gronowicz, G.; Rodan, G.A. )

    1991-01-01

    Parathyroid hormone (PTH) alters the shape of osteoblastic cells both in vivo and in vitro. In this study, we examined the effect of PTH on cytoskeletal actin and myosin, estimated by polyacrylamide gel electrophoresis of Triton X-100 (1%) nonextractable proteins. After 2-5 minutes, PTH caused a rapid and transient decrease of 50-60% in polymerized actin and myosin associated with the Triton X-100 nonextractable cytoskeleton. Polymerized actin returned to control levels by 30 min. The PTH effect was dose-dependent with an IC50 of about 1 nM, and was partially inhibited by the (3-34) PTH antagonist. PTH caused a rapid transient rise in cyclic AMP (cAMP) in these cells that peaked at 4 min, while the nadir in cytoskeletal actin and myosin was recorded around 5 min. The intracellular calcium chelator Quin-2/AM (10 microM) also decreased cytoskeletal actin and myosin, to the same extent as did PTH (100 nM). To distinguish between cAMP elevation and Ca++ reduction as mediators of PTH action, we measured the phosphorylation of the 20 kD (PI 4.9) myosin light chain in cells preincubated with (32P)-orthophosphate. The phosphorylation of this protein decreased within 2-3 min after PTH addition and returned to control levels after 5 min. The calcium ionophore A-23187 did not antagonize this PTH effect. Visualization of microfilaments with rhodamine-conjugated phalloidin showed that PTH altered the cytoskeleton by decreasing the number of stress fibers. These changes in the cytoskeleton paralleled changes in the shape of the cells from a spread configuration to a stellate form with retracting processes. The above findings indicate that the alteration in osteoblast shape produced by PTH involve relatively rapid and transient changes in cytoskeletal organization that appear to be mediated by cAMP.

  7. 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

  8. Role of Gap Junction, Hemichannels, and Connexin 43 in Mineralizing in Response to Intermittent and Continuous Application of Parathyroid Hormone

    PubMed Central

    JIANG, JEAN X.

    2016-01-01

    Intermittent administration stimulates bone formation, whereas sustained elevation of parathyroid hormone (PTH) as in hyperparathyroidism stimulates bone resorption. Even though PTH(1-34) is the only anabolic agent clinically approved for the treatment of osteoporosis, the molecular mechanism whereby PTH mediates these opposing effects depending on timing of administration is not well understood. In this study, we sought to determine the involvement of gap junctions and hemichannels, and the protein that forms them, connexin 43 (Cx43), in the effect of PTH(1-34) on osteoblast mineralization. The osteoblast-like cell line MLO-A5 that rapidly mineralizes in culture was used. Intermittent PTH enhances mineralization, whereas continuous PTH inhibits this process. The mineralization was significantly inhibited by 18 β-glycyrrhetinic acid, an inhibitor known to block gap junctions and hemichannels. When the cells were treated with PTH(1-34), gap junctional coupling was increased; however, the degree of stimulation was similar between intermittent and continuous treatment. The permeabilization to dye was not detected under various intermittent or continuous PTH treatments. On the other hand, the overall level of Cx43 protein increased in response to continuous PTH treatment. In contrast, when the cells were subjected to intermittent treatment overall level of Cx43 was unchanged, but there was an increase of connexons associated with an increase in Cx43 expression on the cell surface. Our results suggest that Cx43 overall expression, connexon formation and cell surface expression are differentially regulated by intermittent and continuous PTH(1-34), implying the involvement of Cx43 and Cx43-forming channels in mediating the effects of PTH on bone formation. PMID:18649177

  9. 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

  10. Regulation of connexin43 expression and function by prostaglandin E2 (PGE2) and parathyroid hormone (PTH) in osteoblastic cells.

    PubMed

    Civitelli, R; Ziambaras, K; Warlow, P M; Lecanda, F; Nelson, T; Harley, J; Atal, N; Beyer, E C; Steinberg, T H

    1998-01-01

    Connexin43 (Cx43) forms gap junctions that mediate intercellular communication between osteoblasts. We have examined the effects of prostaglandin E2 (PGE2) and parathyroid hormone (PTH) on gap junctional communication in the rat osteogenic sarcoma cells UMR 106-01. Incubation with either PGE2 or PTH rapidly (within 30 min) increased transfer of negatively charged dyes between UMR 106-01 cells. This stimulatory effect lasted for at least 4 h. Both PGE2 and PTH increased steady-state levels of Cx43 mRNA, but only after 2-4 h of incubation. Transfection with a Cx43 gene construct linked to luciferase showed that this effect of PTH was the result of transcriptional upregulation of Cx43 promoter. Stimulation of dye coupling and Cx43 gene transcription were reproduced by forskolin and 8Br-cAMP. Exposure to PGE2 for 30 min increased Cx43 abundance at appositional membranes in UMR 106-01, whereas total Cx43 protein levels increased only after 4-6 h of incubation with either PGE2 or PTH. Inhibition of protein synthesis by cycloheximide did not affect this early stimulation of dye coupling, but it significantly inhibited the sustained effect of PTH and forskolin on cell coupling. In summary, both PTH and PGE2, presumably through cAMP production, enhance gap junctional communication in osteoblastic cell cultures via two mechanisms: initial rapid redistribution of Cx43 to the cell membrane, and later stimulation of Cx43 gene expression. Modulation of intercellular communication represents a novel mechanism by which osteotropic factors regulate the activity of bone forming cells. PMID:9407310

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

    PubMed

    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(+)/H(+) 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. PMID:25888790

  12. An Essential Role for Parathyroid Hormone in Gill Formation and Differentiation of Ion-Transporting Cells in Developing Zebrafish.

    PubMed

    Kwong, Raymond W M; Perry, Steve F

    2015-07-01

    In vertebrates, parathyroid hormone (PTH) is important for skeletogenesis and Ca(2+) homeostasis. However, little is known about the molecular mechanisms by which PTH regulates skeleton formation and Ca(2+) balance during early development. Using larval zebrafish as an in vivo model system, we determined that PTH1 regulates the differentiation of epithelial cells and the development of craniofacial cartilage. We demonstrated that translational gene knockdown of PTH1 decreased Ca(2+) uptake at 4 days after fertilization. We also observed that PTH1-deficient fish exhibited reduced numbers of epithelial Ca(2+) channel (ecac)-expressing cells, Na(+)/K(+)-ATPase-rich cells, and H(+)-ATPase-rich cells. Additionally, the density of epidermal stem cells was decreased substantially in the fish experiencing PTH1 knockdown. Knockdown of PTH1 caused a shortening of the jaw and impeded the development of branchial arches. Results from in situ hybridization suggested that the expression of collagen 2a1a (marker for proliferating chondrocytes) was substantially reduced in the cartilage that forms the jaw and branchial aches. Disorganization of chondrocytes in craniofacial cartilage also was observed in PTH1-deficient fish. The results of real-time PCR demonstrated that PTH1 morphants failed to express the transcription factor glial cell missing 2 (gcm2). Coinjection of PTH1 morpholino with gcm2 capped RNA rescued the phenotypes observed in the PTH1 morphants, suggesting that the defects in PTH1-deficient fish were caused, at least in part, by the suppression of gcm2. Taken together, the results of the present study reveal critical roles for PTH1 in promoting the differentiation of epidermal stem cells into mature ionocytes and cartilage formation during development. PMID:25872007

  13. Human granulosa-luteal cells secrete parathyroid hormone-related protein in vivo and in vitro.

    PubMed

    Gutmann, J N; Burtis, W J; Dreyer, B E; Andrade-Gordon, P; Penzias, A S; Polan, M L; Insogna, K L

    1993-05-01

    The presence of mRNA transcripts and/or immunoreactivity for PTH-related protein (PTHrP) in several normal mammalian tissues suggests a possible paracrine or autocrine role for this hormone. Since immunohistochemical studies of human ovary demonstrate the presence PTHrP immunoreactivity in this tissue, we wondered if ovarian follicular fluid (OVFF) might contain PTHrP. We retrospectively analyzed 28 OVFF samples obtained at ova harvest in 21 women undergoing in vitro fertilization. Fourteen samples contained significant adenylate cyclase-stimulating activity in a PTHrP-sensitive bioassay. In a subsequent prospective analysis, 41 of 45 freshly obtained OVFF samples demonstrated significant activity. This bioactivity was completely neutralized by antisera to PTHrP, but was unaffected by antisera to PTH. Fifteen OVFF samples were also analyzed in a sensitive 2-site immunoradiometric assay for PTHrP, and all 15 demonstrated significant levels of the hormone. The PTHrP levels did not correlate with the presence of an ovum in the follicle or with follicular fluid calcium. Short term (24- to 48-h) cultures of granulosa-luteal cells established from 5 OVFF samples demonstrated constitutive secretion of PTHrP using the immunoradiometric assay. Neither progesterone nor estrogen affected basal secretion. RNase protection analysis of cellular RNA prepared from cultured granulosa-luteal cells demonstrated the presence of mRNA for PTHrP in these cells. We conclude that 1) human OVFF obtained after stimulation with FSH and LH contain high concentrations of PTHrP; and 2) the granulosa-luteal cell is capable of secreting PTHrP both in vivo and in vitro. PMID:8496323

  14. Vitamin D, secondary hyperparathyroidism, and preeclampsia123

    PubMed Central

    Scholl, Theresa O; Chen, Xinhua; Stein, T Peter

    2013-01-01

    Background: Secondary hyperparathyroidism, which is defined by a high concentration of intact parathyroid hormone when circulating 25-hydroxyvitamin D [25(OH)D] is low, is a functional indicator of vitamin D insufficiency and a sign of impaired calcium metabolism. Two large randomized controlled trials examined effects of calcium supplementation on preeclampsia but did not consider the vitamin D status of mothers. Objective: We examined the association of secondary hyperparathyroidism with risk of preeclampsia. Design: Circulating maternal 25-hydroxyvitamin D [25(OH)D] and intact parathyroid hormone were measured at entry to care (mean SD: 13.7 5.7 wk) using prospective data from a cohort of 1141 low-income and minority gravidae. Results: Secondary hyperparathyroidism occurred in 6.3% of the cohort and 18.4% of women whose 25(OH)D concentrations were <20 ng/mL. Risk of preeclampsia was increased 2.86-fold (95% CI: 1.28-, 6.41-fold) early in gestation in these women. Gravidae with 25(OH)D concentrations <20 ng/mL who did not also have high parathyroid hormone and women with high parathyroid hormone whose 25(OH)D concentrations were >20 ng/mL were not at increased risk. Intact parathyroid hormone was related to higher systolic and diastolic blood pressures and arterial pressure at week 20 before clinical recognition of preeclampsia. Energy-adjusted intakes of total calcium and lactose and circulating 25(OH)D were correlated inversely with systolic blood pressure or arterial pressure and with parathyroid hormone. Conclusion: Some women who are vitamin D insufficient develop secondary hyperparathyroidism, which is associated with increased risk of preeclampsia. PMID:23885046

  15. Cardiovascular risk in adult hypopituitaric patients with growth hormone deficiency: is there a role for vitamin D?

    PubMed

    Savanelli, Maria Cristina; Scarano, Elisabetta; Muscogiuri, Giovanna; Barrea, Luigi; Vuolo, Laura; Rubino, Manila; Savastano, Silvia; Colao, Annamaria; Di Somma, Carolina

    2016-04-01

    Hypovitaminosis D represent an environmental risk factors for cardiovascular (CV) disease. To investigate the prevalence of hypovitaminosis D and the correlation between GH/IGF-I deficiency and hypovitaminosis D with CV risk in GH deficiency (GHD) patients. A link between these hormones has been shown. Forty-one hypopituitaric patients with GHD (22 males, age 18-84 years) and 41 controls were enrolled in the study. Anthropometric parameters, blood pressure, glucose and lipid profile, parathyroid hormone (PTH), 25(OH) vitamin D (vitamin D), metabolic syndrome (MS), GH peak after GHRH + ARG, IGF-I, and standard deviation score (SDS) of IGF-I (zIGF-I) were assessed. Vitamin D levels were lower in patients than in controls (21.3 ± 12.3 vs. 28.2 ± 9.4, p = 0.006). Deficiency was found in 51 % of patients versus 14.6 % of controls (p < 0.01), insufficiency in 26.8 versus 41.4 % (p = 0.269) and normal vitamin D levels in 21.9 versus 43.9 % (p = 0.060). The prevalence of dyslipidemia was 51.2 % in patients versus 12.1 % in controls (p < 0.001), type 2 diabetes mellitus (DM) was 7.3 versus 17 % (p = 0.292), hypertension was 44 versus 22 % (p = 0.060), and MS was 17 versus 14.6 % (p = 0.957). In patients, an association was found between the presence of hypovitaminosis D and the prevalence of dyslipidemia, hypertension and MS and between zIGF-I and the prevalence of hypertension. Hypovitaminosis D was the most powerful predictor of the prevalence of dyslipidemia and hypertension. GHD patients have an increased prevalence of hypovitaminosis D compared with controls. The presence of hypovitaminosis D was the most powerful predictor of the prevalence of dyslipidemia and hypertension in GHD patients, suggesting the involvement of both factors in the CV risk in these patients. PMID:26511949

  16. Hormone response element binding proteins: novel regulators of vitamin D and estrogen signaling

    PubMed Central

    Lisse, Thomas S.; Hewison, Martin; Adams, John S.

    2011-01-01

    Insights from vitamin D-resistant New World primates and their human homologues as models of natural and pathological insensitivity to sterol/steroid action have uncovered a family of novel intracellular vitamin D and estrogen regulatory proteins involved in hormone action. The proteins, known as “vitamin D or estrogen response element-binding proteins”, behave as potent cis-acting, transdominant regulators to inhibit steroid receptor binding to DNA response elements and is responsible for vitamin D and estrogen resistances. This set of interactors belongs to the heterogeneous nuclear ribonucleoprotein (hnRNP) family of previously known pre-mRNA-interacting proteins. This review provides new insights into the mechanism by which these novel regulators of signaling and metabolism can act to regulate responses to vitamin D and estrogen. In addition the review also describes other molecules that are known to influence nuclear receptor signaling through interaction with hormone response elements. PMID:21236284

  17. Vitamin D and the Immune System from the Nephrologist's Viewpoint

    PubMed Central

    Wang, Min-Hui; Chiang, Chih-Kang; Lu, Kuo-Cheng

    2014-01-01

    Vitamin D and its analogues are widely used as treatments by clinical nephrologists, especially when treating chronic kidney disease (CKD) patients with secondary hyperparathyroidism. As CKD progresses, the ability to compensate for elevations in parathyroid hormone (PTH) and fibroblast growth factor-23 and for decreases in 1,25(OH)2D3 becomes inadequate, which results in hyperphosphatemia, abnormal bone disorders, and extra-skeletal calcification. In addition to its calciotropic effect on the regulation of calcium, phosphate, and parathyroid hormone, vitamin D has many other noncalciotropic effects, including controlling cell differentiation/proliferation and having immunomodulatory effects. There are several immune dysregulations that can be noted when renal function declines. Physicians need to know well both the classical and nonclassical functions of vitamin D. This review is an analysis from the nephrologist's viewpoint and focuses on the relationship between the vitamin D and the immune system, together with vitamin's clinical use to treat kidney diseases. PMID:24587915

  18. 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 indicate that for women PTH is a plausible mediator in the association between MS and a range of explanatory variables, including vit D, magnesium and phosphate. PMID:21306649

  19. 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.

  20. The relative roles of calcium, phosphorus, and parathyroid hormone in glucose- and tolbutamide-mediated insulin release.

    PubMed Central

    Harter, H R; Santiago, J V; Rutherford, W E; Slatopolsky, E; Klahr, S

    1976-01-01

    The relative contributions of Ca++, phosphorus, and parathyroid hormone (PTH) on insulin secretion were evaluated in three groups of dogs. Dogs were studied with glucose infusions (group I) or standard intravenous glucose tolerance tests (IVGTT) (group II) before and after the development of diet-induced hypophosphatemia. Mean serum phosphorus levels for both groups fell from 4.1 to 1.1 mg/100 ml. Animals in group I demonstrated a fall in glucose disappearance rates (Kg) from 5.3+/-0.6% min to 3.5+/-0.5% after induction of hypophosphatemia (P less than 0.001). Mean insulin response was significantly greater in the hypophosphatemic animals than in controls in this group. In group II animals, mean insulin areas obtained during the IVGTT increased from 1,426+/-223 to 2,561+/-141 muU/ml/60 min after induction of hypophosphatemia, and were unaffected by Ca++ or PTH administration. Ca++ administration, but not hypophosphatemia or PTH infusion, increased significantly the mean insulin response to tolbutamide. Secondary hyperparathyroidism was induced by dietary manipulation in four dogs (group III). Mean PTH values increased from 71.4+/-2.1 to 3,012+/-372 pg/ml (P less than 0.001). Mean insulin response to an IVGTT was similar to group III animals, but increased from 1,352+/-128 to 1,894+/-360 muU/ml/60 min after the excessive dietary phosphorus was reduced for 3 mo, and plasma phosphorus fell from 3.2+/-0.1 to 2.8+/-0.3 mg/100 ml. PTH values decreased to 647+/-53 pg/ml. The insulin response to tolbutamide was comparable to that in group II animals, but increased significantly after calcium administration. Immunoreactive insulin disappearance rates were unaffected by hypophosphatemia or diet-induced secondary hyperparathyroidism. These data demonstrate that hypophosphatemia is associated with an augmented glucose-stimulated insulin release, without any effect on tolbutamide-stimulated insulin release. Hypercalcemia produces an augmented tolbutamide-stimulated insulin release with no apparent effect on glucose-stimulated insulin release. Finally, PTH does not appear to be an insulin antagonist and has no apparent effect on either glucose- or tolbutamide-stimulated insulin release in animals with dietary-induced secondary hyperparathyroidism. PMID:956371

  1. Reversal of nicotine-induced alveolar lipofibroblast-to-myofibroblast transdifferentiation by stimulants of parathyroid hormone-related protein signaling.

    PubMed

    Rehan, Virender K; Sakurai, Reiko; Wang, Ying; Santos, Jamie; Huynh, Kyle; Torday, John S

    2007-01-01

    Nicotine exposure disrupts the parathyroid hormone-related protein (PTHrP)-driven alveolar epithelial-mesenchymal paracrine-signaling pathway, resulting in the transdifferentiation of pulmonary lipofibroblasts (LIFs) to myofibroblasts (MYFs), which seems to be central to altered pulmonary development and function in infants born to mothers who smoke during pregnancy. Modulation of PTHrP-driven signaling can almost completely prevent nicotine-induced LIF-to-MYF transdifferentiation. However, once this process has occurred, whether it can be reversed is not known. Our objective was to determine if nicotine-induced LIF-to-MYF transdifferentiation could be reversed by specifically targeting the PTHrP-mediated alveolar epithelial-mesenchymal paracrine signaling. WI38 cells, a human embryonic pulmonary fibroblast cell line, were initially treated with nicotine for 7 days and LIF-to-MYF transdifferentiation was confirmed by determining the downregulation of the key lipogenic marker, peroxisome proliferator-activated receptor gamma (PPARgamma) and upregulation of the key myogenic marker, alpha-smooth muscle actin (alphaSMA). Because downregulation of the PPARgamma signaling pathway is the key determinant of LIF-to-MYF transdifferentiation, cells were treated with three agonists of this pathway, PTHrP, dibutryl cAMP (DBcAMP), or rosiglitazone (RGZ) for 7 days, and the expression of the PTHrP receptor, PPARgamma, alphaSMA, and calponin was determined by Western analysis and immunohistochemistry. Simultaneously, fibroblast function was characterized by measuring their capacity to take up triglycerides. Nicotine-induced LIF-to-MYF transdifferentiation was almost completely reversed by treatment with RGZ, PTHrP, or DBcAMP, as determined by protein and functional assays. Using a specific molecular approach and targeting specific molecular intermediates in the PTHrP signaling pathway, to our knowledge, this for the first time, demonstrates the reversibility of nicotine-induced LIF-to-MYF transdifferentiation, suggesting not only the possibility of prevention but also the potential for reversal of nicotine-induced lung injury. PMID:17401602

  2. Expression of Rho GDIα in rat osteoblasts intermittently exposed to parathyroid hormone in vitro and in vivo

    PubMed Central

    Sun, Zu-feng; Jiang, Hui; Ye, Zheng-qin; Jia, Bing; Zhang, Xiao-le; Zhang, Ke-qin

    2009-01-01

    Aim: To investigate the mechanism of the bone-forming effects of intermittent parathyroid hormone (PTH) administration and to search for novel molecules of bone anabolism via the PTH signaling pathway. Methods: Primary cultures of rat osteoblasts (ROBs) were divided into an intermittent PTH-treated group (Itm) and a control group (Ctr). Imitating the pharmacokinetics of intermittent PTH administration in vivo, the ROBs in the Itm group were exposed to PTH for 6 h in a 24-h incubation cycle, and the ROBs in the Ctr group were exposed to vehicle for the entire incubation cycle. The cells were collected at 6 h and 24 h of the final cycle, and the proteins in the Itm and Ctr groups were analyzed by two-dimensional electrophoresis (2-DE) coupled with peptide mass fingerprinting and matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) to detect proteins that were differentially expressed. The proteins with the most significant changes in vitro were validated by immunohistochemistry (IHC) in a rat model. Results: The proteomics analysis indicated that a total of 26 proteins were up- or down-regulated in the Itm group compared with the Ctr group at 6 h and 24 h; among these, 15 proteins were successfully identified. These proteins mainly belong to the cytoskeleton and molecular chaperone protein families, and most of these have anti-apoptotic effects in various cells. Rho GDP-dissociation inhibitor α (RhoGDIα) and vimentin were the most significantly changed proteins. Further studies by IHC showed that the expression of RhoGDIα in ROBs was significantly higher in PTH-treated sham-operated rats than in vehicle-treated sham-operated rats, but the difference was not significant between PTH-treated and vehicle-treated OVX rats. Vimentin expression was not changed in either PTH-treated sham-operated rats or PTH-treated OVX rats. Conclusion: Our research suggests that intermittent PTH treatment induces changes in expression of many proteins in ROBs in vitro, and it results in RhoGDIα up-regulation in ROBs both in vitro and in vivo when estrogen is present. This up-regulation of RhoGDIα may be one of the mechanisms underlying the synergistic bone-forming effect of PTH and estrogen. PMID:19575003

  3. 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 cancellous bone formation, restores and adds extra cancellous bone to the established, disuse-osteopenic proximal tibial metaphysis of continuously RHLI female rats. These results suggest that PTH may be a useful agent in treatment disuse-induced osteoporosis in humans.

  4. 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 formation, and restores and adds extra cancellous bone to the established, disuse-osteopenic proximal tibial metaphysis of female rats with continuously immobilized right hindlimbs. These results suggest that PTH may be useful in treating disuse-induced osteoporosis in humans.

  5. The single dose pharmacokinetic profile of a novel oral human parathyroid hormone formulation in healthy postmenopausal women.

    PubMed

    Hämmerle, Sibylle P; Mindeholm, Linda; Launonen, Aino; Kiese, Beate; Loeffler, Rolf; Harfst, Evita; Azria, Moise; Arnold, Michel; John, Markus R

    2012-04-01

    Parathyroid hormone (PTH), currently the only marketed anabolic treatment for osteoporosis, is available as the full-length hormone, human PTH1-84, or as the human PTH1-34 fragment (teriparatide). Both must be administered as a daily subcutaneous (sc) injection. A new oral formulation of human PTH1-34 (PTH134) is being developed as a more convenient option for patients. In this single-center, partially-blinded, incomplete cross-over study, the safety, tolerability, and exposure of oral PTH134 (teriparatide combined with 2 different quantities of the absorption enhancer 5-CNAC) were assessed in 32 healthy postmenopausal women. 16 subjects were randomized to receive 4 single doses out of 6 different treatments: placebo, teriparatide 20 μg sc, or 1, 2.5, 5 or 10 mg of oral PTH134 formulated with 200 mg 5-CNAC. Subsequently, another 16 subjects were randomized to receive 4 out of 6 different treatments: placebo, teriparatide 20 μg sc, or 2.5 or 5 mg of oral PTH134 formulated with either 100 or 200 mg 5-CNAC. Doses were given ≥6 days apart. All doses of PTH134 were rapidly absorbed, and showed robust blood concentrations in a dose-dependent manner. Interestingly, PTH1-34 disappeared from blood faster after oral than after sc administration. Specifically, 2.5 and 5 mg PTH134 (containing 200 mg 5-CNAC) demonstrated Cmax and AUC0-last values closest to those of sc teriparatide 20 μg (Forsteo®). Mean+/-SD hPTH134 Cmax values were, respectively, 74+/-59, 138+/-101, 717+/-496, and 1624+/-1579 pg/mL for 1, 2.5, 5, and 10 mg doses of this peptide administered with 200 mg 5-CNAC; while mean+/-SD AUC (0-last) values were, respectively, 30+/-40, 62+/-69, 320+/-269, and 627+/-633 h*pg/mL. The corresponding estimates for teriparatide 20 μg sc were 149+/-35 for Cmax and 236+/-58 for AUC (0-last) Ionized calcium remained within normal limits in all treatment groups except for 3 isolated events. Nine subjects withdrew due to treatment-related AEs. Of those, seven were taking PTH134 2.5 or 5 mg: three withdrew for symptomatic hypotension (two of whom were in the 200 mg 5-CNAC group), three because of delayed vomiting (two from the 200 mg 5-CNAC group), one was proactively withdrawn by the investigator for symptomatic hypercalcemia (receiving 2.5 mg/100 mg 5-CNAC) at slightly supra-normal total calcium but normal ionized serum calcium levels. One subject receiving teriparatide and one receiving placebo withdrew for symptomatic hypotension. No serious AEs were reported. In conclusion, the study demonstrated potential therapeutically relevant PTH1-34 systemic exposure levels after oral administration of PTH1-34 formulated with the absorption enhancer 5-CNAC. Doses of 2.5 and 5 mg of oral PTH134 achieved exposure levels closest to those of teriparatide 20 μg sc, with a comparable incidence of AEs in healthy postmenopausal women. PMID:22289659

  6. Why "Vitamin D" is not a hormone, and not a synonym for 1,25-dihydroxy-vitamin D, its analogs or deltanoids.

    PubMed

    Vieth, Reinhold

    2004-05-01

    Official nutrition committee reports in both North America and Europe now state that Vitamin D is more of a hormone than a nutrient. These statements are wrong, and do not reflect the definitions of either vitamin or hormone. Researchers often compound the problem by referring to calcitriol or other deltanoids as "Vitamin D". These things have serious consequences: (1) The literature is burdened by an ongoing confusion that presumes that the reader will somehow "know" what the writer refers to by "Vitamin D". (2) Medical practitioners not familiar with the ambiguities administer Vitamin D inappropriately when calcitriol or a deltanoid analog would be correct, or vice versa. (3) Attempts to promote Vitamin D nutrition are hindered by alarmist responses justifiably associated with the widespread administration of any hormone. Vitamin D is a vitamin in the truest sense of the word, because "insufficient amounts in the diet may cause deficiency diseases". The term, prohormone, is not relevant to the Vitamin D system, but 25-hydroxy-Vitamin D (calcidiol) is appropriately described as a prehormone, i.e. a glandular secretory product, having little or no inherent biologic potency, that is converted peripherally to an active hormone. PMID:15225841

  7. Parathyroid adenoma without hyperparathyroidism.

    PubMed

    Sekine, Osamu; Hozumi, Yasuo; Takemoto, Nobuyuki; Kiyozaki, Hirokazu; Yamada, Shigeki; Konishi, Fumio

    2004-03-01

    A 45-year-old female patient was admitted to our hospital presenting with a right anterior cervical tumor that was elastic, hard, painless and 3.5 x 3.5 cm in size. Laboratory data including serum calcium level, thyroid and parathyroid hormonal functions revealed no abnormalities. Further examination, consisting of computed tomography (CT), magnetic resonance imaging (MRI), ultrasonography (US) and radioisotope (RI)-imaging demonstrated that it was a solid tumor located behind the right thyroid lobe. The tumor, whose origin was unclear, was successfully removed with right thyroid lobectomy. Macroscopically, it appeared as reddish solid tumor consisting of small cystic lesions storing chocolate-colored mucous. Immunohistology confirmed that there was proliferation of chief cells with positive parathyroid hormone (PTH) staining. Thus the tumor was diagnosed as parathyroid adenoma despite a lack of clinical evidence for hyperparathyroidism. The reason for the lack of clinical features of hyperparathyroidism in this adenoma still remains unclear, however, there might be inactivation of hormone excretion, possibly due to insufficiency of blood supply. This was a very rare case of parathyroid adenoma exhibiting no clinical evidence of hyperparathyroidism. PMID:15078912

  8. Undescended parathyroid adenoma.

    PubMed

    Kanack, Melissa D; Maawy, Ali A; Oh, Deborah K; Bouvet, Michael

    2015-01-01

    Undescended parathyroid adenomas are rare, representing 0.08% of all parathyroid adenomas; however, they make up 7% of the underlying cause of failed cervical exploration in patients with persistent primary hyperparathyroidism. A 43-year-old woman with no significant medical or family history presented with fatigue and was diagnosed with primary hyperparathyroidism; however, preoperative imaging including sestamibi scan and ultrasound was unable to identify the hyperfunctioning gland. She underwent a neck exploration and hemithyroidectomy and partial parathyroidectomy with failure of resolution of her disease. Subsequent work up including a CT of the neck demonstrated a 1.9 cm mass adjacent to the left submandibular gland. This was removed with postoperative normalisation of the patient's serum calcium and parathyroid hormone levels. PMID:25737222

  9. Comparative Mortality-Predictability Using Alkaline Phosphatase and Parathyroid Hormone in Patients on Peritoneal Dialysis and Hemodialysis

    PubMed Central

    Rhee, Connie M.; Molnar, Miklos Z.; Lau, Wei Ling; Ravel, Vanessa; Kovesdy, Csaba P.; Mehrotra, Rajnish; Kalantar-Zadeh, Kamyar

    2014-01-01

    ♦ Background: In hemodialysis (HD) patients, serum alkaline phosphatase (ALP) and parathyroid hormone (PTH) derangements are associated with mortality, but outcome-predictability using ALP and PTH in peritoneal dialysis (PD) patients remains uncertain. ♦ Methods: In a cohort of 9244 adult PD patients from a large national dialysis organization (entry period 2001 - 2006, with follow-up through 2009), we used multivariable Cox models adjusted for case-mix and laboratory covariates to examine the associations of time-averaged ALP and PTH with all-cause mortality. We then compared mortality-predictability using ALP and PTH in 9244 PD and 99 323 HD patients. ♦ Results: In PD patients, ALP concentrations exceeding 150 U/L were associated with increased mortality (reference ALP: 70 to <90 U/L). Hazard ratios (HRs) and 95% confidence intervals (CIs) were 1.18 (1.03 to 1.36), 1.27 (1.08 to 1.50), 1.49 (1.23 to 1.79), and 1.35 (1.19 to 1.53) for ALP concentrations of 150 to <170 U/L, 170 to <190 U/L, 190 to <210 U/L, and ≥210 U/L respectively. In contrast, we observed a U-shaped association between PTH concentration and death risk in PD patients, with PTH concentrations of less than 200 pg/mL and 700 pg/mL or more associated with increased mortality (reference PTH: 200 to <300 pg/mL). Hazard ratios and 95% CIs were 1.25 (1.12 to 1.41), 1.12 (1.02 to 1.23), 1.06 (0.96 to 1.18), 1.09 (0.97 to 1.24), 1.12 (0.97 to 1.29), 1.18 (0.99 to 1.40), and 1.23 (1.09 to 1.38) for PTH concentrations of <100 pg/mL, 100 to <200 pg/mL, 300 to <400 pg/mL, 400 to <500 pg/mL, 500 to <600 pg/mL, 600 to <700 pg/mL, and ≥700 pg/mL respectively. Compared with PD patients having serum concentrations of ALP and PTH within reference ranges, patients on HD experienced increased mortality across all ALP and PTH concentrations, particularly those in the lowest and highest categories. ♦ Conclusions: In summary, higher ALP concentrations are associated with increased mortality, and lower and higher PTH concentrations are both associated with death risk in PD patients. The utility of ALP in the management of chronic kidney disease mineral bone disorders in PD patients warrants further study. PMID:24385335

  10. 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.

  11. Stimulation of 1,25-dihydroxyvitamin D production by parathyroid hormone and dibutyryl 3',5'-cyclic AMP in normal subjects, hypoparathyroidism and pseudohypoparathyroidism.

    PubMed

    Unakami, H; Furukawa, Y; Sohn, H E; Yumita, S; Miura, R; Hanew, K; Yoshinaga, K

    1982-10-01

    Parathyroid extract (PTE) or synthetic 1-34 human parathyroid hormone (1-34 hPTH) was injected intravenously as a bolus in 4 normal subjects, 4 patients with PTH deficient hypoparathyroidism (HP) and 3 patients with pseudohypoparathyroidism (PHP). In normal subjects and HP, plasma 1,25(OH)2D was markedly increased at 6 hr and reached the peak at 12 or 14 hr after administration of 200 units of PTE or 20 to 30 micrograms of 1-34hPTH. On the other hand, 500 units of PTE or 20 micrograms of 1-34hPTH failed to increase plasma 1,25(OH)2D in PHP. However, 2.5 mg/kg of dibutyryl cAMP remarkably increased plasma 1,25(OH)2D in a patient with PHP. Maximal increments of plasma 1,25(OH)2D in 3 patients with HP(21.7 +/- 5.6 pg/ml, mean +/- S.D.) were nearly as high as in normal subjects (20.6 +/- 7.0 pg/ml), whereas those in 3 patients with PHP (2.3 +/- 2.3 pg/ml) were distinctly lower than in normal subjects or HP. It is suggested that 1,25(OH)2D production by PTH is intact in HP, but is impaired in PHP mainly due to a defect in the activation of adenylate cyclase system. PMID:6294914

  12. Vitamin D hormone regulates serotonin synthesis. Part 1: relevance for autism.

    PubMed

    Patrick, Rhonda P; Ames, Bruce N

    2014-06-01

    Serotonin and vitamin D have been proposed to play a role in autism; however, no causal mechanism has been established. Here, we present evidence that vitamin D hormone (calcitriol) activates the transcription of the serotonin-synthesizing gene tryptophan hydroxylase 2 (TPH2) in the brain at a vitamin D response element (VDRE) and represses the transcription of TPH1 in tissues outside the blood-brain barrier at a distinct VDRE. The proposed mechanism explains 4 major characteristics associated with autism: the low concentrations of serotonin in the brain and its elevated concentrations in tissues outside the blood-brain barrier; the low concentrations of the vitamin D hormone precursor 25-hydroxyvitamin D [25(OH)D3]; the high male prevalence of autism; and the presence of maternal antibodies against fetal brain tissue. Two peptide hormones, oxytocin and vasopressin, are also associated with autism and genes encoding the oxytocin-neurophysin I preproprotein, the oxytocin receptor, and the arginine vasopressin receptor contain VDREs for activation. Supplementation with vitamin D and tryptophan is a practical and affordable solution to help prevent autism and possibly ameliorate some symptoms of the disorder. PMID:24558199

  13. Cinacalcet in hyperfunctioning parathyroid diseases.

    PubMed

    Imanishi, Yasuo; Inaba, Masaaki; Kawata, Takehisa; Nishizawa, Yoshiki

    2009-10-01

    The calcium-sensing receptor (CaR) on the parathyroid cell surface senses ionized calcium concentration in the extracellular fluid and regulates minute-to-minute parathyroid hormone (PTH) secretion. Synthetic allosteric modulators of CaR have been developed, and one of the positive modulators (calcimimetics) is cinacalcet HCl or cinacalcet. Cinacalcet increases the sensitivity of CaR to be activated by extracellular calcium, and thus suppresses PTH release. Cinacalcet is an effective treatment for secondary hyperparathyroidism (SHPT) in patients with uremia on hemodialysis. In this review, based on basic experiments using cinacalcet, we postulate the beneficial effects of cinacalcet on hyperfunctioning parathyroid diseases. PMID:19765257

  14. 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

  15. A new immunoenzymometric assay for bioactive N-terminal human parathyroid hormone fragments and its application in pharmacokinetic studies in dogs.

    PubMed

    Mägerlein, M; Hock, D; Adermann, K; Müller-Beckmann, B; Neidlein, R; Forssmann, W G; Stein, K

    1998-02-01

    Advances in the treatment of clinical disorders of mineral in homeostatis and metabolic bone disease with intact parathyroid hormone 1-84 or one of the biologically active N-terminal fragments require a precise and sensitive measurement in serum. Therefore, a two-site immunoenzymometric assay for the quantitative determination of bioactive hPTH-1-37 (human parathyroid hormone) at picomolar concentrations was developed. Monoclonal antibodies (mAB) against hPTH-1-37 were raised by hybridoma cells in serum-free cell culture. Furthermore, sequence-specific polyclonal antibodies were obtained by immunisation of rabbits using multiple antigenic peptides (MAP) representing the conspicuous regions of the primary structure of hPTH-1-37. The polyclonal and monoclonal antibodies were characterised by epitope mapping. The combination of a monoclonal antibody (13C63/5) recognising hPTH fragment 16-24 with a polyclonal antibody (k2) showing a predominant binding sequence at hPTH-1-5 led to a sandwich assay specific for N-terminally intact and therefore biologically active hPTH. The validated assay ranging from 4 to 1000 pmol/l was applied to pharmacokinetic studies of hPTH-1-37. After s.c. administration of 30 mu g/kg in 5 beagles, the maximum serum concentrations of hPTH-1-37 ranging at 2139 +/- 857 pmol/l were observed 45 min after the injection. Clearance of the peptide calculated from the exponential disappearance curve was 32.0 +/- 9.1 ml/min/kg with a mean t1/2 of 37 +/- 10 min. PMID:9541733

  16. 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

  17. Effects of parathyroid hormone-related protein and macrophage inflammatory protein-1α in Jurkat T-cells on tumor formation in vivo and expression of apoptosis regulatory genes in vitro

    PubMed Central

    Shu, Sherry T.; Dirksen, Wessel P.; Lanigan, Lisa G.; Martin, Chelsea K.; Thudi, Nanda K.; Werbeck, Jillian L.; Fernandez, Soledad A.; Hildreth, Blake E.; Rosol, Thomas J.

    2012-01-01

    Parathyroid hormone-related protein (PTHrP) and macrophage inflammatory protein-1α (MIP-1α) have been implicated in the pathogenesis of adult T-cell leukemia/lymphoma, but their effects on T-cells have not been well studied. Here we analyzed the functions of PTHrP and MIP-1α on T-cell growth and death both in vitro and in vivo by overexpressing either factor in human Jurkat T-cells. PTHrP or MIP-1α did not affect Jurkat cell growth in vitro, but PTHrP increased their sensitivity to apoptosis. Importantly, PTHrP and MIP-1α decreased both tumor incidence and growth in vivo. To investigate possible mechanisms, polymerase chain reaction (PCR) arrays and real-time reverse transcription (RT)-PCR assays were performed. Both PTHrP and MIP-1α increased the expression of several factors including signal transducer and activator of transcription 4, tumor necrosis factor α, receptor activator of nuclear factor κB ligand and death-associated protein kinase 1, and decreased the expression of inhibitor of DNA binding 1, interferon γ and CD40 ligand in Jurkat cells. In addition, MIP-1α also increased the expression of transcription factor AP-2α and PTHrP increased expression of the vitamin D3 receptor. These data demonstrate that PTHrP and MIP-1α exert a profound antitumor effect presumably by increasing the sensitivity to apoptotic signals through modulation of transcription and apoptosis factors in T-cells. PMID:21942940

  18. 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

    2015-01-01

    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. PMID:25867375

  19. Use of a parathyroid hormone peptide (PTH(1-34))-enriched fibrin hydrogel for the treatment of a subchondral cystic lesion in the proximal interphalangeal joint of a warmblood filly.

    PubMed

    Fuerst, A; Derungs, S; von Rechenberg, B; Auer, J A; Schense, J; Watson, J

    2007-03-01

    To describe the treatment of a subchondral bone cyst in the proximal phalanx with parathyroid hormone peptide-enriched fibrin hydrogel in a warmblood filly. The cyst was localized with computer-assisted orthopaedic surgery, then curetted and finally filled with parathyroid hormone fragment peptide 1-34 (PTH(1-34)) covalently attached to a fibrin hydrogel. The cyst healed quickly without any complications. This result supports the hypothesis that PTH(1-34) delivered locally in a fibrin hydrogel may improve the postoperative prognosis of surgical management of subchondral bone cysts in horses. Subchondral bone cysts are fairly common in horses. Especially in older horses, the prognosis is poor, even after surgical curettage. Therefore, different management protocols have been investigated in conjunction with surgical curettage to improve prognosis. Locally delivered PTH(1-34) seems to be a new method in the treatment of subchondral bone cysts. PMID:17305975

  20. Expression of osteoclastogenic factor transcripts in osteoblast-like UMR-106 cells after exposure to FGF-23 or FGF-23 combined with parathyroid hormone.

    PubMed

    Teerapornpuntakit, Jarinthorn; Wongdee, Kannikar; Krishnamra, Nateetip; Charoenphandhu, Narattaphol

    2016-03-01

    As a bone-derived hormone, fibroblast growth factor-23 (FGF-23) negatively regulates phosphate and calcium metabolism, while retaining growth-promoting action for mesenchymal cell differentiation. Elevated FGF-23 levels, together with hyperparathyroidism, are often observed in chronic kidney disease, which is associated with impaired bone mineralization and enhanced bone resorption. Although overexpression of osteoblast-derived osteoclastogenic cytokines might contribute to this metabolic bone disease, whether FGF-23 alone and FGF-23 plus parathyroid hormone (PTH) directly modulated the expression of osteoblast-derived osteoclastogenic genes remained elusive. Herein, we demonstrated the direct effects of FGF-23 on proliferation and mRNA expression of osteoblast-specific differentiation and osteoclastogenic markers in rat osteoblast-like UMR-106 cells in the presence or absence of PTH. FGF-23 was found to suppress UMR-106 cell proliferation, while increasing FGF-23 expression, the latter of which suggested the presence of positive feedback regulation of FGF-23 expression in osteoblasts. FGF-23 also upregulated the mRNA expression of osteoblast differentiation markers (e.g., Runx2, osterix, AJ18, Dlx5, alkaline phosphatase, and osteopontin), osteoclastogenic factors (e.g., MCSF, MCP-1, IL-6, and TNF-α), and bone resorption regulators (RANKL and osteoprotegerin). However, combined PTH and FGF-23 exposure did not alter the levels of FGF-23-induced transcripts, suggesting that both hormones had no additive effect. In conclusion, FGF-23 directly suppressed osteoblast proliferation, while inducing osteoclastogenic gene expression in UMR-106 cells, and the FGF-23-induced transcripts were not altered by long-standing PTH exposure. PMID:26694880

  1. Vitamins

    MedlinePlus

    ... are 13 vitamins your body needs. They are Vitamin A B vitamins (thiamine, riboflavin, niacin, pantothenic acid, biotin, ... anemic. Some vitamins may help prevent medical problems. Vitamin A prevents night blindness. The best way to get ...

  2. 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

  3. Novel Role of Parathyroid Hormone-Related Protein in the Pathophysiology of the Diabetic Kidney: Evidence from Experimental and Human Diabetic Nephropathy

    PubMed Central

    Romero, Montserrat; Ortega, Arantxa; Olea, Nuria; Arenas, María Isabel; Izquierdo, Adriana; Bover, Jordi; Esbrit, Pedro

    2013-01-01

    Parathyroid hormone-related protein (PTHrP) and its receptor type 1 (PTH1R) are extensively expressed in the kidney, where they are able to modulate renal function. Renal PTHrP is known to be overexpressed in acute renal injury. Recently, we hypothesized that PTHrP involvement in the mechanisms of renal injury might not be limited to conditions with predominant damage of the renal tubulointerstitium and might be extended to glomerular diseases, such as diabetic nephropathy (DN). In experimental DN, the overexpression of both PTHrP and the PTH1R contributes to the development of renal hypertrophy as well as proteinuria. More recent data have shown, for the first time, that PTHrP is upregulated in the kidney from patients with DN. Collectively, animal and human studies have shown that PTHrP acts as an important mediator of diabetic renal cell hypertrophy by a mechanism which involves the modulation of cell cycle regulatory proteins and TGF-β1. Furthermore, angiotensin II (Ang II), a critical factor in the progression of renal injury, appears to be responsible for PTHrP upregulation in these conditions. These findings provide novel insights into the well-known protective effects of Ang II antagonists in renal diseases, paving the way for new therapeutic approaches. PMID:23984429

  4. Identification of a cDNA encoding a parathyroid hormone-like peptide from a human tumor associated with humoral hypercalcemia of malignancy

    SciTech Connect

    Mangin, M.; Webb, A.C.; Dreyer, B.E.; Posillico, J.T.; Ikeda, K.; Weir, E.C.; Stewart, A.F.; Bander, N.H.; Milstone, L.; Barton, D.E.

    1988-01-01

    Humoral hypercalcemia of malignancy is a common paraneoplastic syndrome that appears to be mediated in many instances by a parathyroid hormone-like peptide. Poly(A)/sup +/ RNA from a human renal carcinoma associated with this syndrome was enriched by preparative electrophoresis and used to construct an enriched cDNA library in phage lambdagt10. The library was screened with a codon-preference oligonucleotide synthesized on the basis of a partial N-terminal amino acid sequence from a human tumor-derived peptide, and a 2.0 kilo-base cDNA was identified. The cDNA encodes a 177 amino acid protein consisting of a 36 amino acid leader sequence and a 141 amino acid mature peptide. The first 13 amino acids of the deduced sequence of the mature peptide display strong homology to human PTH, with complete divergence thereafter. RNA blot-hybridization analysis revealed multiple transcripts in mRNA from tumors associated with the humor syndrome and also in mRNA from normal human keratinocytes. Southern blot analysis of genomic DNA from humans and rodents revealed a simple pattern compatible with a single-copy gene. The gene has been mapped to chromosome 12.

  5. Nucleotide sequence analysis of CDR3 elements of a panel of anti-peptide monoclonal antibodies recognizing parathyroid hormone-related protein.

    PubMed Central

    Rapley, R; Flora, P S; Walsh, D J; Walker, M R

    1993-01-01

    Nucleotide sequences of heavy (VH) and light (VL) chain variable region complementarity determining regions have been determined from in vitro amplified mRNA isolated from a panel of monoclonal antibodies (mAb) raised to a synthetic 34mer peptide representing the N-terminal portion of human parathyroid hormone-related protein (PTHrP or parathyrin) reported to contain an immunodominant epitope. These mAb vary in affinity for the synthetic peptide and native PTHrP (Ka between 5.9 x 10(8) and 1.9 x 10(11)l/M). All 10 mAb studied were found were found to utilized restricted VH2, V kappa 2, JH4 and J kappa 1 family genes. Significant differences in the length and sequence of D elements were found; however 9/10 mAb utilize members of the DSP2 family. Significantly, two broad ranges of affinity could be determined based on the presence of Asp or Ala at residue 101 in JH. Images Figure 2 PMID:8478021

  6. Parathyroid hormone blocks the stimulatory effect of insulin-like growth factor-I on collagen synthesis in cultured 21-day fetal rat calvariae

    SciTech Connect

    Kream, B.E.; Petersen, D.N.; Raisz, L.G. )

    1990-01-01

    We examined the interaction of parathyroid hormone (PTH) and recombinant human insulin-like growth factor I (IGF-I) on collagen synthesis in 21-day fetal rat calvariae as assessed by measuring the incorporation of ({sup 3}H)proline into collagenase-digestible protein. After 96 hours of culture, 10 nM PTH antagonized the stimulation of collagen synthesis and partially blocked the increase in dry weight produced by 10 nM IGF-I. The effect of PTH to block IGF-I stimulated collagen synthesis was observed in the central bone of calvariae and was mimicked by forskolin and phorbol 12-myristate 13-acetate, but not by 1,25-dihydroxyvitamin D3, transforming growth factor-alpha or dexamethasone. Our data are consistent with the concept that the direct effect of PTH is to inhibit basal CDP labeling and fully oppose IGF-I stimulated CDP labeling. The finding that this effect of PTH is mimicked by forskolin and PMA suggests that this block in IGF-I stimulation of CDP labeling involves both cAMP and protein kinase C mediated pathways.

  7. Effects of Intermittent Administration of Parathyroid Hormone (1-34) on Bone Differentiation in Stromal Precursor Antigen-1 Positive Human Periodontal Ligament Stem Cells

    PubMed Central

    Wang, Xiaoxiao; Wang, Yanlan; Dai, Xubin; Chen, Tianyu; Yang, Fanqiao; Dai, Shuangye; Ou, Qianmin; Wang, Yan; Lin, Xuefeng

    2016-01-01

    Periodontitis is the most common cause of tooth loss and bone destruction in adults worldwide. Human periodontal ligament stem cells (hPDLSCs) may represent promising new therapeutic biomaterials for tissue engineering applications. Stromal precursor antigen-1 (STRO-1) has been shown to have roles in adherence, proliferation, and multipotency. Parathyroid hormone (PTH) has been shown to enhance proliferation in osteoblasts. Therefore, in this study, we aimed to compare the functions of STRO-1(+) and STRO-1(−) hPDLSCs and to investigate the effects of PTH on the osteogenic capacity of STRO-1(+) hPDLSCs in order to evaluate their potential applications in the treatment of periodontitis. Our data showed that STRO-1(+) hPDLSCs expressed higher levels of the PTH-1 receptor (PTH1R) than STRO-1(−) hPDLSCs. In addition, intermittent PTH treatment enhanced the expression of PTH1R and osteogenesis-related genes in STRO-1(+) hPDLSCs. PTH-treated cells also exhibited increased alkaline phosphatase activity and mineralization ability. Therefore, STRO-1(+) hPDLSCs represented a more promising cell resource for biomaterials and tissue engineering applications. Intermittent PTH treatment improved the capacity for STRO-1(+) hPDLSCs to repair damaged tissue and ameliorate the symptoms of periodontitis. PMID:27069479

  8. Epidermal Growth Factor and Parathyroid Hormone-related Peptide mRNA in the Mammary Gland and their Concentrations in Milk

    PubMed Central

    Bruder, E. D.; Van Hoof, J.; Young, J. B.; Raff, H.

    2008-01-01

    The physiological adaptations of the neonatal rat to hypoxia from birth include changes in gastrointestinal function and intermediary metabolism. We hypothesized that the hypoxic lactating dam would exhibit alterations in mammary gland function leading to changes in the concentration of milk peptides that are important in neonatal gastrointestinal development. The present study assessed the effects of chronic hypoxia on peptides produced by the mammary glands and present in milk. Chronic hypoxia decreased the concentration of epidermal growth factor (EGF) in expressed milk and pup stomach contents and decreased maternal mammary gland Egf mRNA. The concentration of parathyroid hormone-related protein (PTHrp) was unchanged in milk and decreased in pup stomach contents; however, mammary Pthlh mRNA was increased by hypoxia. There was a significant increase in adiponectin concentrations in milk from hypoxic dams. Chronic hypoxia decreased maternal body weight, and pair feeding normoxic dams an amount of food equivalent to hypoxic dam food intake decreased body weight to an equivalent degree. Decreased food intake did not affect the expression of Egf, Pthlh, or Lep mRNA in mammary tissue. The results indicated that chronic hypoxia modulated mammary function independently of hypoxia-induced decreases in maternal food intake. Decreased EGF and increased adiponectin concentrations in milk from hypoxic dams likely affect the development of neonatal intestinal function. PMID:18401831

  9. 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. PMID:26657065

  10. Evolutionary well-conserved region in the signal peptide of parathyroid hormone-related protein is critical for its dual localization through the regulation of ER translocation.

    PubMed

    Amaya, Yoshihiro; Nakai, Toshiki; Miura, Satoshi

    2016-04-01

    Parathyroid hormone-related protein (PTHrP) has two different targeting signals: an N-terminal signal peptide for the endoplasmic reticulum (ER) targeting and an internal nuclear localization signal. The protein not only functions as a secretory protein, but is also found in the nucleus and/or nucleolus under certain conditions. PTHrP signal peptide is less hydrophobic than most signal peptides mainly due to its evolutionarily well-conserved region (QQWS). The substitution of four tandem leucine residues for this conserved region resulted in a significant inhibition of the signal peptide cleavage. At the same time, proportion of nuclear and/or nucleolar localization decreased, probably due to tethering of the protein to the ER membrane by the uncleaved mutant signal peptide. Almost complete cleavage of the signal peptide accompanied by a lack of nuclear/nucleolar localization was achieved by combining the hydrophobic h-region and an optimized sequence of the cleavage site. In addition, mutational modifications of the distribution of charged residues in and around the signal peptide affect its cleavage and/or nuclear/nucleolar localization of the protein. These results indicate that the well-conserved region in the signal peptide plays an essential role in the dual localization of PTHrP through ER targeting and/or the membrane translocation. PMID:26538570

  11. Postnatal establishment of allelic G?s silencing as a plausible explanation for delayed onset of parathyroid hormone-resistance due to heterozygous G?s 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 G?s activity. G?s 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 G?s, i.e. hypocalcemia and elevated serum PTH, occurs after early postnatal life. To investigate whether this delay could reflect gradual development of paternal G?s 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 G?s 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 G?s mRNA expression are equal at postnatal day 3. In contrast, we found that paternal G?s expression is already markedly repressed in brown adipose tissue at birth. Thus, the mechanisms silencing the paternal G?s 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

  12. Parathyroid Hormone Signaling via Gαs Is Selectively Inhibited by an NH2-Terminally Truncated Gαs: Implications for Pseudohypoparathyroidism

    PubMed Central

    Puzhko, Svetlana; Goodyer, Cynthia Gates; Kerachian, Mohammad Amin; Canaff, Lucie; Misra, Madhusmita; Jüppner, Harald; Bastepe, Murat; Hendy, Geoffrey N

    2013-01-01

    Pseudohypoparathyroid patients have resistance predominantly to parathyroid hormone (PTH), and here we have examined the ability of an alternative Gαs-related protein to inhibit Gαs activity in a hormone-selective manner. We tested whether the G/VAS exon A/B-derived NH2-terminally truncated (Tr) αs protein alters stimulation of adenylate cyclase by the PTH receptor (PTHR1), the thyroid-stimulating hormone (TSH) receptor (TSHR), the β2-adrenergic receptor (β2AR), or the AVP receptor (V2R). HEK293 cells cotransfected with receptor and full-length (FL) Gαs±Tr ±s protein expression vectors were stimulated with agonists (PTH [10−7 to 10−9 M], TSH [1 to 100 mU], isoproterenol [10−6 to 10−8M], or AVP [10−6 to 10−8M]). Following PTH stimulation, HEK293 cells cotransfected with PTHR1 + FL Gαs + Tr αs had a significantly lower cAMP response than those transfected with only PTHR1 + FL Gαs. Tr αs also exerted an inhibitory effect on the cAMP levels stimulated by TSH via the TSHR but had little or no effect on isoproterenol or AVP acting via β2AR or V2R, respectively. These differences mimic the spectrum of hormone resistance in pseudohypoparathyroidism type 1a (PHP-1a) and type 1b (PHP-1b) patients. In opossum kidney (OK) cells, endogenously expressing the PTHR1 and β2AR, the exogenous expression of Tr αs at a level similar to endogenous FL Gαs resulted in blunting of the cAMP response to PTH, whereas that to isoproterenol was unaltered. A pseudopseudohypoparathyroid patient with Albright hereditary osteodystrophy harbored a de novo paternally inherited M1l Gαs mutation. Similar maternally inherited mutations at the initiation codon have been identified previously in PHP-1a patients. The M1l αs mutant (lacking the first 59 amino acids of Gαs) blunted the increase in cAMP levels stimulated via the PTHR1 in both HEK293 and OK cells similar to the Tr αs protein. Thus NH2-terminally truncated forms of Gαs may contribute to the pathogenesis of pseudohypoparathyroidism by inhibiting the activity of Gαs itself in a GPCR selective manner. PMID:21713996

  13. 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 its therapeutic potential in a number of diseases. PMID:11704631

  14. Mechanical stimulation and intermittent parathyroid hormone treatment induce disproportional osteogenic, geometric, and biomechanical effects in growing mouse bone

    PubMed Central

    McAteer, Maureen E.; Niziolek, Paul J.; Ellis, Shana N.; Alge, Daniel L.; Robling, Alexander G.

    2011-01-01

    Mechanical loading and intermittent parathyroid (iPTH) treatment are both osteoanabolic stimuli, and are regulated by partially overlapping cellular signaling pathways. iPTH has been shown clinically to be effective in increasing bone mass and reducing fracture risk. Likewise, mechanical stimulation can significantly enhance bone apposition and prevent bone loss, but its clinical effects on fracture susceptibility are less certain. Many of the osteogenic effects of iPTH are localized to biomechanically suboptimal bone surfaces, whereas mechanical loading directs new bone formation to high-stress areas and not to strain-neutral areas. These differences in localization in new tissue, resulting from load-induced vs iPTH-induced bone accumulation, should affect the relation between bone mass and bone strength, or “tissue economy.” We investigated the changes in bone mass and strength induced by 6 wks mechanical loading, and compared them to changes induced by 6 wks iPTH treatment. Loading and iPTH both increased ulnar bone accrual, as measured by bone mineral density and content, and fluorochrome-derived bone formation. iPTH induced a significantly greater increase in bone mass than loading, but ulnar bone strength was increased approximately the same amount by both treatments. Mechanical loading during growth can spatially optimize new bone formation to improve structural integrity with a minimal increase in mass, thereby increasing tissue economy i.e., the amount of strength returned per unit bone mass added. Furthermore, exercise studies in which only small changes in bone mass are detected might be more beneficial to bone health and fracture resistance than has commonly been presumed. PMID:20306026

  15. Vitamin D Status in Children and Young Adults With Inflammatory Bowel Disease

    PubMed Central

    Pappa, Helen M.; Gordon, Catherine M.; Saslowsky, Tracee M.; Zholudev, Anna; Horr, Brian; Shih, Mei-Chiung; Grand, Richard J.

    2011-01-01

    OBJECTIVES Previous studies of vitamin D status in pediatric patients with inflammatory bowel disease have revealed conflicting results. We sought to report (1) the prevalence of vitamin D deficiency (serum 25-hydroxy-vitamin D concentration ≤15 ng/mL) in a large population with inflammatory bowel disease, (2) factors predisposing to this problem, and (3) its relationship to bone health and serum parathyroid hormone concentration. PATIENTS AND METHODS A total of 130 patients (8–22 years of age) with inflammatory bowel disease, 94 with Crohn disease and 36 with ulcerative colitis, had serum 25-hydroxy-vitamin D, intact parathyroid hormone, and lumbar spine bone mineral density (using dual-energy x-ray absorptiometry) measured at Children’s Hospital Boston. RESULTS The prevalence of vitamin D deficiency was 34.6%. Mean serum 25-hydroxy-vitamin D concentration was similar in patients with Crohn disease and ulcerative colitis, 52.6% lower among patients with dark skin complexion, 33.4% lower during the winter months (December 22 to March 21), and 31.5% higher among patients who were taking vitamin D supplements. Serum 25-hydroxy-vitamin D concentration was positively correlated with weight and BMI z score, disease duration, and serum albumin concentration and negatively correlated with erythrocyte sedimentation rate. Patients with Crohn disease and upper gastrointestinal tract involvement were more likely to be vitamin D deficient than those without it. Serum 25-hydroxy-vitamin concentration was not associated with lumbar spine bone mineral density z score or serum parathyroid hormone concentration. CONCLUSIONS Vitamin D deficiency is highly prevalent among pediatric patients with inflammatory bowel disease. Factors predisposing to the problem include having a dark-skin complexion, winter season, lack of vitamin D supplementation, early stage of disease, more severe disease, and upper gastrointestinal tract involvement in patients with Crohn disease. The long-term significance of hypovitaminosis D for this population is unknown at present and merits additional study. PMID:17079566

  16. PROGESTERONE AND VITAMIN D HORMONE FOR TREATMENT OF TRAUMATIC BRAIN INJURY IN THE AGED1

    PubMed Central

    Stein, Donald G.; Cekic, Milos M.

    2013-01-01

    There is growing recognition that traumatic brain injury (TBI) is a highly variable and complex systemic disorder that is refractory to therapies that target individual mechanisms. It is even more complex in the elderly, in whom frailty, prior comorbidities, altered metabolism, and a long history of medication use are likely to complicate the secondary effects of brain trauma. Progesterone, one of the few neuroprotective agents that has shown promise for the treatment of acute brain injury, is now in national and international Phase III multi-center trial. New findings show that vitamin D hormone (VDH) and vitamin D deficiency in aging (and across the developmental spectrum) may interact with progesterone and TBI treatment. This paper reviews the use of progesterone and VDH as biologics based therapies and recent studies showing that the combination of progesterone and VDH may promote better functional outcomes than either treatment independently. PMID:21703565

  17. The role of vitamin D in malaria.

    PubMed

    Lương, Khanh Vinh Quốc; Nguyễn, Lan Thi Hoàng

    2015-01-01

    An abnormal calcium-parathyroid hormone (PTH)-vitamin D axis has been reported in patients with malaria infection. A role for vitamin D in malaria has been suggested by many studies. Genetic studies have identified numerous factors that link vitamin D to malaria, including human leukocyte antigen genes, toll-like receptors, heme oxygenase-1, angiopoietin-2, cytotoxic T lymphocyte antigen-4, nucleotide-binding oligomerization domain-like receptors, and Bcl-2. Vitamin D has also been implicated in malaria via its effects on the Bacillus Calmette-Guerin (BCG) vaccine, matrix metalloproteinases, mitogen-activated protein kinase pathways, prostaglandins, reactive oxidative species, and nitric oxide synthase. Vitamin D may be important in malaria; therefore, additional research on its role in malaria is needed. PMID:25596566

  18. 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

  19. Theophylline, a methylxanthine drug induces osteopenia and alters calciotropic hormones, and prophylactic vitamin D treatment protects against these changes in rats.

    PubMed

    Pal, Subhashis; Khan, Kainat; China, Shyamsundar Pal; Mittal, Monika; Porwal, Konica; Shrivastava, Richa; Taneja, Isha; Hossain, Zakir; Mandalapu, Dhanaraju; Gayen, Jiaur R; Wahajuddin, Muhammad; Sharma, Vishnu Lal; Trivedi, Arun K; Sanyal, Sabyasachi; Bhadauria, Smrati; Godbole, Madan M; Gupta, Sushil K; Chattopadhyay, Naibedya

    2016-03-15

    The drug, theophylline is frequently used as an additive to medications for people suffering from chronic obstructive pulmonary diseases (COPD). We studied the effect of theophylline in bone cells, skeleton and parameters related to systemic calcium homeostasis. Theophylline induced osteoblast apoptosis by increasing reactive oxygen species production that was caused by increased cAMP production. Bone marrow levels of theophylline were higher than its serum levels, indicating skeletal accumulation of this drug. When adult Sprague-Dawley rats were treated with theophylline, bone regeneration at fracture site was diminished compared with control. Theophylline treatment resulted in a time-dependent (at 4- and 8weeks) bone loss. At 8weeks, a significant loss of bone mass and deterioration of microarchitecture occurred and the severity was comparable to methylprednisone. Theophylline caused formation of hypomineralized osteoid and increased osteoclast number and surface. Serum bone resorption and formation marker were respectively higher and lower in the theophylline group compared with control. Bone strength was reduced by theophylline treatment. After 8weeks, serum 25-D3 and liver 25-hydroxylases were decreased in theophylline group than control. Further, theophylline treatment reduced serum 1, 25-(OH)2 vitamin D3 (1,25-D3), and increased parathyroid hormone and fibroblast growth factor-23. Theophylline treated rats had normal serum calcium and phosphate but displayed calciuria and phosphaturia. Co-administration of 25-D3 with theophylline completely abrogated theophylline-induced osteopenia and alterations in calcium homeostasis. In addition, 1,25-D3 protected osteoblasts from theophylline-induced apoptosis and the attendant oxidative stress. We conclude that theophylline has detrimental effects in bone and prophylactic vitamin D supplementation to subjects taking theophylline could be osteoprotective. PMID:26851681

  20. The C-terminal fragment of parathyroid hormone-related peptide promotes bone formation in diabetic mice with low-turnover osteopaenia

    PubMed Central

    Lozano, D; Fernández-de-Castro, L; Portal-Núñez, S; López-Herradón, A; Dapía, S; Gómez-Barrena, E; Esbrit, P

    2011-01-01

    BACKGROUND AND PURPOSE Current data suggest that parathyroid hormone (PTH)-related peptide (PTHrP) domains other than the N-terminal PTH-like domain contribute to its role as an endogenous bone anabolic factor. PTHrP-107-139 inhibits bone resorption, a fact which has precluded an unequivocal demonstration of its possible anabolic action in vivo. We thus sought to characterize the osteogenic effects of this peptide using a mouse model of diabetic low-turnover osteopaenia. EXPERIMENTAL APPROACH PTHrP-107-139 was administered to streptozotocin-induced diabetic mice, with or without bone marrow ablation, for 13 days. Osteopaenia was confirmed by dual-energy X-ray absorptiometry and microcomputed tomography analysis. Histological analysis was performed on paraffin-embedded bone tissue sections by haematoxylin/eosin and Masson's staining, and tartrate-resistent acid phosphatase immunohistochemistry. Mouse bone marrow stromal cells and osteoblastic MC3T3-E1 cells were cultured in normal and/or high glucose (HG) medium. Osteogenic and adipogenic markers were assessed by real-time PCR, and PTHrP and the PTH1 receptor protein expression by Western blot analysis. KEY RESULTS PTHrP-107-139 reversed the alterations in bone structure and osteoblast function, and also promoted bone healing after marrow ablation without affecting the number of osteoclast-like cells in diabetic mice. This peptide also reversed the high-glucose-induced changes in osteogenic differentiation in both bone marrow stromal cells and the more differentiated MC3T3-E1 cells. CONCLUSIONS AND IMPLICATIONS These findings demonstrate that PTHrP-107-139 promotes bone formation in diabetic mice. This mouse model and in vitro cell cultures allowed us to identify various anabolic effects of this peptide in this scenario. PMID:21175568

  1. 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 drug development for metabolic bone diseases. PMID:26851122

  2. 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

  3. 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. PMID:25218037

  4. Enhancement of recombinant human bone morphogenetic protein-2 (rhBMP-2)-induced new bone formation by concurrent treatment with parathyroid hormone and a phosphodiesterase inhibitor, pentoxifylline.

    TOXLINE Toxicology Bibliographic Information

    Horiuchi H; Saito N; Kinoshita T; Wakabayashi S; Tsutsumimoto T; Otsuru S; Takaoka K

    2004-01-01

    We investigated the enhancement of new bone |formation elicited ectopically by recombinant human bone morphogenetic protein-2 (rhBMP-2), using parathyroid hormone (PTH) and a phosphodiesterase inhibitor (PDEi), pentoxifylline (PTX), in an animal model. Collagen sponge sheet discs containing rhBMP were implanted onto the back muscles of mice. PTX alone (200 mg/kg body weight [BW]), PTH(1-34) (10 microg/kg BW), PTX plus PTH (200 mg/kg BW and 10 microg/kg BW, respectively), or vehicle (control) were injected subcutaneously daily for 3 weeks after implantation. At the end of this period, rhBMP-2-induced ectopic ossicles were harvested from each group of animals. Ossicles from the PTX-treated group were significantly larger in size, with unchanged bone mineral density (BMD), as compared with the ossicles from the controls. In contrast, the ossicles from the PTH-treated group had significantly higher BMD, but showed no difference in size when compared with those from the control animals. The ossicles of the PTX + PTH treatment group were significantly larger than those of the control and PTH treatment groups. In addition, the BMD of the harvested tissues from the PTX + PTH treatment group was signifi-cantly higher than that of tissues from the control and PTX treatment groups. Although the calcium content of ossicles was significantly higher in the PTX-, PTH-, and PTX + PTH-treated groups than in the control group, the Ca content of ossicles from the PTH + PTX-treated group was highest (two times that of controls), followed by the PTH- and PTX-treated groups.

  5. Enhancement of recombinant human bone morphogenetic protein-2 (rhBMP-2)-induced new bone formation by concurrent treatment with parathyroid hormone and a phosphodiesterase inhibitor, pentoxifylline.

    PubMed

    Horiuchi, Hiroshi; Saito, Naoto; Kinoshita, Tetsuya; Wakabayashi, Shinji; Tsutsumimoto, Takahiro; Otsuru, Satoru; Takaoka, Kunio

    2004-01-01

    We investigated the enhancement of new bone |formation elicited ectopically by recombinant human bone morphogenetic protein-2 (rhBMP-2), using parathyroid hormone (PTH) and a phosphodiesterase inhibitor (PDEi), pentoxifylline (PTX), in an animal model. Collagen sponge sheet discs containing rhBMP were implanted onto the back muscles of mice. PTX alone (200 mg/kg body weight [BW]), PTH(1-34) (10 microg/kg BW), PTX plus PTH (200 mg/kg BW and 10 microg/kg BW, respectively), or vehicle (control) were injected subcutaneously daily for 3 weeks after implantation. At the end of this period, rhBMP-2-induced ectopic ossicles were harvested from each group of animals. Ossicles from the PTX-treated group were significantly larger in size, with unchanged bone mineral density (BMD), as compared with the ossicles from the controls. In contrast, the ossicles from the PTH-treated group had significantly higher BMD, but showed no difference in size when compared with those from the control animals. The ossicles of the PTX + PTH treatment group were significantly larger than those of the control and PTH treatment groups. In addition, the BMD of the harvested tissues from the PTX + PTH treatment group was signifi-cantly higher than that of tissues from the control and PTX treatment groups. Although the calcium content of ossicles was significantly higher in the PTX-, PTH-, and PTX + PTH-treated groups than in the control group, the Ca content of ossicles from the PTH + PTX-treated group was highest (two times that of controls), followed by the PTH- and PTX-treated groups. PMID:15221490

  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 Adolescents12

    PubMed Central

    Hill, Kathleen M.; McCabe, George P.; McCabe, Linda D.; Gordon, Catherine M.; Abrams, Steven A.; Weaver, Connie M.

    2010-01-01

    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 derived from relatively small samples and homogeneous cohorts. Our objective was to determine the relationship between serum 25(OH)D and PTH in children and adolescents from a large and diverse U.S. cohort and to identify a point of inflection of serum 25(OH)D for maximal suppression of serum PTH. Data from 735 participants, ages 7–18 y, were pooled from 3 study sites located in Indiana, Texas, and Massachusetts. A two-phase linear spline was used to model the relationship between serum 25(OH)D and PTH. The value of serum 25(OH)D for maximal suppression of serum PTH was identified as the inflection point of the spline. Before adjustment for site, the inflection point of serum 25(OH)D for maximal suppression of serum PTH was 92.4 nmol/L (95% CI: 62.2, 130.7). After adjusting for site, the point of inflection was poorly defined and the relationship between serum 25(OH)D and PTH appeared to be linear. The lack of an inflection point of serum 25(OH)D for maximal suppression of PTH brings into question the value of using maximal suppression of serum PTH as a basis for determining optimal serum 25(OH)D for healthy children and adolescents. PMID:20861214

  7. 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.

  8. Serum Parathyroid Hormone and 25‐Hydroxyvitamin D Concentrations and Risk of Incident Heart Failure: The Multi‐Ethnic Study of Atherosclerosis

    PubMed Central

    Bansal, Nisha; Zelnick, Leila; Robinson‐Cohen, Cassianne; Hoofnagle, Andy N.; Ix, Joachim H.; Lima, Joao A.; Shoben, Abigail B.; Peralta, Carmen A.; Siscovick, David S.; Kestenbaum, Bryan; de Boer, Ian H.

    2014-01-01

    Background Heart failure (HF) is common and is associated with high mortality. We aimed to determine associations of serum parathyroid hormone (PTH) and 25‐hydroxyvitamin D (25[OH]D) with incident HF and left ventricular mass. Methods and Results Among 6459 participants in the community‐based Multi‐Ethnic Study of Atherosclerosis, all of whom were free of prevalent clinical cardiovascular disease, we measured serum concentrations of PTH and 25(OH)D at the baseline examination. In longitudinal analyses, we tested associations of PTH and 25(OH)D with incident HF events, adjudicated by a panel of physicians. In cross‐sectional analyses of a subset of 4763 participants, we tested associations of PTH and 25(OH)D with left ventricular mass, measured by cardiac magnetic resonance imaging at baseline. Multivariable Cox proportional hazard and linear regression models were adjusted for demographics, physical examination measures, comorbidity, kidney function, and other mineral metabolism markers. Mean age was 62 years and 53% of participants were female. There were 180 incident HF events over a median (interquartile range) follow‐up time of 8.46 (7.67 to 8.63) years. Compared with participants with PTH <65 pg/mL, PTH ≥65 pg/mL was associated with a 50% greater risk of incident HF (95% CI: 3% to 210%) and a 5.3 g higher left ventricular mass (95% CI: 2.6, 7.9 g). In contrast, there was no association of 25(OH)D with risk of incident HF or elevated left ventricular mass. Conclusions In a racially/ethnically diverse population without prevalent cardiovascular disease, higher serum PTH concentration was associated with increased left ventricular mass and increased risk of incident HF. Further studies should be pursued to determine whether PTH excess may be a modifiable risk factor for HF. PMID:25468653

  9. 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

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

    PubMed

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

    2012-04-10

    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

  11. Effect of Concurrent Use of Whole-Body Vibration and Parathyroid Hormone on Bone Structure and Material Properties of Ovariectomized Mice.

    PubMed

    Matsumoto, Takeshi; Itamochi, Shinya; Hashimoto, Yoshihiro

    2016-05-01

    This study was designed to determine the effectiveness of whole-body vibration (WBV) and intermittent parathyroid hormone (iPTH) in combination against estrogen deficiency-induced osteoporosis. Female C57BL/6J mice were bilaterally ovariectomized (OVX, n = 40) or sham-operated (sham-OVX, n = 8) at 9 weeks of age. Two weeks later, the OVX mice were randomly divided into four groups (n = 10 each): the control group (c-OVX) and groups treated with iPTH (p-OVX), WBV (w-OVX) and both (pw-OVX). The p-OVX and pw-OVX groups were given human PTH (1-34) at a dose of 30 µg/kg/day. The w-OVX and pw-OVX groups were exposed to WBV at an acceleration of 0.3 g and 45 Hz for 20 min/day. All mice were euthanized after the 18-day treatment, and the left tibiae were harvested. The proximal metaphyseal region was µCT-scanned, and its cortical bone cross-section was analyzed by Fourier transform infrared microspectroscopy and nanoindentation testing. A single application of iPTH or WBV to OVX mice had no effect on bone structure or material properties of cortical bone, which were compromised in comparison to those in sham-OVX mice. The combination of iPTH and WBV improved trabecular bone volume, thickness, and connectivity in OVX mice. Although the combined treatment failed to improve cortical bone structure, its mineral maturity and hardness were restored to the levels observed in sham-OVX mice. There was no evidence of interaction between the two treatments, and the combined effects seemed to be additive. These results suggest combining WBV with iPTH has great potential for treating postmenopausal osteoporosis. PMID:26746476

  12. 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. PMID:26598522

  13. Up-regulation of fetal rat lung parathyroid hormone-related protein gene regulatory network down-regulates the Sonic Hedgehog/Wnt/betacatenin gene regulatory network.

    PubMed

    Torday, John S; Rehan, Virender K

    2006-10-01

    Lung development depends on endodermal Sonic Hedgehog (Shh) signaling to mesodermal Wingless/int/beta catenin (Wnt/betacatenin), followed by parathyroid hormone-related protein (PTHrP) signaling from endoderm to mesoderm. Fluid distension of fetal rat lung explants up-regulates PTHrP signaling and down-regulates Shh/Wnt/betacatenin signaling, marked by decreases in Patched, Gli, Frizzled, and Dishevelled, inducing fibroblast triglyceride uptake, type II cell saturated phosphatidylcholine, and surfactant protein-B expression. Bumetanide, which inhibits fluid distension, blocked down-regulation of the Shh/Wnt/betacatenin pathway and up-regulation of the PTHrP pathway, whereas PTHrP (1-34, 5 x 10(-7) M) treatment overcame bumetanide inhibition, and the PTHrP receptor antagonist PTHrP (7-34) amide (5 x 10(-6) M) mimicked bumetanide, indicating that PTHrP signaling mediates fluid distension-induced alveolar differentiation. Fetal rat lung explant automaturation was characterized by decreased Wnt/betacatenin signaling and increased PTHrP/PTHrP receptor signaling, up-regulating fibroblast-specific adipocyte differentiation related protein (ADRP) and peroxisome proliferator-activated receptor gamma. Wnt/betacatenin agonists (LiCl or SB415268) maintained Shh/Wnt/betacatenin signaling, blocking spontaneous up-regulation of the PTHrP pathway, whereas PTHrP or cAMP down-regulated Shh/Wnt/betacatenin signaling and stimulated PTHrP signaling for fibroblast and type II cell differentiation. This is the first evidence that alveolar fluid distension is an organizing principle for PTHrP signaling down-regulation of the Shh/Wnt/betacatenin pathway. PMID:16940239

  14. Mechanistic analysis for time-dependent effects of cinacalcet on serum calcium, phosphorus, and parathyroid hormone levels in 5/6 nephrectomized rats

    PubMed Central

    Wu-Wong, J Ruth; Nakane, Masaki; Chen, Yung-wu; Mizobuchi, Masahide

    2013-01-01

    This study investigates the time-dependent effects of cinacalcet on serum calcium, phosphorus, and parathyroid hormone (PTH) levels in 5/6 nephrectomized (NX) rats with experimental chronic renal insufficiency. In this study, 5/6 NX male, Sprague–Dawley rats were treated with vehicle or cinacalcet (10 mg/kg, oral, 1× daily). On Day 0 (before treatment), Day 12 and 13 after treatment (to approximate the clinical practice), and also at 0, 1, 4, 8, 16, and 24 hours after the last dosing, blood was collected for analysis. After 12 or 13 days of cinacalcet treatment, modest changes were observed in serum Ca and phosphorus (Pi), while PTH decreased by >45% to Sham levels (152 ± 15 pg/mL). Detailed mapping found that cinacalcet caused a significant time-dependent decrease in serum Ca following dosing, reaching a lowest point at 8 hours (decrease by 20% to 8.43 ± 0.37 mg/dL), and then returning to normal at 24 hours. Cinacalcet also caused a significant increase in serum Pi levels (by 18%). To investigate the potential mechanism of action, a broad approach was taken by testing cinacalcet in a panel of 77 protein-binding assays. Cinacalcet interacted with several channels, transporters, and neurotransmitter receptors, some of which are involved in brain and heart, and may impact Ca homeostasis. Cinacalcet dose-dependently increased brain natriuretic peptide (BNP) mRNA expression by 48% in cardiomyocytes, but had no significant effects on left ventricular hypertrophy and cardiac function. The results suggest that cinacalcet's hypocalcemic effect may be due to its nonspecific interaction with other receptors in brain and heart. PMID:24303131

  15. Achievement of the National Kidney Foundation Kidney Disease Outcomes Quality Initiative: recommended serum calcium, phosphate and parathyroid hormone values with parathyroidectomy in patients with secondary hyperparathyroidism

    PubMed Central

    Kim, Woo Young; Kim, Hoon Yub; Woo, Sang Uk; Son, Gil Soo; Bae, Jeoung Won

    2013-01-01

    Purpose The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI) 2003 has established guidelines for the treatment of secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease - minerals and bone disorder (CKD-MBD). This study evaluated parathyroidectomy in SHPT patients for the achievement of the NKF-K/DOQI-recommended values of serum calcium, phosphate, and parathyroid hormone (PTH). Methods Between January 2005 and December 2010, parathyroidectomy was performed as recommended by the NKF-K/DOQI guidelines in 81 patients with SHPT and CKD-MBD. Serum PTH, calcium, and phosphate levels were measured prior to and 6, 12, 36, and 60 months after parathyroidectomy. Results Calcium, phosphate, and PTH levels dropped shortly after parathyroidectomy; however, a slight increase showed in the long term. Calcium levels increased for up to 60 months. Phosphate and PTH levels increased for up to 36 months but tended to decrease slightly at 60 months. The mean values were within the target ranges, except for PTH at 36 months. The target parameters of serum phosphate (42.9-61.1% of patients) and serum calcium (a peak of 61.1% of patients at 36 months, but only 28.6% at 60 months) were achieved the most. Less than 34% of patients achieved the recommended range for PTH. Conclusion Parathyroidectomy was not an optimal procedure for achieving all the biochemical parameters recommended by the NKF-K/DOQI. Although it was helpful in attaining the recommended values for serum calcium and phosphate in SHPT patients resistant to medical therapy, the PTH levels did not fall within the recommended range. PMID:23833757

  16. Velcalcetide (AMG 416), a novel peptide agonist of the calcium-sensing receptor, reduces serum parathyroid hormone and FGF23 levels in healthy male subjects

    PubMed Central

    Martin, Kevin J.; Bell, Gregory; Pickthorn, Karen; Huang, Saling; Vick, Andrew; Hodsman, Peter; Peacock, Munro

    2014-01-01

    Context Velcalcetide, also known as AMG 416, is a novel, long-acting selective peptide agonist of the calcium sensing receptor. It is being developed as an intravenous treatment of secondary hyperparathyroidism (SHPT) in hemodialysis patients with chronic kidney disease—mineral and bone disorder. Objective To assess the safety, tolerability, pharmacokinetics and pharmacodynamics of velcalcetide in healthy male volunteers. Methods The study was a double-blind, randomized, placebo-controlled, single-dose, dose-escalation study in healthy males aged 18–45 years conducted at a single center. Each cohort included eight subjects randomized 6:2 to velcalcetide or placebo. Intervention Velcalcetide at 0.5, 2, 5 and 10 mg or placebo was administered intravenously. Outcomes Measurements included plasma ionized calcium (iCa), serum total calcium, intact parathyroid hormone (iPTH), phosphorus and fibroblast growth factor-23 (FGF23), 1,25-dihydroxyvitamin D, calcitonin and urine creatinine, calcium and phosphorus and plasma pharmacokinetics for velcalcetide. Vital signs, safety biochemical and hematological indices, and adverse events were monitored throughout the study. Results Intravenous administration of velcalcetide was well tolerated with no adverse reaction of nausea, vomiting or diarrhea reported. Velcalcetide mediated dose-dependent decreases in serum iPTH at 30 min, FGF23 at 24 h and iCa at 12 h post dose (P < 0.05) and in urine fractional excretion of phosphorus and increases in tubular reabsorption of phosphorus. Velcalcetide plasma exposure increased in a dose-related manner and the terminal elimination of half-life was comparable across the dose range evaluated and ranged from 18.4 to 20.0 h. Conclusion Single IV doses of velcalcetide were well tolerated and associated with rapid, sustained, dose-dependent reductions in serum PTH. The results support further evaluation of velcalcetide as a treatment for SHPT in hemodialysis patients. PMID:24235081

  17. Parathyroid hormone-related protein overexpression protects goat mammary gland epithelial cells from calcium-sensing receptor activation-induced apoptosis.

    PubMed

    Li, Hui; Sun, Yongsen; Zheng, Huiling; Li, Lihui; Yu, Qian; Yao, Xiaotong

    2015-01-01

    Normal mammary gland epithelial cells and breast cancer cells express the calcium-sensing receptor (CaSR), which is the master regulator of systemic calcium metabolism. During lactation, activation of the CaSR in mammary epithelial cells downregulates parathyroid hormone-related protein (PTHrP) levels in milk and in the circulation, and increases calcium transport into milk. However, very little information is available on the role of CaSR in goat mammary gland epithelial cells (GMECs) apoptosis. In this investigation, the full-length cDNA of CaSR from Xinong Saanen dairy goats was cloned, which contains an open-reading frame of 3,258 bp encoding 1,085 amino acids with a predicted molecular weight of 121.0 kDa and an isoelectric point of 5.65. The amino acid sequence is highly homologous with sheep, and the goat CaSR gene is mapped to chromosome 1. Quantitative real-time PCR suggested that CaSR was predominantly expressed in the heart, kidney and mammary gland. Then, we found the stimulation of CaSR with its activator gadolinium chloride (GdCl3) contributed to increase CaSR mRNA levels in GMECs and simultaneously promoted cell apoptosis, and these effects were abrogated partially by NPS2390 which is an inhibitor of CaSR. We also demonstrated that Ca(2+) increased CaSR mRNA levels and induced GMECs apoptosis and restrained cell proliferation. In contrast, PTHrP overexpression protected GMECs from calcium-induced apoptosis, and promoted cell proliferation. In conclusion, these results suggest that PTHrP overexpression protects GMECs from CaSR activation-induced apoptosis. PMID:25266236

  18. Parathyroid Hormone-responsive Smad3-related Factor, Tmem119, Promotes Osteoblast Differentiation and Interacts with the Bone Morphogenetic Protein-Runx2 Pathway*

    PubMed Central

    Hisa, Itoko; Inoue, Yoshifumi; Hendy, Geoffrey N.; Canaff, Lucie; Kitazawa, Riko; Kitazawa, Sohei; Komori, Toshihisa; Sugimoto, Toshitsugu; Seino, Susumu; Kaji, Hiroshi

    2011-01-01

    The mechanisms whereby the parathyroid hormone (PTH) exerts its anabolic action on bone are incompletely understood. We previously showed that inhibition of ERK1/2 enhanced Smad3-induced bone anabolic action in osteoblasts. These findings suggested the hypothesis that changes in gene expression associated with the altered Smad3-induced signaling brought about by an ERK1/2 inhibitor would identify novel bone anabolic factors in osteoblasts. We therefore performed a comparative DNA microarray analysis between empty vector-transfected mouse osteoblastic MC3T3-E1 cells and PD98059-treated stable Smad3-overexpressing MC3T3-E1 cells. Among the novel factors, Tmem119 was selected on the basis of its rapid induction by PTH independent of later increases in endogenous TGF-β. The levels of Tmem119 increased with time in cultures of MC3T3-E1 cells and mouse mesenchymal ST-2 cells committed to the osteoblast lineage by BMP-2. PTH stimulated Tmem119 levels within 1 h as determined by Western blot analysis and immunocytochemistry in MC3T3-E1 cells. MC3T3-E1 cells stably overexpressing Tmem119 exhibited elevated levels of Runx2, osteocalcin, alkaline phosphatase, and β-catenin, whereas Tmem119 augmented BMP-2-induced Runx2 levels in mesenchymal cells. Tmem119 interacted with Runx2, Smad1, and Smad5 in C2C12 cells. In conclusion, we identified a Smad3-related factor, Tmem119, that is induced by PTH and promotes differentiation in mouse osteoblastic cells. Tmem119 is an important molecule in the pathway downstream of PTH and Smad3 signaling in osteoblasts. PMID:21239498

  19. The anabolic action of intermittent parathyroid hormone on cortical bone depends partly on its ability to induce nitric oxide-mediated vasorelaxation in BALB/c mice.

    PubMed

    Gohin, S; Carriero, A; Chenu, C; Pitsillides, A A; Arnett, T R; Marenzana, M

    2016-03-01

    There is strong evidence that vasodilatory nitric oxide (NO) donors have anabolic effects on bone in humans. Parathyroid hormone (PTH), the only osteoanabolic drug currently approved, is also a vasodilator. We investigated whether the NO synthase inhibitor L-NAME might alter the effect of PTH on bone by blocking its vasodilatory effect. BALB/c mice received 28 daily injections of PTH[1-34] (80 µg/kg/day) or L-NAME (30 mg/kg/day), alone or in combination. Hindlimb blood perfusion was measured by laser Doppler imaging. Bone architecture, turnover and mechanical properties in the femur were analysed respectively by micro-CT, histomorphometry and three-point bending. PTH increased hindlimb blood flow by >30% within 10 min of injection (P < 0.001). Co-treatment with L-NAME blocked the action of PTH on blood flow, whereas L-NAME alone had no effect. PTH treatment increased femoral cortical bone volume and formation rate by 20% and 110%, respectively (P < 0.001). PTH had no effect on trabecular bone volume in the femoral metaphysis although trabecular thickness and number were increased and decreased by 25%, respectively. Co-treatment with L-NAME restricted the PTH-stimulated increase in cortical bone formation but had no clear-cut effects in trabecular bone. Co-treatment with L-NAME did not affect the mechanical strength in femurs induced by iPTH. These results suggest that NO-mediated vasorelaxation plays partly a role in the anabolic action of PTH on cortical bone. Copyright © 2016 John Wiley & Sons, Ltd. PMID:26834008

  20. Metabolism and action of the hormone vitamin D. Its relation to diseases of calcium homeostasis.

    PubMed

    Coburn, J W; Hartenbower, D L; Norman, A W

    1974-07-01

    Extensive experimental evidence has established a significant role of calciferol in the maintenance of normal calcium homeostasis. Present knowledge indicates that vitamin D(3) must first be converted to 25-OH-D(3) and then to 1,25(OH)(2)D(3), the most active known form of the steroid. Many of the factors regulating the rate of production of this last steroid from its precurser have been evaluated, and the concept that vitamin D functions as a steroid hormone seems to be well established. Deranged action of calciferol, caused by impaired metabolism of the steroid or through altered sensitivity of target tissues, may be involved in the pathophysiology of several disease states with abnormal calcium metabolism. It is noted that liver disease, osteomalacia due to anticonvulsant therapy, chronic renal failure, hypophosphatemic rickets, hypoparathyroidism, hyperparathyroidism, sarcoidosis and idiopathic hypercalciuria have possible relation to alterations in metabolism or action of vitamin D. The future clinical availability of 1,25(OH)(2)D(3) and other analogs of this steroid may offer potential therapeutic benefit in the treatment of certain of the disease entities discussed. PMID:4365934

  1. Effects of Low Dose Parathyroid Hormone on Bone Mass, Turnover, and Ectopic Osteoinduction in a Rat Model for Chronic Alcohol Abuse

    PubMed Central

    Iwaniec, U.T.; Trevisiol, C.H.; Maddalozzo, G.F.; Rosen, C.J.; Turner, R.T.

    2009-01-01

    Parathyroid hormone (PTH) is used clinically in osteoporotic patients to increase bone mass by enhancing bone formation. PTH therapy is not uniformly effective at all skeletal sites and “lifestyle” factors may further modulate the skeletal response to PTH. Alcohol may represent one of those factors. Chronic alcohol abuse is associated with osteoporosis and impaired fracture healing. Therefore, the present study investigated the effects of alcohol on the bone anabolic response to a dose of PTH similar to a human therapeutic dose 1) during normal cancellous and cortical bone growth and turnover, and 2) in a model of demineralized allogeneic bone matrix (DABM)-induced osteoinduction. Three-month-old male Sprague Dawley rats were fed the Lieber-DeCarli liquid diet with 35% of the calories derived from ethanol. The controls were pair-fed an alcohol-free isocaloric diet containing maltose-dextran. Following adaptation to the liquid diets, the rats were implanted subcutaneously with DABM cylinders prepared from cortical bone of rats fed normal chow. The rats were subsequently treated daily with PTH (1 μg/kg/d sc, 5d/wk) or vehicle and measurements on bone and DABM implants performed 6 w later. Total bone mass was evaluated on the day of necropsy using DXA. Tibiae were processed for histomorphometry. Bone mass and architecture in tibial diaphysis and DABM implants was evaluated by μCT. PTH treatment increased whole body bone mineral content (BMC) and bone mineral density (BMD). The hormone also increased bone formation and bone area/tissue area in the proximal tibial metaphysis. In contrast, PTH treatment had no effect on periosteal bone formation and minimal effects on DABM-induced osteoinduction. Alcohol consumption decreased whole body BMC. Alcohol also decreased cancellous as well as cortical bone formation and bone mass in tibia and impaired DABM-mediated osteoinduction. There was no interaction between PTH treatment and alcohol consumption for any of the endpoints evaluated. Our results indicate that the bone anabolic response to a therapeutic dose of PTH in the rat is largely confined to cancellous bone. In contrast, alcohol consumption inhibits bone formation at all sites. Furthermore, alcohol inhibits osteoinduction and reduces periosteal and cancellous bone formation, irrespective of therapeutic PTH administration. Based on the animal model, our findings suggest that alcohol consumption could impair the beneficial effects of PTH therapy in osteoporosis. PMID:18295560

  2. 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 programed administration of PTH is effective in increasing osteoblast number and bone formation and has beneficial effects on bone volume in the absence of weight-bearing and gonadal hormones. We conclude that the actions of PTH on cancellous bone are independent of the level of mechanical usage.

  3. Vitamins

    MedlinePlus

    ... Sledding, Skiing, Snowboarding, Skating Crushes What's a Booger? Vitamins KidsHealth > For Kids > Vitamins Print A A A ... grains help your body make energy from food. Vitamins Hang Out in Water and Fat There are ...

  4. Intermittent parathyroid hormone (PTH) treatment and age-dependent effects on rat cancellous bone and mineral metabolism.

    PubMed

    Friedl, Gerald; Turner, Russell T; Evans, Glenda L; Dobnig, Harald

    2007-11-01

    In recent years, intermittent PTH treatment has been investigated extensively for its efficacy in preventing osteoporotic fractures and to improve fracture healing and implant fixation. Although these tasks concern patients of all ages, very little is known about whether aging impacts the bone anabolic response to PTH. Female Sprague-Dawley rats of 1, 3, and 13 months of age were either treated by hPTH-(1-34) or by vehicle solution (CTR) for 1 week. As main outcome measures, we determined the effects on static and dynamic histomorphometry of cancellous bone. In addition, we measured gene expression in femur and serum parameters reflecting bone turnover and mineral metabolism. There was a profound decrease in bone formation rate (BFR) with aging in CTR rats, whereas PTH treatment resulted in a significant relative 1.5-, 3-, and 4.7-fold increase in BFR, without altering indices of bone resorption. Aging decreased and PTH increased mRNA levels for bone matrix proteins and growth factors in a gene-specific manner. In younger animals, PTH-induced a marked stimulation in the mineral apposition rate with no effect on osteoblast number, whereas the latter was increased in older animals (1.0-, 1.7-, and 3.1-fold). Treatment with PTH in young rats led to a significant increase in trabecular number (1.6-2.6/mm, p < 0.05), whereas older rats demonstrated increases in trabecular thickness only (52.8-77.8 microm, p < 0.001). Although PTH increased bone formation at all ages, we found significant age-related differences in the cellular and molecular mechanisms involved in the bone anabolic response to the hormone. PMID:17557320

  5. [The role of calcium, calcitriol and their receptors in parathyroid regulation].

    PubMed

    Carrillo-López, N; Fernández-Martín, J L; Cannata-Andía, J B

    2009-01-01

    The mechanism of regulation of Parathyroid hormone (PTH) is complex, and diverse factors are involved: the fundamental ones are calcium, calcitriol and phosphorus. Calcium and calcitriol's mechanism of action takes place through its specific receptors, the calcium-sensing receptor (CaR) and the Vitamin D Receptor (VDR). These two factors have an effect not only on its specific receptors, but also they can modify the other receptor in a positive manner, promoting its actions and demonstrating a cooperative effect between the two. Along with calcium and calcitriol, drugs used in the treatment of Chronic Kidney Disease Mineral Bone Disorders (CKD-MBD) also act directly or indirectly on CaR and VDR and therefore are also responsible for the regulation of the parathyroid gland. PMID:19396314

  6. Remedial Parathyroid Surgery

    PubMed Central

    Udelsman, Robert; Donovan, Patricia Irvin

    2006-01-01

    Objective: To review the outcomes in 130 consecutive remedial explorations for primary hyperparathyroidism. Summary Background Data: Remedial surgery for primary hyperparathyroidism is challenging and requires meticulous preoperative evaluation and imaging to expedite a focused surgical exploration that has traditionally been performed under general anesthesia. This prospective series of 130 consecutive remedial operations for primary hyperparathyroidism selectively used minimally invasive techniques and tested the hypothesis that these techniques could improve outcomes. Methods: Between 1990 and 2005, 1090 patients were evaluated and explored for primary hyperparathyroidism. Of these, 130 remedial explorations were performed in 128 patients who underwent either conventional exploration under general anesthesia (n = 107) or minimally invasive parathyroidectomy (n = 23) employing cervical block anesthesia, directed exploration, and curative confirmation with the rapid intraoperative parathyroid hormone assay. Results: The sensitivity of preoperative imaging were: Sestamibi (79%), ultrasound (74%), MRI (47%), CT (50%), venous localization (93%), and ultrasound guided parathyroid fine needle aspiration (78%). The cure rate in the conventional remedial group (n = 107) was 94% and was associated with a mean length of stay of 1.6 ± 0.2 days. Remedial exploration employing minimally invasive techniques (n = 23) resulted in a cure rate of 96% and a mean length of stay of 0.4 ± 0.1 days. Complications were rare in both remedial groups. These results were almost identical to those achieved in 960 unexplored patients. Conclusions: Remedial parathyroid surgery can be accomplished with acceptable cure and complication rates. Minimally invasive techniques can achieve outcomes that are similar to those obtained in unexplored patients. PMID:16926573

  7. Functional importance of Myc-associated zinc finger protein for the human parathyroid hormone (PTH)/PTH-related peptide receptor-1 P2 promoter constitutive activity.

    PubMed

    Leroy, C; Manen, D; Rizzoli, R; Lombès, M; Silve, C

    2004-02-01

    The aim of the present study was to analyze the functional importance for the parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptor (PTHR1) gene P2 promoter activity of the putative proximal Myc-associated zinc finger protein (MAZ) site localized at position bp -45 to -39 bp, taking advantage of a G/A mutation identified at position -40 in the human sequence. Wild-type 'full-length' (1285P2) and truncated (760P2) promoter sequences were inserted upstream to the luciferase basic (pLucB) and enhancer (pLucE) reporter gene expression vectors. Transient transfections in osteoblast-like SaOS-2 cells and renal cells (RC.SV3A2) showed that the -40 G/A mutation significantly impaired transcriptional activity of wild-type 1285P2-pLucB and 760P2-pLucE promoter constructs. Further truncation of the P2 sequence demonstrated that the sequence -109/-37 bp was essential for promoter activity. Co-transfection with a MAZ expression vector did not modify the wild-type 1285P2-pLucB construct reporter activity but significantly increased 2-fold the mutated construction activity (P<0.05). Electrophoretic mobility shift assays using SaOS-2 nuclear extracts and a double-stranded DNA fragment encompassing the -45 to -39 putative MAZ site (ds-MAZ-oligo) disclosed two specific DNA-protein complexes. Complex II (fast moving) had a lower affinity for the mutated MAZ motif than for the wild-type MAZ motif while complex I (slow moving) had the same affinity for both wild-type or mutated MAZ sequences. Competition studies with Sp1 consensus oligonucleotide (ds-Sp1-oligo) markedly reduced complex I intensity, with a concomitant increase in that of complex II. Finally, ribonuclease protection assays showed that P2-specific PTHR1 mRNA transcript expression was significantly decreased in SaOS-2 cells transfected with ds-MAZ-oligo as compared with that for control (P<0.001) and ds-Sp1-oligo (P<0.05). Taken together, our studies suggest that the putative -45 to -39 MAZ-binding site regulates the constitutive activity of human PTHR1 P2 promoter. PMID:14765995

  8. Parathyroid hormone (PTH)/PTH-related protein (PTHrP) receptor expression and mitogenic responses in human breast cancer cell lines.

    PubMed Central

    Birch, M. A.; Carron, J. A.; Scott, M.; Fraser, W. D.; Gallagher, J. A.

    1995-01-01

    Previous reports have shown the production of parathyroid hormone-related protein (PTHrP) by breast cancer cells in vivo and in vitro. We have investigated the expression of the PTH/PTHrP receptor by the human breast cancer cell lines MCF-7, ZR-75-1, T-47-D, SK-BR-3, Hs578T and MDA-MB231. Using reverse transcription-polymerase chain reaction (RT-PCR) and Southern blot analysis, we detected transcripts for the receptor in MCF-7, SK-BR-3 and MDA-MB231 cells. There was no evidence of receptor mRNA in ZR-75-1 and Hs578T cells. Furthermore, Northern blot analysis of mRNA from MCF-7 cells showed two transcripts of 1.5 and 2.4 kb which coded for the PTH/PTHrP receptor. Expression of PTH/PTHrP receptor mRNA by the breast cancer cell lines was also correlated with the detection of PTHrP transcripts. RT-PCR demonstrated PTHrP mRNA in MCF-7, ZR-75-1, T-47-D and Hs578T cells, but not in SK-BR-3 and MDA-MB231 cells. The detection of receptor transcripts was complemented by [3H]thymidine and bromodeoxyuridine incorporation studies, in which mitogenic responses to PTH and PTHrP were observed in MCF-7 cells but not in Hs578T cells. In response to both PTH(1-34) and PTHrP(1-34), quiescent MCF-7 cells proliferated in a similar dose-dependent manner (1.6-100 ng ml-1). No mitogenic effects of these peptides were observed with Hs578T cells. In addition, levels of intracellular cAMP were measured in MCF-7 and Hs578T cells in response to PTHrP(1-34). In MCF-7 cells there was a significant rise in cAMP with 100 ng ml-1 PTHrP(1-34). The expression of PTH/PTHrP receptor by breast cancer cells suggests that PTHrP may be a paracrine/autocrine regulator of breast carcinoma. Images Figure 1 Figure 2 Figure 3 PMID:7599071

  9. Parathyroid hormone treatment improves the cortical bone micro-structure by improving the distribution of type I collagen in postmenopausal women with osteoporosis

    PubMed Central

    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.

    2014-01-01

    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 birefringence 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 48.28±38.78%; 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), decreased non-significantly the semi-homogeneous birefringent osteons (8.36±10.63 vs. 5.41±9.13, p=0.40) and birefringent bright (4.14±8.90 vs. 2.08±3.36, p=0.10) osteons. Further, lamellar thickness significantly increased from 3.78±0.11μm to 4.47±0.14μm (p=0.0002) for bright, and from 3.32±0.12μm to 3.70±0.12μm (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 initial degree of calcification was observed, relative to intermediate-low degree of calcification (57.16±3.08 vs. 32.90±3.69, p=0.04), the 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 point to study the reduction in fracture risk when PTH is used to treat osteoporosis. PMID:22161803

  10. Parathyroid Hormone Induces Bone Cell Motility and Loss of Mature Osteocyte Phenotype through L-Calcium Channel Dependent and Independent Mechanisms

    PubMed Central

    Prideaux, Matthew; Dallas, Sarah L.; Zhao, Ning; Johnsrud, Erica D.; Veno, Patricia A.; Guo, Dayong; Mishina, Yuji; Harris, Stephen E.; Bonewald, Lynda F.

    2015-01-01

    Parathyroid Hormone (PTH) can exert both anabolic and catabolic effects on the skeleton, potentially through expression of the PTH type1 receptor (PTH1R), which is highly expressed in osteocytes. To determine the cellular and molecular mechanisms responsible, we examined the effects of PTH on osteoblast to osteocyte differentiation using primary osteocytes and the IDG-SW3 murine cell line, which differentiate from osteoblast to osteocyte-like cells in vitro and express GFP under control of the dentin matrix 1 (Dmp1) promoter. PTH treatment resulted in an increase in some osteoblast and early osteocyte markers and a decrease in mature osteocyte marker expression. The gene expression profile of PTH-treated Day 28 IDG-SW3 cells was similar to PTH treated primary osteocytes. PTH treatment induced striking changes in the morphology of the Dmp1-GFP positive cells in IDG-SW3 cultures and primary cells from Dmp1-GFP transgenic mice. The cells changed from a more dendritic to an elongated morphology and showed increased cell motility. E11/gp38 has been shown to be important for cell migration, however, deletion of the E11/gp38/podoplanin gene had no effect on PTH-induced motility. The effects of PTH on motility were reproduced using cAMP, but not with protein kinase A (PKA), exchange proteins activated by cAMP (Epac), protein kinase C (PKC) or phosphatidylinositol-4,5-bisphosphonate 3-kinase (Pi3K) agonists nor were they blocked by their antagonists. However, the effects of PTH were mediated through calcium signaling, specifically through L-type channels normally expressed in osteoblasts but decreased in osteocytes. PTH was shown to increase expression of this channel, but decrease the T-type channel that is normally more highly expressed in osteocytes. Inhibition of L-type calcium channel activity attenuated the effects of PTH on cell morphology and motility but did not prevent the downregulation of mature osteocyte marker expression. Taken together, these results show that PTH induces loss of the mature osteocyte phenotype and promotes the motility of these cells. These two effects are mediated through different mechanisms. The loss of phenotype effect is independent and the cell motility effect is dependent on calcium signaling. PMID:25942444

  11. 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

  12. Parathyroid Hormone Induces Bone Cell Motility and Loss of Mature Osteocyte Phenotype through L-Calcium Channel Dependent and Independent Mechanisms.

    PubMed

    Prideaux, Matthew; Dallas, Sarah L; Zhao, Ning; Johnsrud, Erica D; Veno, Patricia A; Guo, Dayong; Mishina, Yuji; Harris, Stephen E; Bonewald, Lynda F

    2015-01-01

    Parathyroid Hormone (PTH) can exert both anabolic and catabolic effects on the skeleton, potentially through expression of the PTH type1 receptor (PTH1R), which is highly expressed in osteocytes. To determine the cellular and molecular mechanisms responsible, we examined the effects of PTH on osteoblast to osteocyte differentiation using primary osteocytes and the IDG-SW3 murine cell line, which differentiate from osteoblast to osteocyte-like cells in vitro and express GFP under control of the dentin matrix 1 (Dmp1) promoter. PTH treatment resulted in an increase in some osteoblast and early osteocyte markers and a decrease in mature osteocyte marker expression. The gene expression profile of PTH-treated Day 28 IDG-SW3 cells was similar to PTH treated primary osteocytes. PTH treatment induced striking changes in the morphology of the Dmp1-GFP positive cells in IDG-SW3 cultures and primary cells from Dmp1-GFP transgenic mice. The cells changed from a more dendritic to an elongated morphology and showed increased cell motility. E11/gp38 has been shown to be important for cell migration, however, deletion of the E11/gp38/podoplanin gene had no effect on PTH-induced motility. The effects of PTH on motility were reproduced using cAMP, but not with protein kinase A (PKA), exchange proteins activated by cAMP (Epac), protein kinase C (PKC) or phosphatidylinositol-4,5-bisphosphonate 3-kinase (Pi3K) agonists nor were they blocked by their antagonists. However, the effects of PTH were mediated through calcium signaling, specifically through L-type channels normally expressed in osteoblasts but decreased in osteocytes. PTH was shown to increase expression of this channel, but decrease the T-type channel that is normally more highly expressed in osteocytes. Inhibition of L-type calcium channel activity attenuated the effects of PTH on cell morphology and motility but did not prevent the downregulation of mature osteocyte marker expression. Taken together, these results show that PTH induces loss of the mature osteocyte phenotype and promotes the motility of these cells. These two effects are mediated through different mechanisms. The loss of phenotype effect is independent and the cell motility effect is dependent on calcium signaling. PMID:25942444

  13. 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 cross-linking. Optimal treatment regimens must address both improvements of bone mass and glycemic control in order to successfully reduce diabetic bone fragility. This article is part of a Special Issue entitled "Bone and diabetes". PMID:25952971

  14. c-myc and skp2 coordinate p27 degradation, vascular smooth muscle proliferation, and neointima formation induced by the parathyroid hormone-related protein.

    PubMed

    Sicari, Brian M; Troxell, Ronnie; Salim, Fatimah; Tanwir, Mansoor; Takane, Karen K; Fiaschi-Taesch, Nathalie

    2012-02-01

    Parathyroid hormone-related protein (PTHrP) contains a classical bipartite nuclear localization signal. Nuclear PTHrP induces proliferation of arterial vascular smooth muscle cells (VSMC). In the arterial wall, PTHrP is markedly up-regulated in response to angioplasty and promotes arterial restenosis. PTHrP overexpression exacerbates arterial restenosis, and knockout of the PTHrP gene results in decreased VSMC proliferation in vivo. In arterial VSMC, expression of the cell cycle inhibitor, p27, rapidly decreases after angioplasty, and replacement of p27 markedly reduces neointima development. We have shown that PTHrP overexpression in VSMC leads to p27 down-regulation, mostly through increased proteosomal degradation. Here, we determined the molecular mechanisms through which PTHrP targets p27 for degradation. S-phase kinase-associated protein 2 (skp2) and c-myc, two critical regulators of p27 expression and stability, and neointima formation were up-regulated in PTHrP overexpression in VSMC. Normalization of skp2 or c-myc using small interfering RNA restores normal cell cycle and p27 expression in PTHrP overexpression in VSMC. These data indicate that skp2 and c-myc mediate p27 loss and proliferation induced by PTHrP. c-myc promoter activity was increased, and c-myc target genes involved in p27 stability were up-regulated in PTHrP overexpression in VSMC. In primary VSMC, PTHrP overexpression led to increased c-myc and decreased p27. Conversely, knockdown of PTHrP in primary VSMC from PTHrP(flox/flox) mice led to cell cycle arrest, p27 up-regulation, with c-myc and skp2 down-regulation. Collectively, these data describe for the first time the role of PTHrP in the regulation of skp2 and c-myc in VSMC. This novel PTHrP-c-myc-skp2 pathway is a potential target for therapeutic manipulation of the arterial response to injury. PMID:22210745

  15. Constitutive production of parathyroid hormone-related protein (PTHrP) by fibroblasts derived from normal and pathological human breast tissue.

    PubMed

    Cros, Magali; Cataisson, Christophe; Cho, Yong Mee; Berthois, Yolande; Bernard-Poenaru, Oana; Denne, Maryannick; Graulet, Anne-Marie; De Vernejoul, Marie-Christine; Foley, John; Bouizar, Zhor

    2002-01-01

    Parathyroid hormone-related protein (PTHrP) is expressed in the mammary gland and appears to be critical to the morphogenesis of this structure. PTHrP production in the breast is generally attributed to epithelial cells. Because the stromal component of the breast produces factors implicated in proliferation and differentiation of mammary epithelial tissue and tumors, the aim of this study was to investigate the PTHrP expression by mammary fibroblasts from breast cancer tumors and normal breast. PTHrP antibodies labeled intralobular fibroblasts in normal breast and stromal fibroblasts that surround tumor cells. PTHrP was constitutively produced by the cultured mammary fibroblasts, independent of serum stimulation. Normal (15.83 +/- 1.72 fmol/10(6) cells) and pathological breast fibroblasts (19.87 +/- 5.76) secreted similar amounts of PTHrP. PTH/PTHrP receptor mRNA was detected by RT-PCR in all the samples tested. Fibroblasts from normal breast were both PTH and PTHrP-cAMP responsive (453 +/- 133% and 513 +/- 133%, respectively, from basal stimulation), whereas pathological breast fibroblasts were minimally PTHrP-cAMP responsive (183 +/- 36%). The production of other fibroblastic factors implicated in tumor growth and invasiveness was also examined. Interleukin-6 (IL-6), tumor necrosis factor-alpha (INF-alpha), and pro-matrix metalloproteinase (MMP)-1 were not affected by the status of the tissue. In contrast, increased levels of pro-MMP-2 were produced in fibroblasts that originated from pathological (290 +/- 62 ng/10(6) cells) samples compared with those from normal donors (125 +/- 41 ng/10(6) cells). PTHrP production was correlated with TNF-alpha and pro-MMP-2 production. However, inhibition with specific neutralizing antibodies against TNF-alpha or PTHrP, or with a PTHrP antagonist, showed that these factors did not regulate each other. In conclusion, breast fibroblasts are constitutive PTHrP-producing cells with the potential for autocrine signaling through the PTH/PTHrP receptor. PMID:12549623

  16. Pamidronate corrects the down-regulation of the renal parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptor mRNA in rats bearing Walker tumors.

    PubMed

    Yaghoobian, J; Morieux, C; Denne, M A; Bouizar, Z; Ureña, P; de Vernejoul, M C

    1998-05-01

    Human hypercalcemia of malignancy (HHM) is generally due to the release into the circulation of parathyroid hormone-related peptide (PTHrP). PTHrP stimulates osteoclastic bone resorption and renal calcium reabsorption through the activation of a receptor similar to that of PTH (PTH-R). However, there is scarce information about the PTH-R regulation in the setting of the hypercalcemia. In the present study, we assessed the molecular basis of renal PTH-R regulation in Walker tumor-bearing rats either treated or not by a bisphosphonate, pamidronate. Twenty-seven 6-week-old rats were randomly divided into three experimental groups: WC- APD- (9 control rats), WC+ APD- (9 Walker tumor-bearing rats), and WC+ APD+ (9 Walker tumor-bearing rats receiving 15 mg/kg/day of sodium pamidronate every day for seven days). Pamidronate induced a significant decrease in the mean tumor weight (9.3+/-0.8 vs 6.3+/-0.6 g). Seven days after the subcutaneous implantation of the Walker cells, plasma total calcium was 10.8+/-0.4, 16.8+/-0.6, and 12.9+/-0.6 mg/dl in WC- APD-, WC+ APD-, and WC+ APD+, respectively. Plasma PTHrP concentration was undetectable, 15.9+/-2.6, and 7.2+/-1.4 pmol/l, respectively. Bone histomorphometric results showed high resorption in WC+ APD-, which returned below the basal level of the WC- APD- with pamidronate treatment. Densitometric analysis of Northern blots revealed that the renal PTH-R mRNA expression in WC+ WPD- rats was a quarter of the levels in the WC- APD- and WC+ APD+ groups. WC+ APD- also had a decreased PTH-stimulated cAMP production in renal membranes. The PTH-R was expressed in the Walker tumor and it was not modified by pamidronate treatment. In conclusion, the expression of PTH-R receptor mRNA is significantly reduced in the kidney of rats bearing Walker carcinoma tumor. Its regulation is tissue-specific: pamidronate, which partially corrected the hypercalcemia and elevated circulating PTHrP, normalized the PTH-R mRNA expression in the kidney but not in the tumor. PMID:9660083

  17. Relationships between concentrations of selected organohalogen contaminants and thyroid hormones and vitamins A, E and D in Faroese pilot whales.

    PubMed

    Hoydal, Katrin S; Ciesielski, Tomasz M; Borrell, Asunción; Wasik, Andrzej; Letcher, Robert J; Dam, Maria; Jenssen, Bjørn M

    2016-07-01

    Pilot whales (Globicephala melas) from the Faroe Islands, North-East Atlantic, have high body concentrations of organohalogenated compounds (OHCs), such as polychlorinated biphenyls (PCBs), organochlorinated pesticides (OCPs) and brominated flame retardants (BFRs). The aim of the present study was to examine if and to what extent blood plasma and liver concentrations of several groups of these OHCs are related to concentrations of relevant nutritional and hormonal biomarkers in pilot whales. Thyroid hormones (THs: total and free thyroxine and total and free triiodothyronine) and vitamin A (retinol), D (25-hydroxyvitamin D3) and E (α-tocopherol) were analysed in plasma (n=27) and vitamin A (total vitamin A, retinol and retinyl palmitate) and E (α- and γ-tocopherol) were analysed in liver (n=37) of Faroe Island pilot whales. Correlative relationships between the biomarkers and OHC concentrations previously analysed in the same tissues in these individuals were studied. The TH concentrations in plasma were significantly higher in juveniles than in adults. Vitamin D concentrations in plasma and α- and γ-tocopherol in liver were higher in adults than in juveniles. Multivariate statistical modelling showed that the age and sex influenced the relationship between biomarkers and OHCs. Some significant positive relationships were found between OHCs and thyroid hormone concentrations in the youngest juveniles (p<0.05). In plasma of juvenile whales α-tocopherol was also positively correlated with all the OHCs (p<0.05). Only few significant correlations were found between single OHCs and retinol and vitamin D in plasma within the age groups. There were significant negative relationships between hepatic PBDE concentrations and retinol (BDE-47) and γ-tocopherol (BDE-49, -47, -100, -99, -153) in liver. The relationships between OHCs and THs or vitamins suggest that in pilot whales OHCs seem to have minor effects on TH and vitamin concentrations. PMID:27131793

  18. Membrane receptors for vitamin D steroid hormones: potential new drug targets.

    PubMed

    Farach-Carson, M C; Nemere, I

    2003-01-01

    There is increasing evidence that steroid hormones derived from vitamin D act through classical nuclear receptors (nVDR), as well as specific binding sites on the plasma membrane of target cells that are coupled to signal transduction systems. These sites are referred to as Membrane Associated, Rapid Response Steroid (MARRS) binding proteins or complexes. In the case of the seco-steroid 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], the two 'receptors' appear to be different proteins with distinct affinities for vitamin D analogs. These differences may be useful in a number of clinical situations. In treating leukemias, it would be useful to promote the actions of the nVDR for differentiation to macrophages while blocking the 1,25D3-MARRS in intestine, which might contribute to the undesirable side effect of hypercalcemia. In contrast, stimulation of the intestinal 1,25D3-MARRS would be desirable in the elderly, since this signalling system appears to decline with age in model systems, potentially contributing to diminished intestinal absorption of calcium and associated bone loss. Bone itself is known to have osteoblasts that respond to 1,25(OH)2D3 through both nVDR and 1,25D3-MARRS mechanisms. Both systems are required for bone-building activities. Osteoclasts lack the nVDR, but may become activated through the 1,25D3-MARRS, offering another site of drug intervention in the treatment of osteoporosis. Finally, during tooth mineralization, immunohistochemical studies reveal an absence of the nVDR and a marked appearance of the 1,25D3-MARRS. In addition to our growing knowledge of 1,25(OH)2D3, the physiological actions of a lesser studied metabolite of vitamin D, 24,25(OH)2D3, are coming to light and may offer additional targets for pharmaceutical modulation. PMID:12528991

  19. Theoretical basis of a beneficial role for vitamin D in viral hepatitis

    PubMed Central

    Lương, Khanh vinh quốc; Nguyễn, Lan Thi Hoàng

    2012-01-01

    Abnormal bone metabolism and dysfunction of the calcium-parathyroid hormone-vitamin D axis have been reported in patients with viral hepatitis. Some studies suggested a relationship between vitamin D and viral hepatitis. Genetic studies have provided an opportunity to identify the proteins that link vitamin D to the pathology of viral hepatitis (i.e., the major histocompatibility complex class II molecules, the vitamin D receptor, cytochrome P450, the renin-angiotensin system, apolipoprotein E, liver X receptor, toll-like receptor, and the proteins regulated by the Sp1 promoter gene). Vitamin D also exerts its effects on viral hepatitis via non-genomic factors, i.e., matrix metalloproteinase, endothelial vascular growth factor, prostaglandins, cyclooxygenase-2, and oxidative stress. In conclusion, vitamin D could have a beneficial role in viral hepatitis. Calcitriol is best used for viral hepatitis because it is the active form of the vitamin D3 metabolite. PMID:23082050

  20. Parathyroid hyperplasia

    MedlinePlus

    ... done to check calcium, phosphorus , magnesium, PTH , and vitamin D levels. A 24-hour urine test may be done to determine how much calcium is being filtered out of the body into the urine. Bone x-rays and a bone density test (DXA) can ...

  1. Nonfunctioning parathyroid carcinoma

    SciTech Connect

    Klink, B.K.; Karulf, R.E.; Maimon, W.N.; Peoples, J.B. )

    1991-07-01

    Parathyroid carcinoma is a rare clinical entity accounting for only 4 per cent of all cases of parathyroid neoplasia. Nonfunctioning parathyroid carcinoma is even rarer. Previously, virtually all patients with these lesions were treated for a nonspecific neck mass. However, in the present case, a preoperative diagnosis of nonfunctioning parathyroid carcinoma was made based on the technetium pertechnetate/thallium 201 subtraction scan. The authors report on the 14th case of nonfunctioning parathyroid carcinoma, a review of the literature, and guidelines for the preoperative and operative evaluation of neck masses suspected to be parathyroid carcinoma.22 references.

  2. Association of Higher Plasma Vitamin D Binding Protein and Lower Free Calcitriol Levels with Tenofovir Disoproxil Fumarate Use and Plasma and Intracellular Tenofovir Pharmacokinetics: Cause of a Functional Vitamin D Deficiency?

    PubMed Central

    Kiser, Jennifer J.; Stephensen, Charles B.; Hazra, Rohan; Flynn, Patricia M.; Wilson, Craig M.; Rutledge, Brandy; Bethel, James; Pan, Cynthia G.; Woodhouse, Leslie R.; Van Loan, Marta D.; Liu, Nancy; Lujan-Zilbermann, Jorge; Baker, Alyne; Kapogiannis, Bill G.; Gordon, Catherine M.

    2013-01-01

    Tenofovir disoproxil fumarate (TDF) causes bone, endocrine, and renal changes by an unknown mechanism(s). Data are limited on tenofovir pharmacokinetics and these effects. Using baseline data from a multicenter study of HIV-infected youth on stable treatment with regimens containing TDF (n = 118) or lacking TDF (n = 85), we measured cross-sectional associations of TDF use with markers of renal function, vitamin D-calcium-parathyroid hormone balance, phosphate metabolism (tubular reabsorption of phosphate and fibroblast growth factor 23 [FGF23]), and bone turnover. Pharmacokinetic-pharmacodynamic associations with plasma tenofovir and intracellular tenofovir diphosphate concentrations were explored among those receiving TDF. The mean age was 20.9 (standard deviation [SD], 2.0) years; 63% were male; and 52% were African American. Compared to the no-TDF group, the TDF group showed lower mean estimated glomerular filtration rates and tubular reabsorption of phosphate, as well as higher parathyroid hormone and 1,25-dihydroxy vitamin D [1,25-OH(2)D] levels. The highest quintile of plasma tenofovir concentrations was associated with higher vitamin D binding protein, lower free 1,25-OH(2)D, higher 25-OH vitamin D, and higher serum calcium. The highest quintile of intracellular tenofovir diphosphate concentration was associated with lower FGF23. Higher plasma tenofovir concentrations were associated with higher vitamin D binding protein and lower free 1,25-OH(2)D, suggesting a functional vitamin D deficiency explaining TDF-associated increased parathyroid hormone. The finding of lower FGF23 accompanying higher intracellular tenofovir diphosphate suggests that different mechanisms mediate TDF-associated changes in phosphate handling. Separate pharmacokinetic properties may be associated with distinct TDF toxicities: tenofovir with parathyroid hormone and altered calcium balance and tenofovir diphosphate with hypophosphatemia and FGF23 regulation. (The clinical trial registration number for this study is NCT00490412 and is available online at http://clinicaltrials.gov/ct2/show/NCT00490412.) PMID:24002093

  3. Relationship between vitamin D deficiency and cardiovascular disease

    PubMed Central

    Ku, Yan-Chiou; Liu, Mu-En; Ku, Chang-Sheng; Liu, Ta-Yuan; Lin, Shoa-Lin

    2013-01-01

    Epidemiological studies have found that low 25-hydroxyvitamin D levels may be associated with coronary risk factors and adverse cardiovascular outcomes. Additionally, vitamin D deficiency causes an increase in parathyroid hormone, which increases insulin resistance and is associated with diabetes, hypertension, inflammation, and increased cardiovascular risk. In this review, we analyze the association between vitamin D supplementation and the reduction in cardiovascular disease. The role of vitamin D deficiency in cardiovascular morbidity and mortality is still controversial, and larger scale, randomized placebo controlled trials are needed to investigate whether oral vitamin D supplementation can reduce cardiovascular risk. Given the low cost, safety, and demonstrated benefit of higher 25-hydroxyvitamin D levels, vitamin D supplementation should become a public health priority for combating common and costly chronic cardiovascular diseases. PMID:24109497

  4. Vitamin D and Clinical Outcomes in Dialysis.

    PubMed

    Parikh, Coral; Gutgarts, Victoria; Eisenberg, Elliot; Melamed, Michal L

    2015-01-01

    Most dialysis patients are vitamin D deficient, including deficiencies in both activated vitamin D (1, 25-dihydroxyvitamin D) and the less active 25-hydroxyvitamin D. These and other abnormalities associated with chronic kidney disease (CKD), if they remain untreated, lead to secondary hyperparathyroidism and bone changes, such as osteitis fibrosa cystica. Activated vitamin D has been proven to decrease parathyroid hormone (PTH) levels in dialysis patients and is currently used for this indication. There are multiple other potential "pleotrophic" effects associated with vitamin D therapy. These include associations with lower all-cause and cardiovascular mortality, lower rates of infections and improved glycemic indexes. Meta-analyses of multiple observational studies have shown activated vitamin D therapy to be associated with improved survival. Observational data also suggest fewer infections and better glucose control. There have been no randomized clinical trials powered to evaluate mortality or other clinical outcomes. Small trials of nutritional vitamin D (ergocalciferol and cholecalciferol) showed increases in 25-hydroxyvitamin D levels without hypercalcemia or hyperphosphatemia, even when given in addition to activated vitamin D therapy. While activated vitamin D therapy is associated with improved outcomes, it also leads to higher fibroblast growth factor 23 (FGF-23) levels, which may be detrimental in dialysis patients. Further research is needed to evaluate whether activated or nutritional vitamin D therapy are beneficial in dialysis patients for outcomes other than secondary hyperparathyroidism. PMID:26424141

  5. [Bilateral papillary thyroid carcinoma concurrent with parathyroid adenoma: one case report].

    PubMed

    Zhao, Hong; Zhao, Hongling; Wang, Cui

    2015-03-01

    Concurrent thyroid carcinoma and parathyroid adenoma is rare, they can and do coexist. We present here a 63-year old man who had bilateral papillary thyroid carcinoma and a parathyroid adenoma in the right thyroid lobe. Thyroid cancer was confirmed surgically. After the operation, the patient was found hypercalcemie and hypophosphatemia along with an elevated parathyroid hormone (PTH), indicating primary hyperparathyroidism. Also, the parathyroid 99mTc-MIBI scan demonstrated parathyroid adenoma in the right lower pole of the thyroid. The abnormal parathyroid tissue was carried out, and then serum calcium and PTH levels decreased to normal ranges. PMID:26211170

  6. Carboxyl-terminal fragments of parathyroid hormone are not secreted preferentially in primary hyperparathyroidism as they are in other hypercalcemic conditions.

    PubMed

    Brossard, J H; Whittom, S; Lepage, R; D'Amour, P

    1993-08-01

    Calcium infusion in normal men decreases immunoreactive PTH (iPTH). Intact iPTH (I) shows the greatest decline, and there is a greater decrease in carboxyl-terminal iPTH (C) than in midcarboxyl-terminal iPTH (M); thus, C/I, M/I, and M/C ratios are increased. To verify whether this adaptive mechanism to hypercalcemia was present in patients with primary hyperparathyroidism (PHP), we measured total serum calcium (Ca), I, C, and M as well as C/I, M/I, and M/C ratios in 32 normocalcemic normal subjects (NN), in the same normal subjects made hypercalcemic (HN), in 31 patients with PHP, and in 12 patients with nonparathyroid hypercalcemia (NPHN). Eight patients with PHP and the 32 NN were submitted to CaCl2 and Na2 EDTA infusions to evaluate their parathyroid function. Ca was lower (P < 0.005) in NN (2.21 +/- 0.06 mmol/L) than in PHP (2.80 +/- 0.25 mmol/L) or NPHN (2.83 +/- 0.20 mmol/L). The HN Ca value (2.80 +/- 0.18 mmol/L) was similar to those in PHP and NPHN subjects. C, M, and I were increased in PHP compared to the other groups (P < 0.005). PHP had C/I and M/I ratios of 2.03 +/- 0.72 and 9.04 +/- 7.69, values similar to NN (2.29 +/- 0.55 and 8.70 +/- 3.0), but lower than HN (5.36 +/- 2.48 and 25.93 +/- 13.86; P < 0.005) and NPHN (11.91 +/- 13.06 and 18.69 +/- 10.81; P < 0.005). NPHN also had a lower M/C ratio than HN (2.76 +/- 2.02 vs. 4.99 +/- 1.81; P < 0.05). PHP and NN could increase their C/I ratio to the same maximum (4.71 +/- 1.26 vs. 5.70 +/- 2.94), but PHP did so at a much higher set-point (2.67 +/- 0.19 vs. 2.24 +/- 0.10 mmol/L; P < 0.005). PHP also had higher set-points for M/I, and M/C ratios even if they failed to increase the ratios to the high values in NN [M/I 11.6 +/- 6.4 vs. 29.3 +/- 18.3 (P < 0.005); M/C, 2.16 +/- 1.20 vs. 5.0 +/- 1.93 (P < 0.005)]. Thus, carboxyl-terminal fragments are not secreted preferentially in PHP as they are in other hypercalcemic conditions. This relates to a higher set-point for the regulation of C/I and M/I ratios, permitting the secretion of more intact hormone relative to C or M fragments. The lower M/C ratio in NPHN and in PHP made more hypercalcemic compared to HN suggests a lower production or a higher clearance of midcarboxyl-terminal fragments in chronic hypercalcemia. PMID:8345045

  7. Women’s Health Initiative Clinical Trials: Interaction of calcium plus vitamin D and Hormone Therapy

    PubMed Central

    Robbins, John A; Aragaki, Aaron; Crandall, Carolyn J; Manson, Joann E; Carbone, Laura; Jackson, Rebecca; Lewis, Cora E.; Johnson, Karen C.; Sarto, Gloria; Stefanick, Marcia L; Wactawski-Wende, Jean

    2013-01-01

    Objective To test the added value of Calcium and vitamin D (CaD) for fracture prevention among women taking postmenopausal hormone therapy (HT). Methods A prospective, partial-factorial design, randomized controlled double blind trial amongst Women’s Health Initiative post-menopausal participants, ages 50–79, at 40 centers in the US, with 7.1 years average follow-up. 27,347 women were randomized to HT (conjugated estrogen 0.625 mg alone, or CEE 0.625 mg daily plus medroxyprogesterone acetate 2.5mg) and 36,282 women randomized to either 1000mg elemental calcium (carbonate) plus 400 IU of vitamin D3 daily each compared to placebo. A total of 16,089 women were in both arms. The predefined outcomes were adjudicated hip fractures and measured bone mineral density. Results Interaction between HT and CaD on hip fracture (P-interaction = 0.01) was shown. The effect of CaD was stronger among women assigned to HT (HR, 0.59; 95%CI, 0.38–0.93) than placebo (HR, 1.20; 95%CI, 0.85, 1.69). The effect of HT on hip fracture was stronger among women assigned to active CaD (HR, 0.43; 0.28–0.66) than placebo (HR, 0.87; 95%CI, 0.60–1.26). CaD supplementation enhanced the anti-fracture effect of the HT at all levels of personal calcium intake. There was no interaction of HT and CaD on change in hip or spine BMD. Conclusions Postmenopausal women at normal risk of hip fracture on HT, supplementation with CaD significantly reduced incident hip fracture beyond HT alone; at all levels of personal baseline total calcium intake. PMID:23799356

  8. Polybrominated diphenyl ether (PBDE)-induced alterations in vitamin A and thyroid hormone concentrations in the rat during lactation and early postnatal development

    SciTech Connect

    Ellis-Hutchings, Robert G.; Cherr, Gary N.; Hanna, Lynn A.; Keen, Carl L. . E-mail: clkeen@ucdavis.edu

    2006-09-01

    In experimental animals fed standard laboratory diets, penta-BDE mixtures can decrease circulating thyroid hormone and liver vitamin A concentrations. A substantial number of pregnant women and their children have marginal vitamin A status, potentially increasing their risk of adverse effects to penta-BDE exposure. The current study investigated the effects of maternal gestational and lactational penta-BDE exposure on thyroid hormone and vitamin A homeostasis in rats of sufficient vitamin A (VAS) or marginal vitamin A (VAM) status and their offspring. Dams were administered daily oral doses of 18 mg/kg DE-71 (a penta-BDE mixture) or a corn oil vehicle from gestation day 6 through lactation day (LD) 18. Thyroid hormone and vitamin A homeostasis were assessed in plasma and tissues of LD 19 dams and postnatal day (PND) 12, 18, and 31 pups. DE-71 exposure induced hepatomegaly in VAS and VAM pups at all timepoints and increased testes weights at PND 31. While liver vitamin A concentrations were low in DE-71 treated dams and pups, plasma retinol concentrations and plasma retinol binding protein levels were only low in VAM animals exposed to DE-71. DE-71 exposure lowered plasma thyroxine concentrations in VAS and VAM dams and pups. Plasma thyroid stimulating hormone concentrations were high in VAM dams exposed to DE-71, suggesting that marginal vitamin A status enhances the susceptibility to thyroid hormone axis disruption by DE-71. These results support the concept that marginal vitamin A status in pregnant women may increase the risk for PBDE-induced disruptions in vitamin A and thyroid hormone homeostasis.

  9. Effects on thyroid hormone metabolism and depletion of lung vitamin A in rats by airborne particulate matter

    SciTech Connect

    Heussen, G.A.; Schefferlie, G.J.; Talsma, M.J.; van Til, H.; Dohmen, M.J.; Brouwer, A.; Alink, G.M. )

    1993-04-01

    Thyroxine (T4) and vitamin A are important regulators of normal epithelial differentiation and proliferation and might act in the promotion phase of carcinogenesis. Thyroid hormone and vitamin A metabolism are linked by a common plasma carrier protein, transthyretin (TTR). Polychlorinated biphenyls (PCBs) and related organochlorine compounds deplete vitamin A and thyroxine by interaction with TTR and alteration of their metabolism in hepatic and other organs. In the present report an outdoor airborne particulate matter (APM) extract was tested for both interaction with thyroid hormone and vitamin A metabolism, in order to address the question of whether APM has the potency to deplete vitamin A and thyroid hormones. Furthermore, studies were performed to characterize compounds present in APM that interact with TTR. A third aim was to compare the interaction of APM extracts with TTR and thyroxine-binding globulin (TBG), the major carrier protein for thyroxine in humans. Results showed that a single treatment of rats with an outdoor APM extract depleted plasma thyroxine and triiodothyronine levels and increased plasma retinol levels gradually over the time period studied, while liver retinol, lung retinol, and retinyl palmitate levels were depleted by 30-50%. As outdoor APM was able to inhibit T4-TTR binding in vitro, this suggests that the reduction in thyroxine levels in vivo is caused by the same phenomenon. Experiments showed that the neutral fraction of the APM extract accounted for most of the inhibitory activity on T4-TTR binding. Polycyclic aromatic hydrocarbons and nitrated derivatives are not likely to be responsible for the activity of the neutral fraction, because several representatives of these compounds showed no or very little interaction with TTR. Pentachlorophenol, a compound with known inhibitory activity on T4-TTR binding, was detected in the organic acid fraction of both a cigarette smoke sample and an outdoor APM sample.

  10. Thyroid hormone and vitamin D regulate VGF expression and promoter activity.

    PubMed

    Lewis, Jo E; Brameld, John M; Hill, Phil; Wilson, Dana; Barrett, Perry; Ebling, Francis J P; Jethwa, Preeti H

    2016-02-01

    The Siberian hamster (Phodopus sungorus) survives winter by decreasing food intake and catabolizing abdominal fat reserves, resulting in a sustained, profound loss of body weight. Hypothalamic tanycytes are pivotal for this process. In these cells, short-winter photoperiods upregulate deiodinase 3, an enzyme that regulates thyroid hormone availability, and downregulate genes encoding components of retinoic acid (RA) uptake and signaling. The aim of the current studies was to identify mechanisms by which seasonal changes in thyroid hormone and RA signaling from tanycytes might ultimately regulate appetite and energy expenditure. proVGF is one of the most abundant peptides in the mammalian brain, and studies have suggested a role for VGF-derived peptides in the photoperiodic regulation of body weight in the Siberian hamster. In silico studies identified possible thyroid and vitamin D response elements in the VGF promoter. Using the human neuroblastoma SH-SY5Y cell line, we demonstrate that RA increases endogenous VGF expression (P<0.05) and VGF promoter activity (P<0.0001). Similarly, treatment with 1,25-dihydroxyvitamin D3 increased endogenous VGF mRNA expression (P<0.05) and VGF promoter activity (P<0.0001), whereas triiodothyronine (T3) decreased both (P<0.01 and P<0.0001). Finally, intra-hypothalamic administration of T3 blocked the short day-induced increase in VGF expression in the dorsomedial posterior arcuate nucleus of Siberian hamsters. Thus, we conclude that VGF expression is a likely target of photoperiod-induced changes in tanycyte-derived signals and is potentially a regulator of seasonal changes in appetite and energy expenditure. PMID:26643910

  11. Thyroid hormone and vitamin D regulate VGF expression and promoter activity

    PubMed Central

    Lewis, Jo E; Brameld, John M; Hill, Phil; Wilson, Dana; Barrett, Perry; Ebling, Francis J P; Jethwa, Preeti H

    2016-01-01

    The Siberian hamster (Phodopus sungorus) survives winter by decreasing food intake and catabolizing abdominal fat reserves, resulting in a sustained, profound loss of body weight. Hypothalamic tanycytes are pivotal for this process. In these cells, short-winter photoperiods upregulate deiodinase 3, an enzyme that regulates thyroid hormone availability, and downregulate genes encoding components of retinoic acid (RA) uptake and signaling. The aim of the current studies was to identify mechanisms by which seasonal changes in thyroid hormone and RA signaling from tanycytes might ultimately regulate appetite and energy expenditure. proVGF is one of the most abundant peptides in the mammalian brain, and studies have suggested a role for VGF-derived peptides in the photoperiodic regulation of body weight in the Siberian hamster. In silico studies identified possible thyroid and vitamin D response elements in the VGF promoter. Using the human neuroblastoma SH-SY5Y cell line, we demonstrate that RA increases endogenous VGF expression (P<0.05) and VGF promoter activity (P<0.0001). Similarly, treatment with 1,25-dihydroxyvitamin D3 increased endogenous VGF mRNA expression (P<0.05) and VGF promoter activity (P<0.0001), whereas triiodothyronine (T3) decreased both (P<0.01 and P<0.0001). Finally, intra-hypothalamic administration of T3 blocked the short day-induced increase in VGF expression in the dorsomedial posterior arcuate nucleus of Siberian hamsters. Thus, we conclude that VGF expression is a likely target of photoperiod-induced changes in tanycyte-derived signals and is potentially a regulator of seasonal changes in appetite and energy expenditure. PMID:26643910

  12. Primary Vitamin D Target Genes Allow a Categorization of Possible Benefits of Vitamin D3 Supplementation

    PubMed Central

    Carlberg, Carsten; Seuter, Sabine; de Mello, Vanessa D. F.; Schwab, Ursula; Voutilainen, Sari; Pulkki, Kari; Nurmi, Tarja; Virtanen, Jyrki; Tuomainen, Tomi-Pekka; Uusitupa, Matti

    2013-01-01

    Vitamin D deficiency has been associated with an increased risk of developing a number of diseases. Here we investigated samples from 71 pre-diabetic individuals of the VitDmet study, a 5-month high dose vitamin D3 intervention trial during Finnish winter, for their changes in serum 25-hydroxyvitamin D3 (25(OH)D3) concentrations and the expression of primary vitamin D target genes in peripheral blood mononuclear cells and adipose tissue. A negative correlation between serum concentrations of parathyroid hormone and 25(OH)D3 suggested an overall normal physiological vitamin D response among the participants. The genes CD14 and thrombomodulin (THBD) are up-regulated primary vitamin D targets and showed to be suitable gene expression markers for vitamin D signaling in both primary tissues. However, in a ranking of the samples concerning their expected response to vitamin D only the top half showed a positive correlation between the changes of CD14 or THBD mRNA and serum 25(OH)D3 concentrations. Interestingly, this categorization allows unmasking a negative correlation between changes in serum concentrations of 25(OH)D3 and the inflammation marker interleukin 6. We propose the genes CD14 and THBD as transcriptomic biomarkers, from which the effects of a vitamin D3 supplementation can be evaluated. These biomarkers allow the classification of subjects into those, who might benefit from a vitamin D3 supplementation, and others who do not. PMID:23923049

  13. Vitamin D and rheumatoid arthritis

    PubMed Central

    Athanassiou, Panagiotis; Lyraki, Aikaterini; Raftakis, Ioannis; Antoniadis, Christodoulos

    2012-01-01

    Objectives: Vitamin D deficiency has been implicated in the pathogenesis of autoimmune diseases, such as diabetes mellitus type 1 and multiple sclerosis. Reduced vitamin D intake has been linked to increased susceptibility to the development of rheumatoid arthritis (RA) and vitamin D deficiency has been found to be associated with disease activity in patients with RA. The objective was to evaluate vitamin D status in patients with RA and to assess the relationship between vitamin D levels and disease activity. Methods: In a cohort of 44 patients with RA, 25-hydroxyvitamin D3 [25(OH)D3] levels, parathyroid hormone levels, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were measured. Disease activity was evaluated by calculating the 28-joint Disease Activity Score (DAS28). A control group (n = 44), matched for age and sex, was evaluated as well. Results: In the cohort of 44 patients with RA 25(OH)D3 levels were found to be low compared with the control group, 25(OH)D3 being 15.26 ± 1.07 ng/ml [mean ± standard error of the mean (SEM)] and 25.8 ± 1.6 ng/ml in the patient and control group respectively (Student’s t test, p < 0.001). Parathyroid hormone levels were 71.08 ± 7.02 pg/ml (mean ± SEM) (normal values 10.0–65.0 pg/ml), CRP 7.6 ± 1.57 mg/litre (mean ± SEM) (normal values < 3 mg/litre) and ESR was 38.0 ± 4.6 mm/h (mean ± SEM) in the group of patients with RA. Levels of 25(OH)D3 were found to be negatively correlated to the DAS28, the correlation coefficient being −0.084. Levels of 25(OH)D3 were also found to be negatively correlated to CRP and ESR, the correlation coefficient being –0.115 and −0.18, respectively. Conclusion: It appears that vitamin D deficiency is highly prevalent in patients with RA, and that vitamin D deficiency may be linked to disease severity in RA. As vitamin D deficiency has been linked to diffuse musculoskeletal pain, these results have therapeutic implications. Vitamin D supplementation may be needed both for the prevention of osteoporosis as well as for pain relief in patients with RA. PMID:23323190

  14. Single-sperm typing: Determination of genetic distance between the sup G. gamma. -globulin and parathyroid hormone loci by using the polymerase chain reaction and allele-specific oligomers

    SciTech Connect

    Cui, Xiangfeng; Li, Honghua; Galas, D.; Arnheim, N. ); Goradia, T.M. Harvard Univ., Cambridge, MA ); Lange, K. ); Kazazian, H.H. Jr. )

    1989-12-01

    The frequency of recombination between the {sup G}{gamma}-globin (HBG2) and parathyroid hormone (PTH) loci on the short arm of human chromosome 11 was estimated by typing >700 single-sperm samples from two males. The sperm-typing technique employed involves the polymerase chain reaction and allele-specific oligonucleotide hybridization. The maximum likelihood recombination fraction estimate of 0.16 falls well within previous estimates based on family studies. With current technology and a sample size of 1000 sperm, recombination fractions down to {approx}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 <0.001.

  15. The effect of vitamin D on thyroid autoimmunity in non-lactating women with postpartum thyroiditis.

    PubMed

    Krysiak, R; Kowalcze, K; Okopien, B

    2016-05-01

    The study included 38 non-lactating l-thyroxine-treated women with postpartum thyroiditis (PPT) and 21 matched healthy postpartum women. Women with vitamin D deficiency were treated with oral vitamin D (4000 IU daily), whereas women with vitamin D insufficiency and women with normal 25-hydroxy vitamin levels were either treated with vitamin D (2000 IU daily) or left untreated. Serum hormone levels and thyroid antibody titers were measured at the beginning of the study and 3 months later. 25-hydroxy vitamin D levels were lower in women with PPT than in healthy women. Thyroid peroxidase and thyroglobulin antibody titers inversely correlated with vitamin D status. Apart from increasing serum levels of 25-hydroxy vitamin D and decreasing serum levels of parathyroid hormone, vitamin D reduced titers of thyroid peroxidase antibodies and this effect was stronger in women with vitamin D deficiency. The study's results suggest that vitamin D supplementation may bring benefits to l-thyroxine-treated women with PPT. PMID:26757834

  16. Vitamin D supplementation in obese type 2 diabetes subjects in Ajman, UAE: a randomized controlled double-blinded clinical trial

    PubMed Central

    Sadiya, A; Ahmed, S M; Carlsson, M; Tesfa, Y; George, M; Ali, S H; Siddieg, H H; Abusnana, S

    2015-01-01

    Objectives: To study the effect of Vitamin D3 supplementation on metabolic control in an obese type 2 diabetes Emirati population. Methods: This randomized double-blind clinical trial was conducted with 87 vitamin D-deficient obese, type 2 diabetic participants. The vitamin D-group (n=45) and the placebo group (n=42) were matched for gender, age, HbA1c and 25-hydroxy vitamin D (25(OH) D) at the baseline. The study was divided into two phases of 3 months each; in phase 1, the vitamin D-group received 6000 IU vitamin D3/day followed by 3000 IU vitamin D3/day in phase 2, whereas the placebo group (n=42) received matching placebo. Results: After supplementation, serum 25(OH) D peaked in the vitamin D-group in phase 1 (77.2±30.1 nmol/l, P=0.003) followed by a decrease in the phase 2 (61.4±18.8 nmol/l, P=0.006), although this was higher compared with baseline. In the placebo group, no difference was observed in the serum 25(OH) D levels throughout the intervention. Relative to baseline serum, parathyroid hormone decreased 24% (P=0.003) in the vitamin D-group in phase 2, but remained unchanged in the placebo group. No significant changes were observed in blood pressure, fasting blood glucose, HbA1c, C-peptide, creatinine, phosphorous, alkaline phosphatase, lipids, C-reactive protein or thyroid stimulating hormone concentrations compared with baseline in either group. Conclusions: Six months of vitamin D3 supplementation to vitamin D-deficient obese type 2 diabetes patients in the UAE normalized the vitamin D status and reduced the incidence of eucalcemic parathyroid hormone elevation but showed no effect on the metabolic control. PMID:25406966

  17. 1,25-Vitamin D3 Deficiency Induces Albuminuria.

    PubMed

    Sonneveld, Ramon; Hoenderop, Joost G J; Stavenuiter, Andrea W D; Ferrantelli, Evelina; Baltissen, Marijke P A; Dijkman, Henry B; Florquin, Sandrine; Rops, Angelique L; Wetzels, Jack F M; Berden, Jo H M; van der Vlag, Johan; Nijenhuis, Tom

    2016-04-01

    Vitamin D plays an important role in renal (patho)physiology. Patients with glomerular diseases have an injured renal filtration barrier, leading to proteinuria and reduced renal function. An impaired renal function also leads to 1,25-vitamin D3 deficiency as a result of reduced renal 1α-hydroxylase activity. Vitamin D treatment to reduce proteinuria remains controversial, although there is an inverse correlation between vitamin D levels and proteinuria. Herein, we showed that 1,25-vitamin D3-deficient 25-hydroxy-vitamin-D3-1α-hydroxylase knockout mice and 1,25-vitamin D3-deficient rats develop podocyte injury and renal dysfunction. Glomerular injury was characterized by proteinuria and partial podocyte foot process effacement. Expression of nephrin, podocin, desmin, and transient receptor potential channel C6 in the podocyte was significantly altered in 1,25-vitamin D3-deficient animals. Supplementation with 1,25-vitamin D3 or 1,25-vitamin D2 prevented podocyte effacement or reversed glomerular and tubulointerstitial damage in 1,25-vitamin D3-deficient animals, thereby preserving and restoring renal function, respectively. The effect of 1,25-vitamin D3 deficiency and 1,25-vitamin D3 and 1,25-vitamin D2 repletion on proteinuria could not be explained by hypocalcemia, changes in parathyroid hormone, or fibroblast growth factor 23. This study demonstrates that 1,25-vitamin D3 deficiency directly leads to renal injury in rodents. Translated to human subjects, this would underline the need for early vitamin D supplementation in patients with glomerular disease and chronic renal insufficiency, which might inhibit or potentially reverse renal injury. PMID:26851346

  18. Copper status and enzyme, hormone, vitamin and immune function in heifers.

    PubMed

    Sharma, M C; Joshi, Chinmay; Pathak, N N; Kaur, Harzit

    2005-10-01

    A survey was conducted in 10 districts of Northern India to record the copper deficiency in soil, fodder and serum samples. Significant deficiency of copper was observed in soil, fodder and serum samples of heifers. The copper deficient animals were listless, showed depigmentation of skin, stiff gait and were anaemic and diahorric. The purpose of the study was to evaluate the magnitude of copper deficiency in Northern India and to examine the various haematobiochemicals, enzymes, vitamin and immune function which are affected by the deficiency of copper, so as to identify the parameters which can be of diagnostic importance in copper deficiency. Forty hypocuperemic heifers were selected from these areas and were randomly divided into two groups A and B. The heifers in group A were provided with mineral mixture containing copper sulphate and in group B without copper sulphate. Significant improvement (P<0.01) was observed in the haemoglobin (Hb), total leukocyte count (TLC) and total erythrocyte count (TEC) level at the 30th day of treatment in the animals of group A. Significant (P<0.01) improvement in serum. Ceruloplasmin (Cp) level was observed within 30 days of treatment, while significant (P<0.01) improvement in monoamine oxidase and liver cytochrome oxidase was observed at the 60th day of treatment in group A animals. Regarding hormones significant improvement was observed in T(3) and T(4), in the animals of group A within 60 days of treatment. The values of vitamin A and E showed significant (P<0.01) improvement within 30th days of treatment. The phagocytic activity of neutrophils against Candida albicans significantly (P<0.01) improved in group A within 60 days of treatment. Similarly significant improvement in superoxide dismutase activity in RBC was observed at the 30th day, and WBC and whole blood at 60th day in group A animals. Significant improvement in liver Cu level was observed at the 30th day of treatment, while in group B the liver Cu was significantly (P<0.01) depleted at the 60th day of experimentation. Additional Cu supplementation improved growth performance significantly in group A. PMID:15924928

  19. [New techniques in parathyroid surgery].

    PubMed

    Calò, P G; Tatti, A; Madas, F; Piga, G; Farris, S; Pisano, G; Nicolosi, A

    2010-01-01

    The diseases of parathyroid glands have assumed a growing importance for innovations in diagnosis and surgery which have enabled a more precise identification and therapy. Use of Sesta-MIBI scintigraphy allows a correct localization of the adenoma; the introduction of intraoperative monitoring of intact parathyroid hormone made possible unilateral neck exploration with a mini-incision above the adenoma. The emergence of videotechnology has led the innovation of endoscopic parathyroidectomy, realized for the first time in 1996 and subsequently performed without the use of CO2. Currently, the SPECT scintigraphy allows a three-dimensional vision of the adenoma and is the more precise localization study, allowing to use mini-invasive access. Prerequisite for the use of minimally invasive techniques is the determination of intraoperative PTH, possible with various techniques. Our experience is based on 135 patients undergoing parathyroidectomy in the last 8 years with 5 cases of persistent hyperparathyroidism submitted to reoperation, an average hospital stay of 2 days and only 6 complications (1 bleeding and 5 temporary hypoparathyroidisms). The use of new technologies in parathyroid surgery can achieve optimal results, a better cosmetic result and quicker postoperative recovery, with a low incidence of recurrence and complications. PMID:20646383

  20. Biological Activity of 1α-Hydroxycholecalciferol, A Synthetic Analog of the Hormonal Form of Vitamin D3

    PubMed Central

    Haussler, Mark R.; Zerwekh, Joseph E.; Hesse, Robert H.; Rizzardo, E.; Pechet, Maurice M.

    1973-01-01

    1,25-Dihydroxycholecalciferol, the apparent active hormonal form of cholecalciferol (vitamin D2), is formed from cholecalciferol by specific and sequential hydroxylations of the sterol at carbons 25 and 1. Recently, 1α-hydroxycholecalciferol was synthesized and we report on its biological activity in rachitic chicks. 1α-Hydroxycholecalciferol is identical in potency to 1,25-dihydroxycholecalciferol in stimulation of intestinal calcium absorption; either sterol elicits a near maximal effect at a dose of 0.3-0.6 nmol. The time-course of action of 1α-hydroxycholecalciferol also parallels that of the active metabolite 1,25-dihydroxycholecalciferol with a maximal increase in calcium transport occurring 5-10 hr after administration of sterol to vitamin D-deficient chicks. 6.5 nmol of 1α-hydroxycholecalciferol causes a doubling in calcium absorption in only 2-3 hr, which is the most rapid physiologic response yet detected for a vitamin D-sterol. 1α-Hydroxycholecalciferol is active also in enhancing bone calcium resorption and, like 1,25-dihydroxycholecalciferol, is at least 10 times as active as cholecalciferol in mobilizing bone calcium and raising plasma calcium concentration. It is concluded that 1α-hydroxycholecalciferol represents a synthetic analog of 1,25-dihydroxycholecalciferol that can be used both to study the mechanism of action of this hormone and as a therapeutic agent in the treatment of patients with certain metabolic bone diseases. PMID:4365368

  1. Intrapericardial parathyroid adenoma†

    PubMed Central

    Long, Kristin L.; Lee, Cortney Y.; Ramaiah, Chand; Sloan, David A.

    2013-01-01

    Primary hyperparathyroidism from a parathyroid adenoma is common. Ectopic parathyroid glands have been reported in numerous locations, including the chest. We present a single case report of an intrapericardial parathyroid gland found after failed bilateral neck exploration. The patient presented with severe, recurrent nephrolithiasis and acute renal failure prior to his surgical intervention. Repeat imaging identified a parathyroid adenoma in the mediastinum that was localized to the aortopulmonary window. After attempts at minimally invasive thoracotomy and posterolateral thoracotomy, a median sternotomy was ultimately required to identify the adenoma. PMID:24964470

  2. Vitamins

    MedlinePlus

    ... Wheat germ and wheat germ oil Vitamin K: Cabbage Cauliflower Cereals Dark green vegetables (broccoli, Brussels sprouts, ... Avocado Broccoli, kale, and other vegetables in the cabbage family Eggs Legumes and lentils Milk Mushroom Organ ...

  3. Vitamin D, thyroid hormones and muscle mass influence natural killer (NK) innate immunity in healthy nonagenarians and centenarians

    PubMed Central

    MARIANI, E; RAVAGLIA, G; FORTI, P; MENEGHETTI, A; TAROZZI, A; MAIOLI, F; BOSCHI, F; PRATELLI, L; PIZZOFERRATO, A; PIRAS, F; FACCHINI, A

    1999-01-01

    Increasing evidence has demonstrated that the immune system closely interacts with other physiological systems, whose communications are mediated by circulating cytokines and hormones. The aim of our study was to test whether the number and cytolytic activity of NK cells in a group of relatively healthy Italian nonagenarians and centenarians were affected by the modifications of endocrine, metabolic and functional parameters that occur during ageing. Because of the extreme age of the study population, a cross-sectional analysis was performed. This study revealed that the group of oldest subjects with the highest number of NK cells and the best preserved cytolytic function also presented a preserved metabolism of thyroid hormones and vitamin D and integrity of muscle mass. In fact, the NK cell number and/or cytolytic activity of healthy subjects > 90 years old was positively associated with serum levels of vitamin D, while T3, FT4, i-PTH hormones and lean body mass were associated only with NK cell number. In conclusion, our results stress the paramount importance of nutritional evaluation in the clinical assessment of elderly people. PMID:10209500

  4. 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. PMID:26329966

  5. The effects of cinacalcet treatment on bone mineral metabolism, anemia parameters, left ventricular mass index and parathyroid gland volume in hemodialysis patients with severe secondary hyperparathyroidism.

    PubMed

    Torun, Dilek; Yildiz, Ismail; Micozkadioglu, Hasan; Nursal, Gul Nihal; Yigit, Fatma; Ozelsancak, Ruya

    2016-01-01

    The aim of this study was to investigate the effects of cinacalcet therapy on anemia parameters, bone mineral metabolism, left ventricular mass index (LVMI) and parathyroid gland volume in hemodialysis (HD) patients with secondary hyperparathyroidism. Twenty-five HD patients (M/F: 11/14, mean age: 45.2±17.9 years, mean HD duration: 96.4±32.7 months) were included in this prospective pilot study. The indication to start calcimimetic therapy was persistent serum levels of parathyroid hormone (PTH)>1000 pg/mL, refractory to intravenous (i.v.) vitamin D and phosphate-binding therapy. The initial and one-year results of adjusted serum calcium (Ca+2), phosphate (P), Ca×P product, PTH, hemoglobin (Hb) and ferritin levels, transferrin saturation index (TSAT), median weekly erythropoietin (EPO) dose, LVMI, and parathyroid volume by parathyroid ultrasonography were determined. There were no differences between pre- and post-treatment levels of serum Ca+2 (P=0.853), P (P=0.447), Ca×P product (P=0.587), PTH (P=0.273), ferritin (P=0.153) and TSAT (P=0.104). After 1 year of calcimimetic therapy, the Hb levels were significantly higher than the initial levels (P=0.048). The weekly dose of EPO decreased with no statistical significance. The dose of cinacalcet was increased from 32.4±12.0 to 60.0±24.4 mg/day (P=0.01). There were no differences between the pre- and post-treatment results regarding weekly vitamin D dose, parenteral iron dose, LVMI and parathyroid volume. The results of our study suggest that cinacalcet therapy might have an additional benefit in the control anemia in HD patients. PMID:26787561

  6. Radionuclide imaging of parathyroid tumors: historical perspectives and newer techniques

    SciTech Connect

    Winzelberg, G.G.; Hydovitz, J.D.

    1985-04-01

    The increasing use of automated blood chemistry screens for serum calcium levels along with improved methods in measuring parathyroid hormone (PTH) levels have made the diagnosis of parathyroid disease a common clinical problem. Parathyroid adenomas account for the majority of primary hyperparathyroidism with diffuse hyperplasia and parathyroid carcinoma occurring less frequently. Early scintigraphic techniques to identify enlarged parathyroids used selenomethionine-75 which was considered to be incorporated into PTH. In general, the sensitivity of scanning the neck using this tracer was related to the size of the enlarged parathyroid, but in large series, the overall sensitivity was less than 50%. Recent work by Ferlin et al, using a Technetium-99m/Thallium-201 subtraction scintigraphic technique has yielded a sensitivity of 92% in identifying pathologically enlarged parathyroid glands. Winzelberg et al modified this technique to allow imaging the mediastinum plus simplifying the subtraction method. In a prospective study with high-resolution sonography, similar sensitivities and specificities were found with sonography and scintigraphy. Tl-201/Tc-99m pertechnetate subtraction scintigraphy appears to be an accurate technique in identifying pathologic parathyroid enlargement. Its ultimate role in the evaluation of patients with suspected hyperparathyroidism still needs to be determined. 37 references.

  7. Phosphate metabolism and vitamin D.

    PubMed

    Fukumoto, Seiji

    2014-01-01

    Phosphate plays many essential roles in our body. To accomplish these functions, serum phosphate needs to be maintained in a certain range. Serum phosphate level is regulated by intestinal phosphate absorption, renal phosphate handling and equilibrium of extracellular phosphate with that in bone or intracellular fluid. Several hormones such as parathyroid hormone, 1,25-dihydroxyvitamin D (1,25(OH)2D) and fibroblast growth factor 23 (FGF23) regulate serum phosphate by modulating intestinal phosphate absorption, renal phosphate reabsorption and/or bone metabolism. In addition, dietary phosphate rapidly enhances renal phosphate excretion, although detailed mechanisms of this adaptation remain to be clarified. Physiologically, extracellular concentrations of phosphate and these hormones are maintained by several negative feedback loops. For example, 1,25(OH)2D enhances FGF23 production and FGF23 reduces 1,25(OH)2D level. In addition, phosphate affects 1,25(OH)2D and FGF23 levels. Dysfunction of these negative feedback loops results in several diseases with abnormal phosphate and 1,25(OH)2D levels. Especially, excess actions of FGF23 cause several hypophosphatemic rickets/osteomalacia with relatively low level of 1,25(OH)2D that had been classified as vitamin D-resistant rickets/osteomalacia. In contrast, deficient actions of FGF23 cause hyperphosphatemic familial tumoral calcinosis. However, there still remain several unanswered questions regarding phosphate and vitamin D metabolism. PMID:24605214

  8. Phosphate metabolism and vitamin D

    PubMed Central

    Fukumoto, Seiji

    2014-01-01

    Phosphate plays many essential roles in our body. To accomplish these functions, serum phosphate needs to be maintained in a certain range. Serum phosphate level is regulated by intestinal phosphate absorption, renal phosphate handling and equilibrium of extracellular phosphate with that in bone or intracellular fluid. Several hormones such as parathyroid hormone, 1,25-dihydroxyvitamin D (1,25(OH)2D) and fibroblast growth factor 23 (FGF23) regulate serum phosphate by modulating intestinal phosphate absorption, renal phosphate reabsorption and/or bone metabolism. In addition, dietary phosphate rapidly enhances renal phosphate excretion, although detailed mechanisms of this adaptation remain to be clarified. Physiologically, extracellular concentrations of phosphate and these hormones are maintained by several negative feedback loops. For example, 1,25(OH)2D enhances FGF23 production and FGF23 reduces 1,25(OH)2D level. In addition, phosphate affects 1,25(OH)2D and FGF23 levels. Dysfunction of these negative feedback loops results in several diseases with abnormal phosphate and 1,25(OH)2D levels. Especially, excess actions of FGF23 cause several hypophosphatemic rickets/osteomalacia with relatively low level of 1,25(OH)2D that had been classified as vitamin D-resistant rickets/osteomalacia. In contrast, deficient actions of FGF23 cause hyperphosphatemic familial tumoral calcinosis. However, there still remain several unanswered questions regarding phosphate and vitamin D metabolism. PMID:24605214

  9. Dietary contaminant exposure affects plasma testosterone, but not thyroid hormones, vitamin A, and vitamin E, in male juvenile arctic foxes (Vulpes lagopus).

    PubMed

    Hallanger, Ingeborg G; Jørgensen, Even H; Fuglei, Eva; Ahlstrøm, Øystein; Muir, Derek C G; Jenssen, Bjørn Munro

    2012-01-01

    Levels of persistent organic pollutants (POP), such as polychlorinated biphenyls (PCB), are high in many Arctic top predators, including the Arctic fox (Vulpes lagopus). The aim of this study was to examine possible endocrine-disruptive effects of dietary POP exposure in male juvenile Arctic foxes in a controlled exposure experiment. The study was conducted using domesticated farmed blue foxes (Vulpes lagopus) as a model species. Two groups of newly weaned male foxes received a diet supplemented with either minke whale (Baleneoptera acutorostrata) blubber that was naturally contaminated with POP (exposed group, n = 5 or 21), or pork (Sus scrofa) fat (control group, n = 5 or 21). When the foxes were 6 mo old and had received the 2 diets for approximately 4 mo (147 d), effects of the dietary exposure to POP on plasma concentrations of testosterone (T), thyroid hormones (TH), thyroid-stimulating hormone (TSH), retinol (vitamin A), and tocopherol (viramin E) were examined. At sampling, the total body concentrations of 104 PCB congeners were 0.1 ± 0.03 μg/g lipid weight (l.w.; n = 5 [mean ± standard deviation]) and 1.5 ± 0.17 μg/g l.w. (n = 5) in the control and exposed groups, respectively. Plasma testosterone concentrations in the exposed male foxes were significantly lower than in the control males, being approximately 25% of that in the exposed foxes. There were no between-treatment differences for TH, TSH, retinol, or tocopherol. The results suggest that the high POP levels experienced by costal populations of Arctic foxes, such as in Svalbard and Iceland, may result in delayed masculine maturation during adolescence. Sex hormone disruption during puberty may thus have lifetime consequences on all aspects of reproductive function in adult male foxes. PMID:23030655

  10. 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, ...

  11. 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 ...

  12. Does Levothyroxine Administration Impact Parathyroid Localization?

    PubMed Central

    Ayers, Rachell R.; Tobin, Kirby; Sippel, Rebecca S.; Balentine, Courtney; Elfenbein, Dawn; Chen, Herbert; Schneider, David F.

    2016-01-01

    Background Proper localization is crucial in performing minimally invasive parathyroidectomy for primary hyperparathyroidism (PHPT). Ultrasonography (US) and Tc-99m sestamibi (MIBI) scintigraphy are common methods used for localization. As the appearance and activity of the thyroid gland may impact parathyroid localization, the purpose of this study was to determine how exogenous use of the thyroid hormone, levothyroxine (LT), affects parathyroid localization. Methods Adult patients with non-familial PHPT who underwent initial parathyroidectomy from 2000 to 2014 were retrospectively identified. Levothyroxine (+LT) and non-levothyroxine (-LT) patients were matched 1:3 based on age, gender, goiter status, and preoperative parathyroid hormone levels. Subgroup analysis was performed on patients previously treated with radioactive iodine and patients undergoing single adenoma resection. Results Of the 1,737 patients that met inclusion criteria, 286 were on LT at the time of their parathyroid localization scan. Use of LT not did impact the percentage of correct MIBI localization scans when compared to −LT patients (p=0.83). Interestingly, use of LT significantly hindered localization by US in comparison to the −LT group (48.4 vs 62.2%, p<0.01). When examining only patients where a single upper gland was removed, the +LT group was less likely to have a correct US compared to the −LT group (50 vs. 72.8%, p<0.01). However, there was no difference in US accuracy for patients who only had a single lower gland removed (p=0.51). Conclusions Exogenous levothyroxine is associated with impaired parathyroid localization with US but not MIBI. Surgeons should be aware of localization efficiency for this subset of patients in the era of personalized medicine and cost effectiveness. PMID:25917998

  13. Spectrum of single photon emission computed tomography/computed tomography findings in patients with parathyroid adenomas

    PubMed Central

    Chakraborty, Dhritiman; Mittal, Bhagwant Rai; Harisankar, Chidambaram Natrajan Balasubramanian; Bhattacharya, Anish; Bhadada, Sanjay

    2011-01-01

    Primary hyperparathyroidism results from excessive parathyroid hormone secretion. Approximately 85% of all cases of primary hyperparathyroidism are caused by a single parathyroid adenoma; 10–15% of the cases are caused by parathyroid hyperplasia. Parathyroid carcinoma accounts for approximately 3–4% of cases of primary disease. Technetium-99m-sestamibi (MIBI), the current scintigraphic procedure of choice for preoperative parathyroid localization, can be performed in various ways. The “single-isotope, double-phase technique” is based on the fact that MIBI washes out more rapidly from the thyroid than from abnormal parathyroid tissue. However, not all parathyroid lesions retain MIBI and not all thyroid tissue washes out quickly, and subtraction imaging is helpful. Single photon emission computed tomography (SPECT) provides information for localizing parathyroid lesions, differentiating thyroid from parathyroid lesions, and detecting and localizing ectopic parathyroid lesions. Addition of CT with SPECT improves the sensitivity. This pictorial assay demonstrates various SPECT/CT patterns observed in parathyroid scintigraphy. PMID:21969785

  14. Identification of a vitamin D-responsive protein on the surface of human osteosarcoma cells.

    PubMed Central

    Shull, S; Tracy, R P; Mann, K G

    1989-01-01

    Monoclonal antibodies were elicited to membrane constituents of the osteoblastic human osteosarcoma cell line Saos-2. Two types of antibody reactivities were characterized: one group of antibodies identified fibroblastic and osteoblastic cultured cells, whereas the other group was specific for the parent cell line, Saos-2. Primary endothelial cells and hepatoma cells were not recognized by either group of antibodies. Through indirect immunofluorescent microscopy, the Saos-2-specific antigen was demonstrated to reside on the surface of these osteosarcoma cells. Metabolic radiolabeling of cultured Saos-2 cells and subsequent immunoprecipitation, electrophoretic separation, and autoradiography revealed this protein to have a Mr of 80,000. Similar experiments in the presence of hormones showed that the expression of this cell surface protein was influenced in an opposing fashion by the bone-regulating hormones parathyroid hormone and vitamin D. Vitamin D stimulated expression by 300%, whereas parathyroid hormone depressed expression by 50%. Thus, Saos-2 human osteoblastic cells demonstrate hormonal regulation through an apparently specific membrane protein. Images PMID:2664784

  15. Clinical Significance of Female-hormones and Cytokines in Breast Cancer Patients Complicated with Aromatase Inhibitor-related Osteoarthropathy - Efficacy of Vitamin E

    PubMed Central

    Kiyomi, Anna; Makita, Masujiro; Iwase, Takuji; Tanaka, Sachiko; Onda, Kenji; Sugiyama, Kentaro; Takeuchi, Hironori; Hirano, Toshihiko

    2015-01-01

    Introduction: Aromatase inhibitor use for postmenopausal hormone-sensitive breast cancer patients often results in drug-induced osteoarthropathy, while its accurate mechanism has not been clarified. We investigated the implication of female hormones and several cytokines in osteoarthropathy complicated with aromatase inhibitor treatment, and the efficacy of vitamin E on the severity of osteoarthropathy, in breast cancer patients. Methods: Sixty two breast cancer patients treated with aromatase inhibitor for average of 1.77 years were included. These patients were orally administered vitamin E (150mg/day) for 29.8 days to alleviate aromatase inhibitor-related osteoarthropathy. Severity of osteoarthropathy was scored, and the patients were grouped based on the severity or vitamin E efficacy. Serum estradiol, progesterone, vitamin E, interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), IL-2, IL-4, IL-6, IL-10, and IL-17A concentrations were measured by ELISA or beads array procedures followed by flow cytometry. Results: There was no significant difference in serum concentrations of the biomarkers between the severe and the mild osteoarthropathy groups before vitamin E administration. The osteoarthropathy scores significantly decreased after vitamin E administration (p=0.0243), while serum-estradiol concentrations did not change. The serum-estradiol concentrations before vitamin E administration in the group sensitive to the vitamin E efficacy were significantly lower, as compared with those in the insensitive group (p=0.0005). The rate of the highly sensitive patients to the vitamin E efficacy in those exhibiting low serum-estradiol concentrations was significantly higher than that in the high serum-estradiol group (p=0.0004). In the sensitive group, serum-estradiol concentrations after taking vitamin E were significantly higher than those before taking vitamin E (p=0.0124). Conclusions: Vitamin E administration seemed to be a potential way for relieving osteoarthropathy complicated with aromatase inhibitor use. Using serum-estradiol concentration, it would be possible to select out the breast cancer patients who will respond well to the vitamin E therapy for osteoarthropathy complicated with aromatase inhibitor. PMID:25767607

  16. Beyond mineral metabolism, is there an interplay between FGF23 and vitamin D in innate immunity?

    PubMed Central

    Bacchetta, Justine; Salusky, Isidro B; Hewison, Martin

    2014-01-01

    Fibroblast Growth Factor 23 (FGF23) is an ‘endocrine’ FGF acting in the kidney as a phosphaturic hormone and a suppressor of active vitamin D, through an inhibition of the 1α hydroxylase and a stimulation of the 24 hydroxylase. Beyond its well-known effects on the bone/kidney/parathyroid axis and its deregulation during chronic kidney disease (CKD), recent evidence has revealed its direct systemic effects on cardiovascular health. In the meantime, studies have highlighted health implications for vitamin D inside and outside CKD that also extend beyond its classical actions on mineral homeostasis and bone metabolism: vitamin D has indeed been shown to exert pluripotent non-classical effects as a modulator of immune function in monocytes, mainly through the stimulation of the antimicrobial cathelicidin. The aim of this review is to provide new insights on the interplay between FGF23 and vitamin D in innate immunity in the context of CKD. PMID:23117582

  17. Combination Treatment with Progesterone and Vitamin D Hormone May Be More Effective than Monotherapy for Nervous System Injury and Disease

    PubMed Central

    Cekic, Milos; Sayeed, Iqbal; Stein, Donald G.

    2010-01-01

    More than two decades of pre-clinical research and two recent clinical trials have shown that progesterone (PROG) and its metabolites exert beneficial effects after traumatic brain injury (TBI) through a number of metabolic and physiological pathways that can reduce damage in many different tissues and organ systems. Emerging data on 1,25-dihydroxyvitamin D3 (VDH), itself a steroid hormone, have begun to provide evidence that, like PROG, it too is neuroprotective, although some of its actions may involve different pathways. Both agents have high safety profiles, act on many different injury and pathological mechanisms, and are clinically relevant, easy to administer, and inexpensive. Furthermore, vitamin D deficiency is prevalent in a large segment of the population, especially the elderly and institutionalized, and can significantly affect recovery after CNS injury. The combination of PROG and VDH in pre-clinical and clinical studies is a novel and compelling approach to TBI treatment. PMID:19394357

  18. Vitamin D Deficiency and Exogenous Vitamin D Excess Similarly Increase Diffuse Atherosclerotic Calcification in Apolipoprotein E Knockout Mice

    PubMed Central

    Ellam, Timothy; Hameed, Abdul; ul Haque, Risat; Muthana, Munitta; Wilkie, Martin; Francis, Sheila E.; Chico, Timothy J. A.

    2014-01-01

    Background Observational data associate lower levels of serum vitamin D with coronary artery calcification, cardiovascular events and mortality. However, there is little interventional evidence demonstrating that moderate vitamin D deficiency plays a causative role in cardiovascular disease. This study examined the cardiovascular effects of dietary vitamin D deficiency and of vitamin D receptor agonist (paricalcitol) administration in apolipoprotein E knockout mice. Methods Mice were fed atherogenic diets with normal vitamin D content (1.5IU/kg) or without vitamin D. Paricalcitol, or matched vehicle, was administered 3× weekly by intraperitoneal injection. Following 20 weeks of these interventions cardiovascular phenotype was characterized by histological assessment of aortic sinus atheroma, soluble markers, blood pressure and echocardiography. To place the cardiovascular assessments in the context of intervention effects on bone, structural changes at the tibia were assessed by microtomography. Results Vitamin D deficient diet induced significant reductions in plasma vitamin D (p<0.001), trabecular bone volume (p<0.01) and bone mineral density (p<0.005). These changes were accompanied by an increase in calcification density (number of calcifications per mm2) of von Kossa-stained aortic sinus atheroma (461 versus 200, p<0.01). Paricalcitol administration suppressed parathyroid hormone (p<0.001), elevated plasma calcium phosphate product (p<0.005) and induced an increase in calcification density (472 versus 200, p<0.005) similar to that seen with vitamin D deficiency. Atheroma burden, blood pressure, metabolic profile and measures of left ventricular hypertrophy were unaffected by the interventions. Conclusion Vitamin D deficiency, as well as excess, increases atherosclerotic calcification. This phenotype is induced before other measures of cardiovascular pathology associated clinically with vitamin D deficiency. Thus, maintenance of an optimal range of vitamin D signalling may be important for prevention of atherosclerotic calcification. PMID:24586387

  19. An emerging view of vitamin D.

    PubMed

    Dabek, J

    1990-01-01

    Vitamin D3 (D2 is 22-ene,24-methyl D3) is a prehormone which is hydroxylated by mixed function mono-oxygenase NADPH-cytochrome P-450 ferredoxin/ferredoxin reductase systems in liver parenchyma and renal proximal tubular cells to 25-hydroxy, then 1,25-dihydroxyvitamin D, the active hormone. 1,25-dihydroxyvitamin D binds to a mainly intranuclear receptor in target cells [classically, bone, kidney and gut; now shown to be wider including parathyroid cells, endocrine cells generally and many cells of ectodermal (brain, skin) and mesodermal (blood forming cells, lymphnode cells) origin as well as tumour cells (breast, lymphoma, leukaemia)] and activates transcription for products such as calcium binding proteins, its own receptor protein, 24-hydroxylase and non-specific esterase which are active in calcium homeostasis and cell differentiation. Advanced methods for measuring components of the vitamin D endocrine system have been developed and involve column extractions, liquid chromatographic purifications (also HPLC) and protein and receptor binding assays as well as mass spectrometry. These have facilitated elucidation of vitamin D physiology (also in pregnancy and lactation) and of metabolic defects in classical, vitamin D resistant and renal rickets and osteomalacia, in sarcoidosis and in the possible involvement of the vitamin in cell differentiation, e.g. in myeloid leukaemia, and breast cancer. PMID:2244181

  20. 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 alternative to daily injection as a route for administration of the hormone.

  1. In vivo distribution of parathyroid hormone receptors in bone: evidence that a predominant osseous target cell is not the mature osteoblast

    SciTech Connect

    Rouleau, M.F.; Mitchell, J.; Goltzman, D.

    1988-07-01

    Previous studies in vitro and in vivo have demonstrated the presence of receptor sites for PTH on cells of the osteoblast phenotype. Nevertheless, it is unclear whether the diverse functions of this hormone in bone can all be attributed to its interaction with a single cell type. In this study, we have used a radioautographic method to examine the competitive binding of /sup 125/I-labeled rat PTH-(1-34) to the long bones of rats in vivo. Our studies confirm the presence of competitive binding to mature osteoblasts and the absence of significant competitive binding to multinucleated osteoclasts. However, by light and electron microscopic radioautographic analysis, the majority of specific competitive PTH binding was present over a cell in the intertrabecular space of the metaphyseal region, which was distinct from the mature osteoblast. This large mononuclear cell with multiple cytoplasmic extensions appeared to interface with both the bone matrix and the microvascular osseous circulation and may provide an additional target to mediate hormonal effects on the skeleton.

  2. Effects of different dress styles on vitamin D levels in healthy young Jordanian women.

    PubMed

    Mishal, A A

    2001-01-01

    Jordan is a sunny Middle Eastern country where no vitamin D fortification of milk is undertaken, and where women wear dress styles that cover the body to a variable extent. This may produce variable effects on vitamin D, parathyroid hormone and bone mineralization. The aim of the present study was to evaluate the vitamin D and parathyroid hormone levels in healthy young women of child-bearing age, and to examine the effects of dress style and season, in a survey of the effects of these parameters on vitamin D metabolism, and the possible bone mineralization consequences. One hundred and forty-six subjects (22 men, 124 women) were selected, according to established inclusion criteria. Of the women, 21 wore Western-type dress styles (group 1), 80 wore dress styles covering the whole body but the sparing face and hands (group 2) and 23 wore dress styles covering the whole body including the face and hands (group 3). The study was conducted in summer and winter. All volunteers underwent initial interviews, answered a food frequency questionnaire, and underwent essential laboratory tests (serum 25-hydroxyvitamin D (25(OH)D) by radioimmunoassay, and serum parathyroid hormone (PTH) by chemiluminescent enzyme immunoassay). The 25(OH) D levels in groups 2 and 3 were significantly lower than in the men (p<0.05 in both comparisons). No significant differences were noted between women wearing different dress styles. PTH levels were in the upper limits of normal but failed to show statistical differences between study groups. The prevalence of hypovitaminosis D was 62.3% in the study groups as a whole. Dress styles covering the whole body, totally or nearly totally, have adverse effects on 25(OH)D levels and may produce a state of secondary hyperparathyroidism on the long run. Although Jordan enjoys plenty of sunshine, these data are suggestive of widespread hypovitaminosis D in Jordan. PMID:11804019

  3. The Role of Vitamin D in Autoimmune Hepatitis

    PubMed Central

    Luong, Khanh vinh quoc; Nguyen, Lan Thi Hoang

    2013-01-01

    Autoimmune hepatitis is an inflammation of the liver characterized by the presence of peri-portal hepatitis, hypergammaglobulinemia, and the serum autoantibodies. The disease is classified into 2 distinct types according to the nature of auto-antibodies. Disturbances of the calcium-parathyroid hormone-vitamin D axis are frequently associated with chronic liver disease. Patients with AIH have a high prevalence of vitamin D deficiency. Genetic studies have provided the opportunity to determine which proteins link vitamin D to AIH pathology, namely, the major histocompatibility complex class II molecules, vitamin D receptors, toll-like receptors, cytotoxic T lymphocyte antigen-4, cytochrome P450 CYP2D6, regulatory T cells (Tregs) and the forkhead/winged helix transcription factor 3. Vitamin D also exerts its effect on AIH through non-genomic factors, namely, mitogen-activated protein kinase signaling pathways, ??T cells, interferon-gamma nitric oxide synthase, and reactive oxygen stress. In conclusion, vitamin D may have a beneficial role in AIH and improves liver function in concanavalin A-induced mouse AIH. Calcitriol is best used for AIH because it is the active form of a vitamin D3 metabolite and its receptors are present in sinusoidal endothelial cells, Kupffer cells, stellate cells of normal livers, and the biliary cell line. PMID:24171052

  4. Invited commentary: The association of low vitamin D with cardiovascular disease--getting at the "heart and soul" of the relationship.

    PubMed

    Schneider, Andrea L C; Michos, Erin D

    2014-06-01

    Low concentrations of 25-hydroxyvitamin D have been consistently associated with cardiovascular disease (CVD) in many observational studies. In an analysis published in this issue of the American Journal of Epidemiology, Welles et al. (Am J Epidemiol. 2014;179(11):1279-1287) used data from 946 participants with stable CVD who were enrolled in the Heart and Soul Study (San Francisco Bay Area, 2000-2012) and found that the association of low 25-hydroxyvitamin D with increased secondary CVD event risk was attenuated after adjustment for parathyroid hormone level, suggesting that parathyroid hormone may mediate this association. They used observational data to gain insight into potential mechanisms underlying the association between vitamin D and CVD risk. Their study focused on secondary CVD events, whereas many previous observational studies have focused on incident CVD events among persons without a history of CVD. In this commentary, we place the study by Welles et al. in context with the existing literature and propose future directions for vitamin D research. We highlight a number of methodological concepts that are important in analyzing vitamin D data, including racial differences in vitamin D concentrations and adjustment for seasonal variation in vitamin D concentrations. We agree that randomized controlled trials should be conducted before making guidelines for screening and treating vitamin D deficiency for the prevention of CVD events. PMID:24699787

  5. Parathyroid carcinoma in pregnancy

    PubMed Central

    Baretić, Maja; Tomić Brzac, Hrvojka; Dobrenić, Margareta; Jakovčević, Antonia

    2014-01-01

    A 24-year-old female patient with parathyroid carcinoma, the rarest endocrine malignancy, had two pregnancies. In the first pregnancy, she had severe nausea and fatigue. Hypercalcemia and hyperparathyroidism were diagnosed in the postpartum period. Hyperemesis gravidarum masked a diagnosis of hypercalcemia. Neck ultrasound and Tc-99m sestamibi found an enlarged lower right parathyroid gland. The gland was surgically removed, and an initial pathology report described atypical adenoma. Shortly afterward, she became pregnant again. During the second pregnancy, her calcium level was frequently controlled but was always in the normal range. Normocalcemia is explained by the specific physiology of pregnancy accompanied by hemodilution, hypoalbuminemia and maternal hypercalciuria (mediated by increased glomerular filtration). During lactation, calcium levels rose, and a new neck ultrasound showed a solitary mass in the area of prior surgery and an enlarged pretracheal lymph node. Fine needle aspiration of the solitary mass and node showed parathyroid carcinoma cells. The tumor mass was resected en bloc with the contiguous tissues and surrounding lymph nodes (pathology report; parathyroid carcinoma with metastases). Over the next five years, four consecutive surgeries were performed to remove malignant parathyroid tissue, lymph nodes and local metastases. Following the surgical procedures, no hypocalcemia was observed. More serious hypercalcemia recurred; the calcium level was difficult to control with a combination of pamidronate, cinacalcet and loop diuretic. No elements of multiple endocrine neoplasia were present. PMID:24868516

  6. Reduced bone density and major hormones regulating calcium metabolism in anorexia nervosa.

    PubMed

    Kiriike, N; Iketani, T; Nakanishi, S; Nagata, T; Inoue, K; Okuno, M; Ochi, H; Kawakita, Y

    1992-11-01

    Bone density of lumbar vertebrae (L2 to L4) and the whole body in 29 patients with anorexia nervosa were measured by dual photon absorptiometry, and the results were compared with those of 10 age-matched normal controls. The patients had significantly lower bone mineral density (BMD) in L3 and L2-4 than controls. However, there was no difference in whole-body BMD. L3 and L2-4 BMD was positively correlated with body weight and was negatively correlated with duration of illness and amenorrhea. Patients who had been more active 6 months before the time of the study had significantly higher L3 BMD than the less active patients. Most patients had an abnormally low serum estrogen level, whereas the mean serum levels of thyroid hormone (T3, T4), cortisol, calcitonin, parathyroid hormone and vitamin D were within the normal range. No correlation was found between L3 or L2-4 BMD and the levels of these hormones. These results suggest that severe weight loss, low physical activity, longer duration of amenorrhea and deficiency of estrogen contribute to bone loss in patients with anorexia nervosa, whereas calcium-regulating hormones such as parathyroid hormone, calcitonin and vitamin D are unlikely to be a primary contributor to bone loss. PMID:1485525

  7. FGF23 as a calciotropic hormone

    PubMed Central

    Rodríguez-Ortiz, María E.; Rodríguez, Mariano

    2015-01-01

    Maintaining mineral metabolism requires several organs and hormones. Fibroblast growth factor 23 (FGF23) is a phosphatonin produced by bone cells that reduces renal production of calcitriol – 1,25(OH) 2D 3 – and induces phosphaturia. The consequences of a reduction in 1,25(OH) 2D 3 involve changes in calcium homeostasis. There are several factors that regulate FGF23: phosphorus, vitamin D, and parathyroid hormone (PTH). More recently, several studies have demonstrated that calcium also modulates FGF23 production. In a situation of calcium deficiency, the presence of 1,25(OH) 2D 3 is necessary to optimize intestinal absorption of calcium, and FGF23 is decreased to avoid a reduction in 1,25(OH) 2D 3 levels.

  8. Molecular Mechanisms for Regulation of Intestinal Calcium Absorption by Vitamin D and Other Factors

    PubMed Central

    Fleet, James C.; Schoch, Ryan D.

    2011-01-01

    Optimal intestinal calcium (Ca) absorption is necessary for the protection of bone and the prevention of osteoporosis. Ca absorption can be represented as the sum of a saturable pathway and a non-saturable pathway that is primarily dependent upon luminal Ca concentration. While models have been proposed to describe these transport components, significant gaps still exist in our understanding of these processes. Habitual low intake of Ca up-regulates the saturable transport pathway, a process mediated by increased renal production of 1,25 dihydroxyvitamin D (1,25(OH)2 D). Consistent with this, low vitamin D status as well as deletion/mutation of the vitamin D receptor (VDR) or 25 hydroxyvitamin D-1α hydroxylase (CYP27B1) genes limit Ca absorption by reducing the saturable pathway. There is some evidence that non-saturable Ca absorption in the ileum is also regulated by vitamin D status, but the mechanism is unclear. Treatment with a number of hormones can regulate Ca absorption in vivo [e.g. parathyroid hormone (PTH), thyroid hormone, growth hormone (GH)/insulin-like growth factor I (IGF-1), estrogen, testosterone]. However, some of these actions are indirect (i.e. mediated through the regulation of vitamin D metabolism or signaling), whereas only a few (e.g. estrogen, IGF-1) have been shown to persist in the absence of vitamin D signaling. PMID:21182397

  9. Resection of a large ectopic parathyroid adenoma: A case report

    PubMed Central

    Sato, Seijiro; Kitahara, Akihiko; Koike, Terumoto; Hashimoto, Takehisa; Ohashi, Riuko; Motoi, Noriko; Tsuchida, Masanori

    2016-01-01

    Introduction Parathyroid adenomas are the most common cause of primary hyperparathyroidism. However, cases of parathyroid adenomas greater than 4 cm with osteitis fibrosa cystica are extremely rare. Herein, we report a case of resection of a large ectopic mediastinal parathyroid adenoma. Case presentations A 46-year-old female with chief complaints of bone pain and gait disturbance was referred to our hospital. Physical examination revealed many mobile teeth in her oral cavity, distortion of the vertebral body, and bowlegs. Laboratory tests showed hypercalcemia, hypophosphatemia, and elevated serum levels of intact parathyroid hormone. Chest CT revealed a 42-mm well–defined, enhancing mass in front of the left-sided tracheal bifurcation. Her findings were diagnosed as primary hyperparathyroidism due to an ectopic mediastinal parathyroid tumor. We performed a median sternotomy and resected the tumor. The tumor was a solid, yellowish-brown mass measuring 42 × 42 mm. Pathologically, the tumor consisted mainly of chief cells with some oxyphil cells; there were no necrotic areas or nuclear atypia, and few mitotic figures. We diagnosed the tumor as an ectopic mediastinal parathyroid adenoma. Eight months after the resection, her serum calcium, phosphorus, and intact PTH levels were normal. Discussion and conclusions Parathyroid adenomas and parathyroid carcinomas have disparate natural histories, but they can be difficult to differentiate on the basis of preoperative clinical characteristics. We believe that long-term follow-up of these cases is required because there have been few reports on the postoperative natural history of large parathyroid adenomas. PMID:27078868

  10. Combination therapy with ONO-KK1-300-01, a cathepsin K inhibitor, and parathyroid hormone results in additive beneficial effect on bone mineral density in ovariectomized rats.

    PubMed

    Ochi, Yasuo; Yamada, Hiroyuki; Mori, Hiroshi; Kawada, Naoki; Tanaka, Makoto; Imagawa, Akira; Ohmoto, Kazuyuki; Kawabata, Kazuhito

    2016-01-01

    This study examined the effects of a novel cathepsin K inhibitor, ONO-KK1-300-01 (KK1-300), used concurrently with parathyroid hormone (PTH) in ovariectomized (OVX) rats. KK1-300 (3 mg/kg, twice daily), alendronate (1 mg/kg, once daily) or vehicle were orally administered to OVX rats for 56 days, starting the day after ovariectomy, followed by combination treatment with or without PTH (3 μg/kg, subcutaneously three times a week) for another 28 days. OVX control animals exhibited a significant increase in both bone resorption (urinary deoxypyridinoline; DPD) and formation markers (serum osteocalcin) as well as microstructural changes associated with decreased bone mineral density (BMD). Combination treatment with KK1-300 and PTH significantly decreased urinary DPD and increased serum osteocalcin, indicating a sustained beneficial effect compared to the effect of each mono-therapy. On the other hand, combination therapy with alendronate and PTH weakened the PTH-induced increase in osteocalcin. In proximal tibia, combination treatment with KK1-300 and PTH increased BMD to a level significantly higher than that achieved following single treatment with KK1-300 or PTH alone. On the other hand, combination treatment with alendronate and PTH failed to produce any significant additive effect on BMD following single treatment with alendronate or PTH alone. Microstructural analysis revealed that the PTH-induced increase in bone formation (MS/BS and BFR/BS) was fully maintained following combination treatment with KK1-300 and PTH, but not following combination treatment with alendronate and PTH. These findings indicate that KK1-300, unlike alendronate, has an additive effect on the preventive action of PTH on bone loss in OVX rats. PMID:25762435

  11. 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

  12. Is there an association between elevated or low serum levels of phosphorus, parathyroid hormone, and calcium and mortality in patients with end stage renal disease? A meta-analysis

    PubMed Central

    2013-01-01

    Background Biochemical markers of altered mineral metabolism have been associated with increased mortality in end stage renal disease patients. Several studies have demonstrated non-linear (U-shaped or J-shaped) associations between these minerals and mortality, though many researchers have assumed linear relationships in their statistical modeling. This analysis synthesizes the non-linear relationships across studies. Methods We updated a prior systematic review through 2010. Studies included adults receiving dialysis and reported categorical data for calcium, phosphorus, and/or parathyroid hormone (PTH) together with all-cause mortality. We performed 2 separate meta-analyses to compare higher-than-referent levels vs referent and lower-than-referent levels vs referent levels. Results A literature review showed that when a linear relationship between the minerals and mortality was assumed, the estimated associations were more likely to be smaller or non-significant compared to non-linear models. In the meta-analyses, higher-than-referent levels of phosphorus (4 studies, RR = 1.20, 95% CI = 1.15-1.25), calcium (3 studies, RR = 1.10, 95% CI = 1.05-1.14), and PTH (5 studies, RR = 1.11, 95% CI = 1.07-1.16) were significantly associated with increased mortality. Although no significant associations between relatively low phosphorus or PTH and mortality were observed, a protective effect was observed for lower-than-referent calcium (RR = 0.86, 95% CI = 0.83-0.89). Conclusions Higher-than-referent levels of PTH, calcium, and phosphorus in dialysis patients were associated with increased mortality risk in a selection of observational studies suitable for meta-analysis of non-linear relationships. Findings were less consistent for lower-than-referent values. Future analyses should incorporate the non-linear relationships between the minerals and mortality to obtain accurate effect estimates. PMID:23594621

  13. The N-terminal region of the third intracellular loop of the parathyroid hormone (PTH)/PTH-related peptide receptor is critical for coupling to cAMP and inositol phosphate/Ca2+ signal transduction pathways.

    PubMed

    Huang, Z; Chen, Y; Pratt, S; Chen, T H; Bambino, T; Nissenson, R A; Shoback, D M

    1996-12-27

    Structural determinants within the parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptor that mediate G-protein activation of adenylate cyclase and phospholipase C are unknown. We investigated the role of the N-terminal region of the third intracellular loop of the opossum PTH/PTHrP receptor in coupling to two signal transduction pathways. We mutated residues in this region by tandem-alanine scanning and expressed these mutant receptors in COS-7 cells and/or Xenopus oocytes. All mutant receptors retained high affinity PTH binding in COS-7 cells, indistinguishable from wild-type receptors. Receptors with tandem-alanine substitutions in two N-terminal segments (377RVL379 and 381TKLR384) demonstrated impaired adenylate cyclase and phospholipase C activation. Receptor mutants with single-alanine substitutions scanning these two segments showed three different signaling defects in COS-7 cells. 1) Two mutant receptors (V378A and L379A) had reduced inositol phosphate (IP), but normal cAMP responses to PTH. 2) Mutant receptor T381A showed reduced cAMP, but wild-type IP responses to PTH. 3) Mutant receptor K382A demonstrated both markedly reduced cAMP and IP production due to PTH. In oocytes, mutants T381A and K382A showed decreased PTH-stimulated cAMP accumulation and intracellular Ca2+ mobilization. Thus, the N-terminal region of the third intracellular loop of this receptor plays a critical role in coupling to both Gs- and Gq-mediated second-messenger generation. PMID:8969199

  14. Regulation of Calcitriol Biosynthesis and Activity: Focus on Gestational Vitamin D Deficiency and Adverse Pregnancy Outcomes

    PubMed Central

    Olmos-Ortiz, Andrea; Avila, Euclides; Durand-Carbajal, Marta; Díaz, Lorenza

    2015-01-01

    Vitamin D has garnered a great deal of attention in recent years due to a global prevalence of vitamin D deficiency associated with an increased risk of a variety of human diseases. Specifically, hypovitaminosis D in pregnant women is highly common and has important implications for the mother and lifelong health of the child, since it has been linked to maternal and child infections, small-for-gestational age, preterm delivery, preeclampsia, gestational diabetes, as well as imprinting on the infant for life chronic diseases. Therefore, factors that regulate vitamin D metabolism are of main importance, especially during pregnancy. The hormonal form and most active metabolite of vitamin D is calcitriol. This hormone mediates its biological effects through a specific nuclear receptor, which is found in many tissues including the placenta. Calcitriol synthesis and degradation depend on the expression and activity of CYP27B1 and CYP24A1 cytochromes, respectively, for which regulation is tissue specific. Among the factors that modify these cytochromes expression and/or activity are calcitriol itself, parathyroid hormone, fibroblast growth factor 23, cytokines, calcium and phosphate. This review provides a current overview on the regulation of vitamin D metabolism, focusing on vitamin D deficiency during gestation and its impact on pregnancy outcomes. PMID:25584965

  15. Thyroid and parathyroid imaging

    SciTech Connect

    Sandler, M.P.; Patton, J.A.; Partain, C.L.

    1986-01-01

    This book describes the numerous modalities currently used in the diagnosis and treatment of both thyroid and parathyroid disorders. Each modality is fully explained and then evaluated in terms of benefits and limitations in the clinical context. Contents: Production and Quality Control of Radiopharmaceutics Used for Diagnosis and Therapy in Thyroid and Parathyroid Disorders. Basic Physics. Nuclear Instrumentation. Radioimmunoassay: Thyroid Function Tests. Quality Control. Embryology, Anatomy, Physiology, and Thyroid Function Studies. Scintigraphic Thyroid Imaging. Neonatal and Pediatric Thyroid Imaging. Radioiodine Thyroid Uptake Measurement. Radioiodine Treatment of Thyroid Disorders. Radiation Dosimetry of Diagnostic Procedures. Radiation Safety Procedures for High-Level I-131 Therapies. X-Ray Fluorescent Scanning. Thyroid Sonography. Computed Tomography in Thyroid Disease. Magnetic Resonance Imaging in Thyroid Disease. Parathyroid Imaging.

  16. Vitamin D3: a helpful immuno-modulator

    PubMed Central

    Di Rosa, Michelino; Malaguarnera, Michele; Nicoletti, Ferdinando; Malaguarnera, Lucia

    2011-01-01

    The active metabolite of vitamin D, 1α, 25-dihydroxyvitamin D3 [1,25(OH)2D3], is involved in calcium and phosphate metabolism and exerts a large number of biological effects. Vitamin D3 inhibits parathyroid hormone secretion, adaptive immunity and cell proliferation, and at the same time promotes insulin secretion, innate immunity and stimulates cellular differentiation. The role of vitamin D3 in immunoregulation has led to the concept of a dual function as both as an important secosteroid hormone for the regulation of body calcium homeostasis and as an essential organic compound that has been shown to have a crucial effect on the immune responses. Altered levels of vitamin D3 have been associated, by recent observational studies, with a higher susceptibility of immune-mediated disorders and inflammatory diseases. This review reports the new developments with specific reference to the metabolic and signalling mechanisms associated with the complex immune-regulatory effects of vitamin D3 on immune cells. PMID:21896008

  17. Oral active vitamin D is associated with improved survival in hemodialysis patients.

    PubMed

    Naves-Díaz, Manuel; Alvarez-Hernández, Daniel; Passlick-Deetjen, Jutta; Guinsburg, Adrian; Marelli, Cristina; Rodriguez-Puyol, Diego; Cannata-Andía, Jorge B

    2008-10-01

    Injection of active vitamin D is associated with better survival of patients receiving chronic hemodialysis. Since in many countries oral active vitamin D administration is the most common form of treatment for secondary hyperparathyroidism we determined the survival benefit of oral active vitamin D in hemodialysis patients from six Latin America countries (FME Register as part of the CORES study) followed for a median of 16 months. Time-dependent Cox regression models, after adjustment for potential confounders, showed that the 7,203 patients who received oral active vitamin D had significant reductions in overall, cardiovascular, infectious and neoplastic mortality compared to the 8,801 patients that had not received vitamin D. Stratified analyses found a survival advantage in the group that had received oral active vitamin D in 36 of the 37 strata studied including that with the highest levels of serum calcium, phosphorus and parathyroid hormone. The survival benefit of oral active vitamin D was seen in those patients receiving mean daily doses of less than 1 microg with the highest reduction associated with the lowest dose. Our study shows that hemodialysis patients receiving oral active vitamin D had a survival advantage inversely related to the vitamin dose. PMID:18633342

  18. Prevalence and Prognostic Implications of Vitamin D Deficiency in Chronic Kidney Disease

    PubMed Central

    Obi, Yoshitsugu; Hamano, Takayuki; Isaka, Yoshitaka

    2015-01-01

    Vitamin D is an important nutrient involved in bone mineral metabolism, and vitamin D status is reflected by serum total 25-hydroxyvitamin D (25[OH]D) concentrations. Vitamin D deficiency is highly prevalent in patients with chronic kidney disease (CKD), and nutritional vitamin D supplementation decreases elevated parathyroid hormone concentrations in subgroups of these patients. Furthermore, vitamin D is supposed to have pleiotropic effects on various diseases such as cardiovascular diseases, malignancies, infectious diseases, diabetes, and autoimmune diseases. Indeed, there is cumulative evidence showing the associations of low vitamin D with the development and progression of CKD, cardiovascular complication, and high mortality. Recently, genetic polymorphisms in vitamin D-binding protein have received great attention because they largely affect bioavailable 25(OH)D concentrations. This finding suggests that the serum total 25(OH)D concentrations would not be comparable among different gene polymorphisms and thus may be inappropriate as an index of vitamin D status. This finding may refute the conventional definition of vitamin D status based solely on serum total 25(OH)D concentrations. PMID:25883412

  19. Radiographic findings in recurrent parathyroid carcinoma

    SciTech Connect

    Krudy, A.G.; Doppman, J.L.; Marx, S.J.; Brennan, M.F.; Spiegel, A.; Aurback, G.D.

    1982-03-01

    Seven cases of recurrent parathyroid carcinoma were reviewed. Subperiosteal resorption was seen in 6, pulmonary nodules in 4, renal calculi in 5, brown tumors in 5, and pancreatic calcifications in 1. Angiography was performed in 5 patients, showing 1 definite and 2 probable cervical recurrences, 1 mediastinal lesion, and 1 case of possible bone metastases. Venous sampling for parathyroid hormone was carried out in 4 patients and suggested residual disease in 2; in addition, there were 1 false and 1 true negative. CT was performed in 4 patients and was useful in delineating metastatic pulmonary nodules, cervical recurrence, and hepatic metastases. The radiographic approach to recurrent parathryoid carcinoma and the use of CT and angiography are discussed.

  20. Vitamin D and genomic stability.

    PubMed

    Chatterjee, M

    2001-04-18

    1alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] has been shown to act on novel target tissues not related to calcium homeostasis. There have been reports characterizing 1,25(OH)(2)D(3) receptors and activities in diverse tissues such as brain, pancreas, pituitary, skin, muscle, placenta, immune cells and parathyroid. The receptor hormone complex becomes localized in the nucleus, and undergoes phosphorylation by reacting with a kinase. This form of the receptor then interacts with the Vitamin D responsive element of target gene and modifies the transcription of those genes to develop the action. The modulation of gene transcription results in either the induction or repression of specific messenger RNAs (m-RNAs), ultimately resulting in changes in protein expression needed to produce biological responses. Genes for carbonic anhydrase that are expressed at high levels in osteoclast are known to be involved in bone resorption and Id genes role in osteoblast-osteoclast differentiation reflects the genomic effect of Vitamin D on bones. Genomic action of Vitamin D also explains the biosynthesis of oncogenes, polyamines, lymphokines and calcium binding proteins. However, there is a possibility that some of the actions of 1,25(OH)(2)D(3) may be mediated by non-genomic mechanisms and may not require the binding to Vitamin D receptor (VDR). Vitamin D offers a protection from genotoxic effects of Vitamin D deficiency by increasing the insulin receptor gene expression and BSP (bone sialoprotein), bone-remodeling by decreasing the osteopontin (OPN) m-RNAs, maintaining the normal epidermal structure and enamel matrix. Gonadal insufficiency in Vitamin D deficiency was corrected by vitamin mediated direct regulation of the expression of aramotase gene. The supportive role of Vitamin D in placental function is also evident by its influence on human placental lactogen (hpl) gene transcription accompanied by increase hpl m-RNA levels. Further role of Vitamin D is envisaged in identifying cyclin C as an important target for Vitamin D in cell-cycle regulation. Vitamin D at physiological concentration has been found to protect cell proteins and membranes against oxidative stress by inhibiting the peroxidative attack on membrane lipids. Vitamin D, at a concentration range of 2x10(-8)-5x10(-8)M, induces apoptosis in most cancer cells, stabilizes chromosomal structure and prevents DNA double-strand breaks induced either by endogenous or exogenous factors. Vitamin D is also effective in stimulating DNA synthesis in adult alveolar II cells and provides a novel mechanism of modulation of epithelial cell proliferation in the context of lung development and repair against injury. The regulation of various proto-oncogenes (c-myc, c-fos, c-jun), differentiation inducing properties, antiproliferative effects on keratinocytes and inhibitory effects in several human malignancy ranks Vitamin D as a novel hormone that may have physiological and clinical implication in the carcinogenic process. PMID:11295155

  1. Prevalence and risk factors of vitamin D deficiency in inherited ichthyosis: A French prospective observational study performed in a reference center

    PubMed Central

    2014-01-01

    Background To date, few studies have investigated serum vitamin D status in patients with inherited ichthyosis. The aim of this study was to determine the prevalence of vitamin D deficiency (defined as serum level <10 ng/mL) in a French cohort of patients and to identify associated risk factors. Methods This was a prospective observational study performed in a hospital reference center with expertise for rare skin diseases. Patients’ clinical characteristics were recorded. Serum concentration of 25-hydroxyvitamin D and parathyroid hormone were determined. For patients with vitamin D deficiency, serum calcium, serum phosphorus and bone mineral density were also investigated. Comparisons between groups (25-hydroxyvitamin D <10 ng/mL versus ≥10 ng/mL) were conducted by univariate and multivariate logistic regression. Results Of the 53 included patients, 47 (88.7%) had serum 25-hydroxyvitamin D below the optimal level of 30 ng/mL: 18 (34%) had vitamin D sufficiency, 14 (26.4%) had vitamin D insufficiency, and 15 (28.3%) had vitamin D deficiency. A negative linear correlation was found between 25-hydroxyvitamin D and parathyroid hormone levels for the whole study population. Serum calcium and phosphorus levels were normal for the 15 patients with vitamin D deficiency. Bone mineral density was investigated for 11 of these latter 15 patients, and six of them had osteopenia. Winter/spring seasons of vitamin D measurement, severity of ichthyosis, and phototypes IV–VI were identified as independent risk factors for vitamin D deficiency. Conclusions Clinicians should be aware of the risk of vitamin D deficiency in the management of patients with inherited ichthyosis, especially in winter and spring, and in case of dark skin or severe disease. PMID:25091406

  2. The effects of palm vitamin E on stress hormone levels and gastric lesions in stress-induced rats

    PubMed Central

    Aziz Ibrahim, Ibrahim Abdel; Kamisah, Yusof; Nafeeza, Mohd Ismail

    2012-01-01

    Introduction This study examines the effects of palm vitamin E (PVE) or α-tocopherol (α-TF) supplementation on adrenocorticotropin hormone (ACTH), corticosterone and gastric lesions in rats exposed to water-immersion restraint stress (WIRS). Material and methods Sixty male Sprague-Dawley rats (200-250 g) were divided into three groups. Group I: 20 rats as a control group were given a normal diet. Group II: 20 rats received oral supplementation of PVE at 60 mg/kg body weight. Group III: 20 rats received oral supplementation of α-TF at 60 mg/kg body weight. After the treatment period of 28 days, each group was further subdivided into two groups: 10 rats not exposed to stress, and the other 10 rats subjected to WIRS for 3.5 h. Blood samples were taken to measure the ACTH and corticosterone levels. The rats were then sacrificed and the stomach excised and opened along the greater curvature and examined for lesions. Results Rats exposed to WIRS had lesions in their stomach mucosa. Our findings showed that dietary supplementation of PVE or α-TF was able to reduce gastric lesions significantly in comparison to the stressed controls. The WIRS increased plasma ACTH and corticosterone significantly. Palm vitamin E and α-TF treatments reduced these parameters significantly compared to the stressed controls. Conclusions Supplementation with either PVE or α-TF reduces the formation of gastric lesions, probably by inhibiting the elevation of ACTH and corticosterone levels induced by stress. PMID:22457670

  3. Vitamin D insufficiency and insulin resistance in obese adolescents

    PubMed Central

    Tosh, Aneesh K.; Belenchia, Anthony M.

    2014-01-01

    Obese adolescents represent a particularly vulnerable group for vitamin D deficiency which appears to have negative consequences on insulin resistance and glucose homeostasis. Poor vitamin D status is also associated with future risk of type 2 diabetes and metabolic syndrome in the obese. The biological mechanisms by which vitamin D influences glycemic control in obesity are not well understood, but are thought to involve enhancement of peripheral/hepatic uptake of glucose, attenuation of inflammation and/or regulation of insulin synthesis/secretion by pancreatic β cells. Related to the latter, recent data suggest that the active form of vitamin, 1,25-dihydroxyvitamin D, does not impact insulin release in healthy pancreatic islets; instead they require an environmental stressor such as inflammation or vitamin D deficiency to see an effect. To date, a number of observational studies exploring the relationship between the vitamin D status of obese adolescents and markers of glucose homeostasis have been published. Most, although not all, show significant associations between circulating 25-hydroxyvitamn D concentrations and insulin sensitivity/resistance indices. In interpreting the collective findings of these reports, significant considerations surface including the effects of pubertal status, vitamin D status, influence of parathyroid hormone status and the presence of nonalcoholic fatty liver disease. The few published clinical trials using vitamin D supplementation to improve insulin resistance and impaired glucose tolerance in obese adolescents have yielded beneficial effects. However, there is a need for more randomized controlled trials. Future investigations should involve larger sample sizes of obese adolescents with documented vitamin D deficiency, and careful selection of the dose, dosing regimen and achievement of target 25-hydroxyvitamn D serum concentrations. These trials should also include clamp-derived measures of in vivo sensitivity and β-cell function to more fully characterize the effects of vitamin D replenishment on insulin resistance. PMID:25489472

  4. [A case of parathyroid adenoma with oxyphil cells].

    PubMed

    Enomoto, Katsuhisa; Sakurai, Kenichi; Amano, Sadao

    2014-11-01

    A 56-year-old woman who was undergoing dialysis for renal failure that occurred 4 years previously was identified with hypercalcemia and high levels of intact parathyroid hormone (iPTH), as observed on blood analysis results. Blood analysis also indicated high levels of Ca (12.7 mg/dL) and parathyroid hormone (PTH 1,280 ng/mL). Secondary hyperparathyroidism was suspected to be the cause of hypercalcemia. Cervical neck ultrasonography revealed a 13-× 4-mm hypoechoic mass in the lower left pole of the thyroid gland. Tc-99 metaiodobenzylguanidine (MIBG )imaging revealed aberrant accumulation at the lower region of the left accessory thyroid. Cervical neck computed tomography revealed a 12-mm mass at the inferior pole of the left thyroid gland. Considering the above observations, a diagnosis of lower left parathyroid adenoma was made. Lumpectomy was performed, and the final pathology report indicated oxyphilic adenoma. Chief cells are often observed in parathyroid adenoma, but, to our knowledge, this is the first case of a parathyroid adenoma with oxyphil cells. PMID:25731384

  5. [Overdose or hypersensitivity to vitamin D?].

    PubMed

    Hmami, F; Oulmaati, A; Amarti, A; Kottler, M-L; Bouharrou, A

    2014-10-01

    Vitamin D intoxication with severe hypercalcemia is rare in the neonatal and infancy period. Through nine cases of hypercalcemia, secondary to taking 600,000 units of vitamin D (Sterogyl(®)), a review of vitamin D requirements and possible mechanisms of toxicity including hypersensitivity to this vitamin will be discussed. We report nine cases of babies admitted to our department between the ages of 25 and 105 days for treatment of severe dehydration. The pregnancies were normal, with no incidents at delivery. Clinical signs were dominated by weight loss, vomiting, and fever. Examination on admission revealed dehydration whose degree ranged from 8 to 15% with preserved diuresis and loss weight between 100 and 1100 g. Laboratory tests objectified hypercalcemia between 113 and 235mg/L, hypercalciuria (urinary calcium/creatinine mmol/mmol >0.5), and a low-level of parathyroid hormone. The vitamin D values in nine patients were toxic (344-749 nmol/L; normal >50 nmol/L; toxicity if >250 nmol/L). Abdominal ultrasound objectified renal nephrocalcinosis in seven patients. The DNA study, performed in eight patients, did not reveal a mutation of the vitamin D 24-hydroxylase gene (CYP24A1). The treatment consisted of intravenous rehydration with treatment of hypercalcemia (diuretics and corticosteroids). Serum calcium returned to the normal range within 4-50 days, with weight gain progressively over the following weeks. The follow-up (2 years for the oldest case) showed the persistence of images of nephrocalcinosis. Genetic susceptibility and metabolic differences appear to modulate the threshold of vitamin D toxicity. However, respect for recommended doses, recognized as safe in a large study population, reduces the risk of toxicity. PMID:25129320

  6. Vitamin D Status and Outcomes After Renal Transplantation

    PubMed Central

    Girard, Delphine; Anglicheau, Dany; Canaud, Guillaume; Souberbielle, Jean Claude; Kreis, Henri; Noël, Laure Hélène; Friedlander, Gérard; Elie, Caroline; Legendre, Christophe; Prié, Dominique

    2013-01-01

    Kidney transplant recipients usually have low vitamin D levels, especially in the early posttransplantation period, but the association between vitamin D status with renal outcomes is not well described in this population. Here, we studied a prospective cohort of 634 kidney recipients who underwent transplantation at a single institution between January 2005 and June 2010. In this cohort, low 25-hydroxyvitamin D concentrations 3 months after transplantation did not predict early death or graft loss but were independently associated with lower measured GFR at 12 months (P=0.001) and higher risk for interstitial fibrosis and tubular atrophy (P=0.01). In contrast, levels of calcium, phosphorus, calcitriol, parathyroid hormone, or fibroblast growth factor-23 were not consistently associated with any of the studied outcomes. In conclusion, low 25-hydroxyvitamin D concentration measured 3 months after transplantation is an independent risk factor for interstitial fibrosis progression and is associated with a lower GFR 1 year after transplantation. PMID:23539758

  7. FGF-23 and vitamin D: don't shoot the messenger?

    PubMed

    Fish, Richard S; Cunningham, John

    2012-06-01

    The discovery of fibroblast growth factor-23 (FGF-23) as a key regulator of phosphate and vitamin D metabolism has forced a rethink about the mineral and bone disorder of chronic kidney disease (CKD). FGF-23 powerfully predicts adverse cardiovascular outcomes in patients with CKD and an important question is whether treatment regimens should now be tailored to address FGF-23 levels in addition to those of calcium, phosphate, parathyroid hormone and vitamin D. Nevertheless, despite the known action of active vitamin D therapies to increase FGF-23, this should probably still form an important part of the management of patients with hyperparathyroidism and perhaps at low doses of essentially all patients with advanced renal disease. PMID:22523113

  8. The effect of supplementation of calcium, vitamin D, boron, and increased fluoride intake on bone mechanical properties and metabolic hormones in rat.

    PubMed

    Ghanizadeh, G; Babaei, M; Naghii, Mohammad Reza; Mofid, M; Torkaman, G; Hedayati, M

    2014-04-01

    Evidence indicates that optimal nutrition plays a role in bone formation and maintenance. Besides major components of mineralization such as calcium, phosphorus, and vitamin D, other nutrients like boron and fluoride have beneficial role, too. In this study, 34 male Wistar rats were divided into five groups: control diet, fluoride, fluoride + boron, fluoride + calcium + vitamin D, and fluoride + boron + calcium + vitamin D. Boron equal to 1.23 mg, calcium and vitamin D equal to 210 mg + 55 IU and fluoride equal to 0.7 mg/rat/day was added to their drinking water for 8 weeks. Plasma blood samples and bones were collected. Findings are evidence that fluoride + boron intake revealed significant positive effects on bone mechanical properties and bone metabolic hormones. These findings suggest that combined intake of these two elements has beneficial effects on bone stiffness and breaking strength comparing to even calcium + vitamin D supplementation. This evidence dealing with health problems related to bone and skeletal system in humans should justify further investigation of the role of boron and fluoride with other elements in relation to bone. PMID:22782709

  9. The renin-angiotensin-aldosterone system and calcium-regulatory hormones.

    PubMed

    Vaidya, A; Brown, J M; Williams, J S

    2015-09-01

    There is increasing evidence of a clinically relevant interplay between the renin-angiotensin-aldosterone system and calcium-regulatory systems. Classically, the former is considered a key regulator of sodium and volume homeostasis, while the latter is most often associated with skeletal health. However, emerging evidence suggests an overlap in regulatory control. Hyperaldosteronism and hyperparathyroidism represent pathophysiologic conditions that may contribute to or perpetuate each other; aldosterone regulates parathyroid hormone and associates with adverse skeletal complications, and parathyroid hormone regulates aldosterone and associates with adverse cardiovascular complications. As dysregulation in both systems is linked to poor cardiovascular and skeletal health, it is increasingly important to fully characterize how they interact to more precisely understand their impact on human health and potential therapies to modulate these interactions. This review describes the known clinical interactions between these two systems including observational and interventional studies. Specifically, we review studies describing the inhibition of renin activity by calcium and vitamin D, and a potentially bidirectional and stimulatory relationship between aldosterone and parathyroid hormone. Deciphering these relationships might clarify variability in outcomes research, inform the design of future intervention studies and provide insight into the results of prior and ongoing intervention studies. However, before these opportunities can be addressed, more effort must be placed on shifting observational data to the proof of concept phase. This will require reallocation of resources to conduct interventional studies and secure the necessary talent. PMID:25631218

  10. Prevalence of vitamin D deficiency and associated factors in women and newborns in the immediate postpartum period

    PubMed Central

    do Prado, Mara Rúbia Maciel Cardoso; Oliveira, Fabiana de Cássia Carvalho; Assis, Karine Franklin; Ribeiro, Sarah Aparecida Vieira; do Prado, Pedro Paulo; Sant'Ana, Luciana Ferreira da Rocha; Priore, Silvia Eloiza; Franceschini, Sylvia do Carmo Castro

    2015-01-01

    Abstract Objective: To assess the prevalence of vitamin D deficiency and its associated factors in women and their newborns in the postpartum period. Methods: This cross-sectional study evaluated vitamin D deficiency/insufficiency in 226 women and their newborns in Viçosa (Minas Gerais, BR) between December 2011 and November 2012. Cord blood and venous maternal blood were collected to evaluate the following biochemical parameters: vitamin D, alkaline phosphatase, calcium, phosphorus and parathyroid hormone. Poisson regression analysis, with a confidence interval of 95%, was applied to assess vitamin D deficiency and its associated factors. Multiple linear regression analysis was performed to identify factors associated with 25(OH)D deficiency in the newborns and women from the study. The criteria for variable inclusion in the multiple linear regression model was the association with the dependent variable in the simple linear regression analysis, considering p<0.20. Significance level was α <5%. Results: From 226 women included, 200 (88.5%) were 20-44 years old; the median age was 28 years. Deficient/insufficient levels of vitamin D were found in 192 (85%) women and in 182 (80.5%) neonates. The maternal 25(OH)D and alkaline phosphatase levels were independently associated with vitamin D deficiency in infants. Conclusions: This study identified a high prevalence of vitamin D deficiency and insufficiency in women and newborns and the association between maternal nutritional status of vitamin D and their infants' vitamin D status. PMID:26100593

  11. 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

  12. An Unusual Presentation of Parathyroid Adenoma in an Adolescent: Calcific Achilles Tendinitis

    PubMed Central

    Kurtoğlu, Selim; Akın, Leyla; Kendirci, Mustafa; Çağlı, Sedat; Özgöçmen, Salih

    2015-01-01

    Primary hyperparathyroidism (PHPT) in children and adolescents is a rare condition. PHPT is usually sporadic and caused by parathyroid adenoma. Patients may present with bone pain, proximal myopathy, bony deformities, fractures, renal calculi, mass on the neck, or acute pancreatitis. A sixteen-year-old boy presented to our outpatient clinic with difficulty in walking due to swelling of both ankles. Ultrasonography revealed intratendinous calcific nodules in both Achilles tendons. Serum biochemistry showed hypercalcemia and hypophosphatemia. Serum parathormone level was high (512 pg/mL). Parathyroid scanning revealed a suspected parathyroid adenoma. The patient underwent parathyroidectomy and the diagnosis of parathyroid adenoma was confirmed by histopathology. Serum levels of parathyroid hormone, phosphate, and calcium returned to normal, and the tenderness over the Achilles tendon and the flow pattern on Doppler examination disappeared as well. In conclusion, hyperparathyroidism should be kept in mind in the differential diagnosis of tendonopathies. Early diagnosis can be crucial for prevention of severe complications. PMID:26777046

  13. An Unusual Presentation of Parathyroid Adenoma in an Adolescent: Calcific Achilles Tendinitis.

    PubMed

    Kurtoğlu, Selim; Akın, Leyla; Kendirci, Mustafa; Çağlı, Sedat; Özgöçmen, Salih

    2015-12-01

    Primary hyperparathyroidism (PHPT) in children and adolescents is a rare condition. PHPT is usually sporadic and caused by parathyroid adenoma. Patients may present with bone pain, proximal myopathy, bony deformities, fractures, renal calculi, mass on the neck, or acute pancreatitis. A sixteen-year-old boy presented to our outpatient clinic with difficulty in walking due to swelling of both ankles. Ultrasonography revealed intratendinous calcific nodules in both Achilles tendons. Serum biochemistry showed hypercalcemia and hypophosphatemia. Serum parathormone level was high (512 pg/mL). Parathyroid scanning revealed a suspected parathyroid adenoma. The patient underwent parathyroidectomy and the diagnosis of parathyroid adenoma was confirmed by histopathology. Serum levels of parathyroid hormone, phosphate, and calcium returned to normal, and the tenderness over the Achilles tendon and the flow pattern on Doppler examination disappeared as well. In conclusion, hyperparathyroidism should be kept in mind in the differential diagnosis of tendonopathies. Early diagnosis can be crucial for prevention of severe complications. PMID:26777046

  14. Complete genomic landscape of a recurring sporadic parathyroid carcinoma.

    PubMed

    Kasaian, Katayoon; Wiseman, Sam M; Thiessen, Nina; Mungall, Karen L; Corbett, Richard D; Qian, Jenny Q; Nip, Ka Ming; He, Ann; Tse, Kane; Chuah, Eric; Varhol, Richard J; Pandoh, Pawan; McDonald, Helen; Zeng, Thomas; Tam, Angela; Schein, Jacquie; Birol, Inanc; Mungall, Andrew J; Moore, Richard A; Zhao, Yongjun; Hirst, Martin; Marra, Marco A; Walker, Blair A; Jones, Steven J M

    2013-07-01

    Parathyroid carcinoma is a rare endocrine malignancy with an estimated incidence of less than 1 per million population. Excessive secretion of parathyroid hormone, extremely high serum calcium level, and the deleterious effects of hypercalcaemia are the clinical manifestations of the disease. Up to 60% of patients develop multiple disease recurrences and although long-term survival is possible with palliative surgery, permanent remission is rarely achieved. Molecular drivers of sporadic parathyroid carcinoma have remained largely unknown. Previous studies, mostly based on familial cases of the disease, suggested potential roles for the tumour suppressor MEN1 and proto-oncogene RET in benign parathyroid tumourigenesis, while the tumour suppressor HRPT2 and proto-oncogene CCND1 may also act as drivers in parathyroid cancer. Here, we report the complete genomic analysis of a sporadic and recurring parathyroid carcinoma. Mutational landscapes of the primary and recurrent tumour specimens were analysed using high-throughput sequencing technologies. Such molecular profiling allowed for identification of somatic mutations never previously identified in this malignancy. These included single nucleotide point mutations in well-characterized cancer genes such as mTOR, MLL2, CDKN2C, and PIK3CA. Comparison of acquired mutations in patient-matched primary and recurrent tumours revealed loss of PIK3CA activating mutation during the evolution of the tumour from the primary to the recurrence. Structural variations leading to gene fusions and regions of copy loss and gain were identified at a single-base resolution. Loss of the short arm of chromosome 1, along with somatic missense and truncating mutations in CDKN2C and THRAP3, respectively, provides new evidence for the potential role of these genes as tumour suppressors in parathyroid cancer. The key somatic mutations identified in this study can serve as novel diagnostic markers as well as therapeutic targets. PMID:23616356

  15. Fat-Soluble Vitamin Status in Self-Neglecting Elderly

    NASA Technical Reports Server (NTRS)

    Kala, G.; Oliver, S. Mathews; Kelly, P. A.; Pickens, S.; Burnett, J.; Dyer, C. B.; Smith, S. M.

    2006-01-01

    Elder self-neglect is a form of elder mistreatment. The systematic characterization of self-neglecting individuals is the goal of the CREST project. Reported here is the evaluation of fat-soluble vitamin status. Self-neglect (SN) subjects were recruited and consented following referral from Adult Protective Services. Control (CN) subjects were matched for age, gender, race, and socioeconomic status, as possible. We report here on 47 SN subjects (age 77 plus or minus 7, mean plus or minus SD; body weight 76 kg plus or minus 26) and 40 CN subjects (77 y plus or minus 7, 79 kg plus or minus 20). Blood samples were analyzed for indices of fat-soluble vitamin status. Plasma retinol (p less than 0.01) was lower in SN subjects. Plasma tocopherol tended (p less than 0.06) to be lower in SN subjects, while gamma-tocopherol was unchanged. SN subjects tended to have lower serum 25-OH vitamin D (p less than 0.11), and to be vitamin D deficient (26% below 23 mmol/L). Hypercalcemia occurred more often in SN subjects (23% had values above 2.56 mmol/L), as did elevated parathyroid hormone concentrations (p less than 0.05). These data demonstrate that many nutrients are affected in the self-neglecting elderly, and that long-term deficits are evident by the nature of changes in fat soluble vitamins.

  16. Localization of abnormal parathyroid glands using thallium-201

    SciTech Connect

    MacFarlane, S.D.; Hanelin, L.G.; Taft, D.A.; Ryan, J.A. Jr.; Fredlund, P.N.

    1984-07-01

    Ectopically located parathyroid adenomas may be difficult to find during initial neck exploration. They account for over 70 percent of missed adenomas found at reexploration. Preoperative localization of parathyroid adenomas would reduce unnecessary dissection and possibly reduce the number of negative results of initial neck exploration. Before reoperative parathyroid surgery is performed, some means of localization is mandatory to detect ectopic adenomas in the neck and mediastinum. Computed tomography and ultrasonography cannot effectively evaluate the mediastinum. Angiography and venous parathyroid hormone sampling are invasive, costly, and tedious to perform. We have shown that thallium-201 will accurately localize ectopic parathyroid adenomas. All 10 adenomas found in positions not immediately adjacent to the thyroid gland were detected by thallium-201 scintigraphy. One was a mediastinal adenoma resected with a median sternotomy. Our results suggest that thallium-201 scintigraphy should be the initial localization procedure of choice before all reexplorations. Its use before initial explorations, as well, will enable the surgeon to immediately direct attention to the area of the localized adenoma. If mediastinal uptake is found to be present, then median sternotomy may be performed during initial surgery provided a thorough neck exploration is performed first.

  17. Regulation of Phosphate Homeostasis by PTH, Vitamin D, and FGF23

    PubMed Central

    Bergwitz, Clemens; Jüppner, Harald

    2015-01-01

    In contrast to the regulation of calcium homeostasis, which has been extensively studied over the past several decades, relatively little is known about the regulation of phosphate homeostasis. Fibroblast growth factor 23 (FGF23) is part of a previously unrecognized hormonal bone-parathyroid-kidney axis, which is modulated by PTH, 1,25(OH)2-vitamin D (1,25(OH)2D), dietary and serum phosphorus levels. Synthesis and secretion of FGF23 by osteocytes are positively regulated by 1,25(OH)2D and serum phosphorus and negatively regulated, through yet unknown mechanisms, by the phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) and by dentin matrix protein 1 (DMP1). In turn, FGF23 inhibits the synthesis of 1,25(OH)2D, and it may negatively regulate the secretion of parathyroid hormone (PTH) from the parathyroid glands. However, FGF23 synergizes with PTH to increase renal phosphate excretion by reducing expression of the renal sodium-phosphate cotransporters NaPi-IIa and NaPi-IIc in the proximal tubules. Most insights gained into the regulation of phosphate homeostasis by these factors are derived from human genetic disorders and genetically engineered mice, which are reviewed in this paper. PMID:20059333

  18. Parathyroid adenoma in patients with Graves' disease: a report of 21 cases.

    PubMed

    Wei, Shuanzeng; Baloch, Zubair W; LiVolsi, Virginia A

    2015-03-01

    Graves' disease (GD) is frequently associated with mild hypercalcemia. The hypercalcemia may be due to the activation of osteoclastic bone resorption caused by the excess thyroid hormone. In some cases of GD, the hypercalcemia can be attributable to concomitant parathyroid diseases. In this study, 21 patients with a history of GD developed parathyroid adenoma based on histology, intraoperative parathyroid hormone (IOPTH) monitoring, and other clinical features. There were 11 patients with a history of radioactive iodine therapy (RAI) for GD. The latency time of RAI was from 12 to 41 years. The case cohort was divided into two groups: patients with (group GR: 11 patients) and patients without a history of RAI (group G: 10 patients). Mean age of patients in group GR was 54.8 years compared to 62.2 years of group G (P = 0.08). There were no statistically significant differences regarding the parathyroid weight, serum calcium, and pre- and post-parathyroidectomy PTH levels. There was no histopathologic difference between the two groups. In conclusion, we report 21 cases of parathyroid adenoma in patients with Graves' disease. There may be a possible link between GD patients with a RAI history and an increased risk of parathyroid adenoma. The parathyroid adenomas showed no clinicopathological differences between GD patient with and without a history of RAI. PMID:25501495

  19. 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

  20. An unusual case of brown tumor of hyperparathyroidism associated with ectopic parathyroid adenoma

    PubMed Central

    Mohan, Mathan; Neelakandan, Ravana Sundaram; Siddharth, D.; Sharma, Ravi

    2013-01-01

    Brown tumor is a giant cell lesion associated with hyperparathyroidism. It is a non-neoplastic condition and represents terminal stage of the remodeling process in hyperparathyroid state. We report a case of brown tumor with multiple lesions in craniofacial region associated with ectopic parathyroid adenoma revealed after acute L-thyroxine poisoning. This case report emphasizes on the need for routine biochemical investigations along with serum calcium, phosphorus and parathyroid hormone levels in patients on thyroxine therapy. PMID:24932128

  1. An unusual case of brown tumor of hyperparathyroidism associated with ectopic parathyroid adenoma.

    PubMed

    Mohan, Mathan; Neelakandan, Ravana Sundaram; Siddharth, D; Sharma, Ravi

    2013-10-01

    Brown tumor is a giant cell lesion associated with hyperparathyroidism. It is a non-neoplastic condition and represents terminal stage of the remodeling process in hyperparathyroid state. We report a case of brown tumor with multiple lesions in craniofacial region associated with ectopic parathyroid adenoma revealed after acute L-thyroxine poisoning. This case report emphasizes on the need for routine biochemical investigations along with serum calcium, phosphorus and parathyroid hormone levels in patients on thyroxine therapy. PMID:24932128

  2. Correlation between total vitamin D levels and psychotic psychopathology in patients with schizophrenia: therapeutic implications for add-on vitamin D augmentation

    PubMed Central

    Altunsoy, Neslihan; Tikir, Baise; Cingi Külük, Merve; Unal, Kubranur; Goka, Sema; Aydemir, Cigdem; Goka, Erol

    2014-01-01

    Objectives: Vitamin D deficiency is one of the implicated factors in ethio-pathogenesis of schizophrenia. Low serum vitamin D levels have been reported in many schizophrenia studies. However, the question is still not answered: Is there a correlation between disease activity and serum vitamin D levels? This is the first study evaluating the relationship between serum total vitamin D levels and disease activity, by comparing total vitamin D levels in two schizophrenia groups abruptly different in terms of disease activity. Methods: 41 patients with schizophrenia in remission, 40 patients with schizophrenia those in an acute episode and 40 age- and sex -matched controls with no major psychopatology were recruited in this study. Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impression – Severety scale (CGI-S) were used to evaluate disease activity. A demographic data form that included entries on age, gender, ethnicity, weight, skin color, daily duration of sun exposure and nutritional assessment were used. Blood samples were taken from all patients and controls. Total vitamin D (D2+D3), calcium, phosphor, parathyroid hormone values were measured. Results: Patients in an acute episode had significantly lower vitamin D levels compared to patients in remission and to healthy controls (in terms of median values respectively, 7.18, 15.03, 15.02, p < 0.001). We observed negative and moderate correlations between vitamin D levels and CGI scores (r = −0.624, p < 0.001), vitamin D levels and PANNS scores (r = −0.508, p < 0.001). There were no significant differences between groups in terms of serum P, Ca and PTH levels (p = 0.099, p = 0.943, p = 0.762). We could not detect any significant impact of weekly duration of sun exposure, skin color, ethnicity or nutrition on total vitamin D levels. Conclusions: Even though important factors for vitamin D synthesis were similar, there was severe vitamin D deficiency in patients presenting with an acute episode, significantly different from those in remission. Is vitamin D deficiency the result or the cause of an acute episode? Our results contribute to the idea that vitamin D deficiency and schizophrenia may have interactions with an unknown pathway. Present data points out a possible influence at a genomic level. Future trials may investigate this association with longer follow up. We recommend that, serum vitamin D levels should be measured in patients with schizophrenia especially in long term care. Appropriate further treatment with add-on vitamin D supplements and diets that are rich in vitamin D should be considered. PMID:25489478

  3. Vitamin A antagonizes calcium response to vitamin D in man.

    PubMed

    Johansson, S; Melhus, H

    2001-10-01

    For unknown reasons, the highest incidence of osteoporosis is found in northern Europe. In these populations, the sunlight exposure is limited and the vitamin A intake is high. The interaction between vitamin A and D has been the subject of several in vitro and animal studies. We have studied the acute effects of vitamin A and D on calcium homeostasis in 9 healthy human subjects. We compared the effect of (i) 15 mg of retinyl palmitate, (ii) 2 microg of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], (iii) 15 mg of retinyl palmitate plus 2 microg of 1,25(OH)2D3, and (iv) placebo in a double-blind crossover study. The subjects took vitamin preparations at 10:00 p.m. and the following day blood samples were collected five times from 8:00 a.m. to 4:00 p.m. Serum levels of 1,25(OH)2D3 and retinyl esters increased (1.7-fold and 8.3-fold, respectively; p < 0.01). As expected, serum calcium (S-calcium) increased (2.3%; p < 0.01) and S-parathyroid hormone (PTH) decreased (-32%; p < 0.05) after 1,25(OH)2D3 intake. In contrast, retinyl palmitate intake resulted in a significant decrease in S-calcium when taken alone (-1.0%; p < 0.05) and diminished the calcium response to 1,25(OH)2D3 after the combined intake (1.4%; p < 0.01). S-PTH was unaffected by retinyl palmitate. No significant changes in serum levels of the degradation product of C-telopeptide of type I collagen (CrossLaps), or U-calcium/creatinine levels were found. In conclusion, an intake of vitamin A corresponding to about one serving of liver antagonizes the rapid intestinal calcium response to physiological levels of vitamin D in man. PMID:11585356

  4. Hotspots for Vitamin-Steroid-Thyroid Hormone Response Elements Within Switch Regions of Immunoglobulin Heavy Chain Loci Predict a Direct Influence of Vitamins and Hormones on B Cell Class Switch Recombination.

    PubMed

    Hurwitz, Julia L; Penkert, Rhiannon R; Xu, Beisi; Fan, Yiping; Partridge, Janet F; Maul, Robert W; Gearhart, Patricia J

    2016-03-01

    Vitamin A deficiencies are common throughout the world and have a significant negative influence on immune protection against viral infections. Mouse models demonstrate that the production of IgA, a first line of defense against viruses at mucosal sites, is inhibited in the context of vitamin A deficiency. In vitro, the addition of vitamin A to activated B cells can enhance IgA expression, but downregulate IgE. Previous reports have demonstrated that vitamin A modifies cytokine patterns, and in so doing may influence antibody isotype expression by an indirect mechanism. However, we have now discovered hundreds of potential response elements among Sμ, Sɛ, and Sα switch sites within immunoglobulin heavy chain loci. These hotspots appear in both mouse and human loci and include targets for vitamin receptors and related proteins (e.g., estrogen receptors) in the nuclear receptor superfamily. Full response elements with direct repeats are relatively infrequent or absent in Sγ regions although half-sites are present. Based on these results, we pose a hypothesis that nuclear receptors have a direct effect on the immunoglobulin heavy chain class switch recombination event. We propose that vitamin A may alter S site accessibility to activation-induced deaminase and nonhomologous end-joining machinery, thereby influencing the isotype switch, antibody production, and protection against viral infections at mucosal sites. PMID:26741514

  5. 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.

  6. Taurine and vitamin E supplementations have minimal effects on body composition, hepatic lipids, and blood hormone and metabolite concentrations in healthy Sprague Dawley rats

    PubMed Central

    Allen, Portia S; Brown, Andrew W; Brown, Michelle M Bohan; Hsu, Walter H; Beitz, Donald C

    2015-01-01

    Background As prescriptions for off-label pharmaceutical use and autonomous administration of over-the-counter nutraceuticals become mainstream, thorough assessments of these compounds are warranted. Objective To determine the effects of gemfibrozil, rosiglitazone, metformin, taurine, and vitamin E on body composition, hepatic lipids, and metabolic hormone and blood metabolite concentrations in a healthy, outbred rat cohort. Methods Male Sprague Dawley rats were fed a purified 10 kcal% from fat diet for 56 days and assigned to diet alone (control) or diet plus oral administration of gemfibrozil (34 mg/kg), metformin (500 mg/kg), rosiglitazone (3 mg/kg), taurine (520 mg/kg), or vitamin E (200 mg/kg). Results Rosiglitazone administration resulted in a 56% increase in carcass adiposity, cautioning potential prescriptive off-label use. Taurine supplementation had no adverse effects on evaluated parameters. A modest but significant increase in liver triacylglycerol content was observed with vitamin E supplementation compared with control (Δ 17.2 g triacylglycerol/100 g liver lipid). Conclusions The evaluated pharmaceuticals had effects in a healthy population similar to the reported effects in their target population and the nutraceuticals had minimal effects on the measured physiological parameters. PMID:26752960

  7. 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 ...

  8. Treatment Option Overview (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 ...

  9. Serum Vitamin D levels in patients with chronic kidney disease

    PubMed Central

    Rozita, Mohd; Noorul Afidza, Mohamad; Ruslinda, Mustafar; Cader, Rizna; Halim, A. Gafor; Kong, Chiew Tong Norella; Nor Azmi, Kamaruddin; Shah, Shamsul Azhar

    2013-01-01

    Introduction: Hypovitaminosis D is reported to be associated with several medical complications. Recent studies have reported a high worldwide prevalence of Vitamin D deficiency in the general population (up to 80 %). This is even higher in patients with chronic kidney disease (CKD) and increases with advancing stages of CKD. Objectives: To determine the difference in serum Vitamin D [25-hydroxyvitamin D, 25(OH) D] levels between CKD patients and normal healthy population. Materials and Methods: A prospective cross-sectional study involving 50 normal volunteers (control) and 50 patients with CKD stages 2-4. Their demographic profiles were recorded and blood samples taken for serum 25(OH) D, intact parathyroid hormone (iPTH) and other routine blood tests. Results: All subjects regardless of renal status had hypovitaminosis D (< 30ng/mL). The mean serum 25(OH) D were comparable in the control and CKD groups (15.3 4.2 ng/mL vs 16.1 6.2 ng/mL, p = NS). However, within the Vitamin D deficient group, the CKD group had lower levels of serum 25(OH) D [12.6(3.7) ng/mL vs 11.2(6.5) ng/mL, p = 0.039]. Female gender [OR 22.553; CI 95 % (2.16-235.48); p = 0.009] and diabetic status [OR 6.456; CI 95 % (1.144-36.433); p = 0.035] were independent predictors for 25(OH) D deficiency. Conclusions: Vitamin D insufficiency and vitamin D deficiency are indeed prevalent and under-recognized. Although the vitamin D levels among the study subjects and their control are equally low, the CKD group had severe degree of vitamin D deficiency. Diabetic status and female gender were independent predictors of low serum 25(OH)D.

  10. [Vitamin D and osteoimmunology].

    PubMed

    Takash, Yuichi; Fukumoto, Seiji; Matsumoto, Toshio

    2016-05-01

    Vitamin D was considered to be one of nutrients which has an important role in the maintenance of calcium and phosphate metabolism. It was then revealed that 1,25-dihydroxyvitamin D metabolized from vitamin D works as a calciotropic hormone. Vitamin D metabolites were further shown to affect cell proliferation and differentiation. In immune system, vitamin D metabolites modulate both innate and adaptive immunity. Epidemiological studies indicated the associations between vitamin D deficiency and various diseases such as autoimmune diseases, allergy, infection and malignancy. In addition, vitamin D supplementation was shown to improve some these diseases. PMID:27117621

  11. Phosphorylation of Ribosomal Protein S6 Mediates Mammalian Target of Rapamycin Complex 1-Induced Parathyroid Cell Proliferation in Secondary Hyperparathyroidism.

    PubMed

    Volovelsky, Oded; Cohen, Gili; Kenig, Ariel; Wasserman, Gilad; Dreazen, Avigail; Meyuhas, Oded; Silver, Justin; Naveh-Many, Tally

    2016-04-01

    Secondary hyperparathyroidism is characterized by increased serum parathyroid hormone (PTH) level and parathyroid cell proliferation. However, the molecular pathways mediating the increased parathyroid cell proliferation remain undefined. Here, we found that the mTOR pathway was activated in the parathyroid of rats with secondary hyperparathyroidism induced by either chronic hypocalcemia or uremia, which was measured by increased phosphorylation of ribosomal protein S6 (rpS6), a downstream target of the mTOR pathway. This activation correlated with increased parathyroid cell proliferation. Inhibition of mTOR complex 1 by rapamycin decreased or prevented parathyroid cell proliferation in secondary hyperparathyroidism rats andin vitroin uremic rat parathyroid glands in organ culture. Knockin rpS6(p-/-)mice, in which rpS6 cannot be phosphorylated because of substitution of all five phosphorylatable serines with alanines, had impaired PTH secretion after experimental uremia- or folic acid-induced AKI. Uremic rpS6(p-/-)mice had no increase in parathyroid cell proliferation compared with a marked increase in uremic wild-type mice. These results underscore the importance of mTOR activation and rpS6 phosphorylation for the pathogenesis of secondary hyperparathyroidism and indicate that mTORC1 is a significant regulator of parathyroid cell proliferation through rpS6. PMID:26283674

  12. Diseases of the parathyroid gland in chronic kidney disease.

    PubMed

    Komaba, Hirotaka; Kakuta, Takatoshi; Fukagawa, Masafumi

    2011-12-01

    During the past few years, remarkable advances have been made in the understanding and the management of parathyroid diseases in patients with chronic kidney disease (CKD). One of the important insights is the identification of fibroblastic growth factor 23, which has greatly reshaped our understanding of secondary hyperparathyroidism (SHPT). The recent introduction of calcimimetic cinacalcet hydrochloride has led to a major breakthrough in the management of SHPT. Recognition of circulating molecular forms of parathyroid hormone (PTH) is also a major milestone in the accurate assessment of parathyroid function in CKD. Primary hyperparathyroidism should also be considered in patients with CKD, because it can cause various renal manifestations and can also occur as a sporadic disease in these patients. Hypoparathyroidism is occasionally seen in dialysis patients in the setting of diabetes mellitus and malnutrition-inflammation complex syndrome, as well as after parathyroidectomy for advanced SHPT. For patients with adynamic bone disease due to hypoparathyroidism and/or skeletal resistance to PTH, teriparatide, a PTH analog, may have potential for improving bone metabolism and reducing the risk of fracture. In this review, we summarize our current knowledge on diseases of the parathyroid gland in CKD patients, with a particular focus on recent work in the field. PMID:21818548

  13. Fetal parathyroids are not required to maintain placental calcium transport

    PubMed Central

    Kovacs, Christopher S.; Manley, Nancy R.; Moseley, Jane M.; Martin, T. John; Kronenberg, Henry M.

    2001-01-01

    We used Hoxa3 knockout mice and other mouse models to study the role of the fetal parathyroids in fetal calcium homeostasis. Hoxa3-null fetuses lack parathyroid glands, and absence of parathyroid hormone (PTH) was confirmed with a rodent PTH immunoradiometric assay. The ionized calcium level of Hoxa3-null fetuses was significantly lower than that of wild-type or heterozygous littermates or of the mother. Both the rate of placental calcium transfer and the plasma PTHrP level were normal in Hoxa3 mutants and their heterozygous siblings. Because we had previously observed an increase in placental calcium transfer in PTH/PTHrP receptor 1–null (Pthr1-null) fetuses, we assayed plasma PTHrP in those mice. Pthr1-null fetuses had plasma PTHrP levels 11-fold higher than those of their littermates. Northern analysis, immunohistochemical, and in situ hybridization studies of Pthr1-null fetuses indicated that liver and placenta had increased expression of PTHrP. In summary, loss of fetal parathyroids in Hoxa3-null fetuses caused marked hypocalcemia but did not alter placental calcium transfer or the circulating PTHrP level. The findings in the Pthr1-null fetuses indicate that several tissues may contribute to the circulating PTHrP level in fetal mice. PMID:11306604

  14. 1 beta, 25 (OH)2-vitamin D3 is an antagonist of 1 alpha,25 (OH)2-vitamin D3 stimulated transcaltachia (the rapid hormonal stimulation of intestinal calcium transport).

    PubMed

    Norman, A W; Nemere, I; Muralidharan, K R; Okamura, W H

    1992-12-30

    The steroid hormone 1 alpha,25-dihydroxyvitamin-D3 [1 alpha,25(OH)2D3] stimulates biological responses via both genomic mechanisms and nongenomic mechanisms (opening of voltage-gated Ca2+ channels). We report here that 1 beta, 25(OH)2-vitamin-D3 (a) is devoid of activity as an agonist for transcaltachia, (b) is a potent stereospecific antagonist of 1 alpha,25 (OH)2D3 stimulation of the nongenomic transcaltachia response and also (c) has less than 1% the ability of 1 alpha,25(OH)2D3 to bind to the chick intestinal nuclear 1 beta,25(OH)2D3 receptor. We conclude that the membrane response element(s) which generates the nongenomic response of transcaltachia has a different ligand specificity than the classic nuclear 1 alpha, 25(OH)2D3 receptor. PMID:1336368

  15. Association of a wide invasive malignant thymoma with myastenia gravis and primary hyperparathyroidism due to parathyroid adenoma: case report and review of the literature.

    PubMed

    Triggiani, Vincenzo; Guastamacchia, Edoardo; Lolli, Ivan; Troccoli, Giuseppe; Resta, Francesco; Sabbà, Carlo; Ruggieri, Nadia; Tafaro, Emilio

    2006-01-01

    There are few cases described in the world literature reporting an association of thymoma (with myasthenia gravis or not) with hyperparathyroidism. In these cases the hyperparathyroidism was due to the presence of an adenoma or hyperplasic parathyroid tissue either in the cervical region or in an ectopic intrathymic location.(12345) In other cases the syndrome of hypercalcemia was due to the secretion of parathyroid-related protein (PTHRP) (6) or parathyroid hormone (PTH) (7) by the thymoma itself. We report the first case, at the best of our knowledge, of a wide invasive malignant thymoma (type B3), associated with myasthenia gravis and hyperparathyroidism caused by parathyroid adenoma. PMID:16873103

  16. Locally recurrent parathyroid neoplasms as a cause for recurrent and persistent primary hyperparathyroidism.

    PubMed Central

    Fraker, D L; Travis, W D; Merendino, J J; Zimering, M B; Streeten, E A; Weinstein, L S; Marx, S J; Spiegel, A M; Aurbach, G D; Doppman, J L

    1991-01-01

    Between 1982 and 1989, 145 patients underwent operations for persistent or recurrent primary hyperparathyroidism (HPT). At re-exploration, 15 patients (10.3%) were found to have locally recurrent parathyroid tumors (11 patients with adenoma and 4 with carcinoma). These 15 patients had 28 previous operations at outside institutions for HPT. Patients with locally recurrent HPT secondary to adenoma had a longer disease-free interval than patients with locally recurrent carcinoma. At the time of evaluation at the National Institutes of Health (NIH) for recurrent or persistent HPT, each patient was symptomatic and patients with carcinoma had significantly more symptoms and higher serum levels of calcium and parathyroid hormone than patients with adenoma. Locally recurrent parathyroid neoplasm was correctly localized by preoperative testing in 14 of 15 patients. These 15 patients underwent 18 reoperations at NIH for excision of locally recurrent parathyroid tumors. Following the final reoperation (two patients had more than one procedure), each patient had normal serum levels of calcium. In addition each patient remains biochemically cured (based on normal serum calcium level), with a median follow-up interval of 21 months. Local recurrence of parathyroid adenoma comprises a small but significant proportion of cases of recurrent or persistent HPT and can be indistinguishable from parathyroid carcinoma. Findings suggestive of carcinoma include shorter disease-free interval, higher serum levels of calcium and parathyroid hormone, and histologic appearance. Whether the locally recurrent parathyroid neoplasm is benign or malignant, aggressive surgery can control serum levels of calcium in these patients with acceptable rates of morbidity. PMID:1985539

  17. THE EFFECTS OF DIETARY VITAMIN E AND SELENIUM DEFICIENCIES ON PLASMA THYROID AND THYMIC HORMONE CONCENTRATIONS IN THE CHICKEN

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Beginning at hatching, male Cornell K strain single comb white leghorn chickens were fed a basal diet, with or without vitamin E (100 IU/kg) and/or selenium (Se, 0.2 ppm). After 3 weeks of treatment, animals fed either the Se-deficient or basal diet had significantly reduced plasma Se-dependent glut...

  18. PREVALENCE AND PREDICTORS OF VITAMIN D DEFICIENCY IN HEALTHY ADULTS

    PubMed Central

    Mitchell, Deborah M.; Henao, Maria P.; Finkelstein, Joel S.; Burnett-Bowie, Sherri-Ann M.

    2013-01-01

    Objective Vitamin D deficiency is highly prevalent in high-risk patient populations, but the prevalence among otherwise healthy adults is less well-defined. The goal of this study was to determine the prevalence and predictors of low 25-hydroxyvitamin D [25(OH)D] levels in healthy younger adults. Methods This was a cross-sectional study of 634 healthy volunteers aged 18-50 years performed between January, 2006 and May, 2008. We measured serum 25(OH) D and parathyroid hormone and recorded demographic variables including age, sex, race, and use of multivitamin supplements. Results Thirty-nine percent of subjects had 25(OH)D ≤20 ng/mL and 64% had 25(OH)D ≤30 ng/mL. Predictors of lower 25(OH)D levels included male sex, black or Asian race, and lack of multivitamin use (P<0.001 for each predictors). Seasonal variation in 25(OH)D levels was present in the overall cohort but was not observed in multivitamin users. Lower 25(OH)D levels were associated with increased risk of elevated parathyroid hormone. Regression models predicted 25(OH)D levels ≤20 or ≤30 ng/mL with areas under the receiver operating characteristic curves of 0.76 and 0.80, respectively. Conclusion Low 25(OH)D levels are prevalent in healthy adults and may confer risk of skeletal disease. Black and Asian adults are at increased risk of deficiency and multivitamin use appears partially protective. Our models predicting low 25(OH)D levels may guide decision-making regarding whom to screen for vitamin D deficiency. PMID:22982792

  19. Calcium absorption in diphosphonate-treated rats: effect of parathyroid function, dietary calcium and phosphorus.

    PubMed Central

    Bonjour, J P; Fleisch, H; Trechsel, U

    1977-01-01

    1. The role of parathyroid hormone (PTH) and 1, 25-dihydroxy-cholecalciferol (1,25-(OH)2D3) in modulation of intestinal Ca absorption was studied in rats, using disodium ethane-1-hydroxy-1,1-diphosphonate (EHDP), which is known to reduce 1,25-(OH)2D3 formation. 2. EHDP decreased intestinal Ca absorption. This effect could be abolished by small amounts of 1,25-(OH)2D3, whereas even large doses of PTH were ineffective. EHDP also decreased Ca absorption in thyroparathyroidectomized (TPTX) rats. Therefore the effect of EHDP on 1,25-(OH)2D3 production is unlikely to be mediated through PTH. 3. The correction by PTH of the decreased Ca absorption in TPTX rats was inhibited by EHDP. Since EHDP inhibits formation of 1,25-(OH)2D3 the effect of PTH on Ca absorption is likely to be mediated through this vitamin D3 metabolite. 4. In normal rats both a low Ca and a low P diet stimulated Ca absorption. In EHDP-treated intact rats low Ca still stimulated Ca absorption, whereas the effect of low P abolished. This indicates that low Ca and low P diets affect Ca absorption through different mechanisms. 5. Intestinal adaptation to a low Ca diet was still observed in EHDP-treated TPTX rats. Thus, in the rat, intestinal adaptation to low Ca diet can occur without PTH. PMID:402471

  20. Optimal scan time for evaluation of parathyroid adenoma with [18F]-fluorocholine PET/CT

    PubMed Central

    Rep, Sebastijan; Lezaic, Luka; Kocjan, Tomaz; Pfeifer, Marija; Sever, Mojca Jensterle; Simoncic, Urban; Tomse, Petra; Hocevar, Marko

    2015-01-01

    Background Parathyroid adenomas, the most common cause of primary hyperparathyroidism, are benign tumours which autonomously produce and secrete parathyroid hormone. [18F]-fluorocholine (FCH), PET marker of cellular proliferation, was recently demonstrated to accumulate in lesions representing enlarged parathyroid tissue; however, the optimal time to perform FCH PET/CT after FCH administration is not known. The aim of this study was to determine the optimal scan time of FCH PET/CT in patients with primary hyperparathyroidism. Patients and methods. 43 patients with primary hyperparathyroidism were enrolled in this study. A triple-phase PET/CT imaging was performed five minutes, one and two hours after the administration of FCH. Regions of interest (ROI) were placed in lesions representing enlarged parathyroid tissue and thyroid tissue. Standardized uptake value (SUVmean), retention index and lesion contrast for parathyroid and thyroid tissue were calculated. Results Accumulation of FCH was higher in lesions representing enlarged parathyroid tissue in comparison to the thyroid tissue with significantly higher SUVmean in the second and in the third phase (p < 0.0001). Average retention index decreased significantly between the first and the second phase and increased significantly between the second and the third phase in lesions representing enlarged parathyroid tissue and decreased significantly over all three phases in thyroid tissue (p< 0.0001). The lesion contrast of lesions representing enlarged parathyroid tissue and thyroid tissue was significantly better in the second and the third phase compared to the first phase (p < 0.05). Conclusions According to the results the optimal scan time of FCH PET/CT for localization of lesions representing enlarged parathyroid tissue is one hour after administration of the FCH. PMID:26834518