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

Microsoft Academic Search

Minerals, vitamin D, and parathyroid hormone in continuous ambulatory peritoneal dialysis. The effects of continuous ambulatory peritoneal dialysis on parathyroid hormone (PTH) and mineral metabolism were evaluated in ten patients. Utilizing a PTH radioimmunoassay, which measures both intact hormone and carboxyl-terminal PTH fragments, it was found that the mean clearance of immunoreactive parathyroid hormone was 1.5 ± 0.73 ml\\/min (SEM)

James A Delmez; Eduardo Slatopolsky; Kevin J Martin; Barbara N Gearing; Herschel R Harter



Influence of Daily Regimen Calcium and Vitamin D Supplementation on Parathyroid Hormone Secretion  

Microsoft Academic Search

Calcium and vitamin D supplementation has been shown to reduce secondary hyperparathyroidism and play a role in the management of senile osteoporosis. In order to define the optimal regimen of calcium and vitamin D supplementation to produce the maximal inhibition of parathyroid hormone secretion, we have compared the administration of a similar amount of Ca and vitamin D, either as

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



Vitamin D status and parathyroid hormone in obese children before and after weight loss  

Microsoft Academic Search

Objective: The roles of vitamin D and parathyroid hormone (PTH) are discussed controversially in obesity, and studies of these hormones in obese children are limited. Therefore, we studied the relationships between PTH, 1,25-dihydroxy-vitamin D (1,25-OH Vit D), 25-hydroxy-vitamin D (25-OH Vit D), weight status, and insulin sensitivity before and after weight loss in obese children. Methods: Fasting serum PTH, 1,25-OH

Thomas Reinehr; Gideon de Sousa; Ute Alexy; M Kersting; Werner Andler



Effects of vitamin D and parathyroid hormone on muscle: potential role in uremic myopathy1' 2  

Microsoft Academic Search

Profound asthenia is an early and almost obligatory finding in rickets and osteomalacia caused by vitamin D deficiency, as well as in primary hyperparathyroidism. The relative roles of changes of electrolyte concentrations in tissue compartments, disturbed vitamin D metabolism, and parathyroid hormone excess have not been well delineated. In patients with primary hyperparathyroidism and secondary hyperparathyroidism associated with osteomalacia, histochemistry

Eberhard Ritz; Ricardo Boland; Wilhelm Kreusser


Relationship between vitamin D, calcium and parathyroid hormone in Cape Town  

Microsoft Academic Search

Aim:The aim of this study was to test the hypothesis that vitamin D deficiency is associated with abnormal levels of calcium and parathyroid hormone (PTH).Methods:Vitamin D requests at a tertiary hospital in South Africa over 2 years were retrospectively analysed along with calcium and PTH levels.Results:Only when the 25-hydroxyvitamin D (25(OH)D) level dropped below 25 nmol\\/l, was there a significant

D Haarburger; M Hoffman; R T Erasmus; T S Pillay



Effects of gastric bypass procedures on bone mineral density, calcium, parathyroid hormone, and vitamin d  

Microsoft Academic Search

Weight loss after gastric bypass procedures has been well studied, but the long-term metabolic sequelae are not known. Data\\u000a on bone mineral density (BMD), calcium, parathyroid hormone, and vitamin D were collected preoperatively and at yearly intervals\\u000a after gastric bypass procedures. A total of 230 patients underwent preoperative BMD scans. Fifteen patients were osteopenic\\u000a preoperatively, and three patients subsequently developed

Jason M. Johnson; James W. Maher; Isaac Samuel; Deborah Heitshusen; Cornelius Doherty; Robert W. Downs



Vitamin D and parathyroid hormone in insulin resistance of abdominal obesity: cause or effect?  

Microsoft Academic Search

The objective was to examine whether there were causal links between vitamin D status, parathyroid hormone, insulin resistance (IR)\\/insulin sensitivity (IS) and the metabolic syndrome (MS). A total of 72 Caucasian men and women, aged 55.7±7.57 years, with body mass index 33.4±4.02 kg\\/m2 and abdominal obesity, were assessed for IR\\/IS based on three commonly used indices before and after 12

M J Soares; W Chan She Ping-Delfos; J L Sherriff; D H Nezhad; N K Cummings; Y Zhao



Vitamin D and parathyroid hormone and bone mineralisation in adults with cystic fibrosis.  

PubMed Central

Vitamin D and parathyroid hormone concentrations were assessed in 31 adults with cystic fibrosis (mean age 24, range 17-52 years), in 28 of whom the bone mineral index in the forearm was also determined. Serum 25-hydroxyvitamin D was subnormal in eight patients, of whom five were receiving vitamin D supplements in standard doses. 1,25-dihydroxyvitamin D and parathyroid hormone concentrations showed no consistent abnormalities. The bone mineral index was lower in patients with cystic fibrosis (p less than 0.02) than in controls. Five patients with unequivocally reduced bone mineral index had a subnormal mean serum 25-hydroxyvitamin D and significantly worse lung function than the other patients. There was a positive correlation between age and bone mineral index (r = 0.68, p less than 0.001). Thus a significant proportion of patients with cystic fibrosis living in a temperate climate are at risk of vitamin D deficiency. Osteopenia is common and is probably related to a combination of hypovitaminosis D, delay in puberty, hypo-oestrogenism in women, and reduced physical activity, rather than to secondary hyperparathyroidism. Since most patients with deficiency of 25-hydroxyvitamin D were receiving oral supplements, parenteral vitamin D supplementation may be appropriate for selected patients who are unable to maintain adequate 25-hydroxyvitamin D concentrations despite oral vitamin D supplements.

Stead, R J; Houlder, S; Agnew, J; Thomas, M; Hodson, M E; Batten, J C; Dandona, P



The interactions of thiazide diuretics with parathyroid hormone and vitamin D  

PubMed Central

In order to clarify the mechanisms of thiazide diuretic-induced hypocalciuria, the effect of a thiazide was studied for 7 days in seven patients with hypoparathyroidism on Vitamin D and one on calcium infusion, and seven euparathyroid patients with hypercalciuria. In the control group, calcium excretion (mg/24 hr) fell by 44% from 415 to 232 within 4 days and remained at this level. Plasma total calcium corrected for total protein did not change. In the hypoparathyroid group, calcium excretion fell by 11% from 351 to 311 and then returned to the base line level. Plasma total calcium (mg/100 ml) increased from 10.09 to 10.88, 11.29 and 10.77 at the end of the 2nd, 4th, and 7th day of thiazide administration. In the patient having i.v. calcium and no Vitamin D, neither plasma nor urinary calcium changed significantly. In both groups sodium excretion increased on the first 2 days and fell to or below base line level thereafter. Urinary phosphate, magnesium, and potassium increased, plasma phosphate rose, and magnesium and potassium fell. It is concluded that: (a) The hypocalciuric effect of thiazides requires the presence of parathyroid hormone and is not solely a result of sodium depletion. (b) The hypercalcemic effect of thiazides in hypoparathyroidism is due to increased release of calcium from bone and requires the presence of a pharmacologic dose of Vitamin D. (c) Thiazides enhane the action of parathyroid hormone on bone and kidney; Vitamin D can replace parathyroid hormone in this interaction in bone but not in kidney. Images

Parfitt, A. M.



Impact of Ergocalciferol Treatment of Vitamin D Deficiency on Serum Parathyroid Hormone Concentrations in Chronic Kidney Disease  

Microsoft Academic Search

Background: Vitamin D deficiency is highly prevalent and associated with secondary hyperparathyroidism in patients with chronic kidney disease (CKD). The Kidney Disease Outcomes Quality Initiative (K\\/DOQI) guidelines recommend treatment of vitamin D deficiency starting with CKD stage 3, though no data are available showing an impact on serum parathyroid hormone (PTH) concentrations. The goal of this analysis, therefore, was to

Anna L. Zisman; Marta Hristova; L. Tammy Ho; Stuart M. Sprague



Vitamin D deficiency and parathyroid hormone levels following renal transplantation in children  

Microsoft Academic Search

The objectives were to determine the prevalence of vitamin D deficiency [25(OH)D?parathyroid hormone (iPTH)\\u000a levels following transplantation. Serum 25(OH)D, 1,25(OH)2D, and iPTH were measured once in 275 healthy controls and at transplantation, and 3 and 12 months posttransplantation in\\u000a 58 RTx recipients.

Shamir Tuchman; Heidi J. Kalkwarf; Babette S. Zemel; Justine Shults; Rachel J. Wetzsteon; Debbie Foerster; C. Frederic Strife; Mary B. Leonard



Relationship between Vitamin D, Parathyroid Hormone, and Bone Health  

PubMed Central

Context: There is a controversy regarding the definition of vitamin D insufficiency as it relates to bone health. Objective: The objective of the study was to examine the evidence for a threshold value of serum 25-hydroxyvitamin D (25OHD) that defines vitamin D insufficiency as it relates to bone health. Design and Participants: This was a cross-sectional analysis of baseline data in 488 elderly Caucasian women, mean age 71 yr, combined with a literature review of 70 studies on the relationship of serum PTH to serum 25OHD. Setting: The study was conducted in independent-living women in the midwest United States. Main Outcome Measure: The relationship between serum 25OHD, serum PTH, and serum osteocalcin and 24-h urine N-telopeptides was evaluated. Results: Serum PTH was inversely correlated with serum 25OHD (r = ?0.256, P < 0.0005), but no threshold as defined by suppression of serum PTH was found within the serum 25OHD range 6–60 ng/ml (15–150 nmol/liter). However, in contrast, there was a threshold for bone markers, serum osteocalcin and urine N-telopeptides, that increased only below a serum 25OHD of approximately 18 ng/ml (45 nmol/liter). Calcium absorption was not correlated with serum PTH and serum 25OHD, and no threshold was found. A literature review of 70 studies generally showed a threshold for serum PTH with increasing serum 25OHD, but there was no consistency in the threshold level of serum 25OHD that varied from 10 to 50 ng/ml (25–125 nmol/liter). Conclusions: Vitamin D insufficiency should be defined as serum 25OHD less than 20 ng/ml (50 nmol/liter) as it relates to bone.

Walters, R. W.; Fang, X.; Gallagher, J. C.



The Association between Parathyroid Hormone, Vitamin D and Bone Mineral Density in 70YearOld Icelandic Women  

Microsoft Academic Search

:   Parathyroid hormone (PTH) may be an important determinant of cortical bone remodeling in the elderly. Vitamin D status is\\u000a one of the determining factors in this relationship. The aim of this study was to quantify the relationship between serum\\u000a PTH, vitamin D and bone mineral density (BMD) in elderly women in Reykjavik (64° N), where daily intake of cod

G. Sigurdsson; L. Franzson; L. Steingrimsdottir; H. Sigvaldason



Dietary vitamin D intake is not associated with 25-hydroxyvitamin D3 or parathyroid hormone in elderly subjects, whereas the calcium-to-phosphate ratio affects parathyroid hormone.  


This cross-sectional study investigates whether serum 25-hydroxyvitamin D3 [25(OH)D3] and intact parathyroid hormone (iPTH) are affected by vitamin D, calcium, or phosphate intake in 140 independently living elderly subjects from Germany (99 women and 41 men; age, 66-96 years). We hypothesized that habitual dietary intakes of vitamin D, calcium, and phosphate are not associated with 25(OH)D3 or iPTH and that body mass index confounds these associations. Serum 25(OH)D3 and iPTH were measured by an electrochemiluminescence immunoassay. Dietary intake was determined using a 3-day estimated dietary record. The median dietary intake levels of vitamin D, calcium, and phosphate were 3 ?g/d, 999 mg/d, and 1250 mg/d, respectively. Multiple regression analyses confirmed that dietary vitamin D and calcium did not affect 25(OH)D3 or iPTH; however, supplemental intakes of vitamin D and calcium were associated with 25(OH)D3 after adjustment for age, sex, body composition, sun exposure, physical activity, and smoking. In addition, phosphate intake and the calcium-to-phosphate ratio were associated with iPTH after multiple adjustments. In a subgroup analysis, calcium and vitamin D supplements, as well as phosphate intake, were associated with 25(OH)D3 and/or iPTH in normal-weight subjects only. Our results indicate that habitual dietary vitamin D and calcium intakes have no independent effects on 25(OH)D3 or iPTH in elderly subjects without vitamin D deficiency, whereas phosphate intake and the calcium-to-phosphate ratio affect iPTH. However, vitamin D and calcium supplements may increase 25(OH)D3 and decrease iPTH, even during the summer, but the impact of supplements may depend on body mass index. PMID:23890356

Jungert, Alexandra; Neuhäuser-Berthold, Monika



Vitamin D receptor genotype influences parathyroid hormone and calcitriol levels in predialysis patients  

Microsoft Academic Search

Vitamin D receptor genotype influences PTH and calcitriol levels in predialysis patients.BackgroundBsmI vitamin D receptor (VDR) gene polymorphism has been associated with the severity of hyperparathyroidism in patients on hemodialysis. The aim of this study was to analyze the influence of this polymorphism on parathyroid function and serum calcitriol levels in patients with different degrees of chronic renal failure (CRF)

Maria Paz Marco; Isabel Martínez; Maria Luisa Amoedo; Mercè Borràs; Ramón Saracho; Jaume Almirall; Joan Fibla; Elvira Fernández



Low levels of 25-hydroxy vitamin D are associated with elevated parathyroid hormone in healthy adolescent females  

Microsoft Academic Search

This study aimed to investigate the relationship between 25-hydroxyvitamin D [25(OH)D)] and parathyroid hormone (PTH) levels in adolescent females residing in a northern climate. Concern regarding vitamin D status in this population is due to limited sunlight exposure in northern latitudes, decreased outdoor recreational activities, as well as decreased conversion in black girls from increased skin pigmentation. In this cross-sectional

Laura Harkness; Barbara Cromer



Correlation of bone histology with parathyroid hormone, vitamin D3, and radiology in end-stage renal disease  

Microsoft Academic Search

Correlation of bone histology with parathyroid hormone, vitamin D3, and radiology in end-stage renal disease. We analyzed transiliac bone biopsy specimens from 30 end-stage renal failure patients, taken at the time of admission for CAPD training. Results were compared with values of iPTH, bone alkaline phosphatase, 1,25-dihydroxyvitamin D3, skeletal survey, quantitative computed tomography (QCT) and single photon absorptiometry (SPA) bone

Alastair J Hutchison; Rick W Whitehouse; Helen F Boulton; Judy E Adams; E Barbara Mawer; Tony J Freemont; Ram Gokal



Vitamin D, parathyroid hormone levels and bone mineral density in community-dwelling older women: The Rancho Bernardo Study  

Microsoft Academic Search

Vitamin D (25(OH)D) increases the efficiency of intestinal calcium absorption. Low levels of serum calcium stimulate the secretion of parathyroid hormone (PTH), which maintains serum calcium levels at the expense of increased bone turnover, bone loss and increased risk of fractures. We studied the association between 25(OH)D and PTH levels, and their associations with bone mineral density (BMD), bone loss,

Denise G. von Mühlen; Gail A. Greendale; Cedric F. Garland; Lori Wan; Elizabeth Barrett-Connor



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

PubMed Central

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

Naveh-Many, T; Silver, J



Cross-Sectional Analysis of Abnormalities of Mineral Homeostasis, Vitamin D and Parathyroid Hormone in a Cohort of Pre-Dialysis Patients  

Microsoft Academic Search

Background: Disturbances in mineral and vitamin D metabolism, which affect parathyroid hormone (PTH) synthesis, are well recognized in patients receiving dialysis. However, it is unclear at what stage of chronic kidney disease (CKD) these abnormalities develop. Methods: The associations between CKD stages 3 and 5, and alterations of calcium, phosphate, vitamin D and PTH concentrations were assessed in 249 patients

Daniel Zehnder; Martin J. Landray; David C. Wheeler; William Fraser; Lisa Blackwell; Sarah Nuttall; Sue V. Hughes; John Townend; Charles Ferro; Colin Baigent; Martin Hewison



Vitamin D, Parathyroid Hormone and Their Associations with Hypertension in a Chinese Population  

PubMed Central

Background Conflicting reports support or refute an association between vitamin D deficiency with high levels of parathyroid hormone (PTH) and raised blood pressure or hypertension. Objective To explore the associations of serum vitamin D and PTH levels with blood pressure and risk of hypertension in a Chinese population. Methods A population-based cross-sectional study was conducted among 1,420 Chinese participants, aged 20–83 years, in 2010. Anthropometric phenotypes and blood pressure were evaluated. Serum lipids, 25-hydroxyvitamin D [25(OH)D] and PTH were measured. Results One thousand four hundred and twenty participants, including 566 women (39.9%), were evaluated in 2010. Four hundred and eighty seven were hypertensive (34.3%), of whom 214 (43.9%) received antihypertensive treatment. The median concentrations of serum 25(OH)D and PTH were 22.0 ng/ml and 2.83 pmol/l, respectively. Serum 25(OH)D and natural log of PTH levels were not independently associated with blood pressure in a multivariable adjusted linear regression analysis of 1,206 participants not receiving antihypertensive treatment (P>0.05). In logistic regression analyses, serum 25(OH)D levels were not associated with risk of hypertension in single and multiple regression models. One unit increments of natural log of PTH levels were significantly associated with risk of hypertension in the crude model (OR?=?1.78, 95% confidence interval 1.38–2.28, P<0.0001) and model adjusted for age and sex (OR?=?1.41, 95% confidence interval 1.08–1.83, P?=?0.01). However, these associations were attenuated and became nonsignificant (OR?=?1.29, 95% confidence interval 0.98–1.70, P?=?0.07) after further adjustment for body mass index, current alcohol intake, current smoking, glomerular filtration rate and family history of hypertension. Conclusions Serum vitamin D and PTH levels are not independently associated with blood pressure or risk of hypertension in a Chinese population.

Li, Lihua; Yin, Xueyan; Yao, Chaoyong; Zhu, Xuechuang; Wu, Xinhua



Plasma levels of parathyroid hormone, vitamin D, calcitonin, and calcium in association with endurance exercise  

Microsoft Academic Search

Summary Nine male marathon runners were investigated during habitual training (week 0), after 3 weeks of training break (week 3), and after 2 weeks (week 5) and 4 weeks (week 7) of retraining. Maximal oxygen uptake, body fat (BF), and plasma levels of 25(OH)D3, 1,25(OH)2D3, parathyroid hormone (PTH), calcitonin (CT), albumin, and albumincorrected calcium were determined throughout weeks 0–7. The

Tom Klausen; Leif Breum; Henrik Ancher Sørensen; Søren Schifter; Bente Sonne



High Prevalence of Vitamin D Insufficiency in China: Relationship with the Levels of Parathyroid Hormone and Markers of Bone Turnover  

PubMed Central

There is a lack of large-scale studies on vitamin D status and its relationship to parathyroid hormone (PTH) and bone turnover markers in adults living in Shanghai. The objectives were to determine the prevalence of vitamin D insufficiency in Shanghai and to investigate the relationship of 25(OH)D with parathyroid function and bone turnover markers. This cross-sectional study involved 649 men and 1939 women aged 20–89 years who were randomly sampled in Shanghai. Serum concentrations of 25(OH)D, PTH, albumin, and bone turnover markers were measured. During the winter season, the prevalence of vitamin D insufficiency (<30 ng/mL) was 84% in males and 89% in females. The prevalence of vitamin D deficiency (<20 ng/mL) was 30% in males and 46% in females. With increasing serum 25(OH)D concentrations categorized as <10, 10–20, 20–30, and ?30 ng/mL, the mean PTH and bone turnover markers levels gradually decreasd in both sexes (p<0.001). There was an inverse relationship between the serum 25(OH)D and PTH concentrations in both genders, but no threshold of 25(OH)D at which PTH levels plateaued was observed. There were modest but significantly inverse relationships between the levels of 25(OH)D and bone turnover markers, but no plateau was observed for serum 25(OH)D levels up to 40 ng/mL.

Ke, Yao-Hua; He, Jin-Wei; Fu, Wen-Zhen; Zhang, Chang-Qing; Zhang, Zhen-Lin



High prevalence of vitamin D insufficiency in China: relationship with the levels of parathyroid hormone and markers of bone turnover.  


There is a lack of large-scale studies on vitamin D status and its relationship to parathyroid hormone (PTH) and bone turnover markers in adults living in Shanghai. The objectives were to determine the prevalence of vitamin D insufficiency in Shanghai and to investigate the relationship of 25(OH)D with parathyroid function and bone turnover markers. This cross-sectional study involved 649 men and 1939 women aged 20-89 years who were randomly sampled in Shanghai. Serum concentrations of 25(OH)D, PTH, albumin, and bone turnover markers were measured. During the winter season, the prevalence of vitamin D insufficiency (<30 ng/mL) was 84% in males and 89% in females. The prevalence of vitamin D deficiency (<20 ng/mL) was 30% in males and 46% in females. With increasing serum 25(OH)D concentrations categorized as <10, 10-20, 20-30, and ?30 ng/mL, the mean PTH and bone turnover markers levels gradually decreasd in both sexes (p<0.001). There was an inverse relationship between the serum 25(OH)D and PTH concentrations in both genders, but no threshold of 25(OH)D at which PTH levels plateaued was observed. There were modest but significantly inverse relationships between the levels of 25(OH)D and bone turnover markers, but no plateau was observed for serum 25(OH)D levels up to 40 ng/mL. PMID:23144810

Lu, Han-Kui; Zhang, Zeng; Ke, Yao-Hua; He, Jin-Wei; Fu, Wen-Zhen; Zhang, Chang-Qing; Zhang, Zhen-Lin



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...


Role of Vitamin D and Parathyroid Hormone in the Regulation of Bone Turnover and Bone Mass in Men: The MINOS Study  

Microsoft Academic Search

We investigated the role of vitamin D and of parathyroid hormone (PTH) in the regulation of bone mineral density (BMD), tone dimensions and seasonal variation of bone turnover in 881 men aged 19–85 years. Bone mineral content (BMC) and BMD of the lumbar spine, hip and whole body were measured with HOLOGIC 1000W and those of distal forearm with an

P. Szulc; F. Munoz; F. Marchand; M. C. Chapuy; P. D. Delmas



Vitamin D and parathyroid hormone relationships with obesity, nitric oxide metabolites, oxidative stress, blood pressure, vascular function and salt sensitivity in African Americans  

Microsoft Academic Search

African Americans relative to white have higher rates of hypertension, nitric oxide (NO)-mediated endothelial dysfunction, oxidative stress\\/inflammation, salt sensitivity and obesity. Moreover, vitamin D deficiency and reactive rises in parathyroid hormone (PTH) are highly prevalent in African Americans, particularly in those who are obese. Furthermore, depressed 25-hydroxyvitamin D (25-OH D) and elevated PTH levels have been linked to obesity, elevated

Anna Liza B Valina-Toth



Associations of Vitamin D Receptor, Calcium-Sensing Receptor and Parathyroid Hormone Gene Polymorphisms with Calcium Homeostasis and Peripheral Bone Density in Adult Finns  

Microsoft Academic Search

Background: Thus far the search for osteoporosis candidate genes has focused less attention on the regulation of calcium homeostasis. Associations of vitamin D receptor (VDR) FokI, calcium-sensing receptor (CaSR) A986S and parathyroid hormone (PTH) BstBI polymorphisms with calcium homeostasis and peripheral bone density were investigated in adult Finns. Methods: The subgroup of the population-based FINRISK survey consists of 339 healthy

M. M. L. Laaksonen; T. A. Outila; M. U. M. Kärkkäinen; V. E. Kemi; H. J. Rita; M. Perola; L. M. Valsta; C. J. E. Lamberg-Allardt



Calcimimetics or vitamin D analogs for suppressing parathyroid hormone in end-stage renal disease: time for a paradigm shift?  

Microsoft Academic Search

Considerable advances have been made in the understanding of the pathogenesis and treatment of secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD). These include the discovery that the calcium-sensing receptor has an important role in the regulation of parathyroid gland function, the development of calcimimetics to target this receptor, the recognition that vitamin D receptor activation has important functions beyond

James B Wetmore; L Darryl Quarles



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

PubMed Central

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 (28.6±12.2 vs. 27.7±12.8%), IMTrad (0.271±0.060 vs. 0.255±0.053 mm), IMTcca (0.688±0.113 vs. 0.680±0.135 mm), or IM-GSM (82.3±17.2 vs. 86.5±15.3), while PWVao was slightly higher in patients (8.68±1.50 vs. 8.13±1.55, 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.

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



Vitamin D status and parathyroid hormone in a urban population in Vietnam  

Microsoft Academic Search

Summary  In this cross-sectional study in Vietnam, the prevalence of vitamin D insufficiency was 46% in adult women and 20% in adult\\u000a men. There was a linear inverse relationship between serum 25(OH)D and PTH concentrations, but there was no threshold of 25(OH)D\\u000a at which PTH levels plateaued.\\u000a \\u000a \\u000a \\u000a \\u000a Introduction  Vitamin D insufficiency is adversely associated with health outcomes. Vitamin D status in Asian

L. T. Ho-Pham; N. D. Nguyen; T. Q. Lai; J. A. Eisman; T. V. Nguyen



Measurement of Circulating Parathyroid Hormone  

Microsoft Academic Search

The measurement of parathyroid hormone (PTH) is important in the investigation of disorders of mineral metabolism. Though the first immunoassay for PTH was described more than 25 years ago, it is only recently that methods have been developed which provide the required sensitivity and specificity to detect small changes in hormone secretion in normal subjects. These new methods take advantage

J. S. Woodhead; A. C. Silver; J. P. Aston; R. C. Brown



Changes in the Calcium-Parathyroid Hormone-Vitamin D Axis and Prognosis for Critically Ill Patients: A Prospective Observational Study  

PubMed Central

Objective Vitamin D deficiency is prevalent in critically ill patients and may contribute to suboptimal clinical outcomes, but little is known about alterations of the calcium-parathyroid hormone (PTH)-vitamin D axis and prognosis in these individuals. Methods A prospective observational study was conducted on 216 patients admitted to a university-affiliated, tertiary-care medical intensive care unit(MICU) between June 2011 and December 2012. Serum levels of 25-hydroxyvitamin D, ionised calcium and intact PTH were determined within 24 h of MICU admission. The primary end point was all-cause hospital mortality within 90-days of admission. Results 95 patients (44%) showed 25-hydroxyvitamin D deficiency. Patients deficient in vitamin D showed significantly higher Acute Physiology and Chronic Health Evaluation II (APACHE II) score, rate of positive blood culture, incidence of multiple organ dysfunction syndrome, and 90-day mortality rate than did patients with vitamin D insufficiency or sufficiency (P<0.05), as well as lower levels of serum IgG. 25-Hydroxyvitamin D deficiency was identified as an independent risk factor for mortality (OR?=?3.018, 95%CI 1.329–6.854, P?=?0.008). Hypovitaminosis D in PTH-responders was associated with higher mortality than was the same condition in non-responders (P<0.05). Conclusions These results suggest that vitamin D deficiency is prevalent among MICU patients, suggesting a significant derangement of the calcium-PTH-vitamin D axis in critically ill patients. Vitamin D deficiency is an independent risk factor for 90-day mortality, and hypovitaminosis D in PTH-responders is associated with higher mortality than is the same condition in non-responders.

Zhao, Xiaoqin; Chen, Qiang; Chen, Zhaoyan; Qin, Hua; Qin, Yingfen; Liang, Xinghuan; Suo, Yingjun



Parathyroid hormone and bone biomechanics  

Microsoft Academic Search

Parathyroid hormone (PTH) treatment, either in the form of teriparatide or recombinant human PTH(1–34), reduces the fracture\\u000a risk of osteoporotic women by enhancing both structural and material biomechanical properties. Cortical bone thickness and\\u000a cross-sectional moment of inertia increase because of new bone formation on periosteal and endocortical surfaces. Intracortical\\u000a porosity is increased yet preferential localization near the endocortical surface limits

Matthew R. Allen; David B. Burr



Parathyroid Hormone and Bone Healing  

Microsoft Academic Search

Fracture healing is a complex process, and a significant number of fractures are complicated by impaired healing and non-union.\\u000a Impaired healing is prevalent in certain risk groups, such as the elderly, osteoporotics, people with malnutrition, and women\\u000a after menopause. Currently, no pharmacological treatments are available. There is therefore an unmet need for medications\\u000a that can stimulate bone healing. Parathyroid hormone

M. Ellegaard; N. R. Jørgensen; P. Schwarz



Dietary Intake of Vitamin D in Premenopausal, Healthy Vegans was Insufficient to Maintain Concentrations of Serum 25-hydroxyvitamin D and Intact Parathyroid Hormone Within Normal Ranges During the Winter in Finland  

Microsoft Academic Search

Objective To study vitamin D status and bone metabolism of premenopausal vegetarians and omnivores during a 1-year period.Design Longitudinal, observational study. Bone mineral density was measured, blood samples from fasting subjects were obtained, and 24-hour urinary samples were collected in February 1994, August 1994, and January 1995. Serum 25-hydroxyvitamin D [S-25(OH)D] and intact parathyroid hormone (Si-PTH) concentrations were measured and




The Calcimimetic Agent AMG 073 Lowers Plasma Parathyroid Hormone Levels in Hemodialysis Patients with Secondary Hyperparathyroidism  

Microsoft Academic Search

Treatment with vitamin D sterols can lower plasma parathyroid hormone (PTH) in many patients with secondary hyperparathyroidism due to end-stage renal disease, but hyper- calcemia, hyperphosphatemia, or both often develop during treatment. As such, alternative therapeutic approaches to man- aging excess PTH secretion are needed. Calcimimetic agents directly inhibit PTH secretion by activating the calcium-sens- ing receptor in the parathyroid



Osteoporotic fracture and parathyroid hormone  

PubMed Central

Osteoporosis and age-related bone loss is associated with changes in bone remodeling characterized by decreased bone formation relative to bone resorption, resulting in bone fragility and increased risk of fractures. Stimulating the function of bone-forming osteoblasts, is the preferred pharmacological intervention for osteoporosis. Recombinant parathyroid hormone (PTH), PTH(1-34), is an anabolic agent with proven benefits to bone strength and has been characterized as a potential therapy for skeletal repair. In spite of PTH’s clinical use, safety is a major consideration for long-term treatment. Studies have demonstrated that intermittent PTH treatment enhances and accelerates the skeletal repair process via a number of mechanisms. Recent research into the molecular mechanism of PTH action on bone tissue has led to the development of PTH analogs to control osteoporotic fractures. This review summarizes a number of advances made in the field of PTH and bone fracture to combat these injuries in humans and in animal models. The ultimate goal of providing an alternative to PTH, currently the sole anabolic therapy in clinical use, to promote bone formation and improve bone strength in the aging population is yet to be achieved.

Datta, Nabanita S



A G Protein-Linked Receptor for Parathyroid Hormone and Parathyroid Hormone-Related Peptide  

Microsoft Academic Search

The complementary DNA encoding a 585-amino acid parathyroid hormone-parathyroid hormone-related peptide (PTH-PTHrP) receptor with seven potential membrane-spanning domains was cloned by COS-7 expression using an opossum kidney cell complementary DNA (cDNA) library. The expressed receptor binds PTH and PTHrP with equal affinity, and both ligands equivalently stimulate adenylate cyclase. Striking homology with the calcitonin receptor and lack of homology with

Harald Juppner; Abdul-Badi Abou-Samra; Mason Freeman; Xiang F. Kong; Ernestina Schipani; Jennifer Richards; Lee F. Kolakowski Jr.; Janet Hock; John T. Potts Jr.; Henry M. Kronenberg; Gino V. Segre



Determination of Hormone Parathyroid by Radioimmunoassay.  

National Technical Information Service (NTIS)

The labelling of bovine parathyroid hormone and its employment for the determination of seric PTH by radioimmunoanalysis is described. The specific activity of exp 131 I PTH is 200-350mCi/mg and the damage 3-5%. The method used for radioimmunoanalysis was...

C. Fisher-Ferraro M. Moos de Ephraim C. Mautalen A. E. A. Mitta



The regulation of parathyroid hormone secretion and synthesis.  


Secondary hyperparathyroidism classically appears during the course of chronic renal failure and sometimes after renal transplantation. Understanding the mechanisms by which parathyroid hormone (PTH) synthesis and secretion are normally regulated is important in devising methods to regulate overactivity and hyperplasia of the parathyroid gland after the onset of renal insufficiency. Rapid regulation of PTH secretion in response to variations in serum calcium is mediated by G-protein coupled, calcium-sensing receptors on parathyroid cells, whereas alterations in the stability of mRNA-encoding PTH by mRNA-binding proteins occur in response to prolonged changes in serum calcium. Independent of changes in intestinal calcium absorption and serum calcium, 1?,25-dihydroxyvitamin D also represses the transcription of PTH by associating with the vitamin D receptor, which heterodimerizes with retinoic acid X receptors to bind vitamin D-response elements within the PTH gene. 1?,25-Dihydroxyvitamin D additionally regulates the expression of calcium-sensing receptors to indirectly alter PTH secretion. In 2°HPT seen in renal failure, reduced concentrations of calcium-sensing and vitamin D receptors, and altered mRNA-binding protein activities within the parathyroid cell, increase PTH secretion in addition to the more widely recognized changes in serum calcium, phosphorus, and 1?,25-dihydroxyvitamin D. The treatment of secondary hyperparathyroidism by correction of serum calcium and phosphorus concentrations and the administration of vitamin D analogs and calcimimetic agents may be augmented in the future by agents that alter the stability of mRNA-encoding PTH. PMID:21164021

Kumar, Rajiv; Thompson, James R



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

Microsoft Academic Search

Summary  It is unclear whether optimal levels of 25-hydroxyvitamin D (25(OH)D) in whites are the same as in minorities. In adult participants\\u000a of NHANES, the relationships between 25(OH)D, bone mineral density (BMD), and parathyroid hormone (PTH) differed in blacks\\u000a as compared to whites and Mexican-Americans, suggesting that optimal 25(OH)D levels for bone and mineral metabolism may differ\\u000a by race.\\u000a \\u000a \\u000a \\u000a \\u000a Introduction  Blacks and

O. M. Gutiérrez; W. R. Farwell; D. Kermah; E. N. Taylor



Decreased parathyroid hormone levels despite persistent hypocalcemia in patients with kidney failure recovering from septic shock.  


Introduction: Hypocalcemia is a common and poorly understood finding in critically ill patients. The current study was designed to assess the association of ionized calcium, vitamin D, phosphorus and Parathyroid hormone levels in a cohort of patients with and without kidney dysfunction admitted for sepsis or non-infectious causes. Methods: Prospective cohort clinical and biochemical study. Results: We confirmed that hypocalcemia and hypovitaminosis D are a common finding in critically ill patients. Parathyroid hormone levels significantly rise in septic shock. In the recovery phase, however, despite persistent hypocalcemia, Parathyroid hormone levels abruptly decrease in patients with kidney dysfunction, but not in patients with normal renal function. Conclusions: The systemic inflammatory response syndrome probably leads to inappropriately high Parathyroid hormone levels during septic shock. In the recovery phase, Parathyroid hormone levels decrease, but calcium levels remain low, displaying evidence that the parathyroid is not responding as expected. Since Parathyroid hormone receptors and calcium-sensing receptors have been described in immune cells and other cell types, we propose that these effects may have a plethora of other deleterious effects, with important implications to the pathogenesis of septic shock. PMID:23270481

Pinheiro da Silva, Fabiano; Zampieri, Fernando Godinho; Barbeiro, Hermes Vieira; Filho, Francisco Torggler; Goulart, Alessandra Carvalho; Jorgetti, Vanda; Velasco, Irineu Tadeu; da Cruz Neto, Luiz Monteiro; de Souza, Heraldo Possolo



Preoperative localization of suspicious parathyroid adenomas by assay of parathyroid hormone in needle aspirates  

Microsoft Academic Search

Objective: To determine the usefulness of parathyroid hormone (PTH) measurement in needle aspirates of a suspicious neck mass to confirm its parathyroid nature in patients with primary hyperpara- thyroidism. Methods: Thirty-three patients with surgically proved primary hyperparathyroidism were submitted to neck ultrasound (US), parathyroid scintigraphy, and assay of PTH in the aspirate (PTHa) of the suspicious cervical mass. Results: Based

C Marcocci; S Mazzeo; G Bruno-Bossio; A Picone; E Vignali; M Ciampi; P Viacava; A G Naccarato; P Miccoli; P Iacconi; A Pinchera



Hypoparathyroidism: clinical features, skeletal microstructure and parathyroid hormone replacement  

PubMed Central

Objective Hypoparathyroidism is a disorder in which parathyroid hormone is deficient in the circulation due most often to immunological destruction of the parathyroids or to their surgical removal. The objective of this work was to define the abnormalities in skeletal microstructure as well as to establish the potential efficacy of PTH(1-84) replacement in this disorder. Subjects and methods Standard histomorphometric and ?CT analyses were performed on iliac crest bone biopsies obtained from patients with hypoparathyroidism. Participants were treated with PTH(1-84) for two years. Results Bone density was increased and skeletal features reflected the low turnover state with greater BV/TV, Tb. Wi and Ct. Wi as well as suppressed MS and BFR/BS as compared to controls. With PTH(1-84), bone turnover and bone mineral density increased in the lumbar spine. Requirements for calcium and vitamin D fell while serum and urinary calcium concentrations did not change. Conclusion Abnormal microstructure of the skeleton in hypoparathyroidism reflects the absence of PTH. Replacement therapy with PTH has the potential to correct these abnormalities as well as to reduce the requirements for calcium and vitamin D.

Rubin, Mishaela R.; Bilezikian, John P.



Rapid Parathyroid Hormone Analysis During Venous Localization  

PubMed Central

Objective To determine the usefulness of the rapid parathyroid hormone (PTH) assay during venous localization for primary hyperparathyroidism (1° HPTH). Summary Background Data Remedial exploration for persistent 1° HPTH poses a significant challenge when noninvasive preoperative localization studies are negative. Based on experience with the intraoperative rapid PTH assay, this technique was extrapolated to the interventional radiology suite and generated near real-time data for the interventional radiologist employing on-site hormone analysis, with a 12-minute turnaround time from blood sampling to assay result. Methods Between November 1997 and July 2002, 446 patients with 1° HPTH were referred for treatment. Of these, 56 (12.5%) represented remedial patients who had each undergone one or more previous cervical explorations. Noninvasive imaging studies were positive for or suggestive of localized disease in 49/56 (87.5%) of these patients, who therefore proceeded directly to surgical exploration. Seven patients with persistent 1° HPTH and negative noninvasive studies underwent selective venous sampling employing a rapid PTH assay in the interventional suite. Results Venous localization demonstrated an apparent PTH gradient in six of the seven patients. In three, a subtle gradient demonstrated in near real-time prompted additional sampling, which confirmed an unequivocal hormone gradient. In an additional case, the absence of a gradient on initial sampling prompted further sampling, which was positive. All of the patients were explored, and in five of the six patients with a positive PTH gradient, a parathyroid adenoma (mean weight 636 ± 196 mg) was resected from a location predicted by venous localization. In the sixth patient with a positive gradient, parathyroid tissue was not identified; however, there was a significant fall in the intraoperative PTH values, and immediate postoperative and follow-up laboratory data at 1 month are indicative of a cure. In the one patient with negative localization, abnormal parathyroid tissue could not be located during surgical exploration. Conclusions The rapid PTH assay is a major adjunct for obtaining informative venous localization in patients with persistent 1° HPTH. This information is extremely helpful to the surgeon in this challenging group of patients and resulted in a 100% cure rate when a venous gradient was demonstrated. The authors now employ this technique routinely in remedial patients with negative noninvasive imaging studies.

Udelsman, Robert; Aruny, John E.; Donovan, Patricia I.; Sokoll, Lori J.; Santos, Florie; Donabedian, Richard; Venbrux, Anthony C.





1. Immunochemical cross-reactivity, but not identity, has been demonstrated between bovine parathyroid hormone and an antigen in biologically active extracts of human parathyroid tissue by quantitative C' fixation and C' fixation inhibition. 2. An antigen that fixes C' with rabbit antibody to bovine parathyroid hormone has been found in urea extracts of six human non-parathyroid neoplasms associated with a hypercalcemic syndrome mimicking primary hyperparathyroidism. Comparable extracts of control tissues and other tumors were serologically negative. 3. It is concluded that the tumor antigen is parathyroid hormone or a very closely related protein, and that its production by these neoplasms was the cause of the hypercalcemic syndrome in these six patients. PMID:14129717




21 CFR 862.1545 - Parathyroid hormone test system.  

Code of Federal Regulations, 2013 CFR




Parathyroid hormone and growth in children with chronic renal failure  

Microsoft Academic Search

Parathyroid hormone and growth in children with chronic renal failure.BackgroundIn pediatric chronic renal failure (CRF) optimal parathyroid hormone (PTH) concentrations that minimize renal osteodystrophy and maximize growth are unknown. The search for optimum concentrations has been complicated as currently used “intact” PTH (iPTH) assays cross-react with long carboxyl-terminal PTH fragments (C-PTH), which antagonize the biologic actions of 1-84 PTH. The




Degradation of parathyroid hormone in macrophage endosomes  

SciTech Connect

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.

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



Parathyroid carcinoma: current understanding and new insights into gene expression and intraoperative parathyroid hormone kinetics.  


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

Abdelgadir Adam, Mohamed; Untch, Brian R; Olson, John A



A longitudinal study of serum 25-hydroxyvitamin D and intact parathyroid hormone levels indicate the importance of vitamin D and calcium homeostasis regulation in multiple sclerosis  

Microsoft Academic Search

Background:Past sun exposure and vitamin D3 supplementation have been associated with a reduced risk of multiple sclerosis (MS). There are no previous longitudinal studies of vitamin D in MS.Objectives:To compare regulation of vitamin D and calcium homeostasis between patients with MS and healthy controls. To study the correlation of parameters of vitamin D metabolism with MS activity.Methods:We measured 25-hydroxyvitamin D

M Soilu-Hänninen; M Laaksonen; I Laitinen; J-P Erälinna; E-M Lilius; I Mononen



Calcium-mediated parathyroid hormone release changes in patients treated with the calcimimetic agent cinacalcet  

Microsoft Academic Search

Background. The parathyroid-calcium (Ca 2+ -PTH) curve expresses modulation of parathyroid hormone (PTH) se- cretion by the parathyroid gland as a function of chang- ing extracellular Ca 2+ concentration. Patients with hyper- parathyroidism (HPT) show a rightward shift of the curve compared with controls, suggesting a reduced sensitivity of parathyroid cells to Ca 2+ . Increasing the sensitivity of the

Angel L. M. de Francisco; Maria Izquierdo; John Cunningham; Celestino Pi; Rosa Palomar



Parathyroid Hormone Suppresses Insulin Signaling in Adipocytes  

PubMed Central

Summary Previous reports suggest that parathyroid hormone (PTH) is associated with insulin resistance. This research investigated the effects of PTH on insulin signaling in differentiated 3T3-L1 adipocytes. PTH (10 nM, 24 h) treatment induced a reduction in insulin-stimulated glucose uptake, AKT activity (phosphorylated AKT/total AKT protein expression) and a decrease in GLUT4 and IRS-1 protein expression compared to vehicle treated controls in differentiated adipocytes. PTH treatment also induced increased phosphorylation of IRS-1 on serine 307, which suppresses insulin signaling. In addition, treatment of cells with adenyl cyclase inhibitor SQ52236 ameliorated the effects of PTH on insulin-stimulated glucose uptake, whereas inhibition of phospholipase C ?(U73122) did not significantly alter the effects of PTH. Thus, PTH treatment of differentiated 3T3-L1 adipocytes suppresses insulin-stimulated glucose uptake and insulin signaling via cAMP pathway, potentially through the phosphorylation of IRS-1 at serine 307.

Chang, Eugene; Donkin, Shawn S.; Teegarden, Dorothy



A calcimimetic agent acutely suppresses parathyroid hormone levels in patients with chronic renal failure Rapid Communication  

Microsoft Academic Search

A calcimimetic agent acutely suppresses parathyroid hormone levels in patients with chronic renal failure. The control of hyperparathyroidism in patients with chronic renal failure continues to be a problem, particularly when parathyroid hormone (PTH) suppression becomes refractory to calcitriol activation of parathyroid cell 1,25-dihydroxyvitamin D receptors. To evaluate whether parathyroid cell calcium receptor activation may be useful in suppressing PTH

John E Antonsen; Donald J Sherrard; Dennis L Andress



Parathyroid hormone: a double-edged sword for bone metabolism  

Microsoft Academic Search

Parathyroid hormone (PTH) is the major hormone regulating calcium metabolism. It is also the only FDA-approved drug for osteoporosis treatment that stimulates bone formation when injected daily. However, continuous infusion of PTH causes severe bone loss in line with its known catabolic effects. Many studies to understand the dual effects of PTH have been carried out, and in recent years

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



Menin Inactivation Leads to Loss of Transforming Growth Factor Inhibition of Parathyroid Cell Proliferation and Parathyroid Hormone Secretion  

Microsoft Academic Search

Primary hyperparathyroidism is a common endocrine disorder caused by parathyroid gland enlargement and excessive parathyroid hormone (PTH) secretion. However, the precise mechanisms of tumorigenesis of the parathyroids are unknown. Here we have investigated the roles of trans- forming growth factor (TGF)- and menin, the product of the multiple endocrine neoplasia type 1 (Men1) gene, in the proliferation and PTH production

Hideaki Sowa; Hiroshi Kaji; Riko Kitazawa; Sohei Kitazawa; Tatsuo Tsukamoto; Shozo Yano; Toshihiko Tsukada; Lucie Canaff; Geoffrey N. Hendy; Toshitsugu Sugimoto; Kazuo Chihara



The effect of growth hormone on parathyroid function in rats.  


The effect of excessive growth hormone (GH) on parathyroid function in rats was evaluated in order to determine whether the GH-induced increase in serum calcium (Ca) may be mediated via stimulation of parathyroid hormone (PTH) secretion. Rats receiving injections of bovine GH 2 mg daily for 4 weeks showed a progressive significant increase in both serum Ca and immunoreactive PTH (iPTH) after the second week. Rats receiving daily injections of rat GH, 0.25 mg daily for 3 weeks, followed by 0.5 mg daily for 3 additional weeks, showed a significant increase in serum iPTH during administration of the higher dose, and also a significantly increased parathyroid gland weight and PTH content. The concomitant increase in serum Ca and iPTH suggest that GH stimulates the parathyroid glands to increase PTH secretion, which in turn causes an increase in serum Ca. The parathyroid response increases with the increase in dose and duration of GH stimulus. The data suggest that the hypercalcemia often observed in acromegaly may be due, at least in part, to GH-induced excessive secretory activity of the parathyroid glands. PMID:1261522

Lancer, S R; Bowser, E N; Hargis, G K



The Renal Handling of Parathyroid Hormone  

PubMed Central

The mechanisms of uptake of parathyroid hormone (PTH) by the kidney was studied in anesthetized dogs before and after ureteral ligation. During constant infusion of bovine PTH (b-PTH 1-84), the renal arteriovenous (A-V) difference for immunoreactive PTH (i-PTH) was 22±2%. After ureteral ligation and no change in renal plasma flow, A-V i-PTH fell to 15±1% (P < 0.01), indicating continued and significant uptake of i-PTH at peritubular sites and a lesser role of glomerular filtration (GF) in the renal uptake of i-PTH. Since, under normal conditions, minimal i-PTH appears in the final urine, the contribution of GF and subsequent tubular reabsorption was further examined in isolated perfused dog kidneys before and after inhibition of tubular reabsorption by potassium cyanide. Urinary i-PTH per 100 ml GF rose from 8±4 ng/min (control) to 170±45 ng/min after potassium cyanide. Thus, i-PTH is normally filtered and reabsorbed by the tubular cells. The physiological role of these two mechanisms of renal PTH uptake was examined by giving single injections of b-PTH 1-84 or synthetic b-PTH 1-34 in the presence of established ureteral ligation. After injection of b-PTH 1-84, renal A-V i-PTH was 20% only while biologically active intact PTH was present (15-20 min). No peritubular uptake of carboxyl terminal PTH fragments was demonstrable. In contrast, after injection of synthetic b-PTH 1-34, renal extraction of N-terminal i-PTH after ureteral ligation (which was 13.4±0.6% vs. 19.6±0.9% in controls) continued for as long as i-PTH persisted in the circulation. These studies indicate that both GF and peritubular uptake are important mechanisms for renal PTH uptake. Renal uptake of carboxyl terminal fragments of PTH is dependent exclusively upon GF and tubular reabsorption, whereas peritubular uptake can only be demonstrated for biologically active b-PTH 1-84 and synthetic b-PTH 1-34.

Martin, Kevin J.; Hruska, Keith A.; Lewis, Jane; Anderson, Charles; Slatopolsky, Eduardo




Technology Transfer Automated Retrieval System (TEKTRAN)

Manipulating diet cation-anion difference to reduce milk fever and hypocalcemia in the periparturient cow is now commonly practiced on dairies. However, how lowering DCAD improves calcium status remains uncertain. Previous work in our lab suggested tissue responsiveness to parathyroid hormone is i...


Intraoperative parathyroid hormone monitoring during parathyroidectomy for secondary hyperparathyroidism  

Microsoft Academic Search

Background. The surgical management of secondary hyperparathyroidism by experienced surgeons is associated with excellent results. The presence of supernumerary glands and inadequate initial parathyroidectomy can lead to reoperations for recurrence. Intraoperative parathyroid hormone monitoring (qPTH), which has been described during parathyroidectomy for primary hyperparathyroidism, may be helpful in preventing or predicting the need for reoperation. This report describes the use

Bryan M Clary; Sanford C Garner; George S Leight



Parathyroid Hormone and Calcium Blood Levels in Acute Renal Failure  

Microsoft Academic Search

Parathyroid hormone (PTH), creatinine, calcium and phosphate blood levels were repeatedly measured in 5 patients with acute renal failure. 1 patient developed hypercalcemia during the recovery phase of the illness. PTH was elevated in all cases before starting hemodialysis treatment and returned to normal when renal function recovered. Calcium and PTH were inversely correlated in 3 patients including the patient

M. Fuss; J. Bagon; E. Dupont; T. Manderlier; H. Brauman; J. Corvilain



Role of Parathyroid Hormone as a Uremic Toxin.  

National Technical Information Service (NTIS)

The final report summarizes the work completed during the period between 7/22/79 and 9/30/81. Five areas of investigation on the effect of parathyroid hormone (PTH) on various organ systems are described. The results demonstrate a wide variety of extraske...

S. G. Massry



Effect of prostaglandin E1 on certain renal actions of parathyroid hormone  

PubMed Central

Parathyroid hormone increased basal adenyl cyclase activity and that increase was inhibited by prostaglandin E1 (PGE1). Tissue cyclic 3?,5?-adenosine monophosphate (cyclic AMP) concentrations were increased by parathyroid hormone and that increase was likewise inhibited by PGE1. Both parathyroid hormone and dibutyryl cyclic AMP increased 32P incorporation into renal cortical phospholipids. PGE1 diminished the effect of parathyroid hormone but not dibutyryl cyclic AMP to influence that parameter. PGE1 likewise modulated the effect of parathyroid hormone but not dibutyryl cyclic AMP to decrease fractional phosphate reabsorption by the renal tubule. It is suggested that PGE1 inhibits the effect of parathyroid hormone by decreasing its effect on adenyl cyclase. Such interaction may be important in modulating the intracellular action of parathyroid hormone on kidney cortex.

Beck, Nama P.; DeRubertis, Frederick R.; Michelis, Michael F.; Fusco, Robert D.; Field, James B.; Davis, Bernard B.



Induction of the vitamin D 24-hydroxylase (CYP24) by 1,25-dihydroxyvitamin D3 is regulated by parathyroid hormone in UMR106 osteoblastic cells.  


The expression of the vitamin D 24-hydroxylase is highly regulated in target tissues for 1,25-dihydroxyvitamin D3 (1,25(OH)2D), where it may modulate the action of 1,25(OH)2D. In UMR106 osteoblastic cells, 1,25(OH)2D and PTH synergistically induce 24-hydroxylase expression. The purpose of these studies was to characterize the interaction between 1,25(OH)2D and PTH with regard to the messenger RNA (mRNA) levels of the cytochrome P450 component of the 24-hydroxylase (CYP24). PTH alone had no effect on CYP24 mRNA levels, and 1,25(OH)2D alone produced only a modest increase. However, 1,25(OH)2D and PTH together synergistically increased CYP24 mRNA levels 3-fold compared with 1,25(OH)2D alone. PTH also increased the sensitivity of UMR cells to 1,25(OH)2D from 10(-8) to 10(-10) M. PTH worked through the cAMP signaling pathway as evidenced by the lack of effect of PTH (3-34) and by the full activity of 8-bromo-cAMP. PTH in the presence of 1,25(OH)2D increased CYP24 gene transcription as shown by nuclear run-on studies and by activation of a CYP24 promoter-reporter construct after transfection. PTH also increased vitamin D receptor number in UMR cells, but this occurred at times later than the increase in transcription. These studies demonstrate that PTH in the presence of 1,25(OH)2D works through the cAMP-dependent signaling pathway to increase transcription of the CYP24 gene, to increase CYP24 protein levels, and to increase 24-hydroxylase activity. PMID:9681485

Armbrecht, H J; Hodam, T L; Boltz, M A; Partridge, N C; Brown, A J; Kumar, V B



Effects of lowering dialysate calcium concentration on mineral metabolism and parathyroid hormone secretion: a multicentric study.  


This prospective study was conducted with the aim of examining the efficacy of lowering dialysate calcium (dCa) in order to: (i) stimulate bone turnover in hemodialysis patients with biochemical signs of adynamic bone disease (ABD) (hypercalcemia, normal alkaline phosphatase and intact parathyroid hormone (iPTH) <150 pg/mL); and (ii) diminish hypercalcemia in patients with secondary hyperparathyroidism (sHPT) (hypercalcemia, high alkaline phosphatase and iPTH > 400 pg/mL), thus permitting the use of calcium-containing phosphorus binders and vitamin D metabolites. Patients were divided into: an ABD-treated group (24 patients), a sHPT-treated group (18 patients), an ABD-control group (12 patients) and a sHPT-control group (11 patients). For the ABD- and sHPT-treated patients, hemodialysis was conducted with dCa 1.5 mmol/L for three months and then with dCa 1.25 mmol/L for an additional three months, while in the control groups hemodialysis was conducted with dCa 1.75 mmol/L during the entire study. Reduction of dCa in patients with ABD caused a slight but insignificant decrease of Ca, but a significant and permanent increase of bone-specific alkaline phosphatase and intact parathyroid hormone level serum levels. Reduction of dCa in patients with sHPT slightly but insignificantly decreased Ca and intact parathyroid hormone level values. Nevertheless, this enabled the calcium-based phosphate binder dose to be raised and vitamin D3 metabolites to be introduced. Logistic regression analysis indicated that milder bone disease (both ABD and sHPT) was associated with more the favorable effect of dCa reduction. Thus, low dCa stimulated parathyroid glands and increased bone turnover in ABD patients, and enabled better control of mineral metabolism in sHPT patients. PMID:17381533

Lezaic, Visnja; Pejanovic, Svetlana; Kostic, Sveta; Pljesa, Stevo; Dimkovic, Nada; Komadina, Ljiljana; Jovanovic, Dragan; Marinkovic, Jelena; Djukanovic, Ljubica



Impact of calcium and vitamin D insufficiencies on serum parathyroid hormone and bone mineral density: analysis of the fourth and fifth Korea National Health and Nutrition Examination Survey (KNHANES IV-3, 2009 and KNHANES V-1, 2010).  


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] concentration to calcium metabolism and bone mass in a population with low calcium intake, a total of 4662 adults (2567 men and 2095 women) ?50 years of age from the 2009-2010 Korea National Health and Nutrition Examination Survey (KNHANES) were divided into groups according to dietary calcium intakes (quintiles means: 154, 278, 400, 557, and 951?mg/d) and serum 25(OH)D concentrations (<50, 50-75, and >75?nmol/L). Serum intact parathyroid hormone (PTH) and femoral neck and lumbar spine BMD were evaluated according to dietary calcium intake and serum 25(OH)D. Mean calcium intake was 485?mg/d; mean serum 25(OH)D concentration was 48.1?nmol/L; PTH was 68.4?pg/mL; femoral neck BMD was 0.692?g/cm(2) ; and lumbar spine BMD was 0.881?g/cm(2) . Lower dietary calcium intakes were significantly associated with higher serum PTH concentrations and lower femoral neck BMD, not only at lower (<50?nmol/L) but also at higher (>75?nmol/L) serum 25(OH)D concentrations. Serum PTH was highest and femoral neck BMD was lowest in the group, with a serum 25(OH)D less than 50?nmol/L. In this low-intake population, calcium intake is a significant determinant of serum PTH and BMD at higher as well as lower 25(OH)D levels. This finding indicates that low calcium intake cannot be compensated for with higher 25(OH)D levels alone. As expected, serum 25(OH)D levels were inversely associated with serum PTH and BMD. A calcium intake of at least 668?mg/d and a serum 25(OH)D level of at least 50?nmol/L may be needed to maintain bone mass in this calcium deficient population. PMID:23045165

Joo, Nam-Seok; Dawson-Hughes, Bess; Kim, Young-Sang; Oh, Kyungwon; Yeum, Kyung-Jin



Dopaminergic stimulation of cyclic AMP accumulation and parathyroid hormone release from dispersed bovine parathyroid cells  

PubMed Central

The effects of dopaminergic agonists and antagonists have been studied in dispersed bovine parathyroid cells. Dopaminergic agonists caused a transient 20- to 40-fold increase in cellular cyclic AMP and a 2- to 3-fold increase in parathyroid hormone release. Dose-response relationships were similar for cyclic AMP accumulation and hormone release, whether studied by increasing agonist concentration or by increasing concentration of antagonist with constant agonist. The effects on the dopamine receptor could be differentiated from those of the previously characterized ?-adrenergic receptor by specific inhibitors. These results appear to represent proof with a homogeneous cell population that dopaminergic receptors linked to adenylate cyclase can regulate a secretory process mediated by cyclic AMP. This system should be useful in further studies on dopamine receptors and should provide a valid tool for determining interactions of radiolabeled ligands with such receptors.

Brown, E. M.; Carroll, R. J.; Aurbach, G. D.



Treatment of osteoporosis with parathyroid hormone and teriparatide.  


Nowadays osteoporosis treatment is based primarily on therapy with antiresorptive agents, like the bisphosphonates. Parathyroid hormone (Preotact) and human recombinant parathyroid hormone peptide 1-34 (Teriparatide) are relatively new for the treatment of osteoporosis and belong to the group of anabolic agents. Both agents demonstrated an increase in bone mineral density and a significant reduction in vertebral fractures in postmenopausal women with osteoporosis when given for 18-24 months. Data on nonvertebral fractures are, however, not clear-cut, and so far only bisphosphonates and strontium ranelate have been demonstrated to reduce all types of fractures and therefore remain the front-line option for treatment of osteoporosis. As the safety, tolerability, and cost of the therapy also influence the choice of therapy, Preotact and Teriparatide might be useful additions to the armamentarium for (second-line) treatment of osteoporosis. PMID:19189037

Pleiner-Duxneuner, Johannes; Zwettler, Elisabeth; Paschalis, Eleftherios; Roschger, Paul; Nell-Duxneuner, Valerie; Klaushofer, Klaus



Parathyroid hormone analogues in the treatment of osteoporosis  

Microsoft Academic Search

Osteoporosis is characterized by the occurrence of fragility fractures. Over the past years, various treatment options have become available, mostly antiresorptive agents such as bisphosphonates. However, antiresorptive therapy cannot restore bone mass and structure that has been lost due to increased remodeling. In this case, recombinant human parathyroid hormone (PTH) analogues—the full-length PTH1–84 or the shortened molecule PTH1–34, which is

Christian Meier; Marius E. Kraenzlin



Serum Parathyroid Hormone Levels in Chronic Endemic Fluorosis  

Microsoft Academic Search

Endemic waterborne fluorosis is a public health problem in Isparta, a city located in southern Turkey. Fluoride is a cumulative\\u000a element that increases metabolic turnover of the bone and also affects the homeostasis of bone mineral metabolism. There are\\u000a number of similarities between the effects of excess parathyroid hormone (PTH) and fluorosis on bone. So fluoride might show\\u000a its effect

Banu Kale Koroglu; Ismail Hakki Ersoy; Mert Koroglu; Ay?e Balkarli; Siddika Ersoy; Simge Varol; Mehmet Numan Tamer


The use of parathyroid hormone in the treatment of osteoporosis  

Microsoft Academic Search

Anabolic skeletal agents have recently broadened our therapeutic options for osteoporosis. By directly stimulating bone formation,\\u000a they reduce fracture incidence by improving bone qualities in addition to increasing bone mass. Teriparatide [recombinant\\u000a human parathyroid hormone(1–34)], the only anabolic agent currently approved in the United States for osteoporosis, has emerged\\u000a as a major therapeutic approach to selected patients with osteoporosis. Teriparatide

Monica Girotra; Mishaela R. Rubin; John P. Bilezikian



Parathyroid hormone-related protein and lung biology  

Microsoft Academic Search

Parathyroid hormone-related protein (PTHrP) is expressed in normal and malignant lung and has roles in development, homeostasis, and pathophysiology of injury and cancer. Its effects in developing lung include regulation of branching morphogenesis and type II cell maturation. In adult lung, PTHrP stimulates disaturated phosphatidylcholine secretion, inhibits type II cell growth, and sensitizes them to apoptosis. In lung cancer, PTHrP

Randolph H. Hastings



The development of parathyroid hormone as anabolic therapy for osteoporosis  

Microsoft Academic Search

At first glance, parathyroid hormone (PTH) peptides seem rather unlikely candidates as treatments for osteoporosis. For the\\u000a better part of the last century, we focused almost exclusively on the catabolic action of these peptides on bone, despite\\u000a the fact that anabolic activity had been demonstrated as early as 1929. The intent of this article is to provide snapshots,\\u000a of the

David W. Dempster; Jonathan Reeve



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

PubMed Central

Parathyroid hormone-related peptide is a regulatory protein implicated in the pathogenesis of bone metastases, particularly in breast carcinoma. Parathyroid hormone-related peptide is widely expressed in primary prostate cancers but there are few reports of its expression in prostatic metastases. The aim of this study was to examine the expression of parathyroid hormone-related peptide and its receptor in matched primary and in bone metastatic tissue from patients with untreated adenocarcinoma of the prostate. Eight-millimetre trephine iliac crest bone biopsies containing metastatic prostate cancer were obtained from 14 patients from whom matched primary tumour tissue was also available. Histological grading was performed by an independent pathologist. The cellular location of mRNA for parathyroid hormone-related peptide and parathyroid hormone-related peptide receptor was identified using in situ hybridization with 35S-labelled probe. Expression of parathyroid hormone-related peptide and its receptor was described as uniform, heterogenous or negative within the tumour cell population. Parathyroid hormone-related peptide expression was positive in 13 out of 14 primary tumours and in all 14 metastases. Receptor expression was evident in all 14 primaries and 12 out of 14 metastases. Co-expression of parathyroid hormone-related peptide and parathyroid hormone-related peptide receptor was common (13 primary tumours, 12 metastases). The co-expression of parathyroid hormone-related peptide and its receptor suggest that autocrine parathyroid hormone-related peptide mediated stimulation may be a mechanism of escape from normal growth regulatory pathways. The high frequency of parathyroid hormone-related peptide expression in metastases is consistent with a role in the pathogenesis of bone metastases. British Journal of Cancer (2002) 86, 322–325. DOI: 10.1038/sj/bjc/6600115 © 2002 The Cancer Research Campaign

Bryden, A A G; Hoyland, J A; Freemont, A J; Clarke, N W; George, N J R



Eldecalcitol is less effective in suppressing parathyroid hormone compared to calcitriol in vivo.  


Eldecalcitol is a vitamin D3 analog under clinical development for the treatment of osteoporosis. Previous studies have shown that the binding activities of eldecalcitol to the serum vitamin D binding protein (DBP) and the vitamin D receptor (VDR) are 421.9% and 44.6% of those of calcitriol, respectively, and also, suppressed parathyroid hormone (PTH) production by only 3.5% of calcitriol in vitro using bovine parathyroid cell primary culture. Here, we compared in vivo activities of eldecalcitol on serum calcium, BMD and PTH with those of calcitriol. Six-week old male rats were given either vehicle (medium chain triglyceride; n=6), eldecalcitol (0.025, 0.05, 0.1, 0.25, 0.5 microg/kg; n=6) or calcitriol (0.25, 0.5, 1.0, 2.5, 5 microg/kg; n=6) daily for 14 days by oral gavages. Eldecalcitol was approximately five-times more potent than calcitriol in increasing serum calcium. Eldecalcitol significantly increased lumbar spine BMD, however, calcitriol had no effect on BMD at any given doses. On the contrary, eldecalcitol did not affect PTH mRNA synthesis at the normocalcemic doses, despite the BMD was higher than normal. These observations indicate that, as previous in vitro study suggested, eldecalcitol is less effective in suppressing PTH compared to calcitriol. PMID:20398764

Harada, Suguru; Takeda, Satoshi; Uno, Akiko; Takahashi, Fumiaki; Saito, Hitoshi



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

SciTech Connect

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.

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.; (SVIMR-A); (Chugai); (Melbourne)



The calcimimetic AMG 073 reduces parathyroid hormone and calcium x phosphorus in secondary hyperparathyroidism  

Microsoft Academic Search

The calcimimetic AMG 073 reduces parathyroid hormone and calcium x phosphorus in secondary hyperparathyroidism.BackgroundA need exists for a therapy that lowers parathyroid hormone (PTH) without increasing calcium x phosphorus in patients with secondary hyperparathyroidism. The calcimimetic AMG 073 increases the sensitivity of the parathyroid calcium-sensing receptor to extracellular calcium, thereby reducing PTH secretion. Consequently, AMG 073 may provide a novel

Jill S Lindberg; Sharon M Moe; William G Goodman; Jack W Coburn; Stuart M Sprague; Wei Liu; Peter W Blaisdell; Robert M Brenner; Stewart A Turner; Kevin J Martin



Parathyroid hormone related protein in hypercalcaemia of Hodgkin's disease.  

PubMed Central

The role of parathyroid hormone related protein (PTHRP) as a humoral mediator of hypercalcaemia was investigated in a patient with lymphocyte depleted Hodgkin's disease during an episode of hypercalcaemia, using an immunohistochemical staining technique for PTHRP on the tumour tissue and an immunoradiometric (IRMA) assay for PTHRP1-86 on the patient's plasma. The plasma PTHRP was less than 0.23 pmol/l in the range found in normocalcaemic controls, and the immunohistochemical staining was not positive for protein. PTHRP did not have a role in the pathogenesis of hypercalcaemia in this patient. Images

Bolo-Deoku, J.; Basu, S.; Lakhani, S.; Dunne, F.; Ratcliffe, W. A.; Clarke, M.; Barron, J. L.



Anomalous effects of hormone fragments on the measurement of parathyroid hormone by radioimmunoassay.  


One of the basic assumptions underlying the use of radioimmunoassay and other competitive protein-binding assays is the homogeneity of the antigen or ligand. This assumption is not valid for the measurement of parathormone (PTH) because of the presence of fragments. Hence, there is a potential for errors and high variability in the measurement of parathyroid hormone (PTH) by radioimmunoassay. Even though region-specific radioimmunological and immunoradiometric assays for PTH measurement can overcome some of the difficulties caused by the presence of hormone fragments, the possibility for serious measurement errors still remains. We therefore examined experimentally and by modeling the impact of fragments on the estimation of the concentration of a highly purified intact bovine parathyroid hormone by radioimmunoassay. Our experimental results show that the mere presence of fragments can lead to a significant underestimation or overestimation of the amount of the intact hormone. The results have been simulated by a model in which fragments bind to the antibodies, thus competing with the intact hormone, and to the intact hormone as well, thereby reducing the amount of free intact hormone in competition with the radioligand. This work indicates that it may be preferable to consider alternative methods, other than competitive protein-binding assays, for the measurement of secreted PTH. PMID:8740240

Mbuyi-Kalala, A; Ehrenstein, G



Influence of parathyroid hormone on bone cell ultrastructure  

SciTech Connect

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)

Matthews, J.L. (Baylor Univ. Medical Center, Dallas, TX); Talmage, R.V.



Desensitization of parathyroid hormone receptors on cultured bone cells  

SciTech Connect

Administration of excessive amounts of parathyroid hormone (PTH) in the treatment of osteoporosis can reverse the beneficial effects of a low-dose, intermittent regime. To investigate the direct actions and the possible cellular mechanisms of PTH in inducing desensitization of PTH receptors, we studied the effects of desensitization on rat osteoblastic UMR-106 cells. When the osteoblasts were preincubated with bPTH-(1-34), complete refractoriness to a subsequent challenge with the hormone developed within 1 h and at hormone concentrations as low as 5 nM. When osteoblasts thus desensitized were incubated in hormone-free medium, recovery of the cAMP responses began within 2 h and reached maximum after 16 h. Cycloheximide did not affect the process of desensitization. (Nle8,Nle18,Tyr34)bPTH-(3-34)amide significantly impaired the desensitization process by PTH-(1-34) but did not have stimulatory effect on cAMP responses. No significant heterologous desensitization was obvious after preincubation with isoprenaline (50 microM), prostaglandin E1 (50 microM), or prostaglandin E2 (50 microM) for 2 h. Binding experiments with (125I)PLP-(1-36)amide after desensitization revealed that there was an approximate twofold decrease in receptor affinities as analyzed by Scatchard analysis, showing that the decrease in affinity was prominent in the process of desensitization. When the cells were treated with monensin during desensitization, PTH challenge after desensitization produced significantly lower cyclic AMP responses. Recovery after desensitization occurred over a period of 16 h. Inclusion of monensin, but not cycloheximide, impaired the recovery. The results show that homologous desensitization of rat osteoblasts to PTH is brought about by the occupancy of receptors by PTH-(1-34) but not by cAMP generation itself.

Pun, K.K.; Ho, P.W.; Nissenson, R.A.; Arnaud, C.D. (Univ. of Hong Kong (Hong Kong))



Effect of acute and chronic metabolic acidosis on serum immunoreactive parathyroid hormone in man  

Microsoft Academic Search

Effect of acute and chronic metabolic acidosis on serum immunoreactive parathyroid hormone in man. The effects of acute and chronic metabolic acidosis on serum immunoreactive parathyroid hormone (iPTH) were studied. Acute metabolic acidosis induced by administration of ammonium chloride (NH4Cl) produced a barely detectable increase in serum iPTH. Chronic NH4Cl administration produced a marked elevation of serum iPTH that was

Fredric L Coe; John J Firpo; Don L Hollandsworth; Laurence Segil; Janet M Canterbury; Eric Reiss; Frederic L Coe



Dopamine enhances the phosphaturic response to parathyroid hormone in phosphate-deprived rats.  


Phosphate deprivation results in a resistance to the phosphaturic effect of parathyroid hormone. Dopamine is phosphaturic and is synthesized by kidney proximal tubule, the nephron subsegment where parathyroid hormone inhibits phosphate transport. Thus, to test the hypothesis that phosphate deprivation is associated with low intrarenal dopamine synthesis and that dopamine infusion will overcome the resistance to the phosphaturic response to parathyroid hormone, the following study was performed. The effect of dietary phosphate intake on intrarenal dopamine synthesis, as reflected by urinary dopamine excretion, was determined. Rats were placed in metabolic cages (N = 5) and were fed a low-phosphate diet (0.07% Pi) for 4 days and then a high-phosphate diet (1.8% Pi) for 4 days. Twenty-four-hour urinary dopamine excretion was significantly lower in rats fed a low-phosphate diet (2.53 +/- 0.06 versus 4.10 +/- 0.30 micrograms/day). Further, the effect of dopamine infusion on the blunted phosphaturic response to parathyroid hormone was studied in rats fed a low-phosphate diet for 1, 2, and 3 days. Control clearances were taken 2 h after thyroparathyroidectomy; then, parathyroid hormone (33 U/kg plus 1 U/kg/min), dopamine (25 micrograms/kg/min), or parathyroid hormone plus dopamine were infused for 60 min. Changes in the fractional excretion of phosphate were significantly greater in rats fed a low-phosphate diet infused with parathyroid hormone plus dopamine than in rats fed a low-phosphate diet infused with parathyroid hormone alone (delta 27.9 +/- 5.8 versus 11.2 +/- 2.6% for day 1; 28.4 +/- 1.4 versus 7.1 +/- 3.6% for day 2; and 10.7 +/- 2.8 versus -0.2 +/- 0.2% for day 3; N = 5 for all groups).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1627764

Isaac, J; Berndt, T J; Chinnow, S L; Tyce, G M; Dousa, T P; Knox, F G



Coordinated control of renal Ca2+ transport proteins by parathyroid hormone  

Microsoft Academic Search

Coordinated control of renal Ca2+ transport proteins by parathyroid hormone.BackgroundThe kidney is one of the affected organs involved in the clinical symptoms of parathyroid hormone (PTH)-related disorders, like primary hyperparathyroidism and familial hypocalciuric hypercalcemia. The molecular mechanism(s) underlying alterations in renal Ca2+ handling in these disorders is poorly understood.MethodsParathyroidectomized and PTH-supplemented rats and mice infused with the calcimimetic compound NPS




A calcimimetic agent lowers plasma parathyroid hormone levels in patients with secondary hyperparathyroidism  

Microsoft Academic Search

A calcimimetic agent lowers plasma parathyroid hormone levels in patients with secondary hyperparathyroidism.BackgroundThe calcimimetic agent R-568 lowers plasma parathyroid hormone (PTH) levels in hemodialysis patients with mild secondary hyperparathyroidism, but its efficacy in those with more severe secondary hyperparathyroidism has not been studied.MethodsTwenty-one patients undergoing hemodialysis three times per week with plasma PTH levels between 300 and 1200 pg\\/mL were

William G. Goodman; Joao M. Frazao; David A. Goodkin; Stewart A. Turner; Wei Liu; Jack W. Coburn



Thymus-Associated Parathyroid Hormone Has Two Cellular Origins with Distinct Endocrine and Immunological Functions  

PubMed Central

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

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



Primary hyperparathyroidism: four- to eight-year postoperative follow-up demonstrating persistent functional insignificance of microscopic parathyroid hyperplasia and decreased autonomy of parathyroid hormone release.  

PubMed Central

Thirty-nine patients with primary hyperparathyroidism were studied four to eight years after their initial operation. In six patients, both the pathologist and surgeon agreed on the diagnosis of solitary adenoma; in 16 patients, the surgeon diagnosed solitary adenoma and the pathologist parathyroid hyperplasia (microscopic hyperplasia). In 16 patients, primary chief cell hyperplasia was agreed upon by the pathologist and surgeon. In the 16 patients with microscopic hyperplasia, there have been no long-term recurrences of hypercalcemia, but, in two patients, plasma parathyroid hormone levels are high. Parathyroid hormone--total calcium regression curves demonstrate significant preoperative correlation in solitary adenoma, p less than 0.01, and primary chief cell hyperplasia, p less than 0.05. After operation, significant correlations were not found between parathyroid hormone and total calcium. T-testing slope differences of pre- and postoperative parathyroid hormone--total calcium regression curves demonstrates a significant (p less than 0.01) shift to the right of the microscopic hyperplasia patients after operation, moving them to a broader range of total calcium per picogram parathyroid hormone. We conclude that 1) in primary hyperparathyroidism, positive regulation of total calcium by autonomously released parathyroid hormone exists in patients with solitary adenoma and chief cell hyperplasia; 2) autonomously functioning parathyroid tissue has been removed by operation for solitary adenoma with coexistent microscopic parathyroid hyperplasia. In this four- to eight-year follow-up period, it is clear that microscopic parathyroid hyperplasia is not associated with recurrent hypercalcemia. Two functionally distinct forms of parathyroid suppression are suggested; positively regulated microscopic hyperplasia and negatively regulated pathologically suppressed glands.

Harrison, T S; Duarte, B; Reitz, R E; Princenthal, R; Seaton, J F; Badder, E M; Graham, W P



High Prevalence of Low Femoral Bone Mineral Density in Elderly Women Living in Nursing Homes or Community-Dwelling: A Plausible Role of Increased Parathyroid Hormone Secretion  

Microsoft Academic Search

:   The present study was designed to visit elderly women living in nursing homes and to compare their femoral neck bone mineral\\u000a density (BMD) and circulating levels of parathyroid hormone (PTH) and 25-OH vitamin D (25-OHD) with those of subjects living\\u000a at home, in the immediate vicinity of the nursing homes. Of 1483 women, aged 70 years and older, who

J.-Y. Reginster; R. Deroisy; H. Pirenne; I. Frederick; W. Dewe; A. Albert; J. Collette; S. X. Zheng; C. Gosset



A new analog of calcitriol, 19-nor-1,25-(OH) 2D 2, suppresses parathyroid hormone secretion in uremic rats in the absence of hypercalcemia  

Microsoft Academic Search

The active metabolite of vitamin D, calcitriol (1?,25-(OH)2D3), suppresses parathyroid hormone (PTH) gene transcription. Although 1?,25-(OH)2D3 is effective in suppressing secondary hyperparathyroidism (SH) in uremic patients, the mandatory use of large amounts of calcium salts to control serum phosphorus may preclude, in some patients, the use of ideal therapeutic doses of 1?,25-(OH)2D3 because of hypercalcemia. We have studied a new

Eduardo Slatopolsky; Jane Finch; Cindy Ritter; Masashi Denda; Jeremiah Morrissey; Alex Brown; Hector DeLuca



Distinctive Tooth Extraction Socket Healing: Bisphosphonate vs. Parathyroid Hormone Therapy.  


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

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



Parathyroid hormone is not an inhibitor of lipoprotein lipase activity.  


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

Arnadottir, M; Nilsson-Ehle, P



Pulsatile Release of Parathyroid Hormone from an Implantable Delivery System  

PubMed Central

Intermittent (pulsatile) administration of parathyroid hormone (PTH) is known to improve bone micro-architecture, mineral density and strength. Therefore, daily injection of PTH has been clinically used for the treatment of osteoporosis. However, this regimen of administration is not convenient and is not a favorable choice of patients. In this study, an implantable delivery system has been developed to achieve pulsatile release of PTH. A well-defined cylindrical device was first fabricated with a biodegradable polymer, poly(lactic acid) (PLLA), using a reverse solid free form fabrication technique. Three-component polyanhydrides composed of sebacic acid, 1,3-bis(p-carboxyphenoxy) propane and poly(ethylene glycol) were synthesized and used as isolation layers. The polyanhydride isolation layers and PTH-loaded alginate layers were then stacked alternately within the delivery device. The gap between the stacked PTH-releasing core and the device frame was filled with PLLA to seal. Multi-pulse PTH release was achieved using the implantable device. The lag time between two adjacent pulses were modulated by the composition and the film thickness of the polyanhydride. The released PTH was demonstrated to be biologically active using an in vitro assay. Timed sequential release of multiple drugs has also been demonstrated. The implantable device holds promise for both systemic and local therapies.

Liu, Xiaohua; Pettway, Glenda J.; McCauley, Laurie K.; Ma, Peter X.



Parathyroid Hormone-Related Protein Promotes Epithelial-Mesenchymal Transition  

PubMed Central

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

Ardura, Juan Antonio; Rayego-Mateos, Sandra; Ramila, David; Ruiz-Ortega, Marta



Serum parathyroid hormone levels in chronic endemic fluorosis.  


Endemic waterborne fluorosis is a public health problem in Isparta, a city located in southern Turkey. Fluoride is a cumulative element that increases metabolic turnover of the bone and also affects the homeostasis of bone mineral metabolism. There are number of similarities between the effects of excess parathyroid hormone (PTH) and fluorosis on bone. So fluoride might show its effect via PTH. We aimed to determine PTH levels in patients with endemic fluorosis to estimate the possible toxic effects of chronic fluoride intake. Fifty-six patients with endemic fluorosis and 28 age-, sex-, and body-mass-index-matched healthy controls were included in this study. Endemic fluorosis was diagnosed according to the clinical diagnosis criteria of Wang. The urine fluoride levels of fluorosis patients were significantly higher than those of control subjects as expected (1.9 ± 0.1 vs. 0.4 ± 0.1 mg/L, respectively; P < 0.001). PTH levels in fluorosis group were significantly higher than control group (65.09 ± 32.91 versus 47.40 ± 20.37, respectively; P = 0.01). The results of our study demonstrate that serum PTH levels are increased in patients with endemic fluorosis. Fluoride, by interfering calcium balance, may be the cause of secondary hyperparathyroidism. PMID:20838920

Koroglu, Banu Kale; Ersoy, Ismail Hakki; Koroglu, Mert; Balkarli, Ay?e; Ersoy, Siddika; Varol, Simge; Tamer, Mehmet Numan



Effect of Parathyroid Hormone on Osmotic Fragility of Human Erythrocytes  

PubMed Central

The survival of erythrocytes (RBC) is shortened in uremia, and it has been shown that calcium influx into RBC evoked crenation and increased their rigidity. The high blood levels of parathyroid hormone (PTH) may augment entry of calcium into RBC and hence affect their integrity. We examined the effect of PTH on osmotic fragility of human RBC and investigated the mechanisms through which PTH interacts with RBC. Both the amino-terminal (1-34) PTH and the intact (1-84) PTH, but not the carboxy-terminal (53-84) PTH, produced significant increases in osmotic fragility. This effect was abolished by prior inactivation of the hormone. There was a dose-response relationship between both moieties of PTH and the increase in osmotic fragility. This action of PTH required calcium, was mimicked by calcium ionophore, and was partially blocked by verapamil. PTH caused significant influx of 45Ca into RBC, which was not associated with potassium leak. The hormone did not affect water content of RBC. Scanning electron microscopy revealed that the incubation of RBC with PTH was associated with the appearance of membrane filamentous extensions, which anchor RBC together. Inhibition of glycolytic activity of RBC with NaF or inhibition of Na-K-activated ATPase with ouabain did not abolish the effect of PTH on osmotic fragility. PTH did not stimulate RBC Na-K-activated ATPase or Mg-dependent ATPase but caused marked and significant stimulation of Ca-activated ATPase. The basal activity of the RBC adenylate cyclase was low and PTH produced only a modest stimulation of this enzyme. Both cyclic AMP and dibutyryl cyclic AMP had no effect on osmotic fragility. The data indicate that: (a) the RBC is a target organ for PTH, (b) the hormone increases osmotic fragility of RBC, and (c) this effect of PTH is due to enhanced calcium entry into RBC. We suggest that the increased calcium influx may affect the spectrin-actin of the cytoskeletal network of the RBC and may alter the stability and integrity of the cell membrane. This action of PTH on the RBC could be, at least in part, responsible for the shortened survival of RBC in uremia, and assign a new role for PTH in the pathogenesis of the anemia of uremia. Images

Bogin, Eitan; Massry, Shaul G.; Levi, Joseph; Djaldeti, Meir; Bristol, Greg; Smith, Jacqueline



Vitamin D: Secosteroid hormone and human reproduction  

Microsoft Academic Search

Vitamin D is a secosteroid with an endocrine mechanism of action which is sequentially synthesized in humans in the skin, liver and kidneys. The active hormone, 1a,25-dihydrocholecalciferol (1,25(OH)2D3), is often considered only in terms of its role in controlling calcium and phosphorus homeostasis. However, cumulative evidence points to the presence of vitamin D receptors in many tissues. The present article




Identification of a renal receptor for parathyroid hormone by photoaffinity radiolabeling using a synthetic analogue  

SciTech Connect

To identify a parathyroid hormone-binding component in renal membranes, a biologically active photoaffinity radioligand of parathyroid hormone was designed using chemical strategies based on the experience of earlier structure-activity studies. The sulfur-free, oxidation-resistant, synthetic analogue of bovine parathyroid hormone (bPTH), (Nle-8,Nle-18,Tyr-34) bPTH-(1-34) amide, was radiolabeled with /sup 125/iodine. Two photolabile moieties, 4-fluoro-3-nitrophenyl azide and N-succinimidyl-6(4' -azido-2' -nitrophenyl amino)-hexanoate, were separately conjugated to iodinated peptide under conditions favoring coupling through lysine side chains rather than the NH/sub 2/-terminal amino group. Concurrent studies established that a photolabile analogue was fully active in the renal adenylate cyclase assay. After incubation of both photolabile analogues in darkness with renal membranes in the presence or absence of competing hormone, exposure to light covalently linked the analogues to membrane components. Membranes were then solubilized, reduced, and fractionated on sodium dodecyl sulfate poly- acrylamide gels. Radioautographs of the gels showed four to six labeled membrane components for each analogue in the absence of competing hormone, but only one band failed to label in the presence of competing hormone. This band labeled in the presence of inactive synthetic fragments of parathyroid hormone, and was not identified in membrane preparations derived from a renal cell line that is not parathyroid hormone-responsive. The migration of the band (M/sub r/ approx. = 70,000) was identical regardless of the photolabile analogue employed. These studies provide a technique useful for further study of the interactions of parathyroid hormone and receptor in various target tissues and for receptor purification and characterization.

Coltera, M.D.; Potts, J.T.; Rosenblatt, M.



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

PubMed Central

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 ?g/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.

Daugaard, H.; Elmengaard, B.; Andreassen, T. T.; Baas, J.; Bechtold, J. E.; S?balle, K.



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...


Parathyroid hormone suppresses osteoblast apoptosis by augmenting DNA repair  

PubMed Central

Daily injection of parathyroid hormone (PTH) is a clinically approved treatment for osteoporosis. It suppresses apoptosis of bone forming osteoblasts although its exact anti-apoptotic mechanism(s) is incompletely understood. In this study, PTH treatment of cultured osteoblasts blocked the pro-apoptotic effects of serum withdrawal and nutrient deprivation; hydrogen peroxide induced oxidative stress, and UV irradiation. We hypothesized that PTH might suppress osteoblast apoptosis by enhancing DNA repair. Evidence is provided showing that post-confluent, non-proliferating osteoblasts treated with PTH exhibited a protein kinase A-mediated activation of two proteins that regulate DNA repair processes (proliferating cell nuclear antigen and forkhead box transcription factor 3a) as well as a suppression of the pro-apoptotic growth arrest and DNA damage protein 153. Additional proof of a connection between DNA damage and osteoblast apoptosis came from an unexpected finding whereby a majority of fixed PTH-treated osteoblasts scored weakly positive for Terminal Deoxynucleotidyl dUTP Nick-End Labeling (TUNEL), even though similar cultures were determined to be viable via a trypsin replating strategy. TUNEL identifies DNA excision repair, not just apoptotic DNA fragmentation, and the most likely explanation of these TUNEL results is that PTH's activation of DNA repair processes would permit nucleotide incorporation as a result of enhanced excision repair. This explanation was confirmed by an enhanced incorporation of bromodeoxyuridine in PTH-treated cells even though a majority of the cell population was determined to be non-replicating. An augmentation of DNA repair by PTH is an unreported finding, and provides an additional explanation for its anti-apoptotic mechanism(s).

Schnoke, Matthew; Midura, Sharon B.; Midura, Ronald J.



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

Microsoft Academic Search

The involvement of sodium\\/potassium-ATPase in regulating parathyroid hormone (PTH) secretion is inferred from in vitro studies. Recently, the ?-klotho-dependent rapid recruitment of this ATPase to the parathyroid cell plasma membrane in response to low extracellular calcium ion was suggested to be linked to increased hormone secretion. In this study, we used an in vivo rat model to determine the importance

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



Sestamibi Scanning and Minimally Invasive Radioguided Parathyroidectomy Without Intraoperative Parathyroid Hormone Measurement  

PubMed Central

Objective To evaluate the results of a large series of patients undergoing minimally invasive radioguided parathyroidectomy (MIRP) in which routine use of the intraoperative parathyroid hormone assay was not used, and to investigate characteristics between patients who had positive preoperative parathyroid scans versus those with negative scans. Summary Background Data The technique of parathyroidectomy has traditionally involved bilateral exploration of the neck under general endotracheal anesthesia. Parathyroid imaging using technetium-99m sestamibi (MIBI) has evolved and can localize the adenomas in 80% to 90% of patients. The MIRP technique combines parathyroid scintigraphy with a hand-held gamma detector used intraoperatively to guide the surgeon to the adenoma in patients with positive MIBI scans. Central to this technique or other unilateral approaches is a positive MIBI scan. Methods One hundred seventy-three atients with primary hyperparathyroidism operated on by a single surgeon between January 1998 and July 2002 were included. One hundred twelve patients underwent the MIRP procedure and by definition had a positive preoperative parathyroid scan. The technique involved injecting 20 mCi MIBI 1 hour before the surgical procedure in patients who preoperatively had positive MIBI imaging. Patients had the choice of general or MAC anesthesia. Using an incision of less than 4 cm, the dissection to the adenoma was guided by the Navigator 11-mm probe. These 112 patients and 4 additional patients who for various reasons did not have the MIRP procedure yet had positive MIBI scans were compared to 57 patients who had clearly negative MIBI parathyroid imaging. Results Follow-up data were available for 108 of 112 patients who underwent MIRP. No patients had persistent hypercalcemia. The long-term success rate for the MIRP group was 98%. Fifty-two percent of the MIRP procedures were performed using MAC anesthesia. Overall, gland weight and serum PTH were related to the probability of a positive MIBI scan. Multiple logistic regression revealed that females were more likely to exhibit positive scans than were males for any fixed serum PTH level. For females, there was a significant relationship between increasing serum parathyroid hormone and a positive MIBI scan. Conversely, in males, the relationship between scan positivity and serum parathyroid hormone was weaker. Conclusions The MIRP technique without routine intraoperative serum parathyroid hormone measurement resulted in an excellent cure rate for primary hyperparathyroidism. As the MIRP technique as well as other techniques for unilateral cervical exploration are predicated on a positive parathyroid scan, the possible effect of gender on the sensitivity of MIBI scintigraphy for the detection of parathyroid adenomas warrants further investigation.

Goldstein, Richard E.; Billheimer, Dean; Martin, William H.; Richards, Ken



Wintertime Vitamin D Deficiency in Male Adolescents: Effect on Parathyroid Function and Response to Vitamin D3 Supplements  

Microsoft Academic Search

:   The first part of this study consisted of an 18 month follow-up of the vitamin D status and parathyroid function in a group\\u000a of 54 French male adolescents, aged from 13 to 16 years old and all pupils of a jockey training school. During the 18 month\\u000a period four samplings were made, one every 6 months. The first was

J. Guillemant; H.-T. Le; A. Maria; A. Allemandou; G. Pérès; S. Guillemant



Conflicting actions of parathyroid hormone-related protein and serum calcium as regulators of 25-hydroxyvitamin D3-1-hydroxylase expression in a nude rat model of humoral hypercalcemia of malignancy  

Microsoft Academic Search

In patients with humoral hypercalcemia of malignancy (HHM), serum levels of 1,25-dihydroxyvitamin D (1,25(OH)2D) are generally low, although the pathophysi- ology of the impaired vitamin D metabolism is not fully understood. In the present study, we have investigated vitamin D metabolism in our newly developed rat model of HHM in which a human infantile fibrosarcoma pro- ducing parathyroid hormone-related protein

T Michigami; H Yamato; H Suzuki; Y Nagai-Itagaki; K Sato; K Ozono


Serum parathyroid hormone levels in the hypercalcaemia of urological malignant disease.  

PubMed Central

Serum parathyroid hormone (PTH) levels have been measured in 8 patients with hypercalcaemia associated with urological malignancy: 3 renal cell carcinomas, 2 adenocarcinomas of prostate, 2 transitional cell carcinomas of bladder and one transitional cell carcinoma of kidney. Five (63%) of these 8 patients had bone metastases. PTH was detectable in the serum of all 8 hypercalcaemic patients, but in only 2 cases was the PTH level above the normal range, and in one of these a coincidental parathyroid adenoma was found to be responsible for the hypercalcaemia. It appears that these tumours can produce a hormone-like substance with biological effects similar to PTH.

Ramsay, J W; Hendry, W F



Gamma Probe Guided Minimally Invasive Parathyroidectomy without Quick Parathyroid Hormone Measurement in the Cases of Solitary Parathyroid Adenomas.  


Objective: In this study, our aim was to study the efficiency of gamma probe guided minimally invasive parathyroidectomy (GP-MIP), conducted without the intra-operative quick parathyroid hormone (QPTH) measurement in the cases of solitary parathyroid adenomas (SPA) detected with USG and dual phase 99mTc-MIBI parathyroid scintigraphy (PS) in the preoperative period. Material and Methods: This clinical study was performed in 31 SPA patients (27 female, 4 male; mean age 51±11years) between February 2006 and January 2009. All patients were operated within 30 days after the detection of the SPA with dual phase 99mTc-MIBI PS and USG. The GP-MIP was done 90-120 min after the iv injection of 740 MBq 99mTc-MIBI. In all cases, except 1 patient, the GP-MIP was performed under local anesthesia; due to the enormity of size of SPA, then general anesthesia is chosen. Results: The operation time was 30-60 min, mean 38,2±7 min. In the first postoperative day, there was a more than 50% decrease in PTH levels in all patients and all but one had normal serum calcium levels. Transient hypocalcemia was detected in one patient. Conclusion: GP-MIP without intra-operative QPTH measurement is a suitable method in the surgical treatment of SPA detected by dual phase 99mTc-MIBI PS and USG. Conflict of interest:None declared. PMID:23610724

Karya?ar, Sava?; Karya?ar, Sevda S; Yalç?n, Orhan; Yüney, Enis; Mülaz?mo?lu, Mehmet; Ozpaçac?, Tevfik; Karatepe, O?uzhan; Ozdenkaya, Ya?ar



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...


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


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

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



Prediction of target range of intact parathyroid hormone in hemodialysis patients with artificial neural network  

Microsoft Academic Search

The application of artificial neural network (ANN) to predict outcome and explore potential relationships among clinical data is increasing being used in many clinical scenarios. The aim of this study was to validate whether an ANN is a useful tool for predicting the target range of plasma intact parathyroid hormone (iPTH) concentration in hemodialysis patients. An ANN was constructed with

Yuh-feng Wang; Tsung-ming Hu; Chia-chao Wu; Fu-chiu Yu; Chao-ming Fu; Shih-hua Lin; Wei-hsin Huang; Jainn-shiun Chiu



Induction of osteoclast formation by parathyroid hormone depends on an action on stromal cells  

Microsoft Academic Search

It is believed that parathyroid hormone (PTH) increases the resorptive activity of pre-existing osteoclasts through a primary interaction with cells of the osteoblastic lineage. Much less is known, however, of the mechanisms by which PTH induces osteoclast formation. It is known that osteoclast formation occurs through a contact-dependent interaction between stromal cells and haemopoietic pre- cursors, but it is not

K Fuller; J M Owens; T J Chambers



Parathyroid hormone activation of the 25-hydroxyvitamin D3-1?-hydroxylase gene promoter  

PubMed Central

The DNA flanking the 5? sequence of the mouse 1?-hydroxylase gene has been cloned and sequenced. A TATA box has been located at ?30 bp and aCCAAT box has been located at ?79 bp. The gene’s promoter activity has been demonstrated by using a luciferase reporter gene construct transfected into a modified pig kidney cell line, AOK-B50. Parathyroid hormone stimulates this promoter-directed synthesis of luciferase by 17-fold, whereas forskolin stimulates it by 3-fold. The action of parathyroid hormone is concentration-dependent. 1,25-Dihydroxyvitamin D3 does not suppress basal promoter activity and marginally suppresses parathyroid hormone-driven luciferase reporter activity. The promoter has three potential cAMP-responsive element sites, and two perfect and one imperfect AP-1 sites, while no DR-3 was detected. These results indicate that parathyroid hormone stimulates 25-hydroxyvitamin D3-1?-hydroxylase by acting on the promoter of the 1?-hydroxylase gene.

Brenza, Holly L.; Kimmel-Jehan, Christine; Jehan, Frederic; Shinki, Toshimasa; Wakino, Shu; Anazawa, Hideharu; Suda, Tatsuo; DeLuca, Hector F.



Effects of carbendazim on rat thyroid, parathyroid, pituitary and adrenal glands and their hormones  

Microsoft Academic Search

The purpose of this study is to determine the effects of low and high dose of carbendazim on the level of certain hormones and endocrine glands (thyroid, parathyroid, adrenal and pituitary glands) of male rats. Carbendazim is a systemic fungicide with activity against a number of plant pathogens. In this study, daily doses of 0, 150, 300 and 600 mg\\/kg

N Barlas; G Selmanoglu; A Kockaya; S Songür



Catch-up growth with normal parathyroid hormone levels in chronic renal failure  

Microsoft Academic Search

The optimum range for parathyroid hormone (PTH) levels in children with chronic renal failure (CRF) remains undefined. We aimed to determine growth velocity in children with CRF managed with normal PTH levels. We performed a retrospective case note review of 99 children (77 boys), with a glomerular filtration rate (GFR) 2, who had at least 2 years of 3-monthly follow-up. The

Simon Waller; Sarah Ledermann; Richard Trompeter; William van’t Hoff; Deborah Ridout; Lesley Rees



Effect of glutaurine, a newly discovered parathyroid hormone on rat thymus cultures.  


Under the effect of the recently discovered parathyroid hormone, gamma-L-glutamyl-taurine (Glutaurine) growth of thymus cultures increased in all tested age groups. Epithelial growth was prominent and signs of activation of the macrophage cells appeared. In cell cultures the nuclei and nucleoli increased in size. PMID:747134

Feuer, L; Török, O; Csaba, G



Direct in vivo assessment of parathyroid hormone-calcium relationship curve in renal patients  

Microsoft Academic Search

Direct in vivo assessment of parathyroid hormone-calcium relation curve in renal patients. Secondary hyperparathyroidism (SHP) is a well documented finding even in the early stages of chronic renal failure (CRF). A sigmoidal relationship, fitting a four parameter model, links PTH secretion rate and calcium concentration changes. To our knowledge, PTH secretory parameters have only been studied in uremic patients who

Piergiorgio Messa; Clotilde Vallone; Giuseppe Mioni; Onelio Geatti; Daniela Turrin; Natalina Passoni; Aldo Cruciatti



Calcimimetic Compounds: a Direct Approach to Controlling Plasma Levels of Parathyroid Hormone in Hyperparathyroidism  

Microsoft Academic Search

The Ca2+ receptor is the primary mechanism regulating the secretion of parathyroid hormone (PTH). Ligands that activate this receptor (calcimimetics) represent a novel means of lowering plasma levels of PTH. Two mechanistically distinct classes of calcimimetics that inhibit PTH secretion have been identified: type I calcimimetics are full agonists of the Ca2+ receptor and include Ca2+ and other polyvalent inorganic

Edward F Nemeth; John Fox




Technology Transfer Automated Retrieval System (TEKTRAN)

How adjusting dietary cation-anion difference (DCAD) reduces milk fever incidence remains debatable. Our hypothesis is that DCAD affects acid-base status of the cow altering the action of parathyroid hormone (PTH) on its target tissues, primarily bone and kidney. PTH normally stimulates renal synt...


Direct and indirect effects of parathyroid hormone on circulating levels of fibroblast growth factor 23 in vivo  

Microsoft Academic Search

Fibroblastic growth factor 23 (FGF23) is a bone-derived hormone that has a pivotal role in the pathogenesis of mineral disorders in chronic kidney disease. To study the effect of parathyroid hormone (PTH) on FGF23, rats were parathyroidectomized for a week and then implanted with constant-delivery infusion pumps to provide vehicle, a physiological, or a threefold supraphysiological dose of parathyroid hormone.

Ignacio López; M Encarnación Rodríguez-Ortiz; Yolanda Almadén; Fátima Guerrero; A Montes de Oca; Carmen Pineda; Vicky Shalhoub; Mariano Rodríguez; Escolástico Aguilera-Tejero



A new analog of 1,25-(OH) 2D 3, 19NOR1,25-(OH) 2D 2, suppresses serum PTH and parathyroid gland growth in uremic rats without elevation of intestinal vitamin D receptor content  

Microsoft Academic Search

We have previously reported that 19-nor-1,25-(OH)2D2, a new analog of 1,25-(OH)2D3, suppresses parathyroid hormone (PTH) secretion in uremic rats in the absence of hypercalcemia or hyperphosphatemia. In the current study, we examined the effect of 19-nor-1,25-(OH)2D2on parathyroid gland growth and intestinal vitamin D receptor (VDR) content. After induction of uremia by 5\\/6 nephrectomy, rats were divided into five experimental groups

Fumiaki Takahashi; Jane L. Finch; Masashi Denda; Adriana S. Dusso; Alex J. Brown; Eduardo Slatopolsky



Ratio of Paricalcitol Dosage to Serum Parathyroid Hormone Level and Survival in Maintenance Hemodialysis Patients  

PubMed Central

Background and objectives: Several observational studies have indicated that vitamin D receptor activators (VDRA), including paricalcitol, are associated with greater survival in maintenance hemodialysis (MHD) patients; however, patients with higher serum parathyroid hormone (PTH), indicative of a more severe secondary hyperparathyroidism and higher death risk, are usually given higher VDRA dosages, which can lead to confounding by medical indication and attenuated survival advantage of high VDRA dosages. It was hypothesized that the ratio of the administered paricalcitol dosage to serum PTH level discloses better the underlying dosage–survival association. Design, setting, participants, & measurements: The 3-yr mortality predictability of the administered paricalcitol during the first 3 mo of the cohort divided by averaged serum intact PTH during the same period was examined in 34,307 MHD patients from all DaVita dialysis clinics across the United States using Cox regression. Results: MHD patients were 60.8 ± 15.4 yr of age and included 47% women, 34% black patients, and 47% patients with diabetes. Initially, the ratio of paricalcitol (?g/wk) to PTH (pg/ml) was divided into four groups: 0 (reference), 1 to <30, 30 to <60, and >60 × 10?3. Unadjusted, case mix–adjusted (demographics, comorbidity, and Kt/V), and malnutrition-inflammation complex syndrome–adjusted models, the death rate ratio for the paricalcitol/PTH index groups, were 0.99, 0.95, and 0.92. Restricted cubic splines analyses were consistent with a linear relation. Conclusions: Higher weekly paricalcitol dosage per each unit of serum PTH seems to have an incremental association with greater survival in MHD patients. The observed dosage-response phenomenon needs to be confirmed in clinical trials.

Shinaberger, Christian S.; Kopple, Joel D.; Kovesdy, Csaba P.; McAllister, Charles J.; van Wyck, David; Greenland, Sander; Kalantar-Zadeh, Kamyar



Upregulation of calcitriol during pregnancy and skeletal recovery after lactation do not require parathyroid hormone.  


Pregnancy invokes a doubling of intestinal calcium absorption whereas lactation programs skeletal resorption to provide calcium to milk. Postweaning bone formation restores the skeleton's bone mineral content (BMC), but the factors that regulate this are not established. We used Pth-null mice to test whether parathyroid hormone (PTH) is required for postweaning skeletal recovery. On a normal 1% calcium diet, wild-type (WT) and Pth-null mice each gained BMC during pregnancy, declined 15% to 18% below baseline during lactation, and restored the skeleton above baseline BMC within 14 days postweaning. A 2% calcium diet reduced the lactational decline in BMC without altering the gains achieved during pregnancy and postweaning. The hypocalcemia and hyperphosphatemia of Pth-null mice normalized during lactation and serum calcium remained normal during postweaning. Osteocalcin and propeptide of type 1 collagen (P1NP) each rose significantly after lactation to similar values in WT and Pth-null. Serum calcitriol increased fivefold during pregnancy in both genotypes whereas vitamin D binding protein levels were unchanged. Absence of PTH blocked a normal rise in fibroblast growth factor-23 (FGF23) during pregnancy despite high calcitriol. A 30-fold higher expression of Cyp27b1 in maternal kidneys versus placenta suggests that the pregnancy-related increase in calcitriol comes from the kidneys. Conversely, substantial placental expression of Cyp24a1 may contribute significantly to the metabolism of calcitriol. In conclusion, PTH is not required to upregulate renal expression of Cyp27b1 during pregnancy or to stimulate recovery from loss of BMC caused by lactation. A calcium-rich diet in rodents suppresses skeletal losses during lactation, unlike clinical trials that showed no effect of supplemental calcium on lactational decline in BMC. PMID:23505097

Kirby, Beth J; Ma, Yue; Martin, Heather M; Buckle Favaro, Kerri L; Karaplis, Andrew C; Kovacs, Christopher S



RenaGel®, a nonabsorbed calcium- and aluminum-free phosphate binder, lowers serum phosphorus and parathyroid hormone  

Microsoft Academic Search

RenaGel®, a nonabsorbed calcium- and aluminum-free phosphate binder, lowers serum phosphorus and parathyroid hormone.Background.This multicenter, open-label, dose-titration study assessed the safety and efficacy of RenaGel®, a nonabsorbed calcium- and aluminum-free phosphate binder, in lowering serum phosphorus. Secondary outcomes were its effects on serum intact parathyroid hormone (iPTH) and serum lipids.Methods.Phosphate binders were discontinued during a two-week washout period. Patients whose




Up-regulation of parathyroid hormone-related protein in folic acid-induced acute renal failure  

Microsoft Academic Search

Up-regulation of parathyroid hormone-related protein in folic acid-induced acute renal failure.BackgroundParathyroid hormone (PTH)-related protein (PTHrP) is present in many normal tissues, including the kidney. Current evidence supports that PTHrP is involved in renal pathophysiology, although its role on the mechanisms of renal damage and\\/or repair is unclear. Our present study examined the changes in PTHrP and the PTH\\/PTHrP receptor (type

Soledad Santos; Ricardo J. Bosch; Arantxa Ortega; Raquel Largo; Teresa Fernández-Agulló; Rosa Gazapo; Jesús Egido; Pedro Esbrit



Role of parathyroid hormone and 1,25-dihydroxyvitamin D 3 in the development of osteopenia in oophorectomized rats  

Microsoft Academic Search

Summary  The effect of ovarian insufficiency on calcium metabolism has been thought to involve an increased bone resorptive effect\\u000a of parathyroid hormone and possible impaired synthesis of 1,25-dihydroxyvitamin D3. In the present study a rat model allowing for controlled serum levels of parathyroid hormone and 1,25-dihydroxyvitamin D3 was used. Oophorectomy in this species is associated with increased serum levels of 1,25-dihydroxyvitamin

Urban Lindgren; Hector F. DeLuca



Anabolic and catabolic bone effects of human parathyroid hormone (1-34) are predicted by duration of hormone exposure  

Microsoft Academic Search

Parathyroid hormone (PTH)(1-34), given once daily, increases bone mass in a variety of animal models and humans with osteoporosis. However, continuous PTH infusion has been shown to cause bone loss. To determine the pharmacokinetic profile of PTH(1-34) associated with anabolic and catabolic bone responses, PTH(1-34) pharmacokinetic and serum biochemical profiles were evaluated in young male rats using dosing regimens that

Charles A Frolik; Elwood C Black; Ricky L Cain; Julie H Satterwhite; Patricia L Brown-Augsburger; Masahiko Sato; Janet M Hock



Serum parathyroid hormone level is associated with body mass index. The 5th Tromso study  

Microsoft Academic Search

Objective: To study whether serum parathyroid hormone (PTH) and serum calcium are associated with body mass index (BMI), and their predicting role in obesity. Design: Population based, cross-sectional study. Methods: In 2001 a population-based health survey was held in Tromsø, North Norway. Question- naires on medical history and life-style factors were completed and anthropometric data were col- lected. Calcium and

Elena Kamycheva; Johan Sundsfjord; Rolf Jorde



Relation of 25-hydroxyvitamin D and parathyroid hormone levels with metabolic syndrome among US adults  

Microsoft Academic Search

Objective: Previous research on the combined association of 25-hydroxyvitamin D (25(OH)D) and parathyroid hormone (PTH) with metabolic syndrome may have been limited by restricted age variability and a lack of representation of the general population. This study examined the combined association of 25(OH)D and PTH with Adult Treatment Panel III-defined MetSyn among a nationally representative sample of US adults. Design

Jared P Reis; Denise von Muhlen; Edgar R Miller III



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

Microsoft Academic Search

Summary  Chronic administration of parathyroid hormone, hPTH 1-34, increased bone mass in normocalcemic, young rats [6]. Since PTH\\u000a can stimulate prostaglandin E2 (PGE2) production in bonein vitro, and since PGE2 can stimulate bone formation, the anabolic effect of PTH could be mediated by PGE2. To test this hypothesis, experiments were done to determine if indomethacin, which blocks endogeneous PG production, would

I. Gera; J. M. Hock; M. Gunness-Hey; J. Fonseca; L. G. Raisz



Parathyroid hormone and bisphosphonate have opposite effects on stress fracture repair  

Microsoft Academic Search

This study was aimed to investigate the effects of Parathyroid hormone (PTH) and alendronate (ALN) on stress fracture repair. Stress fractures were induced in the ulnae of female adult rats. Animals were treated daily with vehicle, PTH (40 µg\\/kg) or alendronate (2µg\\/kg), respectively. Bone mineral content (BMC) and bone mineral density (BMD) of bilateral ulnae were measured at two, four

Ashley V. Sloan; Joseph R. Martin; Shuo Li; Jiliang Li



Extracellular calcium regulates parathyroid hormone-related peptide expression in osteoblasts and osteoblast progenitor cells  

Microsoft Academic Search

Parathyroid hormone-related peptide (PTHrP) has been shown to have anabolic effects on bone in women with postmenopausal osteoporosis. On the cellular level PTHrP promotes the recruitment of osteogenic cells and prevents apoptotic death of osteoblasts and osteocytes. The calcium concentration is considerably higher in the vicinity of resorbing osteoclasts than in the plasma. Therefore the osteoblasts are likely to be

Mikael Ahlstrom; Minna Pekkinen; Ulrike Riehle; Christel Lamberg-Allardt



Parathyroid hormone-related peptide and Indian hedgehog expression patterns in naturally acquired equine osteochondrosis  

Microsoft Academic Search

Early changes in parathyroid hormone-related peptide (PTH-rP) and Indian hedgehog (Ihh) expression were examined in equine articular osteochondrosis (OC) as a model of a naturally acquired dyschondroplasia. Cartilage was harvested from OC-affected femoropatellar or scapulohumeral joints from immature horses and normal control horses of similar age. PTH-rP expression levels were assessed by semi-quantitative PCR, in situ hybridization, and immunohistochemistry. Ihh

Stacy A. Semevolos; Brent D. Brower-Toland; Stephen J. Bent; Alan J. Nixon



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

Microsoft Academic Search

OBJECTIVE--To examine the relation between bone density and indices of calcium metabolism including parathyroid hormone and 25-hydroxyvitamin D concentrations in middle aged women. DESIGN--A cross sectional study. SETTING AND SUBJECTS--138 women volunteers aged 45-65 with no known osteoporosis and unselected for disease status recruited for a dietary assessment study from the community using general practice registers. Volunteer rate was 20%.

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



Parathyroid Hormone-Related Protein Purified from a Human Lung Cancer Cell Line  

Microsoft Academic Search

A protein with biological activities similar to parathyroid hormone (PTH) has been purified from serum-free culture medium obtained from a human lung cancer cell line (BEN). A major protein band of 18 kDa was obtained on NaDodSO4\\/polyacrylamide gels, with faint bands at 35 kDa and 67 kDa. Biological activity was associated only with the 18-kDa band. Amino acid sequence analysis

J. M. Moseley; M. Kubota; H. Diefenbach-Jagger; R. E. H. Wettenhall; B. E. Kemp; C. P. Rodda; P. R. Ebeling; P. J. Hudson; J. D. Zajac; T. J. Martin



Serum 25-hydroxyvitamin D and parathyroid hormone in patients with acute renal failure  

Microsoft Academic Search

Serum 25-hydroxyvitamin D and parathyroid hormone in patients with acute renal failure. The concentration of 25-hydroxyvitamin D (25-OH-D) in the serum of 18 patients with acute renal failure was measured serially using a sensitive radiocompetitive assay. In normal subjects, the mean concentration of serum 25-OH-D was 16.6 ng\\/ml (range, 7.7 to 36 ng\\/ml). In patients with acute renal failure, the

Jerzy Pietrek; Franciszek Kokot; Jadwiga Kuska



The influence of parathyroid hormone on the adult hematopoietic stem cell niche  

Microsoft Academic Search

Adult hematopoietic stem cells (HSCs) reside in the bone marrow in stable microenvironments known as the stem cell niche.\\u000a One key component of the stem cell niche is cells of the osteoblastic lineage. Factors that are known to affect osteoblast\\u000a activity, such as parathyroid hormone (PTH), have also been shown to affect the HSCs. Treatment of mice with PTH has

Narges Rashidi; Gregor B. Adams



Staurosporine enhances parathyroid hormone-induced calcium signal in UMR-106 osteoblastic cells  

Microsoft Academic Search

Parathyroid hormone (PTH) treatment of bone and kidney-derived cells not only activates adenylyl cyclase but also increases\\u000a intracellular free calcium, and translocates protein kinase C (PKC) from cytosol to plasma membranes. We have found that acute\\u000a phorbol ester pretreatment significantly decreases PTH-induced calcium transients and the effect of phorbol ester was antagonized\\u000a by staurosporine (ST). Although the major effect of

Suk Kyeong Lee; Paula H. Stern



20-HETE mediates the effect of parathyroid hormone and protein kinase C on renal phosphate transport  

Microsoft Academic Search

Parathyroid hormone (PTH) is a major inhibitor of renal proximal tubule (PT) sodium-dependent phosphate (Na+?Pi) cotransport. PTH is thought to exert its effect on Pi transport in the PT via the protein kinase A (PKA) and C (PKC) intracellular signalling pathways. PKC-dependent phosphorylation of phospholipase A2 stimulates arachidonic acid (AA) release, the latter a potent inhibitor of Pi transport. In

D. M. Silverstein; M. Barac-Nieto; J. R. Falck; A. Spitzer



Parathyroid hormone is associated with decreased fat mass in young healthy women  

Microsoft Academic Search

Objective:To investigate the relationship of parathyroid hormone (PTH) with dietary calcium and changes in body composition.Design:Cross-sectional and 1-year longitudinal trial.Subjects:Normal-weight young women (age: 18–31), 155 subjects analyzed at baseline, and data for 41 subjects analyzed prospectively between baseline and 12 months.Measurements:Levels of fasting serum calcium and PTH, intakes of calcium (3-day diet records), and total body weight and body composition

C W Gunther; P A Legowski; R M Lyle; C M Weaver; L D McCabe; G P McCabe; M Peacock; D Teegarden



Intact serum parathyroid hormone levels increase during running exercise in well-trained men  

Microsoft Academic Search

The purpose of this study was to examine the influence of exercise on the serum concentrations of intact parathyroid hormone (PTH). Serum PTH and plasma lactate were measured in 15 well-trained men, 9 long-distance runners and 6 fire-fighters, during two running exercises. Test one consisted of 40-minute treadmill running with a stepwise increased load and test two consisted of 50-minute

H. Salvesen; A. G. Johansson; P. Foxdal; L. Wide; K. Piehl-Aulin; S. Ljunghall



Acute Effects of 2 Hours of Moderate-Intensity Cycling on Serum Parathyroid Hormone and Calcium  

Microsoft Academic Search

Previous studies have found that serum parathyroid hormone (PTH) increases in response to relatively short (<60 minutes),\\u000a intense bouts of exercise, possibly as a result of decreases in serum calcium. Whether longer, less intense exercise also\\u000a stimulates an increase in PTH is not known. The effects of 2 hours of moderate-intensity cycling on serum PTH and calcium\\u000a were investigated in

Daniel W. Barry; Wendy M. Kohrt



Parathyroid hormone-related peptide expression in rat collagen-induced arthritis  

Microsoft Academic Search

Objectives. The aim of this study was to describe expression of parathyroid hormone-related peptide (PTHrP) in collagen-induced arthritis (CIA), a well-established animal model for rheumatoid arthritis. Methods. CIA was induced in female dark agouti rats. Inguinal (ILNs) and popliteal (PLNs) lymph nodes and distal interphalangeal joints (DIP) were retrieved at different time points. Tissues were processed for detection of PTHrP

D. E. Godler; A. N. Stein; O. Bakharevski; M. M. L. Lindsay; P. F. J. Ryan



Parathyroid hormone-related protein and regulation of cell survival in the kidney.  


Parathyroid hormone-related protein (PTHrP) is a pleiotropic factor with multiple physiological functions in morphogenesis, cell proliferation, differentiation, apoptosis, and calcium homeostasis. In the kidney, PTHrP is known to be expressed abundantly and to be upregulated in various experimental nephropathies, showing growth-modulatory and proinflammatory properties. Ardura et al. demonstrate a possible link between PTHrP-induced Runx2 expression and an antiapoptotic effect in tubular epithelial cells. PMID:23633047

Kramann, Rafael; Schneider, Rebekka K



Disturbance of parathyroid hormone-related protein signaling in the nitrofen-induced hypoplastic lung  

Microsoft Academic Search

Purpose  Despite remarkable progress in resuscitation and intensive care, the morbidity and mortality rates in congenital diaphragmatic\\u000a hernia (CDH) remain high due to severe pulmonary hypoplasia. The pathogenesis of pulmonary hypoplasia associated with CDH\\u000a is still not clearly understood. Pulmonary parathyroid hormone-related protein (PTHrP) is expressed in the type II epithelial\\u000a cells and stimulates surfactant production by a paracrine feedback loop

Takashi Doi; Aušra Lukoši?t?; Elke Ruttenstock; Jens Dingemann; Prem Puri



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

Microsoft Academic Search

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

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



Serum parathyroid hormone and risk of adverse outcomes in patients with stable coronary heart disease  

Microsoft Academic Search

Background and objectiveRecent longitudinal studies have suggested an association of high serum parathyroid hormone levels (PTH) with elevated cardiovascular risk in the general population. This study presents analyses of the prognostic value of baseline PTH for subsequent cardiovascular events and all-cause mortality in a high-risk population with stable coronary heart disease.MethodsBased on measurements of PTH levels in 1133 patients recruited

Norma Christine Grandi; Lutz Philipp Breitling; Harry Hahmann; Bernd Wüsten; Winfried März; Dietrich Rothenbacher; Hermann Brenner



Expression and Signaling of Parathyroid Hormone-Related Protein in Cultured Podocytes  

Microsoft Academic Search

Podocyte function appears to be regulated by vasoactive factors. In vivo podocytes express parathyroid hormone-related protein (PTHrP), the N-terminal fragment of which has vasoactive properties. Since the signaling pathway(s) of PTHrP(1–36) are unknown in podocytes, differentiated cells of a conditionally immortalized mouse podocyte cell line were studied. Gene expression of PTHrP and the PTH\\/PTHrP receptor was investigated by RT-PCR; protein

Nicole Endlich; Rainer Nobiling; Wilhelm Kriz; Karlhans Endlich



Bone anabolic effects of separate and combined therapy with growth hormone and parathyroid hormone on femoral neck in aged ovariectomized osteopenic rats  

Microsoft Academic Search

Previous studies have demonstrated that growth hormone (GH) has a marked anabolic effect on cortical bone and parathyroid hormone (PTH) has been shown to increase cancellous bone and cortical bone markedly in ovariectomized (OVX) rats. Most previous combination therapies used the bone anabolic agent (PTH) and the anti-resorptive agents. In this study, two bone anabolic hormones, GH and PTH, were

Liping Wang; Paul B. Orhii; Jameela Banu; Dike N. Kalu



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  

Microsoft Academic Search

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

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




PubMed Central

Acute hypercalcemia inhibits plasma renin activity. How this occurs is unknown. We hypothesized that acute hypercalcemia inhibits plasma renin activity via the calcium-sensing receptor due to parathyroid hormone-mediated increases in renal cortical interstitial calcium via TRPV5. To test our hypothesis, acute in vivo protocols were run in sodium-restricted, anesthetized rats. TRPV5 messenger RNA expression was measured with real-time quantitative reverse-transcriptase polymerase chain reaction. Acute hypercalcemia significantly decreased plasma renin activity by 37% from 32.0 ± 3.3 to 20.3 ± 2.6 ng Ang I/ml/hr (p<0.001). Acute hypercalcemia also significantly increased renal cortical interstitial calcium by 38% (1.73±0.06 mmol/L) compared to control values (1.25±0.05 mmol/L, p<0.001). Plasma renin activity did not decrease in hypercalcemia in the presence of a calcium-sensing receptor antagonist, Ronacaleret (22.8±4.3 vs. 21.6±3.6 ng Ang I/ml/hr). Increasing plasma calcium did not decrease plasma renin activity in parathyroidectomized rats (22.5 ± 2.6 vs. 22.0 ± 3.0 ng Ang I/ml/hr). Parathyroidectomized rats were unable to increase their renal cortical interstitial calcium in response to hypercalcemia (1.01±0.11 mmol/L). Acutely replacing plasma parathyroid hormone levels did not modify the hypercalcemic inhibition of plasma renin activity in parathyroid-intact rats (39.1±10.9 vs. 16.3±3.2 ng Ang I/ml/hr, p<0.05). Renal cortical TRPV5 messenger RNA expression decreased by 67% in parathyroidectomized (p<0.001) compared to intact rats. Our data suggest that acute hypercalcemia inhibits plasma renin activity via the calcium-sensing receptor due to parathyroid hormone-mediated increases in renal cortical interstitial calcium via TRPV5.

Atchison, Douglas K.; Harding, Pamela; Beierwaltes, William H.



Relationship between parathyroid hormone and subclinical myocardial dysfunction in patients with severe psoriasis.  


BACKGROUND: Psoriasis is associated with an increased risk of cardiovascular disease although the mechanism remains unclear. Recent studies have shown that such patients have a high prevalence of vitamin D (vit-D) deficiency and elevated parathyroid hormone (PTH) level. We hypothesized that vit-D deficiency and/or elevated PTH in psoriasis may contribute to left ventricular (LV) dysfunction. METHODS: Seventy-four patients with severe psoriasis with no known cardiovascular disease and 53 age- and gender-matched controls were recruited. All patients underwent detailed transthoracic echocardiography, including speckle tracking derived strains, and plasma levels of 25-hydoxyvitamin D (25-OHD), PTH and cardiac biomarkers including high sensitive C-reactive protein (hs-CRP), high sensitive troponin I (hs-TNI) and brain natriuretic peptide (BNP) were measured. RESULTS: Despite similar systolic and diastolic LV function, patients with severe psoriasis had impaired LV global longitudinal (-18.1 ± 2.6 vs.-19.6 ± 2.9%, P < 0.01) and circumferential strain (-18.7 ± 3.6 vs. -20.8 ± 4.3%, P < 0.01) compared with controls. Patients with severe psoriasis also had a significantly higher PTH (49.9 ± 18.0 vs. 40.5 ± 15.4 pmol/mL, P < 0.01) and hs-CRP (5.7 ± 6.9 vs. 1.9 ± 2.5 pg/mL, P < 0.01), but similar levels of 25-OHD, hs-TNI and BNP (all P > 0.05) compared with controls. Importantly, PTH level was negatively correlated with LV global longitudinal strain (R = -0.30, P < 0.01); and higher PTH level was independently associated with impaired global LV longitudinal strain (R = -0.33, P = 0.04), independent of cardiovascular risk factors, vit-D status and serum biomarkers. CONCLUSIONS: Severe psoriasis patients had an elevated PTH level and suffered from subclinical LV systolic dysfunction as detected by impaired global LV longitudinal strain. Importantly, a higher PTH level was independently associated with impaired global LV longitudinal strain. PMID:23489223

Zhao, C-T; Yeung, C-K; Siu, C-W; Tam, S; Chan, J; Chen, Y; Chan, H-H; Tse, H-F; Yiu, K-H



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


Adult growth hormone deficiency (AGHD) is associated with osteoporosis. Reports have associated parathyroid hormone (PTH) circadian rhythm abnormalities with osteoporosis. Furthermore, there is evidence of relative PTH insensitivity in AGHD patients. Factors regulating PTH circadian rhythm are not fully understood. There is evidence that serum phosphate is a likely determinant of PTH rhythm. The aim of this study was to investigate PTH circadian rhythm and its circulating activity and association with bone turnover in untreated AGHD patients compared to healthy individuals. We sampled peripheral venous blood at 30-min and urine at 3-h intervals during the day over a 24-h period from 1400 h in 14 untreated AGHD patients (7 M, 7 W; mean age, 49.5 +/- 10.7 years) and 14 age (48.6 +/- 11.4 years; P = NS) and gender-matched controls. Cosinor analysis was performed to analyze rhythm parameters. Cross-correlational analysis was used to determine the relationship between variables. Serum PTH (1-84), phosphate, total calcium, urea, creatinine, albumin, type I collagen C-telopeptides (CT(x)), a bone resorption marker, and procollagen type I amino-terminal propeptide (PINP), a bone formation marker, were measured on all samples. Nephrogenous cyclic adenosine monophosphate (NcAMP), which reflects the renal activity of PTH, was calculated from plasma and urinary cAMP. Urinary calcium and phosphate were measured on all urine samples. Significant circadian rhythms were observed for serum PTH, phosphate, CT(x), and PINP in AGHD and healthy subjects (P < 0.001). No significant rhythm was observed for serum-adjusted calcium. PTH MESOR (rhythm-adjusted mean) was significantly higher (P < 0.05), whereas the MESOR values for phosphate, CT(x) (P < 0.05), and PINP (P < 0.001) were lower in AGHD patients than in controls. AGHD patients had significantly lower 24-h NcAMP (P < 0.001) and higher urinary calcium excretion (P < 0.05). Maximum cross-correlation between PTH and phosphate (r = 0.75) was observed when PTH was lagged by 1.5 h in healthy individuals, suggesting that changes in phosphate precede changes in PTH concentration. PTH/CT(x) and PTH/PINP showed maximum correlation when CT(x) (r = 0.68) and PINP (r = 0.71) were lagged by 3 h. In AGHD patients, compared to controls the maximum correlation between PTH/phosphate (r = 0.88, P = 0.007), PTH/CTx (r = 0.61, P = 0.027), and PTH/PINP (r = 0.65, P = 0.028) was observed when the lag time was reduced by 1.5 h in all variables, with changes in PTH and phosphate occurring at concurrent time points. Our data suggest decreased end-organ sensitivity to the effects of PTH in AGHD patients, resulting in a significantly lower NcAMP, low bone turnover, and higher calcium excretion in the presence of significantly higher PTH concentrations. We have also demonstrated that changes in serum phosphate precede those of PTH, which in turn precede changes in bone resorption and formation in healthy individuals. This relationship was altered in AGHD patients. These results suggest a possible role for GH in regulating PTH secretion and the bone remodeling process. PMID:12633789

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



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

SciTech Connect

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.

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



Effects of 25-hydroxyvitamin D level and its change on parathyroid hormone in premenopausal Chinese women  

Microsoft Academic Search

Summary  Optimal levels of 25-hydroxyvitamin D [25(OH)D] were investigated in premenopausal Chinese women. Parathyroid hormone (PTH)\\u000a change at 3 months was associated with change in 25(OH)D but not with baseline levels, and PTH fell even when starting levels\\u000a of 25(OH)D were >40 nmol\\/L, consistent with optimal values for 25(OH)D of ?40 nmol\\/l.\\u000a \\u000a \\u000a \\u000a \\u000a Introduction  The upper level of 25-hydroxyvitamin D [25(OH)D] which constitutes a long-term bone

C. J. Bacon; J. Woo; E. M. C. Lau; C. W. K. Lam; G. D. Gamble; I. R. Reid



Effect of parathyroid hormone on hypogonadism induced bone loss of proximal femur of orchiectomized rat  

Microsoft Academic Search

Purpose  Management of hypogonadism-induced osteoporosis in elderly men is still a challenge. We investigated the short-term effects\\u000a of parathyroid hormone (PTH) treatments on strength, micro-architecture, and mineral density of trochanteric region of orchiectomized\\u000a rat femur.\\u000a \\u000a \\u000a \\u000a \\u000a Methods  Eight-month-old male Sprague–Dawley rats (n = 44) were divided into two groups: (1) orchiectomized (ORX) and (2) sham group. Twelve weeks after orchiectomy, half of\\u000a the orchiectomized animals

M. Tezval; G. Serferaz; T. Rack; L. Kolios; S. Sehmisch; U. Schmelz; H. Tezval; K. M. Stuermer; E. K. Stuermer


Hypocalcaemia and Parathyroid Hormone Assay Following Total Thyroidectomy: Predicting the Future  

Microsoft Academic Search

Background  Ambulatory surgery (23:59-hour hospital stay) is gaining popularity in endocrine surgery. Hypocalcaemia is common following\\u000a total thyroidectomy. Identifying patients with low risk of hypocalcaemia may facilitate early discharge (24-hour stay).\\u000a \\u000a \\u000a \\u000a Methods  We conducted a prospective study including all patients undergoing total thyroidectomy. Blood samples were taken immediately\\u000a following skin closure and the following morning for parathyroid hormone (PTH) and calcium measurement.

C. Wong; S. Price; D. Scott-Coombes



Normochromic normocytic anemia in a postmenopausal woman with severe osteoporosis treated with intermittent parathyroid hormone  

Microsoft Academic Search

Intermittent exogenous parathyroid hormone (PTH) is a potent osteoanabolic agent used for the treatment of severe osteoporosis.\\u000a Two molecules of recombinant PTH are commercially available: the full-length PTH (PTH 1–84) and teriparatide (PTH 1–34). We\\u000a present the first report of PTH-induced mild, asymptomatic, normochromic normocytic anemia in a postmenopausal woman treated\\u000a sequentially with PTH 1–84 and PTH 1–34. Anemia was

Athanasios D. Anastasilakis; Mattheos Savvides; Stergios A. Polyzos; Christos Georgopoulos; Sideris Delaroudis



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

SciTech Connect

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.

Pioszak, Augen A.; Xu, H. Eric (Van Andel)



Relationship between serum magnesium and parathyroid hormone levels in hemodialysis patients  

Microsoft Academic Search

Acute magnesium (Mg) infusion decreases patathyroid hormone (PTH) secretion. However, the effect of chronic hypermagnesemia on PTH levels in dialysis patients is not well established. We studied 110 hemodialysis patients (mean age, 55 ± 14 years; time on dialysis, 35 ± 28 months) not receiving vitamin D and undergoing dialysis with an Mg dialysate concentration of 1.2 mg\\/dL. The primary

Juan F. Navarro; Carmen Mora; Alejandro Jiménez; Armando Torres; Manuel Macía; Javier García



Dual role of parathyroid hormone in endothelial progenitor cells and marrow stromal mesenchymal stem cells.  


Hematopoietic stem cells derive regulatory information also from parathyroid hormone (PTH). To explore the possibility that PTH may have a role in regulation of other stem cells residing in bone marrow, such as mesenchymal stem cells (MSCs) and endothelial progenitor cells (EPCs) we assessed the effect of this hormone on the in vitro behavior of MSCs and EPCs. We evidenced that MSCs were much more responsive to PTH than EPCs. PTH increased the proliferation rate of MSCs with a diminution of senescence and apoptosis. Taken together, our results may suggest a protective effect of PTH on MSCs that reduces stress phenomena and preserve genome integrity. At the opposite, PTH did not modify the fate of EPCs in culture. PMID:19918796

Di Bernardo, Giovanni; Galderisi, Umberto; Fiorito, Carmela; Squillaro, Tiziana; Cito, Letizia; Cipollaro, Marilena; Giordano, Antonio; Napoli, Claudio



Ultrasound exposure during pregnancy affects rabbit foetal parathyroid hormone (PTH) level  

PubMed Central

The aim of this study was to investigate the changes in parathyroid hormone (PTH) level of rabbit foetal bodies exposed to ultrasound at different gestational stages. A total of 9 pregnant rabbits (Oryctolagus cuniculus) were insonated for 60 minutes at the middle of 1st, 2nd and 3rd gestational stages for group A (n=14 newborns), group B (n=7 newborns) and group C (n=24 newborns) respectively. Seven pregnant rabbits with 41 newborns severed as negative control group. Blood samples were withdrawn from each newborn rabbits for Parathyroid Hormone-Intact (PTH-I) test. Results of the independent samples t-test implied statistically significant differences (P<0.05) between the control group and the 1st stage (P=0.001), the 2nd stage (P<0.001) and the 3rd stage group (P<0.001). This in-vivo study revealed diagnostic ultrasound heating has the potential of affecting foetal PTH level. This study observed significantly low PTH level for all the treated groups. A further study should be instituted to determine whether this finding in rabbit may also occur in human by means of clinical trials.

Abdul Razak, Hairil Rashmizal; Ahmad Zaiki, Farah Wahida; Saat, Nurul Hidayah; Abd Manan, Khairunnisa; Che Isa, Iza Nurzawani; Hashim, Ummi Farhana



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

SciTech Connect

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.

Fujiwara, Saeko; Yokoyama, Naokata; Sasaki, Hideo; Kodama, Kazunori; Sposto, R.; Shimaoka, Katsutaro [Radiation Effects Research Foundation (Japan); Shiraki, Mastaka [Tokyo Metropolitan Geriatric Hospital (Japan)



Characterization of the major parathyroid hormone target cell in the endosteal metaphysis of rat long bones  

SciTech Connect

The majority of in vivo competitive binding of parathyroid hormone (PTH) in the endosteal metaphysis of rat long bones was recently shown to be localized in the intertrabecular tissue to a cell that is distinct from a differentiated osteoblast. In the present report we have further characterized this cell, termed a parathyroid hormone target (PT) cell, by light and electron microscopy using radioautography and histochemical techniques. These studies demonstrate that the PT cell is a mononuclear cell with a large cell body located at times between clusters of differentiated osteoblasts, as well as in other regions of the intertrabecular tissue. Its long cytoplasmic processes extend from the bone matrix through the intertrabecular region toward vascular structures, interdigitating with various cells of the endosteum. A distinctive tubular structure originating in the Golgi system and often associated with long mitochondria and glycogen particles extends throughout the cytoplasmic processes of the PT cell. Based on its capacity to incorporate ({sup 3}H)thymidine, the PT cell appears to divide rather slowly. The identification of occasional hybrid cells with ultrastructural features of both the PT cell and the differentiated osteoblast and the presence of histochemical evidence for alkaline phosphatase activity suggest that the PT cell is of the osteoblast lineage. These studies therefore morphologically define a major osseous target cell for PTH that, although of the osteoblast lineage, is not a differentiated osteoblast and provide in vivo evidence that characteristics of the 'osteoblast phenotype' are not restricted to a sole osseous cell type.

Rouleau, M.F.; Mitchell, J.; Goltzman, D. (McGill Univ., Montreal, Quebec (Canada))



Parathyroid-hormone-related protein-mediated hypercalcemia in benign congenital mesoblastic nephroma.  


Parathyroid hormone-related protein (PTHrP) mediated hypercalcemia of malignancy is rare in children, and even more so in the setting of a benign tumor. We report two infants with PTHrP-mediated hypercalcemia secondary to congenital mesoblastic nephroma and their outcome after removal of the benign tumor. Pre-operatively hypercalcemia was corrected with saline hydration, furosemide, calcitonin and/ or pamidronate. Following resection of the tumor serum PTHrP normalized. Immunohistochemical staining of tumor cells was positive for PTHrP. Post-operatively the infants developed elevated serum parathyroid hormone with low- normal serum Ca and P, and undetectable urinary Ca and P, probably due to their movement into bone. Children needed treatment with calcitriol, Ca and P supplementation for 6-12 weeks until PTH normalized and urinary Ca and P were detected, suggesting bone replenishment. We conclude that benign congenital mesoblastic nephroma can secrete PTHrP that can cause severe hypercalcemia; and following excision one should anticipate the development of a transient modified "hungry bone"-like condition requiring Ca, P and calcitriol therapy for several weeks accompanied by careful monitoring of mineral homeostasis. PMID:21161280

Srivastava, Tarak; Kats, Alexander; Martin, T John; Pompolo, Suelli; Alon, Uri S



Associations of Sun Exposure with 25-Hydroxyvitamin D and Parathyroid Hormone Levels in a Cohort of Hypertensive Patients: The Graz Endocrine Causes of Hypertension (GECOH) Study  

PubMed Central

Sunlight-induced vitamin D, synthesis in the skin is the major source of vitamin D, but data on the relationship of sun-related behaviour with vitamin D and parathyroid hormone (PTH) levels are relatively sparse. We evaluated whether habitual sun exposure is associated with 25-hydroxyvitamin D (25[OH]D) and PTH levels and whether there exist seasonal variations. We examined 111 hypertensive patients in Austria (latitude 47°?N). Frequent sunbathing at home and outdoor sports were associated with higher 25(OH)D levels (P < 0.05 for both). Red or blond scalp hair as a child, memory of sunburns, preferring sunbathing, frequent stays on the beach or in open-air pools, and solarium use were associated with lower PTH levels (P < 0.05 for all). Multiple linear regression analyses including age, sex, and body mass index showed that sun exposure score was significantly associated with 25(OH)D (beta coefficient = 0.27; P = 0.004) and by trend with PTH (beta coefficient = ?0.16; P = 0.09). These associations were more prominent in summer in which 25(OH)D levels were significantly higher compared to winter. Translation of these findings into recommendations for the prevention and treatment of vitamin D deficiency remains a challenge for the future.

Pilz, Stefan; Kienreich, Katharina; Stuckler, Daniel; Meinitzer, Andreas; Tomaschitz, Andreas



Parathyroid diseases and animal models.  


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

Imanishi, Yasuo; Nagata, Yuki; Inaba, Masaaki



Parathyroid Diseases and Animal Models  

PubMed Central

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.

Imanishi, Yasuo; Nagata, Yuki; Inaba, Masaaki



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


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 p



Evidence that resistance to the calcemic action of parathyroid hormone in rats with acute uremia is caused by phosphate retention  

Microsoft Academic Search

Evidence that resistance to the calcemic action of parathyroid hormone in rats with acute uremia is caused by phosphate retention. An animal model was developed to examine the cause of resistance to the calcemic action of PTH in renal failure. Thyroparathyroidectomized (TPTX) rats were repeatedly reinfused with their excreted urine, over a 5-hour period, to produce an acute uremic animal

Peter J Somerville; Michael Kaye



Relationship between intact 1–84 parathyroid hormone and bone histomorphometric parameters in dialysis patients without aluminum toxicity  

Microsoft Academic Search

With the markedly reduced usage of aluminum salts in renal failure, parathyroid hormone (PTH) has become the major determinant of currently seen bone disease. Clinicians now must consider what PTH level should be sought. Too low a level may lead to the aplastic bone lesion (low turnover bone), and too high a level may cause osteitis fibrosa. Furthermore, conventional normal

Mei Wang; Gavril Hercz; Donald J. Sherrard; Norma A. Maloney; Gino V. Segre; York Pei



Human Parathyroid Hormone-(1-38) Restores Cancellous Bone to the Immobilized, Osteopenic Proximal Tibial Metaphysis in Rats.  

National Technical Information Service (NTIS)

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 S...

Y. F. Ma W. S. S. Jee H. Z. Ke B. Y. Lin X. G. Liang



Vitamin D Therapy of Osteoporosis: Plain Vitamin D Therapy Versus Active Vitamin D Analog (D-Hormone) Therapy  

Microsoft Academic Search

.   Normal intestinal calcium (Ca) absorption is an essential feature of bone homeostasis. As with many other organ systems,\\u000a intestinal Ca absorption declines with aging, and this is one pathological factor that has been identified as a cause of senile\\u000a osteoporosis in the elderly. This abnormality leads to secondary hyperparathyroidism, which is characterized by high serum\\u000a parathyroid hormone (PTH) and

K.-H. W. Lau; D. J. Baylink



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

PubMed Central

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.

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



Interleukin1? and interleukin-4 increase parathyroid hormone—related protein secretion by human umbilical vein endothelial cells in culture  

Microsoft Academic Search

OBJECTIVE: Our purpose was to learn whether cytokines such as interleukin-1? and related (or antagonistic) cytokines, hormones, and growth factors could regulate secretion of the vasorelaxant parathyroid hormone—related protein in human umbilical vein endothelial cells in culture.STUDY DESIGN: Secondary cultures of human umbilical vein endothelial cells were grown to confluence and treated with interleukin-1?, an array of factors with possible

J. E. Ferguson; Regina M. Seaner; David E. Bruns; M. Elizabeth Bruns



Serum 25(OH)D Level and Parathyroid Hormone in Chinese Adult Population: A Cross-Sectional Study in Guiyang Urban Community from Southeast of China  

PubMed Central

Objective. To evaluate vitamin D status and serum parathyroid hormone (IPTH) of healthy adults living in Guiyang. Design and Participants. We conducted a cross-sectional evaluation in the General Community in Guiyang by cluster sampling method. The data was a part of 1510 participants (634 men, 876 women) aged 20–79 years median 45.2 years from November 2009 to February 2010 in Guiyang Health Measures Survey. Measurements. Aradioimmunoassay was used to measure the level of 25-hydroxyvitamin D [25(OH)D] and intact parathyroid hormone (iPTH). Results.The mean serum 25(OH)D level was (20.4 ± 9.0)?ng/mL and the highest level among participants aged 40–59 years (22.8?ng/mL). The mean serum PTH level was (32.1 ± 13.7)?pg/mL and the lowest level among participants aged 40–50 years (30.8?ng/mL). Serum 25(OH)D was below 50?nmol/liter in 52.3%, below 75?nmol/liter in 84.6%, and above 75?nmol/liter in 15.4% of the respondents. Secondary hyperparathyroidism was 5.4% (5.4% among men and 4.6% among women). The prevalence of secondary hyperparathyroidism increased (5.8%, 6.5%, and 7.1%, resp.) with decreasing serum 25(OH)D levels among subjects who were 30 to 20, 19.9 to 10, and <10?ng/mL, respectively. Serum 25(OH)D was inversely associated with serum PTH. Conclusions. Vitamin D insufficiency and its complication of secondary hyperparathyroidism are common.

Qiao, Zhang; Li-xing, Shi; Nian-chun, Peng; Shu-jing, Xu; Miao, Zhang; Hong, Li; Hui-jun, Zhuang; Ming-xian, Gong; Song, Zhang; Rui, Wang; Ying, Hu; Jing-lu, Zhang; Shuang, Chen



Increased Plasma Concentrations of Vitamin D Metabolites and Vitamin D Binding Protein in Women Using Hormonal Contraceptives: A Cross-Sectional Study  

PubMed Central

Use of hormonal contraceptives (HC) may influence total plasma concentrations of vitamin D metabolites. A likely cause is an increased synthesis of vitamin D binding protein (VDBP). Discrepant results are reported on whether the use of HC affects free concentrations of vitamin D metabolites. Aim: In a cross-sectional study, plasma concentrations of vitamin D metabolites, VDBP, and the calculated free vitamin D index in users and non-users of HC were compared and markers of calcium and bone metabolism investigated. Results: 75 Caucasian women aged 25–35 years were included during winter season. Compared with non-users (n = 23), users of HC (n = 52) had significantly higher plasma concentrations of 25-hydroxyvitamin D (25OHD) (median 84 interquartile range: [67-111] vs. 70 [47-83] nmol/L, p = 0.01), 1,25-dihydroxyvitamin D (1,25(OH)2D) (198 [163-241] vs. 158 [123-183] pmol/L, p = 0.01) and VDBP (358 [260-432] vs. 271 [179-302] µg/mL, p < 0.001). However, the calculated free indices (FI-25OHD and FI-1,25(OH)2D) were not significantly different between groups (p > 0.10). There were no significant differences in indices of calcium homeostasis (plasma concentrations of calcium, parathyroid hormone, and calcitonin, p > 0.21) or bone metabolism (plasma bone specific alkaline phosphatase, osteocalcin, and urinary NTX/creatinine ratio) between groups. In conclusion: Use of HC is associated with 13%–25% higher concentrations of total vitamin D metabolites and VDBP. This however is not reflected in indices of calcium or bone metabolism. Use of HC should be considered in the interpretation of plasma concentrations vitamin D metabolites.

M?ller, Ulla K.; vi? Streym, Susanna; Jensen, Lars T.; Mosekilde, Leif; Schoenmakers, Inez; Nigdikar, Shailja; Rejnmark, Lars



Parathyroid function in chronic vitamin D deficiency in man: A model for comparison with chronic renal failure  

Microsoft Academic Search

Summary  It has become obvious, from the elegantin vitro studies of Cohnet al. (3) and of others, that calcium may act at various steps in the biosynthesis, storage, degradation and secretory release\\u000a of parathyroid hormone. It would be premature to attempt to interpret our simple clinical observations in terms of these still\\u000a incompletely defined mechanisms. These clinical studies have, however, identified

S. W. Stanbury; G. A. Lumb



Does it matter how parathyroid hormone levels are suppressed in secondary hyperparathyroidism?  


Because secondary hyperparathyroidism is associated with morbidity and mortality in patients with chronic kidney disease, suppression of parathyroid hormone (PTH) and minimization of associated derangements in mineral metabolism are cardinal therapeutic goals. There is an ongoing debate regarding the proper treatment strategy for PTH suppression in this population. While some practitioners believe that calcitriol analogues should be the primary therapy in this setting, others contend that calcimimetics offer unique treatment benefits. Recent advancements in the understanding of the pathophysiology of secondary hyperparathyroidism and the secondary effects of these agents may help clarify this debate. Here, we review the classical actions of calcitriol analogues and calcimimetics on mineral metabolism. We also examine the potential nonclassical effects of these therapies on the renin-angiotensin-aldosterone system, proteinuria, vascular calcification, fibroblast growth factor-23, inflammation, and overall survival. PMID:21682772

Stubbs, Jason R; Wetmore, James B


Parathyroid hormone and anaemia--an erythrocyte osmotic fragility study in primary and secondary hyperparathyroidism.  

PubMed Central

Parathyroid hormone (PTH) has been shown in vitro to enhance erythrocyte osmotic fragility (EOF) and has been incriminated as a factor in the anaemia seen in patients with primary hyperparathyroidism and in patients with renal disease and secondary hyperparathyroidism. Enhanced EOF has also been shown in patients with chronic renal failure but did not correlate with PTH levels. We studied a group of patients with primary hyperparathyroidism with and without anaemia, and patients with secondary hyperparathyroidism and anaemia. We found that EOF studies in these patients did not differ from normal control groups and that there was no relation between PTH, EOF, and haematocrit in either study group. We conclude that PTH over a range of concentrations seen in vivo does not affect erythrocyte osmotic fragility or cause anaemia.

Foulks, C. J.; Mills, G. M.; Wright, L. F.



Cinacalcet for Hypercalcemia Caused by Pulmonary Squamous Cell Carcinoma Producing Parathyroid Hormone-Related Peptide  

PubMed Central

Background Current treatments for hypercalcemia caused by lung cell carcinomas producing parathyroid hormone-related peptide (PTH-rp) have limited efficacy, probably because of their lack of effect on PTH-rp secretion. In this case study we explored the efficacy of the calcimimetic cinacalcet as suppressor of PTH-rp production. Patient A 57-year-old male with severe and recurrent hypercalcemia induced by a PTH-rp-producing squamous cell lung carcinoma, stage cT4N3M1b, poorly responding to standard treatments. Results Serum PTH-rp levels were not affected by saline, calcitonin or zoledronate. PTH-rp decreased during chemotherapy and cinacalcet monotherapy. The combination of chemotherapy plus cinacalcet was most effective in rapidly reducing serum calcium and PTH-rp. Conclusion This case study is the first to suggest that cinacalcet may be of value in some cases of PTH-rp-dependent hypercalcemia. Corroborative evidence is needed.

Bech, Anneke; Smolders, Koen; Telting, Darryl; de Boer, Hans



[Treatment with recombinant parathyroid hormone of advanced osteoporosis--series of cases].  


Osteoporosis is a systemic skeletal disorder characterized by impaired bone strength, leading to an increased risk of fracture. Patients with severe osteoporosis and multiple vertebral fractures are particularly at risk for subsequent osteoporotic fractures independently of antiresorptive therapy. The effective treatment of osteoporosis should prevent fractures through normalization of bone mass and improving bone microarchitecture. Recombinant human parathyroid hormone (teriparatide) is an anabolic (bone forming) agent. The aim of this study was to describe the results of treatment with teriparatide (Forsteo) of three patients with severe osteoporosis. Teriparatide has proved to be effective in preventing bone loss. New osteoporotic fracture has not occurred in two patients. Treatment with teriparatide was safe and well tolerated. PMID:22010479

Skiba, Katarzyna; Adamczak, Marcin; Wiecek, Andrzej



Molecular cloning and chromosomal mapping of DNA rearranged with the parathyroid hormone gene in a parathyroid adenoma.  


Parathyroid adenomas are common benign neoplasms for which no chromosomal defects have been described. We recently found two parathyroid adenomas bearing clonal restriction fragment abnormalities involving the PTH locus, and now show that in one of these tumors: (a) a DNA rearrangement occurred at the PTH locus; (b) the rearrangement separated the PTH gene's 5' flanking region from its coding exons, conceivably placing a newly adjacent gene under the influence of PTH regulatory elements; (c) the DNA that recombined with PTH normally maps to 11q13, the known chromosomal location of several oncogenes and the gene for multiple endocrine neoplasia type I; and (d) the rearrangement was a reciprocal, conservative recombination of the locus on 11q13 (Human Gene Mapping Library assignment D11S287) with PTH (on 11p15). These data provide molecular cytogenetic evidence for the clonal occurrence of a major chromosome 11 aberrancy in this benign parathyroid tumor. The D11S287 clone could prove useful in genetic linkage analyses, in determining precise 11q13 breakpoints in other neoplasms, and in identifying a gene on chromosome 11 that may participate in parathyroid tumor development. PMID:2723071

Arnold, A; Kim, H G; Gaz, R D; Eddy, R L; Fukushima, Y; Byers, M G; Shows, T B; Kronenberg, H M



'Biasing' the parathyroid hormone receptor: A novel anabolic approach to increasing bone mass?  

PubMed Central

‘Functional selectivity’ refers to the ability of a ligand to activate and/or inhibit only a subset of the signals capable of emanating from its cognate G-protein-coupled receptor (GPCR). Whereas conventional GPCR agonism and antagonism can be viewed as modulating the quantity of efficacy, functionally selective or ‘biased’ ligands qualitatively change the nature of information flow across the plasma membrane, raising the prospect of drugs with improved therapeutic efficacy or reduced side effects. Nonetheless, there is little experimental evidence that biased ligands offer advantages over conventional agonists/antagonists in vivo. Recent work with the type I parathyroid hormone receptor (PTH1R) suggests that biased ligands that selectively activate G-protein-independent arrestin-mediated signalling pathways may hold promise in the treatment of osteoporosis. Parathyroid hormone (PTH) is a principle regulator of bone and calcium metabolism. In bone, PTH exerts complex effects; promoting new bone formation through direct actions on osteoblasts while simultaneously stimulating bone loss through indirect activation of osteoclastic bone resorption. Although the conventional PTH1R agonist teriparatide, PTH(1–34), is effective in the treatment of osteoporosis, its utility is limited by its bone-resorptive effects and propensity to promote hypercalcaemia/hypercalcuria. In contrast, d-Trp12,Tyr34-bPTH(7–34) (PTH-?arr), an arrestin pathway-selective agonist for the PTH1R, induces anabolic bone formation independent of classic G-protein-coupled signalling mechanisms. Unlike PTH(1–34), PTH-?arr appears to ‘uncouple’ the anabolic effects of PTH1R activation from its catabolic and calcitropic effects. Such findings offer evidence that arrestin pathway-selective GPCR agonists can elicit potentially beneficial effects in vivo that cannot be achieved using conventional agonist or antagonist ligands.

Gesty-Palmer, Diane; Luttrell, Louis M



RAGE supports parathyroid hormone-induced gains in femoral trabecular bone  

PubMed Central

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 ?g·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.

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



FGF23 Fails to Inhibit Uremic Parathyroid Glands  

PubMed Central

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.

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



FGF23 fails to inhibit uremic parathyroid glands.  


Fibroblast growth factor 23 (FGF23) modulates mineral metabolism by promoting phosphaturia and decreasing the production of 1,25-dihydroxyvitamin D(3). 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

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



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

SciTech Connect

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.

Pioszak, Augen A.; Parker, Naomi R.; Gardella, Thomas J.; Xu, H. Eric; (Van Andel); (Mass. Gen. Hosp.)



Humoral hypercalcemia associated with gastric carcinoma secreting parathyroid hormone: a case report and review of the literature.  


Hypercalcemia with concomitant elevation of serum parathyroid hormone (PTH) and PTH-related protein (PTHrP) levels was found in a patient with advanced gastric carcinoma and multiple liver metastases. The most common features are hypercalcemia associated with hypersecretion of PTHrP and physiological suppression of PTH secretion in the syndrome of humoral hypercalcemia of malignancy (HHM). Although we initially made a diagnosis of primary hyperparathyroidism concomitant with HHM due to gastric cancer, diagnostic imaging studies, such as echography, CT, sestamibi scintigraphy, and autopsy findings, did not reveal evidence of any parathyroid tumors or ectopic parathyroid glands in the mediastinum. Both primary and metastatic tumor cells showed positive staining with PTH-specific antibody as well as PTHrP-specific antibody on immunohistochemical examination. PTH concentration in the cytosolic fraction of the metastatic tumor was elevated compared to that from a control patient with no calcium metabolic disorders in vitro. These findings indicated that PTH secreted ectopically by gastric cancer cells, not by parathyroid glands, caused hypercalcemia in this patient. To our knowledge, this is the first case report of PTH-secreting gastric carcinoma cells. We report the case and a review of the previous reported PTH-secreting non-parathyroid tumors along with the mechanisms of secretion. PMID:23303131

Nakajima, Koji; Tamai, Masataka; Okaniwa, Shinji; Nakamura, Yoshiyuki; Kobayashi, Mutsuhiro; Niwa, Tomohiro; Horigome, Naoto; Ito, Nobuo; Suzuki, Satoru; Nishio, Shinichi; Komatsu, Mitsuhisa



Expression Cloning of a Common Receptor for Parathyroid Hormone and Parathyroid Hormone-Related Peptide from Rat Osteoblast-Like Cells: A Single Receptor Stimulates Intracellular Accumulation of Both cAMP and Inositol Trisphosphates and Increases Intracellular Free Calcium  

Microsoft Academic Search

Parathyroid hormone (PTH), a major regulator of mineral ion metabolism, and PTH-related peptide (PTHrP), which causes hypercalcemia in some cancer patients, stimulate multiple signals (cAMP, inositol phosphates, and calcium) probably by activating common receptors in bone and kidney. Using expression cloning, we have isolated a cDNA clone encoding rat bone PTH\\/PTHrP receptor from rat osteosarcoma (ROS 17\\/2.8) cells. The rat

Abdul-Badi Abou-Samra; Harald Juppner; Thomas Force; Mason W. Freeman; Xiang-Fu Kong; Ernestina Schipani; Pablo Urena; Jennifer Richards; Joseph V. Bonventre; John T. Potts Jr.; Henry M. Kronenberg; Gino V. Segre



Monocyte chemoattractant protein-1 is a mediator of the anabolic action of parathyroid hormone on bone.  


Parathyroid hormone (PTH) has a significant role as an anabolic hormone in bone when administered by intermittent injection. Previous microarray studies in our laboratory have shown that the most highly regulated gene, monocyte chemoattractant protein-1 (MCP-1), is rapidly and transiently induced when hPTH(1-34) is injected intermittently in rats. Through further in vivo studies, we found that rats treated with hPTH(1-34) showed a significant increase in serum MCP-1 levels 2 hours after PTH injection compared with basal levels. Using immunohistochemistry, increased MCP-1 expression in osteoblasts and osteocytes is evident after PTH treatment. PTH also increased the number of marrow macrophages. MCP-1 knockout mice injected daily with hPTH(1-34) showed less trabecular bone mineral density and bone volume compared with wild-type mice as measured by peripheral quantitative computed tomography (pQCT) and micro-computed tomography (µCT). Histomorphometric analysis revealed that the increase in osteoclast surface and osteoclast number observed with intermittent PTH treatment in the wild-type mice was completely eliminated in the MCP-1 null mice, as well as much lower numbers of macrophages. Consequently, the lack of osteoclast and macrophage activity in the MCP-1 null mice was paralleled by a reduction in bone formation. We conclude that osteoblast and osteocyte MCP-1 expression is an important mediator for the anabolic effects of PTH on bone. PMID:23519994

Tamasi, Joseph A; Vasilov, Anatoliy; Shimizu, Emi; Benton, Noah; Johnson, Joshua; Bitel, Claudine L; Morrison, Nigel; Partridge, Nicola C



Regional myocardial blood flow distribution during intracoronary infusion of parathyroid hormone  

SciTech Connect

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.

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



Parathyroid hormone induces bone formation in phosphorylation-deficient PTHR1 knockin mice  

PubMed Central

Activation of G protein-coupled receptors by agonists leads to receptor phosphorylation, internalization of ligand receptor complexes, and desensitization of hormonal response. The role of parathyroid hormone (PTH) receptor 1, PTHR1, is well characterized and known to regulate cellular responsiveness in vitro. However, the role of PTHR1 phosphorylation in bone formation is yet to be investigated. We have previously demonstrated that impaired internalization and sustained cAMP stimulation of phosphorylation-deficient (PD) PTHR1 leads to exaggerated cAMP response to subcutaneous PTH infusion in a PD knockin mouse model. To understand the physiological role of receptor internalization on PTH bone anabolic action, we examined bone parameters of wild-type (WT) and PD knockin female and male mice following PTH treatment. We found a decrease in total and diaphyseal bone mineral density in female but not in male PD mice compared with WT controls at 3–6 mo of age. This effect was attenuated at older age groups. PTH administration displayed increased bone volume and trabecular thickness in the vertebrae and distal femora of both WT and PD animals. These results suggest that PTHR1 phosphorylation does not play a major role in the anabolic action of PTH.

Samra, Tareq A.; Abou-Samra, Abdul B.



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


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

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



Effect of eplerenone on parathyroid hormone levels in patients with primary hyperparathyroidism: a randomized, double-blind, placebo-controlled trial  

PubMed Central

Background Increasing evidence suggests the bidirectional interplay between parathyroid hormone and aldosterone as an important mechanism behind the increased risk of cardiovascular damage and bone disease observed in primary hyperparathyroidism. Our primary object is to assess the efficacy of the mineralocorticoid receptor-blocker eplerenone to reduce parathyroid hormone secretion in patients with parathyroid hormone excess. Methods/design Overall, 110 adult male and female patients with primary hyperparathyroidism will be randomly assigned to eplerenone (25 mg once daily for 4 weeks and 4 weeks with 50 mg once daily after dose titration] or placebo, over eight weeks. Each participant will undergo detailed clinical assessment, including anthropometric evaluation, 24-h ambulatory arterial blood pressure monitoring, echocardiography, kidney function and detailed laboratory determination of biomarkers of bone metabolism and cardiovascular disease. The study comprises the following exploratory endpoints: mean change from baseline to week eight in (1) parathyroid hormone(1–84) as the primary endpoint and (2) 24-h systolic and diastolic ambulatory blood pressure levels, NT-pro-BNP, biomarkers of bone metabolism, 24-h urinary protein/albumin excretion and echocardiographic parameters reflecting systolic and diastolic function as well as cardiac dimensions, as secondary endpoints. Discussion In view of the reciprocal interaction between aldosterone and parathyroid hormone and the potentially ensuing target organ damage, the EPATH trial is designed to determine whether eplerenone, compared to placebo, will effectively impact on parathyroid hormone secretion and improve cardiovascular, renal and bone health in patients with primary hyperparathyroidism. Trial registration ISRCTN33941607



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

SciTech Connect

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

Flanagan, J.L.



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

NASA Astrophysics Data System (ADS)

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 [?25(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 ?25(OH)D3, although the summer and winter 25(OH)D3 concentrations were well-correlated. Since ?25(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.

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


Alteration of the circadian rhythm of intact parathyroid hormone and serum phosphate in women with established postmenopausal osteoporosis  

Microsoft Academic Search

Several studies have established that the circulating concentration of intact parathyroid hormone, PTH (1–84), over 24 h follows\\u000a a circadian rhythm. The importance of this circadian rhythm is not known although some authors have detected alterations in\\u000a the rhythm in metabolic bone disease and following dietary manipulation. We have studied the circadian rhythm of PTH (1–84)\\u000a in 8 premenopausal women,

W. D. Fraser; F. C. Logue; J. P. Christie; S. J. Gallacher; D. Cameron; D. St. J. O’Reilly; G. H. Beastall; I. T. Boyle



Time-related changes in the ultrastructure of osteoclasts after injection of parathyroid hormone in young rats  

Microsoft Academic Search

Summary  The effects of parathyroid hormone (PTH) on the size of the osteoclasts, nuclei, ruffled borders, and clear zones in long\\u000a bones of thyroparathyroidectomized (TPTX) rats were quantitated as a function of time. These data were compared with the number\\u000a of osteoclasts in the bone and with plasma calcium levels. A significant increase in the average size of the ruffled borders

Marijke E. Holtrop; Gregory J. King; Karen A. Cox; Barry Reit



Effects of cyclic vs. daily treatment with human parathyroid hormone (1–34) on murine bone structure and cellular activity  

Microsoft Academic Search

Previously, we demonstrated that the human parathyroid hormone (1–34) fragment (hPTH(1–34)) increased bone strength in proportion to its effects on BMD and cortical bone structure in the murine femur by comparing cyclic vs. daily administration of hPTH(1–34). Both cyclic and daily regimens increased vertebral BMD similarly at 7 weeks. Here, we have examined the effects of daily and cyclic PTH regimens

Akiko Iida-Klein; Shi Shou Lu; Felicia Cosman; Robert Lindsay; David W. Dempster



Alkaline phosphatase inhibition by parathyroid hormone and isoproterenol in a clonal rat osteosarcoma cell line. Possible mediation by cyclic AMP  

Microsoft Academic Search

Summary  The effect of parathyroid hormone (PTH 1–34 bovine) on alkaline phosphatase activity was investigated in an osteoblast-like\\u000a clonal cell line derived from rat osteosarcoma (ROS 17\\/2). ROS 17\\/2 alkaline phosphatase resembled the bone enzyme in levamisole\\u000a sensitivity and electrophoretic mobility but differed in heat stability. The specific activity of ROS 17\\/2 alkaline phosphatase\\u000a increased with time in culture. This increase

Robert J. Majeska; Gideon A. Rodan



Pregnancy and labor increase the capacity of human myometrial cells to secrete parathyroid hormone-related protein  

Microsoft Academic Search

Parathyroid hormone-related protein (PTHrP), a oncofetal gene product possessing smooth muscle relaxant properties, has been found in rat and human uterine smooth muscle cells (USMC) where it is postulated to regulate myometrial tone and\\/or blood flow. Studies investigating the gestational regulation of PTHrP in human USMC have not been performed. This study was conducted to determine if pregnancy alters the

Jeffrey S. Shenberger; Patricia S. Dixon; Jerome Choate; Kenneth Helal; Ronald L. Shew; William Barth



Third-generation parathyroid hormone assays and all-cause mortality in incident dialysis patients: the CHOICE study  

Microsoft Academic Search

Background. There has been controversy about the utility of new third-generation parathyroid hormone (PTH) assays measuring only 1-84 PTH, with few large studies com- paring second- and third-generation PTH measurements in patients with ESRD. Methods. We measured 1-84 PTH ('biointact' or 'whole' PTH) and total PTH ('intact' PTH) in a national cohort of 515 incident dialysis patients from banked frozen

Michal L. Melamed; Joseph A. Eustace; Laura C. Plantinga; Bernard G. Jaar; Nancy E. Fink; Rulan S. Parekh; Josef Coresh; Tom Cantor; Neil R. Powe



Calcium-phosphorus homeostasis and changes in parathyroid hormone secretion in cats with various stages of spontaneous chronic renal failure  

Microsoft Academic Search

Feline chronic renal failure was recognized with increased frequency in Maine coon, Abyssinian, Siamese, Russian blue, and\\u000a Burmese cats. The objective of this study was to investigate the relationship between parathyroid hormone (PTH) level, calcium,\\u000a and phosphorus homeostasis and the development of various stages of the naturally occurring chronic renal failure (CRF) in\\u000a cats. Thirty-two CRF cats without history of

Rosama Pusoonthornthum; Pinit Pusoonthornthum; Nateetip Krishnamra



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

Microsoft Academic Search

Parathyroid hormone-related protein (PTHrP) has been shown to have anabolic effects in women with postmenopausal osteoporosis. PTHrP promotes the recruitment of osteogenic cells and prevents apoptotic death of osteoblasts and osteocytes. The receptor responsible for the effects of PTHrP is the common PTH\\/PTHrP receptor (PTH1R). Glucocorticoids (GC) are commonly used as drugs to treat inflammatory diseases. Long-term GC treatments are

Mikael Ahlström; Minna Pekkinen; Christel Lamberg-Allardt



Effect of parathyroid hormone on acid\\/base transport in rabbit renal proximal tubule S3 segment  

Microsoft Academic Search

The effect of parathyroid hormone (PTH) on acid\\/base transport in isolated rabbit renal proximal tubule S3 segment was investigated with double-barreled and conventional microelectrodes. PTH (10 nM) induced a small depolarization and enhanced the initial rates of cell pH (pHi) increase and cell Cl- ([Cl-]i) decrease in response to bath Cl- removal by 28.0±2.1% and 31.0±6.4% respectively. The calculated initial

George Seki; Shigeo Taniguchi; Shu Uwatoko; Keiji Suzuki; Kiyoshi Kurokawa



Secretion of Parathyroid Hormone Oscillates Depending on the Change in Serum Ionized Calcium during Hemodialysis and May Affect Bone Metabolism  

Microsoft Academic Search

Background: The current study was undertaken to clarify the dynamic response of parathyroid hormone (PTH) during hemodialysis and to determine whether or not such dynamic change of PTH affects bone turnover. Methods: Serum ionized calcium (iCa) and intact PTH (iPTH) were measured in 66 dialysis patients before (basal) and after each hemodialysis. The changes of iCa (?iCa) and iPTH (?iPTH)

Tokuyuki Kitahara; Kazue Ueki; Takashi Kuroiwa; Yoriaki Kaneko; Keiju Hiromura; Yoshihisa Nojima



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

Microsoft Academic Search

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.

Farrokh Asadi; Mohammad Farraj; Rohollah Sharifi; Sadegh Malakouti; Salah Antar; Subhash Kukreja



Calcium Bioavailability and Parathyroid Hormone Acute Changes after Oral Intake of Dairy and Nondairy Products in Healthy Volunteers  

Microsoft Academic Search

:   This study was designed to compare calcium bioavailability and serum parathyroid hormone acute changes after oral intake\\u000a of 500 mg of elemental calcium from liquid milk, yogurt, calcium-citrate-enriched powdered milk or a calcium carbonate pill;\\u000a or after intake of soybean imitation-milk. After a 12-h fast, blood samples were drawn both at baseline and 1, 2, 3 and 4\\u000a h

J. R. Talbot; P. Guardo; S. Seccia; L. Gear; D. R. Lubary; G. Saad; M. L. Roberts; E. Fradinger; A. Marino; J. R. Zanchetta



Parathyroid hormone: A novel tool for treating bone marrow depletion in cancer patients caused by chemotherapeutic drugs and ionizing radiation  

Microsoft Academic Search

Between 1958 and the late 1970s it was learned that PTH (the parathyroid hormone) could directly stimulate the initiation of DNA replication by murine CFU-S (colony-forming unit-spleen) cells via cyclic AMP, stimulate the proliferation of normal and X-irradiated murine and rat bone marrow cells, control hematopoiesis, and increase the survival of X-irradiated mice and rats when injected any time between

James F. Whitfield



Single-column purification and bio-characterization of recombinant human parathyroid hormone-related protein (1–139)  

Microsoft Academic Search

Recombinant human parathyroid hormone-related protein (hPTHrP) (1–139) was expressed using the IMPACT T7 (intein-mediated purification with an affinity chitin-binding tag) system, allowing purification of free recombinant peptide in a single chromatographic step. This system utilizes an intein, which is a protein splicing element from the Saccharomyces cerevisiaeVMA1 gene. The intein has been modified so that it undergoes a self-cleavage reaction

Cai Wu; Patricia K. Seitz; Miriam Falzon



Parathyroid Hormone versus Bisphosphonate Treatment on Bone Mineral Density in Osteoporosis Therapy: A Meta-Analysis of Randomized Controlled Trials  

Microsoft Academic Search

BackgroundBisphosphonates and parathyroid hormone (PTH) represent the antiresorptive and anabolic classes of drugs for osteoporosis treatment. Bone mineral density (BMD) is an essential parameter for the evaluation of anti-osteoporotic drugs. The aim of this study was to evaluate the effects of PTH versus bisphosphonates on BMD for the treatment of osteoporosis.Methods\\/Principal FindingsWe performed a literature search to identify studies that

Longxiang Shen; Xuetao Xie; Yan Su; Congfeng Luo; Changqing Zhang; Bingfang Zeng; Maria Moran



Parathyroid Hormone-Like Hormone (PTHLH) Represses Decidualization of Human Uterine Fibroblast Cells by an Autocrine/Paracrine Mechanism  

PubMed Central

Context: Parathyroid hormone-like hormone (PTHLH) is abundantly expressed by human endometrial stromal cells during decidualization. However, the role for PTHLH in the decidualization process is unknown. Objective: To examine the effects of PTHLH on the induction and maintenance of decidualization of human uterine fibroblast (HUF) cells in vitro. Design: HUF cells were treated with a PTHLH siRNA or a PTHLH receptor antagonist (bPTH7-34) before or after decidualization with medroxyprogesterone acetate (MPA), estradiol (E2), and prostaglandin E2 (PGE2). Decidualization was monitored by immunocytochemistry and the induction of decidualization-specific marker genes, including IGFBP-1, prolactin, lefty, and transcription factor FOXO1. Results: HUF cells decidualized after pretreatment with a PTHLH siRNA showed greater morphologic changes of decidualization, greater IGFBP-1 protein, and two- to threefold more IGFBP-1, prolactin, lefty, and FOXO1 mRNAs than cells pretreated with a nonsilencing RNA. The PTHLH siRNA pretreated cells also had 31% less DNA fragmentation (TUNEL assay) and 30–35% less caspase 3 levels during decidualization than cells pretreated treated with nonsilencing RNA. Treatment of HUF cells with PTHLH siRNA or bPTH7-34 at 9 d after the induction of decidualization also resulted in 2.1- to 3.2-fold greater IGFBP-1, prolactin, lefty, and FOXO1 mRNA levels than that noted in control cells treated with nonsilencing RNA. Conclusions: These finding strongly suggest that PTHLH represses the induction of human decidualization, stimulates stromal cell apoptosis, and limits the extent of uterine stromal cell differentiation. Because PTHLH and its receptor are expressed by HUF cells and placental cells, the inhibitory effect of PTHLH on decidualization appears to be due, at least in part, to an autocrine/paracrine mechanism.

Sherafat-Kazemzadeh, Rosa; Schroeder, Jennifer K.; Kessler, Cherie A.



The effect of endogenous parathyroid hormone in iliac bone structure and turnover in healthy postmenopausal women.  


Little is known about the effect of endogenous parathyroid hormone (PTH) on the skeleton in postmenopausal women without hyperparathyroidism. In this study, the effects of PTH on bone were investigated in iliac crest biopsies obtained from 37 healthy white postmenopausal women aged 50-73 years. The results showed that neither cancellous nor cortical bone structure changed with serum PTH levels. In cancellous bone, bone formation (wall thickness, osteoid surface, osteoblast surface, mineralizing surface, and mineral apposition rate) and turnover (bone formation rate at the surface, volume levels, and activation frequency) variables increased with increasing serum PTH levels (all p < 0.05) in univariate analysis. Multiple linear regressions, adjusted for serum 25-OHD, calcium, alkaline phosphatase, age, and BMI, showed that serum PTH level was independently associated with wall thickness, osteoid surface, osteoblast surface, mineralizing surface, and bone formation rate (all p < 0.05). In cortical bone, no histomorphometric variable was correlated with PTH levels. On the endosteal surface, some of the bone formation (osteoid surface, osteoblast surface, mineralizing surface) and turnover (bone formation rate at the bone surface levels and activation frequency) variables were positively correlated with PTH levels (all p < 0.05). None of these variables could be independently predicted by PTH status. We conclude that in healthy postmenopausal women endogenous PTH has a positive effect on bone formation on the cancellous surface. The effects of PTH on the endosteal surface are probably confounded by other factors. PMID:23842963

Rao, D Sudhaker; Parikh, Nayana; Palnitkar, Saroj; Qiu, Shijing



Regulation of the osterix (Osx, Sp7) promoter by osterix and its inhibition by parathyroid hormone  

PubMed Central

Osterix (Osx, Sp7) is a zinc-finger transcription factor belonging to the specificity protein (Sp) family expressed in cells of the osteoblast lineage in the developing skeleton where it regulates expression of a number of osteoblastic genes. We previously reported inhibition of osterix mRNA and protein by parathyroid hormone (PTH) stimulation of cAMP in osteoblasts. We here show that Osx expression in osteoblasts is regulated by Sp proteins as demonstrated by mithramycin A inhibition of Osx mRNA and OSX protein levels. Mutation of putative transcription factor binding sites within the Osx promoter demonstrated a tandem repeat sequence that selectively binds OSX but not other Sp factors expressed in osteoblasts (Sp1, Sp3, or Tieg (Klf10)). Mutation of either or both the repeat sequences inhibited 90% of the promoter activity and also abrogated some of the PTH-mediated inhibition of the promoter. Previous studies have shown growth factor regulation of Osx expression by MAPK proteins, particularly p38 phosphorylation of OSX that increases its transcriptional activity. PTH stimulation of osteoblasts inhibits MAPK components (ERK, JNK, and p38) but inhibition of Osx mRNA and protein expression by PTH was selectively mimicked by p38 inhibition and expression of constitutively active MKK6, which stimulates p38, blocked PTH inhibition of OSX. Together, our studies suggest that OSX autoregulation is a major mechanism in osteoblasts and that PTH stimulation inhibits osterix by inhibition of p38 MAPK regulation of OSX.

Barbuto, Richard; Mitchell, Jane



Discovery of a calcimimetic with differential effects on parathyroid hormone and calcitonin secretion.  


Calcimimetics are positive allosteric modulators to the calcium-sensing receptor (CaSR). Activation of the CaSR inhibits the secretion of parathyroid hormone (PTH), stimulates the secretion of calcitonin, and decreases serum calcium (Ca(2+)). Cinacalcet, a second-generation calcimimetic, is used therapeutically to control PTH in patients with chronic kidney disease who are on dialysis with secondary hyperparathyroidism. A calcimimetic that displays increased separation of PTH versus Ca(2+) lowering in patients would potentially allow the use of calcimimetics to treat patients in earlier stages of renal disease because hypocalcemia can develop in this population. Toward this end, we developed a third-generation calcimimetic, determined the molecular pharmacological properties of it using an operation model of allosteric modulation/agonism, and measured the compound effects on PTH, serum ionized Ca(2+), and calcitonin levels in 5/6 nephrectomized rats. We found the new molecule effectively reduced PTH levels without promoting calcitonin secretion or hypocalcemia. Furthermore, our third-generation molecule was less efficacious at promoting calcitonin secretion from human thyroid carcinoma cells compared with 3-(2-chlorophenyl)-N-((1R)-1-(3-methoxyphenyl)ethyl)-1-propanamine (R-568), a first-generation calcimimetic. These data provide evidence that calcimimetics with increased potency can be used to lower PTH without production of significant hypocalcemia because the threshold for inhibition of PTH secretion is much lower than the threshold for calcitonin secretion. PMID:21422163

Henley, Charles; Yang, Yuhua; Davis, James; Lu, Jenny Ying Lin; Morony, Sean; Fan, Wei; Florio, Monica; Sun, Banghua; Shatzen, Edward; Pretorius, James K; Richards, William G; St Jean, David J; Fotsch, Christopher; Reagan, Jeff D



Regulation of Articular Chondrocyte Proliferation and Differentiation by Indian Hedgehog and Parathyroid Hormone-related Protein  

PubMed Central

Objective The chondrocytes of the epiphyseal growth zone are regulated by the Indian hedgehog (Ihh)-parathyroid hormone-related protein (PTHrP) axis. In weight-bearing joints, this growth zone comes to be subdivided by the secondary ossification center into distinct articular and growth cartilage structures. Here, we explored the cells of origin, localization, regulation of expression, and putative functions of Ihh and PTHrP in articular cartilage in the mouse. Methods We assessed Ihh and PTHrP expression in an allelic PTHrP-lacZ knockin mouse and several versions of PTHrP-null mice. Selected joints were unloaded surgically to examine load-induction of PTHrP and Ihh. Results The embryonic growth zone appears to serve as the source of PTHrP-expressing proliferative chondrocytes that populate both the forming articular cartilage and growth plate structures. In articular cartilage, these cells take the form of articular chondrocytes in the mid-zone. In PTHrP-knockout mice, mineralizing chondrocytes encroach upon developing articular cartilage but appear to be prevented from mineralizing the joint space by Ihh-driven surface chondrocyte proliferation. In growing and adult mice, PTHrP expression in articular chondrocytes is load-induced, and unloading is associated with rapid changes in PTHrP expression and articular chondrocyte differentiation. Conclusion We conclude that the PTHrP-Ihh axis participates in the maintenance of articular cartilage. Dysregulation of this system might contribute to the pathogenesis of arthritis.

Chen, Xuesong; Macica, Carolyn; Nasiri, Ali; Broadus, Arthur E.



Pharmacokinetics, tissue distribution and excretion of recombinant human parathyroid hormone 1-84 in animals.  


To study the plasma pharmacokinetics and accumulation of the recombinant human parathyroid hormone (rhPTH) (1-84) in rhesus monkeys, and the tissue distribution and excretion profiles of (125)I-rhPTH (1-84) in rats. The concentration of rhPTH (1-84) in plasma samples were determined by an enzyme immunoassay (EIA) method after subcutaneous and intravenous bolus injection. The tissue distribution and urinary, fecal and biliary excretion patterns of (125)I-rhPTH (1-84) were investigated by trichloroacetic acid (TCA) precipitation method. Following subcutaneous (sc) administration rhPTH (1-84) in rhesus monkeys, rhPTH (1-84) exhibited rapid absorption and elimination and had no accumulated tendency after successive sc administration. Following sc administration (125)I-rhPTH (1-84) in rats, the TCA-precipitated radioactivity was widely distributed and rapidly diminished in most tissues. Approximately 83.9 and 6.8 % of the total radioactivity was recovered in urine and feces by 72 h postdosing, respectively; whereas 4.1 % excreted into bile up to 24 h postdosing. The pharmacokinetics of rhPTH (1-84) complied with linear kinetics within the examined dose range following a single sc administration had no accumulated tendency following multiple sc administration in rhesus monkeys. The accumulation of (125)I-rhPTH (1-84) in tissues/organs examined, appeared to be low in rats. The major elimination route was by urinary excretion. PMID:23314825

Bai, Hua; Jing, Danqing; Jiang, Hua; Yin, Shinan



Proteoglycan 4, a Novel Immunomodulatory Factor, Regulates Parathyroid Hormone Actions on Hematopoietic Cells  

PubMed Central

Proteoglycan 4 (PRG4), a critical protective factor in articular joints, is implicated in hematopoietic progenitor cell expansion and megakaryopoiesis. PRG4 loss-of-function mutations result in camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome, which is characterized primarily by precocious joint failure. PRG4 was identified as a novel parathyroid hormone (PTH) responsiveness gene in osteoblastic cells in bone, and was investigated as a potential mediator of PTH actions on hematopoiesis. Sixteen-week-old Prg4?/? mutant and Prg4+/+ wild-type mice were treated daily with intermittent PTH (residues 1–34) or vehicle for 6 weeks. At 22 weeks of age, Prg4 mutant mice had increased peripheral blood neutrophils and decreased marrow B220+ (B-lymphocytic) cells, which were normalized by PTH. The PTH-induced increase in marrow Lin?Sca-1+c-Kit+ (hematopoietic progenitor) cells was blunted in mutant mice. Basal and PTH-stimulated stromal cell-derived factor-1 (SDF-1) was decreased in mutant mice, suggesting SDF-1 as a candidate regulator of proteoglycan 4 actions on hematopoiesis in vivo. PTH stimulation of IL-6 mRNA was greater in mutant than in wild-type calvaria and bone marrow, suggesting a compensatory mechanism in the PTH-induced increase in marrow hematopoietic progenitor cells. In summary, proteoglycan 4 is a novel PTH-responsive factor regulating immune cells and PTH actions on marrow hematopoietic progenitor cells.

Novince, Chad M.; Koh, Amy J.; Michalski, Megan N.; Marchesan, Julie T.; Wang, Jason; Jung, Younghun; Berry, Janice E.; Eber, Matthew R.; Rosol, Thomas J.; Taichman, Russell S.; McCauley, Laurie K.



Structural Features of Parathyroid Hormone Receptor Coupled to G?S-Protein  

PubMed Central

The molecular basis of the activation of G-proteins by the G-protein coupled receptor for parathyroid hormone (PTH) is unknown. Employing a combination of NMR methods and computer-based structural refinement, structural features involved in the activation of G?s by the PTH receptor (PTH1R) have been determined. Focusing on the C-terminus of the third intracellular loop (IC3), previously shown to be important for G?s activation by PTH1R, the structure of this region, PTH1R(402–408), while bound to G?s, was determined by transferred nuclear Overhauser effect spectroscopy. The relative topological orientation of the IC3 while associated with G?s was determined by saturation transfer difference spectroscopy. These experimental data were incorporated into molecular dynamics simulations of the PTH1R and G?s to provide atomic insight into the receptor-protein interactions important for PTH signaling and a structural framework to analyze previous mutagenesis studies of G?s. These data provide the first step toward development of a molecular mechanism for the signaling profile of PTH1R, an important regulator of calcium levels in the bloodstream.

Plati, Jessica; Tsomaia, Natia; Piserchio, Andrea; Mierke, Dale F.



Direct Inhibitory Effect of Hypercalcemia on Renal Actions of Parathyroid Hormone  

PubMed Central

The effects of calcium on the renal actions of parathyroid hormone (PTH) were studied in vivo and in vitro. In parathyroidectomized rats, variable levels of blood calcium concentration were induced by intravenous infusion of calcium. The renal responses to the injected PTH, i.e. phosphate and cyclic AMP excretion, were compared in these animals. After PTH injection, the increases of both phosphate and cyclic AMP excretion were less in the calcium-infused animals than in the control group without calcium infusion. There was an inverse correlation between the renal responses to PTH and plasma calcium concentration of 4.2-13.5 mg/100 ml. But calcium had no effect on phosphate excretion induced by infusion of dibutyryl cyclic AMP. In the in vitro experiments, the increase of cyclic AMP concentration in response to PTH was less in renal cortical slices taken from the calcium-infused animals than in ones from the control group without calcium infusion. Calcium also inhibited the activation of renal cortical adenylate cyclase in response to PTH, but calcium had no effect on phosphodiesterase. The data indicate that calcium directly inhibits renal actions of PTH both in vivo and in vitro. Such inhibitory mechanism is probably at or before the step of PTH-dependent cyclic AMP generation in the kidney.

Beck, Nama; Singh, Harbans; Reed, Sarah W.; Davis, Bernard B.



Expression of parathyroid hormone-related protein confers malignant potential to mucoepidermoid carcinoma  

PubMed Central

Parathyroid hormone-related protein (PTHrP) is known to induce bone resorption by activating RANKL as well as PTH. PTHrP plays a central role in humoral hypercalcemia, and its expression has been reported to be closely associated with bone metastasis of breast carcinoma. PTHrP expression in oral squamous carcinoma cell lines was investigated, and PTHrP was expressed in oral squamous cell carcinoma cell lines similar to that in a prostate carcinoma cell line. Mucoepidermoid carcinoma is the most common malignant salivary gland tumor composed of different types of cells including a squamous component. Its clinical behavior is highly variable and ranges from slow-growing and indolent to locally aggressive and highly metastatic. We examined the PTHrP expression in mucoepidermoid carcinoma and assessed the significance of its correlation with clinicopathological features. Immunohistochemical detection of PTHrP was carried out in 21 cases of mucoepidermoid carcinoma in the head and neck region. PTHrP was highly detectable in intermediate and epidermoid cells, and abundant expression of PTHrP in intermediate cells had a significant association with cancer malignancy, including lymph node metastasis and/or tumor recurrence. These results suggest that PTHrP expression can be used as a prognostic factor for mucoepidermoid carcinoma.




Expression of parathyroid hormone-related protein confers malignant potential to mucoepidermoid carcinoma.  


Parathyroid hormone-related protein (PTHrP) is known to induce bone resorption by activating RANKL as well as PTH. PTHrP plays a central role in humoral hypercalcemia, and its expression has been reported to be closely associated with bone metastasis of breast carcinoma. PTHrP expression in oral squamous carcinoma cell lines was investigated, and PTHrP was expressed in oral squamous cell carcinoma cell lines similar to that in a prostate carcinoma cell line. Mucoepidermoid carcinoma is the most common malignant salivary gland tumor composed of different types of cells including a squamous component. Its clinical behavior is highly variable and ranges from slow-growing and indolent to locally aggressive and highly metastatic. We examined the PTHrP expression in mucoepidermoid carcinoma and assessed the significance of its correlation with clinicopathological features. Immunohistochemical detection of PTHrP was carried out in 21 cases of mucoepidermoid carcinoma in the head and neck region. PTHrP was highly detectable in intermediate and epidermoid cells, and abundant expression of PTHrP in intermediate cells had a significant association with cancer malignancy, including lymph node metastasis and/or tumor recurrence. These results suggest that PTHrP expression can be used as a prognostic factor for mucoepidermoid carcinoma. PMID:23588777

Nagamine, Kyosuke; Kitamura, Tetsuya; Yanagawa-Matsuda, Aya; Ohiro, Yoichi; Tei, Kanchu; Hida, Kyoko; Higashino, Fumihiro; Totsuka, Yasunori; Shindoh, Masanobu



Characterization of the molecular motions of constitutively active G protein-coupled receptors for parathyroid hormone.  


The molecular mechanism of constitutive activity of the G protein-coupled receptor for human parathyroid hormone (PTH1) has been examined by molecular dynamics (MD) simulations. The single point mutations H223R, T410P, and I458R, of the PTH1 receptor result in ligand-independent receptor activation. Extensive MD simulations indicate that each of the mutations, through different mechanisms, lead to very similar conformational changes of the third intracellular loop. The structural changes, centered on K405 in the C-terminus of the third intracellular loop, can be traced back to the single-point mutations by calculation of the forces and torques responsible for the collective motions of the receptor. This analysis indicates a direct correlation between the conformational preferences of the cytoplasmic loop and the mutations in different locations of the receptor: TM2 (H223R), TM6 (T410P), and TM7 (1458R). Given the pivotal role of the third intracellular loop of PTH1 in coupling to the G proteins, the structural changes induced by these single-point mutations may be responsible for the ligand-free activation of the receptor. These results coupled with the high-resolution structure of the third cytoplasmic loop of PTH1, previously determined in our laboratory, provide unique insight into the mechanism of ligand free activation of the PTH1 receptor. PMID:11254206

Rölz, C; Mierke, D F



Full length parathyroid hormone (1-84) in the treatment of osteoporosis in postmenopausal women  

PubMed Central

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

Jodar-Gimeno, Esteban



Human Parathyroid Hormone Is Secreted Primarily into the Bloodstream After Rat Parotid Gland Gene Transfer  

PubMed Central

Abstract Hypoparathyroidism is a hormone deficiency syndrome that leads to low blood calcium levels and for which current replacement therapy is inadequate. Gene transfer to salivary glands leads to safe and abundant secretion of therapeutic protein into either saliva or the bloodstream. We previously reported the successful transduction of rat submandibular glands with an adenoviral vector encoding human parathyroid hormone (Ad.hPTH), but unfortunately most of the hPTH was secreted into saliva. Because submandibular and parotid glands are morphologically and functionally different, we hypothesized that hPTH sorting might be different in parotid glands. After 2 days, the pattern of hPTH secretion from transduced parotid glands of intact rats was reversed from that of transduced submandibular glands, that is, most transgenic hPTH was detected in serum (5?×?1010 viral particles per gland; the saliva-to-serum ratio of total hPTH secreted was 0.04). Vector copies were localized to the targeted parotid glands, with none detected in liver or spleen. Ad.hPTH next was administered to parotid glands of parathyroidectomized rats. Two days after delivery no hPTH was detectable in saliva, but high levels were found in serum, leading to normalization of serum calcium and a significant increase in the urinary phosphorus-to-creatinine ratio. This study demonstrates for the first time differential sorting of transgenic hPTH between submandibular and parotid glands, suggesting that hPTH may be a valuable model protein for understanding the molecular basis of transgenic secretory protein sorting in these exocrine glands. We also show the clinical potential of salivary gland hPTH gene therapy for patients with hypoparathyroidism.

Adriaansen, J.; Perez, P.; Zheng, C.; Collins, M.T.



Suppressor of Fused (Sufu) Mediates the Effect of Parathyroid Hormone-like Hormone (Pthlh) on Chondrocyte Differentiation in the Growth Plate*  

PubMed Central

Growth plate chondrocytes undergo a coordinated process of differentiation, regulating long bone growth. Parathyroid hormone-like hormone (Pthlh) inhibits hypertrophic differentiation in the growth plate chondrocytes and reduces Hedgehog (Hh) signaling. In mice lacking the Hh mediator Suppressor of fused (Sufu), Pthlh treatment resulted in the up-regulation of Hh activity and an increased number of hypertrophic chondrocytes. Furthermore, Pthlh increased Sufu protein levels, and in chondrocytes lacking Sufu, it was unable to process Hh-regulated Gli transcription factors. Pthlh regulates chondrocyte differentiation and Gli activity in a Sufu-dependent manner, with Sufu acting as a molecular switch in its regulation of differentiation.

Hsu, Shu-Hsuan C.; Zhang, Xiaoyun; Cheng, Steven; Wunder, Jay S.; Hui, Chi-Chung; Alman, Benjamin A.



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

Microsoft Academic Search

The effect of antidiuretic hormone (arginine vasopressin, AVP, 10?10mol.l?1), parathyroid hormone (PTH, 10?8 mol.l?8) and glucagon (10?8 mol.l?1) on the transepithelial potential difference (PDte) and the transepithelial resistance (Rte) were tested in in vitro perfused cortical (cTAL) and medullary (mTAL) thick ascending limbs of Henle's loop of the mouse\\u000a nephron. When compared with mTAL segments (PDte: 8.5±0.4 mV,n=16), cTAL segments

M. Wittner; A. Di Stefano



The acute effect of chlorothiazide on serum-ionized calcium. Evidence for a parathyroid hormone-dependent mechanism.  

PubMed Central

The acute effects of chlorothiazide (CTZ) on total (TSCA) and ionized (SCA-plus 2) serum calcium concentrations were studied in three groups of people: (a) eight subjects with normal parathyroid function; (b) six patients with hypoparathyroidism; and (c) two patients with hyperparathyroidism. Most subjects were studied on four occasions; at least 3 days intervened between studies on an individual subject. During each experiment the subject received an i.v. influsion of 5% dextrose in water at 1 ml/min from 8 a.m. to 4 p.m. Additions to the infusions were (a) none; (b) CTZ to deliver 3.33 mg/kg/h; (c) parathyroid extract to deliver 1 U/kg/h; or (d) both CTZ and parathyroid extract at the rates previously indicated. CTZ, when used, was added to the infusion at 10 a.m., parathyroid extract at 8 a.m. When CTZ was infused, the diuretic-induced losses of Na and water were replaced by i.v. infusion. In normal subjects 2 h after the start of CTZ infusion, there was a transient increase in SCA-plus 2 which coincided in time of day with a transient decrease in SCA-plus 2 in control experiments. At that time of day SCA-plus 2 was 4.18 plus or minus 0.12 mg/100 ml in control experiments and 4.56 plus or minus 0.08 in experiments with CTZ, P smaller than 0.025. The corresponding values for (TSCA) were 9.32 plus or minus 0.15 and 9.80 plus or minus 0.30, P smaller than 0.01. Such differences were not observed in the group with hypoparathyroidism. In the two patients with hyperparathyroidism, CTZ produced sustained increases in TSCA and SCA-plus 2. In normal subjects and those with hypoparathyroidism, CTZ plus parathyroid extract infusion resulted in sustained increases in both SCA-plus 2 and TSCA throughout the periods of observation when compared to experiments in which only parathyroid extract was infused, P smaller than 0.01 in all instances. The results suggest that the acute hypercalcemic action of CTZ requires the presence of circulating parathyroid hormone.

Popovtzer, M M; Subryan, V L; Alfrey, A C; Reeve, E B; Schrier, R W



Increased Parathyroid Hormone Gene Expression in Secondary Hyperparathyroidism of Experimental Uremia Is Reversed by Calcimimetics: Correlation with Posttranslational Modification of the Trans Acting Factor AUF1  

Microsoft Academic Search

Most patients with chronic kidney disease develop secondary hyperparathyroidism with disabling systemic complications. Calcimimetic agents are effective tools in the management of secondary hyperparathyroidism, acting through allosteric modification of the calcium-sensing receptor (CaR) on the parathyroid gland (PT) to decrease parathyroid hormone (PTH) secretion and PT cell proliferation. This study showed that rats that were fed an adenine high-phosphorus diet

Ronen Levi; Iddo Z. Ben-Dov; Vardit Lavi-Moshayoff; Maya Dinur; David Martin; Tally Naveh-Many; Justin Silver


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

PubMed Central

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.

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



Anabolic and catabolic bone effects of human parathyroid hormone (1-34) are predicted by duration of hormone exposure.  


Parathyroid hormone (PTH)(1-34), given once daily, increases bone mass in a variety of animal models and humans with osteoporosis. However, continuous PTH infusion has been shown to cause bone loss. To determine the pharmacokinetic profile of PTH(1-34) associated with anabolic and catabolic bone responses, PTH(1-34) pharmacokinetic and serum biochemical profiles were evaluated in young male rats using dosing regimens that resulted in either gain or loss of bone mass. Once-daily PTH(1-34) or 6 PTH(1-34) injections within 1 h, for a total daily dose of 80 microg/kg, induced equivalent increases in proximal tibia bone mass. In contrast, 6 PTH(1-34) injections/day over 6 h for a total dose of 80 microg/kg/day or 3 injections/day over 8 h for a total of 240 microg/kg/day decreased tibia bone mass. The PTH(1-34) pharmacokinetics of the different treatment regimens were distinctive. The magnitude of the maximum serum concentrations (Cmax) of PTH(1-34) and area under the curve (AUC) did not predict the catabolic bone outcome. Compared to the anabolic pharmacokinetic profile of a transient increase in PTH(1-34) with rapid decreases in serum calcium and phosphate, the catabolic regimen was associated with PTH(1-34) concentrations remaining above baseline values during the entire 6-h dosing period with a trend toward an increase in serum calcium and a prolonged decrease in phosphate. The pharmacokinetic profiles suggest that the anabolic or catabolic response of bone to PTH(1-34) is determined primarily by the length of time each day that serum concentrations of PTH(1-34) remain above baseline levels of endogenous PTH and only secondarily by the Cmax or AUC of PTH(1-34) achieved. PMID:13678779

Frolik, Charles A; Black, Elwood C; Cain, Ricky L; Satterwhite, Julie H; Brown-Augsburger, Patricia L; Sato, Masahiko; Hock, Janet M



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

NASA Astrophysics Data System (ADS)

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.

Torday, J.


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

NASA Astrophysics Data System (ADS)

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

Torday, J. S.



Sampling and storage conditions influencing the measurement of parathyroid hormone in blood samples: a systematic review.  


Abstract Parathyroid hormone (PTH) is relatively unstable: optimisation of pre-analytical conditions, including specimen type, sampling time and storage conditions, is essential. We have undertaken a systematic review of these pre-analytical conditions. An electronic search of the PubMed, Embase, Cochrane, Centre for Research and Dissemination and Bandolier databases was undertaken. Of 5511 papers identified, 96 underwent full text review, of which 83 were finally included. At room temperature PTH was stable in ethylenediaminetetraacetic acid (EDTA) preserved whole blood for at least 24 h and in EDTA plasma for at least 48 h after venepuncture. Losses were observed in clotted blood samples after 3 h and in serum after 2 h. At 4°C PTH was more stable in EDTA plasma (at least 72 h) than serum (at least 24 h). Central venous PTH concentrations were higher than peripheral venous concentrations. In the northern hemisphere, PTH concentrations were higher in winter than summer. PTH has a circadian rhythm characterised by a nocturnal acrophase and mid-morning nadir. Data related to frozen storage of PTH (-20°C and -80°C) were limited and contradictory. We recommend that blood samples for PTH measurement should be taken into tubes containing EDTA, ideally between 10:00 and 16:00, and plasma separated within 24 h of venepuncture. Plasma samples should be stored at 4°C and analysed within 72 h of venepuncture. Particular regard must be paid to the venepuncture site when interpreting PTH concentration. Further research is required to clarify the suitability of freezing samples prior to PTH measurement. PMID:24072573

Hanon, Elodie A; Sturgeon, Catharine M; Lamb, Edmund J



Parathyroid hormone receptor in intact embryonic chicken bone: characterization and cellular localization  

PubMed Central

The specific localization and the characterization of the parathyroid hormone (PTH) receptor in bone have been studied using 18-d embryonic chick calvariae and biologically active, electrolytically labeled [125I] bovine PTH(1-34). Binding was initiated by adding [125I]-bPTH(1- 34) to bisected calvariae at 30 degrees C. Steady state binding was achieved at 90 min at which time 10 mg drg wt of calvaria specifically bound 17% of the added [125I]bPTH(1-34). Nonspecific binding in the presence of 244 nM unlabeled bPTH(1-34) was less than 2%. Insulin, glucagon, and calcitonin (1 microgram/ml) did not compete for PTH binding sites. Half-maximal inhibition of binding was achieved at concentrations of unlabeled bPTH(1-34) or bPTH(1-84) of about 10 nM. The range of concentration (2-100 nM) over which bPTH(1-34) and bPTH(1- 84) stimulated cyclic 3'5'adenosine monophosphate (cAMP) production was similar to that which inhibited the binding of [125I]bPTH(1-34). Light microscope autoradiograms showed that grains were concentrated over cells (osteoblasts and progenitor cells) at the external surface of the calvariae and in trabeculae. In the presence of excess unlabeled PTH, labeling of control autoradiograms was reduced to near background levels. No labeling of osteocytes or osteoclasts was observed. At the electron microscopic level, grains were localized primarily over cell membranes. A quantitative analysis of grain distribution suggested that cellular internalization of PTH occurred.



Assessment of calcium balance in patients on hemodialysis, based on ionized calcium and parathyroid hormone responses.  


Background: Identification of the underlying causes of secondary hyperparathyroidism (SHPT) in individual patients on hemodialysis (HD) is hampered by the lack of clinically reliable information on calcium balance. The aim of this study was to assess calcium balance during HD sessions with a method that is applicable in day-to-day practice.?Methods: Plasma ionized calcium (pCa2+) and ?parathyroid hormone (PTH) were measured at the beginning and end of HD to evaluate calcium fluxes in 23 patients on a dialysate calcium (DCa) concentration of 1.25 mmol/L.?Results: HD with a DCa of 1.25 mmol/L caused a ?decrease in pCa2+ from 1.15 ± 0.01 mmol/L to 1.09 ± 0.01 mmol/L (p<0.0001) and increased plasma PTH from 26.7 ± 1.8 pmol/L to 37.0 ± 2.9 pmol/L (p<0.0001). The changes in pCa2+ were inversely related to the predialysis pCa2+ levels (R2 = 0.86, p<0.001). Patients with a predialysis pCa2+ >1.06 mmol/L had a calcium efflux, whereas those with a predialysis pCa2+ <1.06 mmol/L had a calcium influx during HD. ?Conclusion: The results suggest that measurement of pCa2+ and PTH at the beginning and the end of HD provides useful information about calcium fluxes in individual patients. Further validation of this approach ?is warranted. PMID:23475464

Bech, Anneke; Reichert, Louis; Telting, Darryl; de Boer, Hans



Activated Effects of Parathyroid Hormone-Related Protein on Human Hepatic Stellate Cells  

PubMed Central

Background & Aims After years of experiments and clinical studies, parathyroid hormone-related protein(PTHrP) has been shown to be a bone formation promoter that elicits rapid effects with limited adverse reaction. Recently, PTHrP was reported to promote fibrosis in rat kidney in conjunction with transforming growth factor-beta1 (TGF-?1), which is also a fibrosis promoter in liver. However, the effect of PTHrP in liver has not been determined. In this study, the promoting actions of PTHrP were first investigated in human normal hepatic stellate cells (HSC) and LX-2 cell lines. Methods TGF-?1, alpha-smooth muscle actin (?-SMA), matrix metalloproteinase 2 (MMP-2), and collagen I mRNA were quantified by real-time polymerase chain reaction (PCR) after HSCs or LX-2 cells were treated with PTHrP(1–36) or TGF-?1. Protein levels were also assessed by western-blot analysis. Alpha-SMA were also detected by immunofluorescence, and TGF-?1 secretion was measured with enzyme-linked immunosorbent assay (ELISA) of HSC cell culture media. Results In cultured human HSCs, mRNA and protein levels of ?-SMA, collagen I, MMP-2, and TGF-?1 were increased by PTHrP treatment. A similar increasing pattern was also observed in LX-2 cells. Moreover, PTHrP significantly increased TGF-?1 secretion in cultured media from HSCs. Conclusions PTHrP activated HSCs and promoted the fibrosis process in LX-2 cells. These procedures were probably mediated via TGF-?1, highlighting the potential effects of PTHrP in the liver.

Liang, Fen-Fen; Liu, Cui-Ping; Li, Li-Xuan; Xue, Min-Min; Xie, Fang; Guo, Yu; Bai, Lan



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

SciTech Connect

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.

Pirih, Flavia Q. [Division of Diagnostic and Surgical Sciences, UCLA School of Dentistry, Los Angeles, CA 90095 (United States)]. E-mail:; Aghaloo, Tara L. [Division of Diagnostic and Surgical Sciences, UCLA School of Dentistry, Los Angeles, CA 90095 (United States)]. E-mail:; Bezouglaia, Olga [Division of Diagnostic and Surgical Sciences, UCLA School of Dentistry, Los Angeles, CA 90095 (United States)]. E-mail:; Nervina, Jeanne M. [Section of Orthodontics, UCLA School of Dentistry, Los Angeles, CA 90095 (United States)]. E-mail:; Tetradis, Sotirios [Division of Diagnostic and Surgical Sciences, UCLA School of Dentistry, Los Angeles, CA 90095 (United States); UCLA Molecular Biology Institute, Los Angeles, CA 90095 (United States); E-mail:



Connexin43 interacts with ?arrestin: a pre-requisite for osteoblast survival induced by parathyroid hormone  

PubMed Central

Parathyroid hormone (PTH) promotes osteoblast survival through a mechanism that depends on cAMP-mediated signaling downstream of the G protein-coupled receptor PTHR1. We present evidence herein that PTH-induced survival signaling is impaired in cells lacking connexin43 (Cx43). Thus, expression of functional Cx43 dominant negative proteins or Cx43 knock-down abolished the expression of cAMP-target genes and anti-apoptosis induced by PTH in osteoblastic cells. In contrast, cells lacking Cx43 were still responsive to the stable cAMP analog dibutyril-cAMP. PTH survival signaling was rescued by transfecting wild type Cx43 or a truncated dominant negative mutant of ?arrestin, a PTHR1-interacting molecule that limits cAMP signaling. On the other hand, Cx43 mutants lacking the cytoplasmic domain (Cx43?245) or unable to be phosphorylated at serine 368 (Cx43S368A), a residue crucial for Cx43 trafficking and function, failed to restore the anti-apoptotic effect of PTH in Cx43-deficient cells. In addition, overexpression of wild type ?arrestin abrogated PTH survival signaling in Cx43-expressing cells. Moreover, ?arrestin physically associated in vivo to wild type Cx43 and to a lesser extent to Cx43S368A; and this association and the phosphorylation of Cx43 in serine 368 were reduced by PTH. Furthermore, induction of Cx43S368 phosphorylation or overexpression of wild type Cx43, but not Cx43?245 or Cx43S368A, reduced the interaction between ?arrestin and the PTHR1. These studies demonstrate that ?arrestin is a novel Cx43-interacting protein and suggest that, by sequestering ?arrestin, Cx43 facilitates cAMP signaling, thereby exerting a permissive role on osteoblast survival induced by PTH.

Bivi, Nicoletta; Lezcano, Virginia; Romanello, Milena; Bellido, Teresita; Plotkin, Lilian I.



Extracellular calcium regulates parathyroid hormone-related peptide expression in osteoblasts and osteoblast progenitor cells.  


Parathyroid hormone-related peptide (PTHrP) has been shown to have anabolic effects on bone in women with postmenopausal osteoporosis. On the cellular level PTHrP promotes the recruitment of osteogenic cells and prevents apoptotic death of osteoblasts and osteocytes. The calcium concentration is considerably higher in the vicinity of resorbing osteoclasts than in the plasma. Therefore the osteoblasts are likely to be confronted by elevated extracellular calcium concentrations in the areas of resorptive activity. The present study was designed to assess the possibility that extracellular calcium could regulate PTHrP expression in osteoblastic cells. Adult human mesenchymal stem cells (hMSC) were cultured and differentiated by standard methods. The PTHrP release into the culture media was measured by an immunoradiometric assay and the expression of PTHrP, osteocalcin and Runx2 mRNA was assayed by real-time PCR. Increasing the extracellular calcium from 1 mM to 5 mM for 24 h resulted in a 4-6-fold increase in the PTHrP release. PTHrP mRNA was also increased by elevated calcium levels. The effect of calcium stimulation on PTHrP release could be seen within 60 min of treatment. The extracellular calcium sensing receptor (CaR) agonist neomycin mimicked the effects of calcium and the MEK/MAPK inhibitor PD98059 abolished the effect of calcium and neomycin. High extracellular calcium increased the mineralization of hMSC and the expression of osteocalcin, but this effect was not mimicked by neomycin. Our results show that in hMSC, elevated extracellular calcium levels increases both released PTHrP and PTHrP mRNA expression. The effect of calcium on PTHrP can be mimicked by activation of the CaR and can be diminished by inhibition of the MAPK signalling pathway. PMID:18096456

Ahlstrom, Mikael; Pekkinen, Minna; Riehle, Ulrike; Lamberg-Allardt, Christel



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


Previous studies have demonstrated that endogenous parathyroid hormone-related peptide (PTHrP) plays a central role in the physiological regulation of bone formation. However, it is unclear whether endogenous PTHrP plays an important function in enhancing bone fracture healing. To determine whether endogenous PTHrP haploinsufficiency impaired bone fracture healing, closed mid-diaphyseal femur fractures were created in 8-week-old wild-type and Pthrp(+/-) mice. Callus tissue properties were analysed 1, 2 and 4 weeks after fracture by radiography, histology, histochemistry, immunohistochemistry and molecular biology. The size of the calluses was reduced 2 weeks after fracture, and the fracture repairs were poor 4 weeks after fractures, in Pthrp(+/-) compared with wild-type mice. Cartilaginous callus areas were reduced 1 week after fracture, but were increased 2 weeks after fracture in Pthrp(+/-) mice. There was a reduction in the number of ostoblasts, alkaline phosphatase (ALP)-positive areas, Type I collagen immunopositive areas, mRNA levels of ALP, Runt-related transcription factor 2 (Runx2) and Type I collagen, Runx2 and insulin-like growth factor-1 protein levels, the number of osteoclasts and the surface in callus tissues in Pthrp(+/-) compared with wild-type mice. These results demonstrate that endogenous PTHrP haploinsufficiency impairs the fracture repair process by reducing cartilaginous and bony callus formation, with downregulation of osteoblastic gene and protein expression and a reduction in endochondral bone formation, osteoblastic bone formation and osteoclastic bone resorption. Together, the results indicate that endogenous PTHrP plays an important role in fracture healing. PMID:23937065

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



Acute parathyroid hormone differentially regulates renal brush border membrane phosphate cotransporters.  


Renal phosphate reabsorption across the brush border membrane (BBM) in the proximal tubule is mediated by at least three transporters, NaPi-IIa (SLC34A1), NaPi-IIc (SLC34A3), and Pit-2 (SLC20A2). Parathyroid hormone (PTH) is a potent phosphaturic factor exerting an acute and chronic reduction in proximal tubule phosphate reabsorption. PTH acutely induces NaPi-IIa internalization from the BBM and lysosomal degradation, but its effects on NaPi-IIc and Pit-2 are unknown. In rats adapted to low phosphate diet, acute (30 and 60 min) application of PTH decreased BBM phosphate transport rates both in the absence and the presence of phosphonoformic acid, an inhibitor of SLC34 but not SLC20 transporters. Immunohistochemistry showed NaPi-IIa expression in the S1 to the S3 segment of superficial and juxtamedullary nephrons; NaPi-IIc was only detectable in S1 segments and Pit-2 in S1 and weakly in S2 segments of superficial and juxtamedullary nephrons. PTH reduced NaPi-IIa staining in the BBM with increased intracellular and lysosomal appearance. NaPi-IIa internalization was most prominent in S1 segments of superficial nephrons. We did not detect changes in NaPi-IIc and Pit-2 staining over this time period. Blockade of lysosomal protein degradation with leupeptin revealed NaPi-IIa accumulation in lysosomes, but no lysosomal staining for NaPi-IIc or Pit-2 could be detected. Immunoblotting of BBM confirmed the reduction in NaPi-IIa abundance and the absence of any effect on NaPi-IIc expression. Pit-2 protein abundance was also significantly reduced by PTH. Thus, function and expression of BBM phosphate cotransporters are differentially regulated allowing for fine-tuning of renal phosphate reabsorption. PMID:20526720

Picard, Nicolas; Capuano, Paola; Stange, Gerti; Mihailova, Marija; Kaissling, Brigitte; Murer, Heini; Biber, Jürg; Wagner, Carsten A



Parathyroid hormone suppression by intravenous 1,25-dihydroxyvitamin D. A role for increased sensitivity to calcium.  

PubMed Central

Numerous in vitro studies in experimental animals have demonstrated a direct suppressive effect of 1,25-dihydroxyvitamin D (1,25(OH)2D) on parathyroid hormone (PTH) synthesis. We therefore sought to determine whether such an effect could be demonstrated in uremic patients undergoing maneuvers designed to avoid changes in serum calcium concentrations. In addition, the response of the parathyroid gland in patients undergoing hypercalcemic suppression (protocol I) and hypocalcemic stimulation (protocol II) before and after 2 wk of intravenous 1,25(OH)2D was evaluated. In those enlisted in protocol I, PTH values fell from 375 +/- 66 to 294 +/- 50 pg (P less than 0.01) after 1,25(OH)2D administration. During hypercalcemic suppression, the "set point" (PTH max + PTH min/2) for PTH suppression by calcium fell from 5.24 +/- 0.14 to 5.06 +/- 0.15 mg/dl (P less than 0.05) with 1,25(OH)2D. A similar decline in PTH levels after giving intravenous 1,25(OH)2D was noted in protocol II patients. During hypocalcemic stimulation, the parathyroid response was attenuated by 1,25(OH)2D. We conclude that intravenous 1,25(OH)2D directly suppresses PTH secretion in uremic patients. This suppression, in part, appears to be due to increased sensitivity of the gland to ambient calcium levels.

Delmez, J A; Tindira, C; Grooms, P; Dusso, A; Windus, D W; Slatopolsky, E



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

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.

Pietrogrande, Luca



Vitamin D in the aging musculoskeletal system: An authentic strength preserving hormone  

Microsoft Academic Search

Until recently, vitamin D was only considered as one of the calciotrophic hormones without major significance in other metabolic processes in the body. Several recent findings have demonstrated that vitamin D plays also a role as a factor for cell differentiation, function and survival. Two organs, muscle and bone, are significantly affected by the presence, or absence, of vitamin D.

Manuel Montero-Odasso; Gustavo Duque



Effect of Vitamin D Nutrition on Parathyroid Adenoma Weight: Pathogenetic and Clinical Implications  

Microsoft Academic Search

In primary hyperparathyroidism, adenoma size is a major deter- minant of disease severity and manner of presentation, but the reason for the large variation in size (.100-fold) is unknown. One factor could be the level of vitamin D nutrition, because in India, where vitamin D deficiency is endemic, adenomas are larger and the disease more severe than in the U.S.




Metabolism and Action of the Hormone Vitamin D  

PubMed Central

Extensive experimental evidence has established a significant role of calciferol in the maintenance of normal calcium homeostasis. Present knowledge indicates that vitamin D3 must first be converted to 25-OH-D3 and then to 1,25(OH)2D3, 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)2D3 and other analogs of this steroid may offer potential therapeutic benefit in the treatment of certain of the disease entities discussed.

Coburn, Jack W.; Hartenbower, David L.; Norman, Anthony W.



Cinacalcet HCl prevents development of parathyroid gland hyperplasia and reverses established parathyroid gland hyperplasia in a rodent model of CKD  

PubMed Central

Background. Secondary hyperparathyroidism (sHPT) represents an adaptive response to progressively impaired control of calcium, phosphorus and vitamin D in chronic kidney disease (CKD). It is characterized by parathyroid hyperplasia and excessive synthesis and secretion of parathyroid hormone (PTH). Parathyroid hyperplasia in uremic rats can be prevented by calcium-sensing receptor (CaSR) activation with the calcimimetic cinacalcet (Sensipar®/Mimpara®); however, it is unknown, how long the effects of cinacalcet persist after withdrawal of treatment or if cinacalcet is efficacious in uremic rats with established sHPT. Methods. We sought to determine the effect of cinacalcet discontinuation in uremic rats and whether cinacalcet was capable of influencing parathyroid hyperplasia in animals with established sHPT. Results. Discontinuation of cinacalcet resulted in reversal of the beneficial effects on serum PTH and parathyroid hyperplasia. In rats with established sHPT, cinacalcet decreased serum PTH and mediated regression of parathyroid hyperplasia. The cinacalcet-mediated decrease in parathyroid gland size was accompanied by increased expression of the cyclin-dependent kinase inhibitor p21. Prevention of cellular proliferation with cinacalcet occurred despite increased serum phosphorus and decreased serum calcium. Conclusions. The animal data provided suggest established parathyroid hyperplasia can be reversed by modulating CaSR activity with cinacalcet and that continued treatment may be necessary to maintain reductions in PTH.

Miller, Gerald; Davis, James; Shatzen, Edward; Colloton, Matthew; Martin, David



Molecular dissection of the importin beta1-recognized nuclear targeting signal of parathyroid hormone-related protein.  


Produced by various types of solid tumors, parathyroid hormone-related protein (PTHrP) is the causative agent of humoral hypercalcemia of malignancy. The similarity of PTHrP's amino-terminus to that of parathyroid hormone enables it to share some of the latter's signalling properties, but its carboxy-terminus confers distinct functions including a role in the nucleus/nucleolus in reducing apoptosis and enhancing cell proliferation. PTHrP nuclear import occurs via a novel importin beta1-mediated pathway. The present study uses several different direct binding assays to map the interaction of PTHrP with importin beta using a series of alanine mutated PTHrP peptides and truncated human importin beta1 derivatives. Our results indicate that PTHrP amino acids 83-93 (KTPGKKKKGK) are absolutely essential for importin beta1 recognition with residues 71-82 (TNKVETYKEQPL) additionally required for high affinity binding; residues 380-643 of importin beta1 are required for the interaction. Binding of importin beta1 to PTHrP is reduced in the presence of the GTP-bound but not GDP-bound form of the guanine nucleotide binding protein Ran, consistent with the idea that RanGTP binding to importin beta is involved in the release of PTHrP into the nucleus following translocation across the nuclear envelope. This study represents the first detailed examination of a modular, non-arginine-rich importin beta1-recognized nuclear targeting signal. PMID:11401507

Lam, M H; Hu, W; Xiao, C Y; Gillespie, M T; Jans, D A



The guanine nucleotide exchange factor Vav2 is a negative regulator of parathyroid hormone receptor/Gq signaling.  


The parathyroid hormone receptor (PTHR) is a class B G protein-coupled receptor (GPCR) that mediates the endocrine and paracrine effects of parathyroid hormone and related peptides through the activation of phospholipase C?-, adenylyl cyclase-, mitogen-activated protein kinase-, and ?-arrestin-initiated signaling pathways. It is currently not clear how specificity among these downstream signaling pathways is achieved. A possible mechanism involves adaptor proteins that affect receptor/effector coupling. In a proteomic screen with the PTHR C terminus, we identified vav2, a guanine nucleotide exchange factor (GEF) for Rho GTPases, as a PTHR-interacting protein. The core domains of vav2 bound to the intracellular domains of the PTHR independent of receptor activation. In addition, vav2 specifically interacted with activated G?(q) but not with G?(s) subunits, and it competed with PTHR for coupling to G?(q). Consistent with its specific interaction with G?(q), vav2 impaired G(q)-mediated inositol phosphate generation but not G(s)-mediated cAMP generation. This inhibition of G(q) signaling was specific for PTHR signaling, compared with other G(q)-coupled GPCRs. Moreover, the benefit for PTHR-mediated inositol phosphate generation in the absence of vav2 required the ezrin binding domain of Na(+)/H(+)-exchanger regulatory factor 1. Our results show that a RhoA GEF can specifically interact with a GPCR and modulate its G protein signaling specificity. PMID:22554804

Emami-Nemini, Alexander; Gohla, Antje; Urlaub, Henning; Lohse, Martin J; Klenk, Christoph



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

PubMed Central

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

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



Vitamin D Deficiency in the Absence of Enteropathy in Three Cases with Common Variable Immunodeficiency  

Microsoft Academic Search

Background: Common variable immunodeficiency (CVID) is characterized by hypogammaglobulinemia and a defect in antibody production. Herein we describe 3 patients diagnosed with CVID in whom vitamin D deficiency was detected in the absence of enteropathy. Methods: Biochemical and immunological analysis, serum osteocalcin, parathyroid hormone, 25-OH vitamin D, 1,25(OH)2 vitamin D, vitamin A, vitamin E, urinary calcium, and deoxypyridinoline measurements were

Ömür Ardeniz; Aytul Sin; Gökhan Özgen; Fulya Gunsar; Nihal Mete; Okan Gulbahar; Ali Kokuludag



Role of parathyroid hormone in the glucose intolerance of chronic renal failure.  

PubMed Central

Evidence has accumulated suggesting that the state of secondary hyperparathyroidism and the elevated blood levels of parathyroid hormone (PTH) in uremia participate in the genesis of many uremic manifestations. The present study examined the role of PTH in glucose intolerance of chronic renal failure (CRF). Intravenous glucose tolerance tests (IVGTT) and euglycemic and hyperglycemic clamp studies were performed in dogs with CRF with (NPX) and without parathyroid glands (NPX-PTX). There were no significant differences among the plasma concentrations of electrolytes, degree of CRF, and its duration. The serum levels of PTH were elevated in NPX and undetectable in NPX-PTX. The NPX dogs displayed glucose intolerance after CRF and blood glucose concentrations during IVGTT were significantly (P less than 0.01) higher than corresponding values before CRF. In contrast, blood glucose levels after IVGTT in NPX-PTX before and after CRF were not different. K-g rate fell after CRF from 2.86 +/- 0.48 to 1.23 +/- 0.18%/min (P less than 0.01) in NPX but remained unchanged in NPX-PTX (from 2.41 +/- 0.43 to 2.86 +/- 0.86%/min) dogs. Blood insulin levels after IVGTT in NPX-PTX were more than twice higher than in NPX animals (P less than 0.01) and for any given level of blood glucose concentration, the insulin levels were higher in NPX-PTX than NPX dogs. Clamp studies showed that the total amount of glucose utilized was significantly lower (P less than 0.025) in NPX (6.64 +/- 1.13 mg/kg X min) than in NPX-PTX (10.74 +/- 1.1 mg/kg X min) dogs. The early, late, and total insulin responses were significantly (P less than 0.025) greater in the NPX-PTX than NPX animals. The values for the total response were 143 +/- 28 vs. 71 +/- 10 microU/ml, P less than 0.01. There was no significant difference in the ratio of glucose metabolized to the total insulin response, a measure of tissue sensitivity to insulin, between the two groups. The glucose metabolized to total insulin response ratio in NPX (5.12 +/- 0.76 mg/kg X min per microU/ml) and NPX-PTX (5.18 +/- 0.57 mg/kg X min per microU/ml) dogs was not different but significantly (P less than 0.01) lower than in normal animals (9.98 +/- 1.26 mg/kg X min per microU/ml). The metabolic clearance rate of insulin was significantly (P less than 0.02) reduced in both NPX (12.1 +/- 0.7 ml/kg X min) and NPX-PTX (12.1 +/- 0.9 ml/kg X min) dogs, as compared with normal animals (17.4 +/- 1.8 ml/kg X min). The basal hepatic glucose production was similar in both groups of animals and nor different from normal dogs; both the time course and the magnitude of suppression of hepatic glucose production by insulin were similar in both in groups. There were no differences in the binding affinity, binding sites concentration, and binding capacity of monocytes to insulin among NPX, NPX-PTX, and normal dogs. The data show that (a) glucose intolerance does not develop with CRF in the absence of PTH, (b) PTH does not affect metabolic clearance of insulin or tissue resistance to insulin in CRF, and (c) the normalization of metabolism in CRF in the absence of PTH is due to increased insulin secretion. The results indicate that excess PTH in CRF interferes with the ability of the beta-cells to augment insulin secretion appropriately in response to the insulin-resistant state. Images

Akmal, M; Massry, S G; Goldstein, D A; Fanti, P; Weisz, A; DeFronzo, R A



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

PubMed Central

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

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



Defective renal maintenance of the vitamin D endocrine system impairs vitamin D renoprotection: a downward spiral in kidney disease  

Microsoft Academic Search

In kidney disease, the progressive loss of renal capacity to produce calcitriol, the vitamin D hormone, is a key contributor to elevations in parathyroid hormone (PTH) and mineral and skeletal disorders predisposing to renal and cardiovascular damage, ectopic calcifications, and high mortality rates. Thus, the safe correction of calcitriol deficiency to suppress PTH has been the treatment of choice for

Adriana S Dusso; Masanori Tokumoto



Chicken Parathyroid Hormone Gene Expression in Response to Gastrin, Omeprazole, Ergocalciferol, and Restricted Food Intake  

Microsoft Academic Search

.   Treatment with omeprazole, a long-acting proton pump inhibitor of acid secretion, induces hypergastrinemia. In chickens,\\u000a omeprazole induces growth not only of the acid-producing mucosa (probably reflecting the trophic action of gastrin), but also\\u000a of the parathyroid glands (hypertrophy + hyperplasia), while suppressing bone density and body weight gain without affecting\\u000a blood calcium. The first part of the present study

R. Gagnemo-Persson; A. Samuelsson; R. Håkanson; P. Persson



Low molecular weight iron dextran increases fibroblast growth factor-23 concentration, together with parathyroid hormone decrease in hemodialyzed patients.  


Fibroblast growth factor (FGF)-23 inhibits PTH production. Elevated FGF-23 and parathyroid hormone (PTH) levels are characteristic of hemodialyzed patients. Iron polymaltose was shown to increase FGF-23 concentration. The effect of intravenous low molecular weight iron dextran (LMID) on these hormones and bone metabolism has not been studied in hemodialysis (HD). Twelve HD patients were prospectively followed up for 3 weeks after a single infusion of LMID. Calcium, phosphate, FGF-23, PTH, degradation products of C-terminal telopeptides of type I collagen (CTX) and procollagen I N-terminal propeptide (PINP) were measured prior to, and at week 1 and week 3 after the LMID administration. FGF-23 increased significantly from 453.4 (68.6-3971.5) pg/mL at baseline to 971.8 (779.5-3361.4) pg/mL (P = 0.001) at week 1 and started to decrease toward the initial value at week 3. The changes were accompanied by a significant decline in PTH from 367.6 (21.4-1487.4) pg/mL at baseline to 315.7 (16.4-1339.8) pg/mL (P = 0.018) at week 1 and subsequently began to increase toward the initial values. Phosphate, calcium, CTX and PINP did not change over the study course. LMID causes an increase in FGF-23 concentration together with a decrease in PTH. Our study highlights a pathophysiological element, which may connect suppression of parathyroid glands with intravenous iron supplementation. PMID:22458393

Hryszko, Tomasz; Rydzewska-Rosolowska, Alicja; Brzosko, Szymon; Koc-Zorawska, Ewa; Mysliwiec, Michal



The calcimimetic agent KRN 1493 lowers plasma parathyroid hormone and ionized calcium concentrations in patients with chronic renal failure on haemodialysis both on the day of haemodialysis and on the day without haemodialysis  

PubMed Central

Aims Treatment with vitamin D sterols can lower plasma parathyroid hormone (PTH) in patients with secondary hyperparathyroidism; however, hypercalcaemia, hyperphosphataemia, or both, often develop. Calcimimetic agents, employed in alternative therapeutic approaches, directly inhibit PTH secretion by activating the calcium-sensing receptor in the parathyroid glands. Methods In this study, patients were given orally 25, 50, and 100 mg doses of the calcimimetic agent KRN 1493 each on two occasions, on the day of haemodialysis and on the day without haemodialysis. Results In the pharmacokinetic results, because the clearance of KRN 1493 by haemodialysis was much smaller than the systemic clearance, the influence of haemodialysis was not remarkable. In the pharmacodynamic study, on both the days with or without haemodialysis, plasma PTH concentrations decreased in a dose-dependent manner. Serum calcium concentrations decreased in association with the decrease in plasma PTH concentrations. Mild dose-dependent adverse effects (mainly nausea) were seen after the administration of KRN 1493 on both the day of haemodialysis and the day without haemodialysis. Conclusions We conclude that the pharmacokinetics of KRN 1493 after a single administration were similar on the day of haemodialysis and the day without haemodialysis. KRN 1493 is safe and effective in suppressing PTH secretion and serum calcium concentrations on the day of haemodialysis and on the day without haemodialysis in patients with secondary hyperparathyroidism.

Ohashi, Naro; Uematsu, Toshihiko; Nagashima, Satoru; Kanamaru, Mitsutaka; Togawa, Akashi; Hishida, Akira; Uchida, Eiji; Akizawa, Tadao; Koshikawa, Shozo



The neuroendocrine-derived peptide parathyroid hormone-related protein promotes prostate cancer cell growth by stabilizing the androgen receptor.  


During progression to an androgen-independent state following androgen ablation therapy, prostate cancer cells continue to express the androgen receptor (AR) and androgen-regulated genes, indicating that AR is critical for the proliferation of hormone-refractory prostate cancer cells. Multiple mechanisms have been proposed for the development of AR-dependent hormone-refractory disease, including changes in expression of AR coregulatory proteins, AR mutation, growth factor-mediated activation of AR, and AR protein up-regulation. The most prominent of these progressive changes is the up-regulation of AR that occurs in >90% of prostate cancers. A common feature of the most aggressive hormone-refractory prostate cancers is the accumulation of cells with neuroendocrine characteristics that produce paracrine factors and may provide a novel mechanism for the regulation of AR during advanced stages of the disease. In this study, we show that neuroendocrine-derived parathyroid hormone-related protein (PTHrP)-mediated signaling through the epidermal growth factor receptor (EGFR) and Src pathways contributes to the phenotype of advanced prostate cancer by reducing AR protein turnover. PTHrP-induced accumulation of AR depended on the activity of Src and EGFR and consequent phosphorylation of the AR on Tyr(534). PTHrP-induced tyrosine phosphorylation of AR resulted in reduced AR ubiquitination and interaction with the ubiquitin ligase COOH terminus of Hsp70-interacting protein. These events result in increased accumulation of AR and thus enhanced growth of prostate cancer cells at low levels of androgen. PMID:19706771

DaSilva, John; Gioeli, Daniel; Weber, Michael J; Parsons, Sarah J



Prevalence and Impact of Vitamin D Insufficiency in Southern Chinese Adults  

Microsoft Academic Search

Introduction: Vitamin D is a vital element for bone health but the problem of vitamin D deficiency is underestimated in Hong Kong. Methods: Serum 25(OH)D and parathyroid hormone (PTH) levels were evaluated in 382 community dwelling Chinese adults >50 years for their relation with bone mineral density (BMD) and risks of osteoporotic fractures and falls. Results: The mean age of

W. Z. M. Wat; J. Y. Y. Leung; S. Tam; A. W. C. Kung



Parathyroid hormone (PTH) decreases sodium-phosphate cotransporter type IIa (NpT2a) mRNA stability.  


The acute inhibitory effects of parathyroid hormone (PTH) on proximal tubule Na(+)-K(+)-ATPase (Na-K) and sodium-dependent phosphate (NaPi) transport have been extensively studied, while little is known about the chronic effects of PTH. Patients with primary hyperparathyroidism, a condition characterized by chronic elevations in PTH, exhibit persistent hypophosphatemia but not significant evidence of salt wasting. We postulate that chronic PTH stimulation results in differential desensitization of PTH responses. To address this hypothesis, we compared the effects of chronic PTH stimulation on Na-P(i) cotransporter (Npt2a) expression and Na-K activity and expression in Sprague Dawley rats, transgenic mice featuring parathyroid-specific cyclin D1 overexpression (PTH-D1), and proximal tubule cell culture models. We demonstrated a progressive decrease in brush-border membrane (BBM) expression of Npt2a from rats treated with PTH for 6 h or 4 days, while Na-K expression and activity in the basolateral membranes (BLM) exhibited an initial decrease followed by recovery to control levels by 4 days. Npt2a protein expression in PTH-D1 mice was decreased relative to control animals, whereas levels of Na-K, NHERF-1, and PTH receptor remained unchanged. In PTH-D1 mice, NpT2a mRNA expression was reduced by 50% relative to control mice. In opossum kidney proximal tubule cells, PTH decreased Npt2a mRNA levels. Both actinomycin D and cycloheximide treatment prevented the PTH-mediated decrease in Npt2a mRNA, suggesting that the PTH response requires transcription and translation. These findings suggest that responses to chronic PTH exposure are selectively regulated at a posttranscriptional level. The persistence of the phosphaturic response to PTH occurs through posttranscriptional mechanisms. PMID:23344572

Murray, Rebecca D; Holthouser, Kristine; Clark, Barbara J; Salyer, Sarah A; Barati, Michelle T; Khundmiri, Syed J; Lederer, Eleanor D



[Ectopic mediastinal parathyroid adenoma].  


We experienced 3 surgical cases with ectopic mediastinal parathyroid adenoma. All patients checked elevated serum calcium levels and parathyroid hormone levels above normal range so we diagnosed their illness as primary hyperparathyroidism. Two had treated urinary tract lithiasis for long time, and the other had no symptoms by hypercalcemia. To determine the location of abnormal parathyroid glands, 99mTc-methoxy-isobutyl-isonitrile (MIBI) scintigraphy, chest computed tomography (CT) scan and/or magnetic resonance imaging (MRI) were done, then posterior and anterior mediastinal tumors were revealed. Especially MIBI scintigraphy was very useful as diagnostic procedure for small ectopic parathyroid adenoma. It's considered that large tumor in the posterior mediastinum like case 1 is originated from upper parathyroid gland, and small tumor in the anterior mediastinum like case 2, 3 is originated from lower parathyroid gland. Tumors were resected via small thoracotomy with thoracoscope, cervical incision and partial median sternotomy respectively. Serum calcium and parathyroid hormone levels were normalized immediately. If we can detect the accurate location of small ectopic parathyroid adenoma using some intraoperative method, the tumor is resected by less invasive procedure. PMID:20715458

Sato, Nobuyuki; Nakagawa, Takayuki; Kanno, Masaaki; Nakamura, Yoshihiro; Kishimoto, Kouji; Imai, Tadashi



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

PubMed Central

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.

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



Effects of parathyroid hormone and N 6 ,O 2? -dibutyryl cyclic AMP on Ca 2+ transport across the rabbit distal nephron segments perfused in vitro  

Microsoft Academic Search

Effects on Ca2+ transport of parathyroid hormone (PTH) and N6,O2'-dibutyryl adenosine 3',5'-cyclic monophosphate (DB-cAMP) were examined in the rabbit distal nephron segments including the cortical thick ascending limb of Henle's loop (CAL), the connecting tubule (CNT) and the cortical collecting tubule (CCT) by the in vitro perfusion technique. When PTH (10-8 mol·l-1) was added to the bath, efflux of Ca2+

Masashi Imai



Study on preparation and activity of a novel recombinant human parathyroid hormone(1–34) analog with N-terminal Pro–Pro extension  

Microsoft Academic Search

A recombinant human parathyroid hormone fragment, Pro–Pro–hPTH(1–34), with molecular weight of 4311.46 was acquired through gene engineering. It was then isolated and purified. The homogeneity of this fragment was characterized by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), high performance liquid chromatography(HPLC), isoelectronic focusing (IEF) electrophoresis and mass spectrometry(MS) methods. Its isoelectric point is 8.0 which was determined by IEF.

Wang Chunxiao; Liu Jingjing; Xiao Yire; Ding Min; Wang Zhaohui; Qi gaofu; Shen Xiangchun; Wang Xuejun; Wu Jie; Li Taiming



Dietary boron supplementation enhanced the action of estrogen, but not that of parathyroid hormone, to improve trabecular bone quality in ovariectomized rats  

Microsoft Academic Search

This study investigated whether boron would enhance the ability of 17?-estradiol (E2) or parathyroid hormone (PTH) to improve bone quality in ovariectomized OVX rats. Adult OVX rats were treated for 5 wk with\\u000a vehicle, boron (5 ppm as boric acid), E2 (30 µg\\/kg\\/d, sc), PTH (60 µg\\/kg\\/d, sc), or a combination of boron and E2 or PTH, respectively. The E2

Matilda H.-C. Sheng; L. Janette Taper; Hugo Veit; Hao Qian; Sanford J. Ritchey; K.-H. William Lau



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  

Microsoft Academic Search

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?µg\\/kg BW), PTX plus PTH (200?mg\\/kg BW

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



Combined effects of recombinant human BMP7 (rhBMP7) and parathyroid hormone (1–34) in metaphyseal bone healing  

Microsoft Academic Search

Fracture healing involves multiple stages of repair and coordinated actions of multiple cell types. Consequently, it may be possible to enhance healing through treatment strategies that target more than one repair process or cell type. The goal of this study was to determine the combined effects of recombinant human bone morphogenetic protein 7 (rhBMP-7) and parathyroid hormone (PTH(1–34)) on metaphyseal

Elise F. Morgan; Zachary D. Mason; Gavin Bishop; A. David Davis; Nathan A. Wigner; Louis C. Gerstenfeld; Thomas A. Einhorn



Influence of a low calcium and phosphorus diet on the anabolic effect of human parathyroid hormone (1-38) in female rats  

Microsoft Academic Search

Parathyroid hormone (PTH) or synthetic N-terminal PTH fragments administered intermittently have been established as anabolic agents in animal and human bones. In the present study, the influence of a low calcium diet on the anabolic effect of human PTH(1-38) [hPTH(1-38)] was investigated. Forty-eight 10-week-old female Sprague-Dawley rats were randomly assigned to a diet with a low calcium content (LCa) or

P. D Steiner; R Forrer; M Kneissel; J. A Gasser; J. S Thomsen; Li Mosekilde; J.-L Riond



Expression of parathyroid hormone-related protein during immortalization of human peripheral blood mononuclear cells by HTLV1: Implications for transformation  

Microsoft Academic Search

BACKGROUND: Adult T-cell leukemia\\/lymphoma (ATLL) is initiated by infection with human T-lymphotropic virus type-1 (HTLV-1); however, additional host factors are also required for T-cell transformation and development of ATLL. The HTLV-1 Tax protein plays an important role in the transformation of T-cells although the exact mechanisms remain unclear. Parathyroid hormone-related protein (PTHrP) plays an important role in the pathogenesis of

Murali VP Nadella; Sherry T Shu; Wessel P Dirksen; Nanda K Thudi; Kiran S Nadella; Soledad A Fernandez; Michael D Lairmore; Patrick L Green; Thomas J Rosol



Serum Levels of 1–84 and 7–84 Parathyroid Hormone in Predialysis Patients with Chronic Renal Failure Measured by the Intact and Bio-PTH Assay  

Microsoft Academic Search

Background: The intact parathyroid hormone (PTH) assay detects both PTH(1–84) and the PTH(7–84)-like fragment, which is reported to be an antagonist of the biological action of PTH(1–84). It is debatable which of the two assays is clinically more useful, the intact or bio-PTH assay, the latter of which only detects PTH(1–84). It is also unknown whether serum levels of the

Takao Tsuchida; Eiji Ishimura; Kaname Hirowatari; Naoki Matsumoto; Yasuo Imanishi; Shuichi Jono; Takami Miki; Masaaki Inaba; Yoshiki Nishizawa



Capillary electrophoretic characterization of PEGylated human parathyroid hormone with matrix-assisted laser desorption\\/ionization time-of-flight mass spectrometry  

Microsoft Academic Search

A capillary electrophoretic method (CE) for characterizing PEGylated human parathyroid hormone 1–34 (PTH) with matrix-assisted laser desorption\\/ionization time-of-flight mass spectrometry (MALDI-TOF MS) is described. CE was used to optimize the PEGylation of PTH through control of the reaction pH and the molar ratio of reactants with the advantages of minimal sample consumption and high separation capacity. The mono-PEGylated PTH (mono-PEG-PTH)

Dong Hee Na; Kang Choon Lee



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  

Microsoft Academic Search

Pulmonary delivery of therapeutic peptides and proteins has many advantages including high relative bioavailability, rapid\\u000a systemic absorption and onset of action and a non-invasive mode of administration which improves patient compliance. In this\\u000a study, we investigated the effect of spray-drying (SD) and spray freeze-drying processes on the stability and aerosol performance\\u000a of parathyroid hormone (PTH) (1-34) microparticles. In this study,

Sunday A. Shoyele; Neeraj Sivadas; Sally-Ann Cryan



Parathyroid Hormone Induces Receptor Activity Modifying Protein3 (RAMP3) Expression Primarily Via 3?,5?Cyclic Adenosine Monophosphate Signaling in Osteoblasts  

Microsoft Academic Search

Parathyroid hormone (PTH) has significant anabolic and catabolic effects on bone. We hypothesize that PTH-induced primary response genes are important determinants of osteoblast function. PTH induces osteoblastic gene expression through PTHR1, a heptahelical receptor that triggers cyclic adenosine monophosphate (cAMP)–protein kinase A (PKA), protein kinase C (PKC), and calcium signaling. By using representational difference analysis we found that receptor activity

E. Phelps; O. Bezouglaia; S. Tetradis; J. M. Nervina



The anabolic effects of parathyroid hormone on cortical bone mass, dimensions and strength—assessed in a sexually mature, ovariectomized rat model  

Microsoft Academic Search

The aim of the study was to determine the effect of parathyroid hormone (PTH), the antiresorptive agents estrogen and bisphosphonate (risedronate), and also the combination of PTH with these antiresorptive drugs on femoral cortical bone mass, dimensions and strength in a sexually mature, ovariectomized rat model. A total of 138, 3-month-old SpragueDawley rats were randomized into seven groups: 1—sham operated

Li. Mosekilde; C. C. Danielsen; C. H. Søgaard; J. E. McOsker; T. J. Wronski



Cancellous and cortical bone architecture and turnover at the iliac crest of postmenopausal osteoporotic women treated with parathyroid hormone 1–84  

Microsoft Academic Search

Treatment with parathyroid hormone [PTH(1–84)] increases lumbar spine bone mineral density and decreases vertebral fractures, but its effects on bone microarchitecture are unknown. We obtained iliac crest biopsies from postmenopausal osteoporotic women given placebo (n=8) or 100 ?g PTH(1–84) for 18 (n=8) or 24 (n=7) months to assess cancellous and cortical bone formation and structure. At 18 months, cancellous bone volume (BV\\/TV)

R. R. Recker; S. P. Bare; S. Y. Smith; A. Varela; M. A. Miller; S. A. Morris; J. Fox



Effects of daily treatment with parathyroid hormone 1–84 for 16 months on density, architecture and biomechanical properties of cortical bone in adult ovariectomized rhesus monkeys  

Microsoft Academic Search

Treatment with parathyroid hormone 1–84 (PTH) or teriparatide increases osteonal remodeling and decreases bone mineral density (BMD) at cortical (Ct) bone sites but may also increase bone size. Decreases in BMD and increases in size exert opposing effects on bone strength. In adult ovariectomized (OVX) rhesus monkeys, we assessed the effects of daily PTH treatment (5, 10 or 25 ?g\\/kg) for

J. Fox; M. A. Miller; M. K. Newman; R. R. Recker; C. H. Turner; S. Y. Smith



Associations of Serum 25-Hydroxyvitamin D, Parathyroid Hormone and Calcium with Cardiovascular Risk Factors: Analysis of 3 NHANES Cycles (2001-2006)  

Microsoft Academic Search

BackgroundIncreasing evidence suggests a role for mineral metabolism in cardiovascular disease risk. 25-hydroxyvitamin D (25(OH)D), parathyroid hormone (PTH), and calcium may be directly associated with cardiovascular risk factors or mediated by each other.Methodology\\/Principal FindingsWe combined data for adult participants in three cycles of the National Health and Nutrition Examination Survey (2001–2, 2003–4, 2005–6), a representative sample of the civilian, non-institutionalized

Abigail Fraser; Dylan Williams; Debbie A. Lawlor; Harald H. H. W. Schmidt



Effect of intermittent parathyroid hormone (1-34) treatment on the bone response after placement of titanium implants into the tibia of ovariectomized rats  

Microsoft Academic Search

Purpose: This study investigated the effect of parathyroid hormone (1-34) [lsqb ]PTH(1-34)[rsqb ] on bone reactions after tibial placement of titanium screw implants into ovariectomized rats. Materials and Methods: Twelve-week-old female Wistar rats were divided into 3 groups of 24. The first group (Sham group) was sham-operated; the second group (OVX group) was ovariectomized only; and the third group (PTH

Tatsuo Shirota; Mie Tashiro; Kohsuke Ohno; Akira Yamaguchi



Induction of Parathyroid Hormone-related Peptide by the Ras Oncogene: Role of Ras Farnesylation Inhibitors as Potential Therapeutic Agents for Hypercalcemia of Malignancy1  

Microsoft Academic Search

Parathyroid hormone related peptide (PTHRP) is the major causal agent in the syndrome of malignancy-associated hypercalcemia (MAH). Several studies have shown that PTHRP production is increased in re sponse to growth factors and oncogenes, such as Tpr-Met, that are asso ciated with the tyrosine kinase signaling pathway. Using site-directed mutagenesis of Tpr-Met and chemical inhibitors of phosphotidylinositol-3 kinase and Ras

Fasika Aklilu; Morag Park; David Goltzman; Shafaat Ahmed Rabbani


The parathyroid hormone-related protein receptor is expressed in breast cancer bone metastases and promotes autocrine proliferation in breast carcinoma cells  

Microsoft Academic Search

Overproduction of parathyroid hormone-related protein (PTHRP) occurs in a high proportion of primary breast cancers (PBC) and is strongly implicated in their metastatic spread to bone. Although the PTHRP-receptor (PTHRP-R) is often coexpressed with PTHRP in PBC, its role in regulating breast cancer cell proliferation and metastases to bone remains unclear. The aims of this study were to determine the

R P Hoey; C Sanderson; J Iddon; G Brady; N J Bundred; N G Anderson



Chondrogenic differentiation of clonal mouse embryonic cell line ATDC5 in vitro: differentiation-dependent gene expression of parathyroid hormone (PTH)\\/PTH-related peptide receptor  

Microsoft Academic Search

The regulatory role of parathyroid hormone (PTH)\\/PTH-related peptide (PTHrP) signaling has been implicated in embryonic skeletal development. Here, we studied chondrogenic differentiation of the mouse embryonal carcinoma-derived clonal cell line ATDC5 as a model of chondrogenesis in the early stages of endochondral bone development. ATDC5 cells retain the properties of chondroprogenitor cells, and rapidly proliferate in the presence of 5%

Chisa Shukunami; Chohei Shigeno; Tadao Atsumi; Kiyoto Ishizeki; Fujio Suzuki; Yuji Hiraki



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

PubMed Central

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

Muresan, Z; MacGregor, R R



Successful autotransplantation of parathyroid adenomas in seven patients.  


The autotransplantation of normal as well as adenomatous parathyroid tissue is currently being used with increasing frequency. In the present report, we describe our experiences with the successful transplantation of adenomatous or hyperplastic parathyroid tissue in seven patients. Prior to transplant surgery, six of these patients had recurrent or persistent primary hyperparathyroidism. The last patient was on hemodialysis for chronic renal failure and was presumed to have tertiary hyperparathyroidism. A large superior mediastinal parathyroid adenoma was found at a second neck exploration. In all patients, the only remaining parathyroid tissue was either adenomatous or hyperplastic. A total of 30 to 75 mg of this parathyroid tissue was diced and transplanted into single subfascial pockets of the forearm muscles (6) or sternocleidomastoid muscle (1). Following transplantation, all patients required transient calcium and vitamin D supplements for six to 12 weeks. In follow-up studies of ten months to 12 years, all patients have remained eucalcemic with normal parathyroid hormone levels. The use of a single subfascial pocket (versus the popular method of multiple implants) may explain the lack of recurrent hyperparathyroidism in our small population. PMID:6859673

Calandra, D; Paloyan, E; Oslapas, R; Hofmann, C; Ernst, K; Shah, K H; Lawrence, A M



A rare case of double parathyroid lipoadenoma with hyperparathyroidism.  


: 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

Ogrin, Cristina



Immunohistochemical analysis of low-grade and high-grade prostate carcinoma: relative changes of parathyroid hormone-related protein and its parathyroid hormone 1 receptor, osteoprotegerin and receptor activator of nuclear factor-kB ligand  

PubMed Central

Aim To investigate multiple bone cytokines produced by prostate carcinoma (PCa) as a novel strategy to differentiate potential aggressiveness in localised PCa using immunohistochemical analysis. Methods A total of 47 cases of PCa undergoing radical prostatectomy or transurethral prostatic resection at our institution (Fundación Jiménez Díaz (Grupo Capio), Madrid, Spain) between January 1991 and June 1998 were identified as low?grade (?4; n?=?22) or high?grade (?7, excluding 7 (3+4) cases; n?=?25) PCa according to Gleason grade. PCa specimens were immunostained for: parathyroid hormone (PTH)?related protein (PTHrP), the PTH1 receptor, osteoprotegerin and receptor activator of nuclear factor?? B ligand (RANKL), as well as Ki67 (a proliferation marker) and CD34 (an angiogenesis marker). Results PCa samples showed an increased immunostaining for both osteoprotegerin and RANKL, associated with tumour grade and PTHrP positivity, in the tumoral epithelium. Using a score value of 4—corresponding to moderate staining—as cut?off, the best sensitivity value was for PTHrP (with C?terminal antiserum C6; 100 %); wheras the best specificity value was for RANKL (95 %). Conclusions All the evaluated factors are overexpressed mainly in the high?grade tumours. Our findings indicate that, in most patients with PCa (with Ki67 values between 1% and 9%), sequential determination of C?terminal PTHrP and RANKL immunoreactivities is a useful approach to discriminate low?grade and high?grade tumours.

Perez-Martinez, Francisco C; Alonso, Veronica; Sarasa, Jose L; Nam-Cha, Syon-Ghyun; Vela-Navarrete, Remigio; Manzarbeitia, Felix; Calahorra, Francisco J; Esbrit, Pedro



The mRNA decay promoting factor K-homology splicing regulator protein post-transcriptionally determines parathyroid hormone mRNA levels.  


Serum calcium and phosphate concentrations and experimental chronic kidney failure control parathyroid hormone (PTH) gene expression post-transcriptionally through regulated binding of the trans-acting proteins AUF1 and upstream of N-ras (Unr) to an AU-rich element (ARE) in PTH mRNA 3'-untranslated region (3'UTR). We show that the mRNA decay promoting K-homology splicing regulator protein (KSRP) binds to PTH mRNA in intact parathyroid glands and in transfected cells. This binding is decreased in glands from calcium-depleted or experimental chronic kidney failure rats in which PTH mRNA is more stable compared to parathyroid glands from control and phosphorus-depleted rats in which PTH mRNA is less stable. PTH mRNA decay depends on the KSRP-recruited exosome in parathyroid extracts. In transfected cells, KSRP overexpression and knockdown experiments show that KSRP decreases PTH mRNA stability and steady-state levels through the PTH mRNA ARE. Overexpression of isoform p45 of the PTH mRNA stabilizing protein AUF1 blocks KSRP-PTH mRNA binding and partially prevents the KSRP mediated decrease in PTH mRNA levels. Therefore, calcium or phosphorus depletion, as well as chronic kidney failure, regulate the interaction of KSRP and AUF1 with PTH mRNA and its half-life. Our data indicate a novel role for KSRP in PTH gene expression. PMID:18583400

Nechama, Morris; Ben-Dov, Iddo Z; Briata, Paola; Gherzi, Roberto; Naveh-Many, Tally



Epigenetic Methylation of Parathyroid CaR and VDR Promoters in Experimental Secondary Hyperparathyroidism  

PubMed Central

Secondary hyperparathyroidism (s-HPT) in uremia is characterized by decreased expression in the parathyroids of calcium sensing (CaR) and vitamin D receptors (VDR). Parathyroid hormone (PTH) is normalized despite low levels of CaR and VDR after experimental reversal of uremia. The expression of CaR in parathyroid cultures decreases rapidly. Methylation of promoter regions is often detected during epigenetic downregulation of gene expression. Therefore, using an experimental rat model, we examined changes in methylation levels of parathyroid CaR and VDR promoters in vivo and in vitro. Methods. Uremia was induced by 5/6 nephrectomy. Melting temperature profiling of CaR and VDR PCR products after bisulfite treatment of genomic DNA from rat parathyroids was performed. Real-time PCR measured expression of PTH, CaR, VDR, and klotho genes in vitro. Results. Parathyroids from uremic rats had similar low levels of methylation in vivo and in vitro. In culture, a significant downregulation of CaR, VDR, and klotho within two hours of incubation was observed, while housekeeping genes remained stable for 24 hours. Conclusion. In uremic s-HPT and in vitro, no overall changes in methylation levels in the promoter regions of parathyroid CaR and VDR genes were found. Thus, epigenetic methylation of these promoters does not explain decreased parathyroid expression of CaR and VDR genes in uremic s-HPT.

Hofman-Bang, Jacob; Gravesen, Eva; Olgaard, Klaus; Lewin, Ewa



Glucocorticoid regulation of parathyroid hormone-related peptide gene transcription in a human neuroendocrine cell line.  


A PTH-related peptide (PTHRP) has been identified and its cDNA cloned from tumors associated with the syndrome of humoral hypercalcemia of malignancy. The PTHRP and PTH genes appear to represent members of a gene family. Whereas the PTH gene is expressed exclusively in the parathyroids, the PTHRP gene appears to be widely expressed, but little is known concerning the regulation of its expression in any site. We studied the regulation of PTHRP gene expression in a human carcinoid cell line (NCI-H727) which has neuroendocrine features and also produces calcitonin, calcitonin gene-related peptide, and chromogranin-A. We found that the synthetic glucocorticoid triamcinolone produced time- and dose-dependent decreases in steady state PTHRP and calcitonin mRNA levels in NCI-H727 cells. This effect was blocked by the competitive glucocorticoid inhibitor RU-486. Messenger RNA stability and transcription run-off experiments revealed that triamcinolone decreased PTHRP and calcitonin expression by repressing the transcription rates of both genes. PMID:2628737

Lu, C; Ikeda, K; Deftos, L J; Gazdar, A F; Mangin, M; Broadus, A E



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

SciTech Connect

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.

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



A novel calcium-sensing receptor antagonist transiently stimulates parathyroid hormone secretion in vivo.  


Circulating calcium (Ca(2+)) is a primary regulator of bone homeostasis through its action on PTH secretion. Extracellular Ca(2+) modulates PTH secretion through a cell surface G protein-coupled receptor, the calcium-sensing receptor (CaR). The expression of the CaR suggests a critical role in cellular regulation by calcium in various organs, including parathyroid gland, bone, and kidney. Despite an obvious pharmacological utility for CaR antagonists in the treatment of disease, only a limited number of such classes of compounds exist. We have identified a novel class of small molecules with specific activity at the CaR. This class of compounds is represented by compound 1. It possesses potent antagonist activity at the human CaR with IC(50) values of 64 nm and 230 nm in inhibiting intracellular Ca(2+) flux and inositol phosphate generation in vitro, respectively. When administered to male rats in vivo, compound 1 robustly increased serum PTH levels. The stimulation of PTH secretion was rapid and transient when administered either iv or orally. The pharmacokinetic profile of compound 1 after oral administration revealed that maximal plasma levels of compound were reached within 1 h and the half-life of the compound to be approximately 2 h in rats. These data describe a representative compound of a novel chemical class than previously described allosteric modulators that offer a new avenue for the development of improved treatments of osteoporosis. PMID:15637285

Arey, Brian J; Seethala, Ramakrishna; Ma, Zhengping; Fura, Aberra; Morin, Jennifer; Swartz, Joann; Vyas, Viral; Yang, Wu; Dickson, John K; Feyen, Jean H M



Impact of hypercalcemia and parathyroid hormone level on the sensitivity of preoperative sestamibi scanning for primary hyperparathyroidism.  


Technetium 99m sestamibi scanning (MIBI) can direct unilateral parathyroidectomy. However, the clinical application remains variable with sensitivities ranging from 55 to 100 per cent. We examined whether patient factors including serum calcium (Ca) and parathyroid hormone (PTH) levels impact the sensitivity of MIBI. We completed a retrospective review of 102 patients with primary hyperparathyroidism and mild hypercalcemia who underwent preoperative MIBI. All patients underwent bilateral neck explorations with abnormalities confirmed by histopathology. MIBI sensitivity was correlated with preoperative Ca and PTH levels using univariate and logistic regression analysis. The mean preoperative Ca was 11.0 mg/dL and the mean PTH was 158 pg/mL. More than 95 per cent of patients with Ca greater than 11.3 mg/dL had a positive scan as compared with 60 per cent of those with lesser values (P = 0.0024). Similarly a serum PTH level greater than 160 pg/mL correlated with positive scans in 93 per cent as opposed to 57 per cent in those with lower levels (P = 0.006). Using a scan-directed approach 65 of 74 patients would have undergone unilateral exploration; this would yield a 7.7 per cent operative failure rate because of contralateral multigland disease. Lower Ca and PTH levels seem to correlate with reduced sensitivity of MIBI. Increasing acceptance of surgery for hyperparathyroidism with minimal hypercalcemia may make MIBI less attractive without ancillary diagnostic measures such as rapid parathormone assays. PMID:12769210

Parikshak, Manesh; Castillo, Eduardo D; Conrad, Mark F; Talpos, Gary B



KSRP-PMR1-exosome association determines parathyroid hormone mRNA levels and stability in transfected cells  

PubMed Central

Background Parathyroid hormone (PTH) gene expression is regulated post-transcriptionally through the binding of the trans-acting proteins AU rich binding factor 1 (AUF1), Upstream of N-ras (Unr) and KH-type splicing regulatory protein (KSRP) to an AU rich element (ARE) in PTH mRNA 3'-UTR. AUF1 and Unr stabilize PTH mRNA while KSRP, recruiting the exoribonucleolytic complex exosome, promotes PTH mRNA decay. Results PTH mRNA is cleaved by the endoribonuclease polysomal ribonuclease 1 (PMR1) in an ARE-dependent manner. Moreover, PMR1 co-immunoprecipitates with PTH mRNA, the exosome and KSRP. Knock-down of either exosome components or KSRP by siRNAs prevents PMR1-mediated cleavage of PTH mRNA. Conclusion PTH mRNA is a target for the endonuclease PMR1. The PMR1 mediated decrease in PTH mRNA levels involves the PTH mRNA 3'-UTR ARE, KSRP and the exosome. This represents an unanticipated mechanism by which the decay of an ARE-containing mRNA is facilitated by KSRP and is dependent on both the exosome and an endoribonuclease.

Nechama, Morris; Peng, Yong; Bell, Osnat; Briata, Paola; Gherzi, Roberto; Schoenberg, Daniel R; Naveh-Many, Tally



Organization of the Indian hedgehog--parathyroid hormone-related protein system in the postnatal growth plate.  


In embryonic growth cartilage, Indian hedgehog (Ihh) and parathyroid hormone-related protein (PTHrP) participate in a negative feedback loop that regulates chondrocyte differentiation. Postnatally, this region undergoes major structural and functional changes. To explore the organization of the Ihh–PTHrP system in postnatal growth plate, we microdissected growth plates of 7-day-old rats into their constituent zones and assessed expression of genes participating in the h–PTHrP feedback loop. Ihh, Patched 1, Smoothened, Gli1, Gli2, Gli3, and Pthr1 were expressed in regions analogous to the expression domains in embryonic growth cartilage. However, PTHrP was expressed in resting zone cartilage, a site that differs from the embryonic source, the periarticular cells. We then used mice in which lacZ has replaced coding sequences of Gli1 and thus serves as a marker for active hedgehog signaling. At 1, 4, 8, and 12 weeks of age, lacZ expression was detected in a pattern analogous to that of embryonic cartilage. The findings support the hypothesis that the embryonic Ihh–PTHrP feedback loop is maintained in the postnatal growth plate except that the source of PTHrP has shifted to a more proximal location in the resting zone. PMID:21642420

Chau, Michael; Forcinito, Patricia; Andrade, Anenisia C; Hegde, Anita; Ahn, Sohyun; Lui, Julian C; Baron, Jeffrey; Nilsson, Ola



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

PubMed Central

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.

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



Structural requirements for the action of parathyroid hormone-related protein (PTHrP) on bone resorption by isolated osteoclasts  

SciTech Connect

Parathyroid hormone-related protein (PTHrP) plays a major role in the syndrome of humoral hypercalcemia of malignancy (HHM) by its actions on bone and kidney. In this study an isolated osteoclast bone resorption assay was used to investigate the actions of this peptide and the structure-activity relationships for its resorption effect. As with PTH, neither synthetic nor recombinant PTHrP preparations stimulated resorption within highly purified osteoclast populations. Resorption was stimulated only in the presence of contaminating osteoblasts or in cocultures with the osteoblast-like cell line UMR-106. In the presence of osteoblasts PTHrP-(1-34) and PTHrP-(1-84) stimulated bone resorption in a dose-dependent manner with a potency comparable to that of PTH-(1-34) on a molar basis. The biologic activity of the PTHrP was shown to reside in the first 34 amino acids, and within that region the structural requirements for promotion of osteoclastic resorption resembled closely those for promotion of cyclic AMP formation in osteoblast-like cells. Using emulsion autoradiography with iodinated PTHrP-(1-34) and PTHrP-(1-84) on mixed bone cell preparations from neonatal rats, specific binding was demonstrated only to osteoblasts, not to osteoclasts. These results clearly demonstrate that PTHrP is a potent stimulator of bone resorption and that these effects are, like those of PTH, mediated by initial actions upon cells of the osteoblast lineage.

Evely, R.S.; Bonomo, A.; Schneider, H.G.; Moseley, J.M.; Gallagher, J.; Martin, T.J. (St. Vincent's Institute of Medical Research, Melbourne (Australia))



The calcium-sensing receptor complements parathyroid hormone-induced bone turnover in discrete skeletal compartments in mice.  


Although the calcium-sensing receptor (CaSR) and parathyroid hormone (PTH) may each exert skeletal effects, it is uncertain how CaSR and PTH interact at the level of bone in primary hyperparathyroidism (PHPT). Therefore, we simulated PHPT with 2 wk of continuous PTH infusion in adult mice with deletion of the PTH gene (Pth(-/-) mice) and with deletion of both PTH and CaSR genes (Pth(-/-)-Casr (-/-) mice) and compared skeletal phenotypes. PTH infusion in Pth(-/-) mice increased cortical bone turnover, augmented cortical porosity, and reduced cortical bone volume, femoral bone mineral density (BMD), and bone mineral content (BMC); these effects were markedly attenuated in PTH-infused Pth(-/-)-Casr(-/-) mice. In the absence of CaSR, the PTH-stimulated expression of receptor activator of nuclear factor-?B ligand and tartrate-resistant acid phosphatase and PTH-stimulated osteoclastogenesis was also reduced. In trabecular bone, PTH-induced increases in bone turnover, trabecular bone volume, and trabecular number were lower in Pth(-/-)-Casr(-/-) mice than in Pth(-/-) mice. PTH-stimulated genetic markers of osteoblast activity were also lower. These results are consistent with a role for CaSR in modulating both PTH-induced bone resorption and PTH-induced bone formation in discrete skeletal compartments. PMID:22275754

Xue, Yingben; Xiao, Yongjun; Liu, Jingning; Karaplis, Andrew C; Pollak, Martin R; Brown, Edward M; Miao, Dengshun; Goltzman, David



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


Mice null for Cyp27b1, which encodes the 25-hydroxyvitamin D-1?-hydroxylase [1?(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 1?(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 1?(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 1?(OH)ase(-/-) mice, compared with WT. Osteoclast numbers and surface and ratio of RANKL/OPG-relative mRNA levels decreased significantly after BMX in 1?(OH)ase(-/-) mice, compared with WT. In the cortex, alkaline phosphatase-positive osteoblasts and osteoclast numbers increased significantly after BMX in 1?(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

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



Parathyroid hormone inhibits renal phosphate transport by phosphorylation of serine 77 of sodium-hydrogen exchanger regulatory factor-1  

PubMed Central

Parathyroid hormone (PTH), via activation of PKC and/or protein kinase A, inhibits renal proximal tubular phosphate reabsorption by facilitating the internalization of the major sodium-dependent phosphate transporter, Npt2a. Herein, we explore the hypothesis that the effect of PTH is mediated by phosphorylation of serine 77 (S77) of the first PDZ domain of the Npt2a-binding protein sodium-hydrogen exchanger regulatory factor–1 (NHERF-1). Using recombinant polypeptides representing PDZ I, S77 of NHERF-1 is phosphorylated by PKC but not PKA. When expressed in primate kidney epithelial cells (BSC-1 cells), however, activation of either protein kinase phosphorylates S77, suggesting that the phosphorylation of PDZ I by PKC and PKA proceeds by different biochemical pathways. PTH and other activators of PKC and PKA dissociate NHERF-1/Npt2a complexes, as assayed using quantitative coimmunoprecipitation, confocal microscopy, and sucrose density gradient ultracentrifugation in mice. Murine NHERF-1–/– renal proximal tubule cells infected with adenovirus-GFP-NHERF-1 containing an S77A mutation showed significantly increased phosphate transport compared with a phosphomimetic S77D mutation and were resistant to the inhibitory effect of PTH compared with cells infected with wild-type NHERF-1. These results indicate that PTH-mediated inhibition of renal phosphate transport involves phosphorylation of S77 of the NHERF-1 PDZ I domain and the dissociation of NHERF-1/Npt2a complexes.

Weinman, Edward J.; Biswas, Rajat S.; Peng, Quihong; Shen, Lily; Turner, Christina L.; E, Xiaofei; Steplock, Deborah; Shenolikar, Shirish; Cunningham, Rochelle



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


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

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



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

PubMed Central

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

Sprague, Stuart M.; Metcalfe, Wendy



Overexpression of parathyroid hormone-related protein in the pancreatic islets of transgenic mice causes islet hyperplasia, hyperinsulinemia, and hypoglycemia.  


Parathyroid hormone-related protein (PTHrP) is produced by the pancreatic islet. It also has receptors on islet cells, suggesting that it may serve a paracrine or autocrine role within the islet. We have developed transgenic mice, which overexpress PTHrP in the islet through the use of the rat insulin II promoter (RIP). Glucose homeostasis in these mice is markedly abnormal; RIP-PTHrP mice are hypoglycemic in the postprandial and fasting states and display inappropriate hyperinsulinemia. At the end of a 24-hour fast, blood glucose values are 49 mg/dl in RIP-PTHrP mice, as compared to 77 mg/dl in normal littermates; insulin concentrations at this time are 6.3 and 3.9 ng/ml, respectively. Islet perifusion studies failed to demonstrate abnormalities in insulin secretion. In contrast, quantitative islet histomorphometry demonstrates that the total islet number and total islet mass are 2-fold higher in RIP-PTHrP mice than in their normal littermates. PTHrP very likely plays a normal physiologic role within the pancreatic islet. This role is most likely paracrine or autocrine. PTHrP appears to regulate insulin secretion either directly or indirectly, through developmental or growth effects on islet mass. PTHrP may have a role as an agent that enhances islet mass and/or enhances insulin secretion. PMID:8557651

Vasavada, R C; Cavaliere, C; D'Ercole, A J; Dann, P; Burtis, W J; Madlener, A L; Zawalich, K; Zawalich, W; Philbrick, W; Stewart, A F



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


Osteoporosis is a skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, and it is a serious threat to human lives. We previously showed that the N-terminal peptide analog of human parathyroid hormone (Pro-Pro-PTH(1-34)) enhanced plasma calcium concentration. In this paper, we study the impact of PTH N-terminal fragment analog on the structure, component, and mechanical properties of the rat bones. Daily subcutaneous injections of Pro-Pro-hPTH (1-34) induces 26.5-32.8% increase in femur bone mineral density (BMD), 23.0-34.2% decrease the marrow cavity or increase in trabecular bone area. The peptide also increases 16.0-59.5%, 28.8-48.2% and 14.0-17.8% of bone components of calcium, phosphorus and collagen, respectively. In terms of mechanic properties, administration of the peptide elevates the bone rigidity by 45.4-76.6%, decreases the flexibility by 23.0-31.6%, and improves modulus of elasticity by 32.8-63.4%. The results suggest that Pro-Pro-hPTH (1-34) has a positive effect on bone growth and strength, and possesses anti-fracture capability, thus a potential candidate for the application for the treatment of osteoporosis. PMID:23046835

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



Immunohistochemical analyses of parathyroid hormone-dependent downregulation of renal type II Na-Pi cotransporters by cryobiopsy.  


The "in vivo cryotechnique" (IVCT) is a new method of morphological analysis which has the advantage of freezing tissues in living animals without stopping their blood circulation. The purpose of this study was to investigate the effect of parathyroid hormone (PTH) on renal type II Na-Pi transporters (NaPi-IIa and NaPi-IIc) and "cryobiopsy" (CB) using special cryoforceps as a simple method of the IVCT. The kidney tissues were biopsied at various time points after PTH administration by CB using liquid nitrogen as the cryogen. By hematoxylin-eosin (HE) staining the kidney tissues, well-frozen areas without visible ice crystals were obtained in the tissue surface areas, and the brush border membrane (BBM) of proximal tubules was well preserved at a light microscopic level. Immunohistochemical evaluation showed that PTH downregulated NaPi-IIa and NaPi-IIc at the BBM, being controlled by a different mechanism. In this method, the PTH-induced internalization of NaPi-IIc from microvilli to subapical compartments was not observed in the tissue preparations. NaPi-IIc protein appears to be degraded in microvilli of the proximal tubular cells after the injection of PTH. We suggest that CB using liquid nitrogen is useful to investigate renal type II Na-Pi transporters at the light microscopic level. PMID:20299753

Matsumoto, Natsuki; Hemmi, Akihiro; Yamato, Hideyuki; Ohnishi, Ritsuko; Segawa, Hiroko; Ohno, Shinichi; Miyamoto, Ken-ichi



Cryopreserved cord blood progenitors and their cell adhesion molecules are increased by coculture with osteoblasts and parathyroid hormone.  


Despite advantages of cord blood (CB) cells, such as their high capacity for proliferation and low immunogenicity, CB transplantation is also associated with delayed neutrophil and platelet recovery relative to bone marrow transplantation. These limitations arise from the reduced abundances of primitive hematopoietic stem cells expressing adhesion molecules in CB relative to bone marrow. To address this limitation, we evaluated whether human parathyroid hormone (hPTH) could increase the number of primitive hematopoietic stem cells with adhesion molecules in cryopreserved CB. When cryopreserved CB cells were cocultured with differentiated osteoblasts in the presence of hPTH, numbers of CD34CD38 cells increased 4-fold after 7 days. Exposure to hPTH promoted clonogenic cell expansion and significantly increased the expression of adhesion molecules, such as CD44 (a cell surface glycoprotein) and VLA-4 (?4 integrin) in CD34 cells. This result shows that short-term coculture of cryopreserved CB with differentiated osteoblasts in the presence of hPTH may improve the rate of engraftment of CD34 cells through increasing the abundances of primitive cells bearing adhesion molecules. PMID:23426002

Jang, Yun Kyung; Kim, Miyeon; Jin, Hye Jin; Choi, Soo Jin; Oh, Wonil; Lee, Young-Ho



Osteoblastic expansion induced by parathyroid hormone receptor signaling in murine osteocytes is not sufficient to increase hematopoietic stem cells  

PubMed Central

Microenvironmental expansion of hematopoietic stem cells (HSCs) is induced by treatment with parathyroid hormone (PTH) or activation of the PTH receptor (PTH1R) in osteoblastic cells; however, the osteoblastic subset mediating this action of PTH is unknown. Osteocytes are terminally differentiated osteoblasts embedded in mineralized bone matrix but are connected with the BM. Activation of PTH1R in osteocytes increases osteoblastic number and bone mass. To establish whether osteocyte-mediated PTH1R signaling expands HSCs, we studied mice expressing a constitutively active PTH1R in osteocytes (TG mice). Osteoblasts, osteoclasts, and trabecular bone were increased in TG mice without changes in BM phenotypic HSCs or HSC function. TG mice had progressively increased trabecular bone but decreased HSC function. In severely affected TG mice, phenotypic HSCs were decreased in the BM but increased in the spleen. TG osteocytes had no increase in signals associated with microenvironmental HSC support, and the spindle-shaped osteoblastic cells that increased with PTH treatment were not present in TG bones. These findings demonstrate that activation of PTH1R signaling in osteocytes does not expand BM HSCs, which are instead decreased in TG mice. Therefore, osteocytes do not mediate the HSC expansion induced by PTH1R signaling. Further, osteoblastic expansion is not sufficient to increase HSCs.

Bromberg, Olga; Rhee, Yumie; Weber, Jonathan M.; Smith, Julianne N. P.; Basil, Miles J.; Frisch, Benjamin J.



The calcium-sensing receptor regulates mammary gland parathyroid hormone-related protein production and calcium transport  

PubMed Central

The transfer of calcium from mother to milk during lactation is poorly understood. In this report, we demonstrate that parathyroid hormone–related protein (PTHrP) production and calcium transport in mammary epithelial cells are regulated by extracellular calcium acting through the calcium-sensing receptor (CaR). The CaR becomes expressed on mammary epithelial cells at the transition from pregnancy to lactation. Increasing concentrations of calcium, neomycin, and a calcimimetic compound suppress PTHrP secretion by mammary epithelial cells in vitro, whereas in vivo, systemic hypocalcemia increases PTHrP production, an effect that can be prevented by treatment with a calcimimetic. Hypocalcemia also reduces overall milk production and calcium content, while increasing milk osmolality and protein concentrations. The changes in milk calcium content, milk osmolality, and milk protein concentration were mitigated by calcimimetic infusions. Finally, in a three-dimensional culture system that recapitulates the lactating alveolus, activation of the basolateral CaR increases transcellular calcium transport independent of its effect on PTHrP. We conclude that the lactating mammary gland can sense calcium and adjusts its secretion of calcium, PTHrP, and perhaps water in response to changes in extracellular calcium concentration. We believe this defines a homeostatic system that helps to match milk production to the availability of calcium.

VanHouten, Joshua; Dann, Pamela; McGeoch, Grace; Brown, Edward M.; Krapcho, Karen; Neville, Margaret; Wysolmerski, John J.



Mechanism-based pharmacokinetic/pharmacodynamic model of parathyroid hormone-calcium homeostasis in rats and humans.  


The purpose of this study was to develop a mechanism-based pharmacokinetic/pharmacodynamic model that describes the regulation of the parathyroid hormone (PTH)-Ca(2+) system in rats and humans. Temporal concentration data for endogenous PTH and Ca(2+) were extracted from literature for rats (normal adult males) and humans. In addition, exogenous PTH was administered subcutaneously to male Sprague-Dawley rats with jugular vein catheters, and plasma concentrations were measured over time. A mathematical model was developed and fitted simultaneously to endogenous PTH, Ca(2+), and exogenous PTH concentrations in rats. Ca(2+) concentrations were described using a turnover model, with its depletion being induced by a chelating agent, and PTH concentrations were characterized using a precursor-dependent indirect response model. The same structural model was used for fitting data obtained in humans. PTH stimulation was driven by occupancy of the Ca(2+) sensing receptor, and lowering of physiological Ca(2+) concentrations increased PTH secretion, with PTH profiles being adequately described by the model. PTH stimulatory capacity was baseline-dependent in rats [S(max_rats) = 34.8 x PTH(0)] and humans [S(max_humans) = 392/PTH(0)]. Modeling results suggest that normal rats are twice as sensitive to Ca(2+)-induced PTH stimulation compared with humans. In conclusion, the developed model adequately characterizes the PTH-Ca(2+) regulation across species and may be useful in the development of therapeutic drugs targeting this system. PMID:19386792

Abraham, Anson K; Mager, Donald E; Gao, Xiang; Li, Mei; Healy, David R; Maurer, Tristan S



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


Tuberoinfundibular peptide of 39 residues (TIP39) is a member of the parathyroid hormone (PTH) family of peptide hormones that exerts its function by interacting with the PTH type 2 receptor (PTH2R). Presently, no known function has been attributed to this signaling pathway in the developing skeleton. We observed that TIP39 and PTH2R were present in the newborn mouse growth plate, with the receptor localizing in the resting zone whereas ligand expression was restricted exclusively in prehypertrophic and hypertrophic chondrocytes. By 8 wk of life, PTH2R, and to a lesser degree TIP39, immunoreactivity was present in articular chondrocytes. We therefore sought to investigate the role of TIP39/PTH2R signaling in chondrocytes by generating stably transfected CFK2 chondrocytic cells overexpressing PTH2R (CFK2R). TIP39 treatment of CFK2R clones in culture inhibited their proliferation by restricting cells at the G(0)/G(1) phase of the cell cycle, coupled with decreased expression and activity of cyclin-dependent kinases Cdk2 and Cdk4, while p21, an inhibitor of Cdks, was upregulated. In addition, TIP39 treatment decreased expression of differentiation markers in these cells associated with marked alterations in extracellular matrix and metalloproteinase expression. Transcription of Sox9, the master regulator of cartilage differentiation, was reduced in TIP39-treated CFK2R clones. Moreover, Sox9 promoter activity, as measured by luciferase reporter assay, was markedly diminished after TIP39 treatment. In summary, our results show that TIP39/PTH2R signaling inhibits proliferation and alters differentiation of chondrocytes by modulating SOX9 expression, thereby substantiating the functional significance of this signaling pathway in chondrocyte biology. PMID:19706789

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



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  

Microsoft Academic Search

Clinical studies have been performed to determine the effect of cinacalcet HCl (cinacalcet), an allosteric modulator of the\\u000a calcium-sensing receptor (CaR), on primary hyperparathyroidism (PHPT) and secondary hyperparathyroidism of uremia (SHPT).\\u000a However, no in vitro studies on human parathyroid cells have been reported to date. In this study, the inhibitory effect of\\u000a cinacalcet on PTH secretion was analyzed in primary

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



Vitamin D — Soltriol The heliogenic steroid hormone: Somatotrophic activator and modulator  

Microsoft Academic Search

Evidence from autoradiographic studies with 3H 1,25(OH)2 vitamin D3 (soltriol) about its many sites of nuclear binding and multiple actions suggests that the traditional view of “vitamin D and calcium” is too limited and requires modification. A new concept has been developed which proposes that the skin-derived hormone of sunshine, soltriol, is a somatotrophic activator and modulator that affects all

W. E. Stumpf



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

Microsoft Academic Search

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 altera1tion of their metabolism

G. A. H. Heussen; G. J. Schefferlie; M. J. G. Talsman; H. van Til; M. J. W. Dohmen; A. Brouwer; G. M. Alink



Calcium and Vitamin D Depletion and Elevated Parathyroid Hormone following Biliopancreatic Diversion  

Microsoft Academic Search

Background: Biliopancreatic diversion (BPD) is associated with a 70% excess weight loss (EWL) at 10 years, but there are concerns\\u000a regarding long-term nutritional sequelae. Metabolic bone disease has been documented following Roux-en-Y gastric bypass. Methods:\\u000a Patients who underwent a BPD from 1998 to 2001 were studied. A questionnaire was designed to review BPD patients and collect\\u000a information on weight loss,

Leyanne Newbury; Kevin Dolan; Michael Hatzifotis; Nadeen Low; George Fielding



Synovium as a source of increased amino-terminal parathyroid hormone-related protein expression in rheumatoid arthritis. A possible role for locally produced parathyroid hormone-related protein in the pathogenesis of rheumatoid arthritis.  

PubMed Central

Proinflammatory cytokines, including tumor necrosis factor (TNF) and interleukin 1 (IL-1), mediate the joint destruction that characterizes rheumatoid arthritis (RA). Previous studies have shown that parathyroid hormone-related protein (PTHrP) is a member of the cascade of proinflammatory cytokines induced in parenchymal organs during lethal endotoxemia. To test the hypothesis that NH2-terminal PTHrP, a potent bone resorbing agent, could also be a member of the synovial cascade of tissue-destructive cytokines whose expression is induced in RA, PTHrP expression was examined in synovium and synoviocytes obtained from patients with RA and osteoarthritis (OA). PTHrP production, as determined by measurement of immunoreactive PTHrP(1-86) in tissue explant supernatants, was increased 10-fold in RA versus OA synovial tissue. Synovial lining cells and fibroblast-like cells within the pannus expressed both PTHrP and the PTH/PTHrP receptor, findings that were confirmed by in vitro studies of cultured synoviocytes. TNF-alpha and IL-1beta stimulated PTHrP expression in synoviocytes, while dexamethasone and interferon-gamma, agents with some therapeutic efficacy in the treatment of RA, inhibited PTHrP release. Treatment of synoviocytes with PTHrP(1-34) stimulated IL-6 secretion. These results suggest that proinflammatory cytokine-stimulated production of NH2-terminal PTHrP by synovial tissue directly invading cartilage and bone in RA may mediate joint destruction through direct effects on cartilage or bone, or, indirectly, via the induction of mediators of bone resorption in the tumor-like synovium.

Funk, J L; Cordaro, L A; Wei, H; Benjamin, J B; Yocum, D E



Single-dose cholecalciferol suppresses the winter increase in parathyroid hormone concentrations in healthy older men and women: a randomized triaI?3  

Microsoft Academic Search

A randomized double-blind controlled trial of a single oral dose of 2.5 mg(100 000 IU) cholecalciferol (vitamin D3) was conducted in the winter in 189 healthy free-living men and women aged 63-76 y. The mean baseline serum concentra- tion for 25-hydroxyvitamin D was 34.5 nmolfL and for parathy- roid hormone 3.18 pmolIL. After 5 wk, mean serum 25-hydroxy- vitamin D

Kay-Tee Khaw; Robert Scragg; Sean Murphy


Control of parathyroid cell growth by calcimimetics  

Microsoft Academic Search

Parathyroid cell hyperplasia is commonly observed in patients with chronic renal insufficiency and largely accounts for refractory secondary hyperparathyroid- ism. Calcimimetics are newly synthesized compounds that activate a calcium receptor on the parathyroid cell and can suppress parathyroid hormone secretion. The calcimimetic compound AMG 073 has been examined in clinical trials, and the data obtained so far demon- strate that

Michihito Wada; Nobuo Nagano


Increase in cell-surface localization of parathyroid hormone receptor by cytoskeletal protein 4.1G  

PubMed Central

The cell-surface localization of GPCRs (G-protein-coupled receptors) has emerged as one of critical factors of the GPCR-mediated signal transduction. It has been reported that the C-termini of GPCRs contain the sequences for sorting the receptors to cell surface. In the present study, we have searched for proteins that interact with the C-terminus of PTH (parathyroid hormone)/PTH-related protein receptor (PTHR) by using the yeast two-hybrid system, and identified a cytoskeletal protein 4.1G (generaltype 4.1 protein) as an interactant with the C-terminus. Immunohistochemical study revealed that both PTHR and 4.1G were co-localized on plasma membranes, when they were transiently expressed in COS-7 cells. When 4.1G or the C-terminal domain of 4.1G (4.1G-CTD), a dominant-negative form of 4.1G, was co-expressed with PTHR in COS-7 cells, 4.1G, but not 4.1G-CTD, facilitated the cell-surface localization of PTHR, determined by cell-surface biotinylation assay. PTH-(1–34) caused phosphorylation of ERK (extracellular-signal-regulated kinase) 1/2 in PTHR-expressed cells mainly mediated through EGF (epidermal growth factor) receptor. The phosphorylation was enhanced by the expression of 4.1G, but not 4.1G-CTD. PTH-(1–34) elevated [Ca2+]i (intracellular Ca2+ concentration) independent of EGF receptor activation, and the elevation was enhanced by the expression of 4.1G, but not 4.1G-CTD. These data indicate that 4.1G facilitates the cell-surface localization of PTHR through its interaction with the C-terminus of the receptor, resulting in the potentiation of PTHR-mediated signal transduction.



Combinatorial library discovery of small molecule inhibitors of lung cancer proliferation and parathyroid hormone-related protein expression.  


PTHrP (parathyroid hormone-related protein) is abnormally expressed in a substantial majority of lung cancers, especially non-small cell lung cancers, and plays a key role in tumor progression. Thus, this oncoprotein could be a target for treating patients with lung cancer. This study screened combinatorial libraries of heterocyclic amines for inhibitory effects on PTHrP expression and cell proliferation. Two libraries of over 780,000 bis-cyclic thiourea and guanidine compounds each were tested in BEN lung carcinoma cells. The number of PTHrP inhibitors and the magnitude of the reduction in PTHrP were greater for thioureas. Selected lead thiourea compounds decreased cell PTHrP protein content in dose-dependent fashion, reduced relative abundance of PTHrP mRNA, decreased transcripts derived from the PTHrP P3 promoter and reduced activity of a full length PTHrP promoter luciferase construct. Similar effects on PTHrP mRNA were observed in A549 and H441 lung adenocarcinoma cells and in H727 lung carcinoid cells. However, the compounds only inhibited PTHrP protein levels in BEN cells and H727 cells. The compounds reduced the rate of cell proliferation in BEN cells and H727 cells, but not in lines that showed no inhibition of PTHrP protein. These results suggest that cyclic thiourea compounds inhibit PTHrP expression mediated by the P3 promoter, which is widely used in the majority of PTHrP-expressing cells, and that they may inhibit growth of lung cancer cells through the same mechanism. Further work will be necessary to investigate their mechanism for effects on growth of PTHrP-positive tumors in vivo. PMID:20890111

Hastings, Randolph H; Burton, Douglas W; Nefzi, Adel; Montgrain, Philippe R; Quintana, Rick; Deftos, Leonard J



Differential modulation of the molecular dynamics of the type IIa and IIc sodium phosphate cotransporters by parathyroid hormone.  


The kidney is a key regulator of phosphate homeostasis. There are two predominant renal sodium phosphate cotransporters, NaPi2a and NaPi2c. Both are regulated by parathyroid hormone (PTH), which decreases the abundance of the NaPi cotransporters in the apical membrane of renal proximal tubule cells. The time course of PTH-induced removal of the two cotransporters from the apical membrane, however, is markedly different for NaPi2a compared with NaPi2c. In animals and in cell culture, PTH treatment results in almost complete removal of NaPi2a from the brush border (BB) within 1 h whereas for NaPi2c this process in not complete until 4 to 8 h after PTH treatment. The reason for this is poorly understood. We have previously shown that the unconventional myosin motor myosin VI is required for PTH-induced removal of NaPi2a from the proximal tubule BB. Here we demonstrate that myosin VI is also necessary for PTH-induced removal of NaPi2c from the apical membrane. In addition, we show that, while at baseline the two cotransporters have similar diffusion coefficients within the membrane, after PTH addition the diffusion coefficient for NaPi2a initially exceeds that for NaPi2c. Thus NaPi2c appears to remain "tethered" in the apical membrane for longer periods of time after PTH treatment, accounting, at least in part, for the difference in response times to PTH of NaPi2a versus NaPi2c. PMID:21593452

Lanzano, Luca; Lei, Tim; Okamura, Kayo; Giral, Hector; Caldas, Yupanqui; Masihzadeh, Omid; Gratton, Enrico; Levi, Moshe; Blaine, Judith



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

SciTech Connect

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.

Egan, J.J.; Gronowicz, G.; Rodan, G.A. (National Institutes of Diabetes, Digestive, and Kidney Diseases, Bethesda, MD (USA))



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


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

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



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

SciTech Connect

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.

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



Association of 25-hydroxy-vitamin D levels with semen and hormonal parameters  

PubMed Central

Vitamin D levels have been linked to various health outcomes including reproductive disorders. The purpose of this study was to explore the association between serum vitamin D level (25-hydroxy-vitamin D, or 25OHD) and semen and hormonal parameters. This is a cross-sectional study that included 170 healthy men recruited for the study of spermatogenesis from the general population. Men completed general and reproductive health questionnaires, and donated blood and semen samples. The main measures were hormonal (total and free testosterone, sex hormone-binding globulin, estradiol, follicle-stimulating hormone and luteinizing hormone) and semen parameters, adjusted (n=147) for age, body mass index (BMI), season, alcohol intake and smoking, in relation to categories of vitamin D levels, determined a priori. The mean age of the study population was 29.0±8.5 years and mean BMI was 24.3±3.2 kg m?2. The mean 25OHD was 34.1±15.06 ng ml?1. BMI showed a negative association with 25OHD. Sperm concentration, sperm progressive motility, sperm morphology, and total progressively motile sperm count were lower in men with ‘25OHD?50 ng ml?1' when compared to men with ‘20 ng ml?1?25OHD<50 ng ml?1'. Total sperm count and total progressive motile sperm count were lower in men with ‘25OHD<20 ng ml?1' when compared to men with ‘20 ng ml?1?25OHD<50 ng ml?1'. The adjusted means of various hormonal parameters did not show statistical difference in the different categories of 25OHD. In conclusion, serum vitamin D levels at high and low levels can be negatively associated with semen parameters.

Hammoud, Ahmad O; Wayne Meikle, A; Matthew Peterson, C; Stanford, Joseph; Gibson, Mark; Carrell, Douglas T



Pakistani immigrant children and adults in Denmark have severely low vitamin D status  

Microsoft Academic Search

Objective:To determine vitamin D and bone status in adolescent girls, pre-menopausal women and men of Pakistani origin, to single out determinants of vitamin D status and to determine the association between vitamin D status, bone metabolism and bone status.Subjects\\/Methods:Cross-sectional study, Copenhagen (55°N), January-November. Serum 25-hydroxyvitamin D (S-25OHD), serum intact parathyroid hormone (S-iPTH), bone turnover markers and whole body and lumbar

R Andersen; C Mølgaard; L T Skovgaard; C Brot; K D Cashman; J Jakobsen; C Lamberg-Allardt; L Ovesen



Vitamin D Status and Its Relation to Age and Body Mass Index  

Microsoft Academic Search

Background\\/Aims: While numerous studies have examined 25(OH)-vitamin D3 (25-D) concentrations and their relation to parathyroid hormone (PTH) levels there is only limited information on the interrelation between 25-D, 1,25(OH)2-vitamin D3 (1,25-D) and PTH. It was the aim of this study to assess the vitamin D endocrine system and its relation to age and body mass index (BMI). Methods: This cross-sectional

Martin G. Bischof; Georg Heinze; Heinrich Vierhapper



Study on preparation and activity of a novel recombinant human parathyroid hormone(1-34) analog with N-terminal Pro-Pro extension.  


A recombinant human parathyroid hormone fragment, Pro-Pro-hPTH(1-34), with molecular weight of 4311.46 was acquired through gene engineering. It was then isolated and purified. The homogeneity of this fragment was characterized by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), high performance liquid chromatography(HPLC), isoelectronic focusing (IEF) electrophoresis and mass spectrometry(MS) methods. Its isoelectric point is 8.0 which was determined by IEF. It was found that the hormone fragment significantly induced calcium increment as compared to the control group (P<0.001) in Parsons's Chicken Assay, an established bioassay for the evaluation of the PTH effect. After the 3-month-old ovariectomized (OVXed) rats, the OVXed rat is one of the two models required by the U.S. Food and Drug Administration for the preclinical assessment of drugs for treating osteoporosis [DeLuca PP, Dani BA. Skeletal effects of parathyroid hormone (1-34) in ovariectomized rats with or without concurrent administration of salmon calcitonin. Am Assoc Pharm Sci 2001;3(4):E27 [1

Chunxiao, Wang; Jingjing, Liu; Yire, Xiao; Min, Ding; Zhaohui, Wang; Gaofu, Qi; Xiangchun, Shen; Xuejun, Wang; Jie, Wu; Taiming, Li



Conjugated linoleic acid is related to bone mineral density but does not affect parathyroid hormone in men.  


The relationships between conjugated linoleic acid (CLA) status, bone, body composition, and the effect of CLA on calciotropic hormones are unclear. A cross-sectional study was designed to examine the association between c9, t11 CLA status in erythrocyte membranes (RBC) and body composition. This preceded a dose-response trial investigating if c9, t11 CLA affected parathyroid hormone (PTH). It was hypothesized that (1) higher c9, t11 CLA status in RBC will be associated with a lower fat and higher bone mass and that (2) PTH will be reduced by 30% after supplementation of c9, t11 CLA. Fifty-four men (age, 19-53 years) were included in the cross-sectional analysis, of which 31 were studied in the dose-response trial and randomized to 1 of 3 groups: placebo (n = 10), 1.5 g/d (n = 11), or 3.0 g/d (n = 10) of c9, t11 CLA for 16 weeks. Men with RBC c9, t11 CLA status above the median had higher whole body bone mineral density (BMD) (1.359 ± 0.024 vs 1.287 ± 0.023 g/cm(2); P = .04) and whole body lean mass (WBL) percentage (78.8% ± 0.9% vs 75.3% ± 1.0%; P = .01), whereas body mass index (24.8 ± 0.5 kg/m(2) vs 27.3 ± 0.9 kg/m(2); P = .01) and whole body fat mass percentage (17.3% ± 0.9% vs 21.3% ± 1.1%; P = .007) were lower. In regression analysis, RBC c9, t11 CLA status accounted for a significant proportion (r(2) = 0.10) of the variation in whole body BMD (P = .03). There were no time or treatment differences among any bone or biomarkers of bone metabolism including PTH. These findings indicate that RBC c9, t11 CLA status, a reflection of long-term (~4 months) dietary CLA intake, positively relates to BMD. However, c9, t11 CLA supplementation does not appear to affect PTH in healthy men. PMID:23244536

Deguire, Jason R; Makarem, Nour; Vanstone, Catherine A; Morin, Suzanne; Duque, Gustavo; Weiler, Hope A



Vitamin D: More than just affecting calcium and bone  

Microsoft Academic Search

Vitamin D is a fat-soluble steroid that is essential for main-taining normal calcium metabolism. In vitamin D deficiency,\\u000a calcium absorption is insufficient and cannot satisfy the body’s needs. Consequently, parathyroid hormone produc-tion increases\\u000a and calcium is mobilized from bones and reabsorbed in the kidneys to maintain normal serum calcium levels—a condition defined\\u000a as secondary hyper-parathyroidism. Most organs, including the gut,

Roland Staud



Comparison of parathyroid hormone and calcium ionophore A23187 effects on bone resorption and nucleic acid synthesis in cultured fetal rat bone  

Microsoft Academic Search

Summary  It has recently been demonstrated that calcium ionophore A23187 mimics certain of the effects of parathyroid hormone (PTH)\\u000a on bone in vitro, including stimulation of45Ca release and cAMP formation. To further examine the relative effects of these two agents on bone cell metabolism, we compared\\u000a the effects of synthetic PTH 1–34 (50 ng\\/ml) and calcium ionophore A23187 (0.5µg\\/ml) on45Ca release,

T. F. DeBartolo; L. E. Pegg; C. Shasserre; T. J. Hahn



Enhanced suppression of 1,25(OH) 2 D 3 and intact parathyroid hormone in Graves' disease as compared to toxic nodular goiter  

Microsoft Academic Search

Summary  1,25(OH)2D3, 25OHD3, and intact parathyroid hormone, as well as various parameters of calcium-phosphorus metabolism were measured in 38 patients\\u000a with Graves' disease (GD) and in 24 patients with toxic nodular goiter (TNG). Plasma 1,25(OH)2D3 levels were lower in GD patients (82 ±29 pmol\\/liter) than in those with TNG (155±32 pmol\\/liter) (P2D3 in 45 controls was intermediate between the two groups

Helen Czernobilsky; Stephan Scharla; Heinrich Schmidt-Gayk; Reinhard Ziegler



Effects of parathyroid hormone alone or in combination with antiresorptive therapy on bone mineral density and fracture risk – a meta-analysis  

Microsoft Academic Search

Aim   The effects of parathyroid hormone (PTH) alone or in combination with antiresorptive therapy on changes in bone mineral density\\u000a (BMD) and fracture risk were studied.\\u000a \\u000a \\u000a \\u000a Materials and methods   Randomised placebo controlled trials were retrieved from the PubMed, Web of Science or Embase databases.\\u000a \\u000a \\u000a \\u000a Results   PTH alone or in combination with antiresorptive drugs reduced vertebral [relative risk (RR)=0.36, 95% confidence

P. Vestergaard; N. R. Jorgensen; L. Mosekilde; P. Schwarz



gamma-Pyrones from Gonystylus keithii, as new inhibitors of parathyroid hormone (PTH)-induced Ca release from neonatal mouse calvaria.  


New gamma-pyrones, 9'-oxopodopyrone (3) and 8-methyl-9'-oxopodopyrone (4) were isolated from the leaves of Gonystylus keithii, along with known gamma-pyrones, 10'-oxopodopyrone (1) and 8-methyl-10'-oxopodopyrone (2). These gamma-pyrones markedly inhibited the bovine parathyroid hormone (PTH)-induced Ca release from neonatal mouse calvaria in vitro. It is the first time that gamma-pyrones showed inhibitory effects on bone resorption, and these compounds may be seed compounds of new drugs for osteoporosis. PMID:9214710

Kanazawa, T; Ohkawa, Y; Kuda, T; Minobe, Y; Tani, T; Nishizawa, M



Systemic and acute administration of parathyroid hormone-related peptide(1–36) stimulates endogenous beta cell proliferation while preserving function in adult mice  

Microsoft Academic Search

Aims\\/hypothesis  A major focus in the treatment of diabetes is to identify factors that stimulate endogenous beta cell growth while preserving\\u000a function. The first 36 amino acids of parathyroid hormone-related protein (PTHrP) are sufficient to enhance proliferation\\u000a and function in rodent and human beta cells in vitro. This study examined whether acute and systemic administration of the\\u000a amino-terminal PTHrP(1–36) peptide can

K. Williams; D. Abanquah; S. Joshi-Gokhale; A. Otero; H. Lin; N. K. Guthalu; X. Zhang; A. Mozar; A. Bisello; A. F. Stewart; A. Garcia-Ocaña; R. C. Vasavada


Parathyroid hormone exerts disparate effects on osteoblast differentiation depending on exposure time in rat osteoblastic cells.  

PubMed Central

It has been reported that PTH exerts bone-forming effects in vivo when administered intermittently. In the present study, the anabolic effects of PTH(1-34) on osteoblast differentiation were examined in vitro. Osteoblastic cells isolated from newborn rat calvaria were cyclically treated with PTH(1-34) for the first few hours of each 48-h incubation cycle. When osteoblastic cells were intermittently exposed to PTH only for the first hour of each 48-h incubation cycle and cultured for the remainder of the cycle without the hormone, osteoblast differentiation was inhibited by suppressing alkaline phosphatase activity, bone nodule formation, and mRNA expression of alkaline phosphatase, osteocalcin, and PTH/PTHrP receptor. Experiments using inhibitors and stimulators of cAMP/protein kinase A (PKA) and Ca2+/PKC demonstrated that cAMP/PKA was the major signal transduction system in the inhibitory action of PTH. In contrast, the intermittent exposure to PTH for the first 6 h of each 48-h cycle stimulated osteoblast differentiation. Both cAMP/ PKA and Ca2+/PKC systems appeared to be involved cooperatively in this anabolic effect. Continuous exposure to PTH during the 48-h incubation cycle strongly inhibited osteoblast differentiation. Although both cAMP/PKA and Ca2+/PKC were involved in the effect of continuous exposure to PTH, they appeared to act independently. A neutralizing antibody against IGF-I blocked the stimulatory effect on alkaline phosphatase activity and the expression of osteocalcin mRNA induced by the 6-h intermittent exposure. The inhibitory effect induced by the 1-h intermittent exposure was not affected by anti-IGF-I antibody. These results suggest that PTH has diverse effects on osteoblast differentiation depending on the exposure time in vitro mediated through different signal transduction systems. These in vitro findings explain at least in part the in vivo action of PTH that varies with the mode of administration.

Ishizuya, T; Yokose, S; Hori, M; Noda, T; Suda, T; Yoshiki, S; Yamaguchi, A



Vitamin D Deficiency, Rickets, and Fluorosis in India  

Microsoft Academic Search

\\u000a Data on the vitamin D status of the populations in a tropical country like India have seldom been documented. Vitamin D deficiency\\u000a is presumed to be rare. Population studied by the author and others in the country has proved otherwise. Studies were carried\\u000a out to document the dietary habits, serum calcium, 25-hydroxyvitamin D [25(OH)D], and parathyroid hormone levels of urban

C. V. Harinarayan; Shashank R. Joshi


Hormonal and Anthropometric Predictors of Bone Mass in Healthy Elderly Men: Major Effect of Sex Hormone Binding Globulin, Parathyroid Hormone and Body Weight  

Microsoft Academic Search

:   Osteoporosis in men is a significant health problem, and factors associated with bone mass are being investigated. Although\\u000a osteoporosis is a typical feature of hypogonadism, the influence of testosterone levels and other hormonal factors on bone\\u000a mass of eugonadal males is unknown. Our aim was to identify several anthropometric and hormonal predictors that could be responsible\\u000a for the variability

G. Martínez Díaz-Guerra; F. Hawkins; A. Rapado; M. A. Ruiz Díaz; M. Díaz-Curiel



Parathyroid Carcinoma  

Microsoft Academic Search

\\u000a Parathyroid carcinoma is a rare cause of primary hyperparathyroidism (PHPT) (<1%) and is usually associated with more severe\\u000a clinical manifestations than its much more common benign counterpart, the parathyroid adenoma [1–3].

Claudio Marcocci; Filomena Cetani; John P. Bilezikian


Severe Hyperparathyroidism Versus Parathyroid Carcinoma  

PubMed Central

No clinical or laboratory data allow a preoperative diagnosis of parathyroid carcinoma and only occasionally does a definitive finding differentiate an adenoma from a carcinoma. We present a case of primary hyperparathyroidism presenting with severe elevation of parathyroid hormone and serum calcium as well as complications. We go on to discuss the case in the light of a literature review. The severity of the elevation of the parathyroid hormone, other biochemical alterations, the presence of skeletal and renal complications and of a neck mass should alert the clinician to a possible parathyroid carcinoma. Radical surgery is the only effective therapy for parathyroid carcinoma, and should always be performed if a preoperative suspicion is entertained.

Al-Fadhli, Mariam; Doi, Suhail A R; Muttikkal, Thomas; Al-Sumait, Basel



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

PubMed Central

Parathyroid hormone-related protein (PTHrP) and macrophage inflammatory protein-1? (MIP-1?) 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-1? on T-cell growth and death both in vitro and in vivo by overexpressing either factor in human Jurkat T-cells. PTHrP or MIP-1? did not affect Jurkat cell growth in vitro, but PTHrP increased their sensitivity to apoptosis. Importantly, PTHrP and MIP-1? 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-1? increased the expression of several factors including signal transducer and activator of transcription 4, tumor necrosis factor ?, receptor activator of nuclear factor ?B ligand and death-associated protein kinase 1, and decreased the expression of inhibitor of DNA binding 1, interferon ? and CD40 ligand in Jurkat cells. In addition, MIP-1? also increased the expression of transcription factor AP-2? and PTHrP increased expression of the vitamin D3 receptor. These data demonstrate that PTHrP and MIP-1? exert a profound antitumor effect presumably by increasing the sensitivity to apoptotic signals through modulation of transcription and apoptosis factors in T-cells.

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.



Giant anterior mediastinal parathyroid adenoma.  


A 57-year-old woman with type 2 diabetes was admitted to our hospital presenting with generalized bone pains, hypercalcemia, and elevated parathyroid hormone level. Enhanced CT scan demonstrated a large soft tissue mass in the right anterior mediastinum. Tc-MIBI scintigraphy revealed the focal accumulation of radiotracer uptake in the anterior mediastinum. Tc-MIBI SPECT/CT imaging also corroborated the same finding. The patient underwent surgery to have a giant ectopic parathyroid adenoma (7 × 4.5 × 1.5 cm) removed. The patient has been observed for 2 years, with normal parathyroid hormone and calcium levels. PMID:22889780

Li, Lianxi; Chen, Libo; Yang, Yi; Han, Junfeng; Wu, Songhua; Bao, Yuqian; Jia, Weiping



Effects of the calcium-sensing receptor A986S polymorphism on serum calcium and parathyroid hormone levels in healthy individuals: a meta-analysis.  


The calcium-sensing receptor (CaSR) is involved in maintaining calcium homeostasis via the regulation of parathyroid hormone (PTH) secretion. The associations between serum calcium concentrations, parathyroid hormone (PTH) level and CaSR polymorphism A986S have been studied, but results are inconsistent. Therefore, we performed a meta-analysis to clarify the role of this polymorphism on this topic. Weighted mean difference (WMD) and 95% confidence interval (CI) were calculated with random-effects model or fixed-effects model based on the heterogeneity analysis. Overall 2820, 1135 and 3149 healthy individuals were included for total calcium concentration, ionized calcium concentration and PTH level meta-analyses, respectively. Most of the individuals in this meta-analysis were healthy women. Healthy individuals with the AS+SS genotype had significantly higher total and ionized calcium concentrations than those with the AA genotype. However, there was no statistical significance concerning serum PTH level. The pooled WMD for total calcium concentration was 0.028 (95% CI: 0.012-0.045, P=0.001); for ionized calcium concentration was 0.016 (95% CI: 0.013-0.020, P<0.0001); and for PTH level was -0.027 (95% CI: -0.360-0.306, P=0.874). In conclusion, our meta-analysis indicates that the CaSR A986S polymorphism might be associated with total and ionized calcium concentrations in healthy individuals. PMID:22024717

He, Yonghan; Han, Liyuan; Li, Wen; Shu, Xiang; Zhao, Chen; He, Ying; Bi, Mingxin; Li, Ying; Sun, Changhao



The Calcium-Sensing Receptor Mediates Bone Turnover Induced by Dietary Calcium and Parathyroid Hormone in Neonates  

PubMed Central

We have investigated, in neonates, whether the calcium-sensing receptor (CaR) mediates the effects of dietary calcium on bone turnover and/or modulates parathyroid hormone (PTH)–induced bone turnover. Wild-type (WT) pups and pups with targeted deletion of the Pth (Pth–/–) gene or of both Pth and CaR (Pth–/–CaR–/–) genes were nursed by dams on a normal or high-calcium diet. Pups nursed by dams on a normal diet received daily injections of vehicle or of PTH(1–34) (80 µg/kg) for 2 weeks starting from 1 week of age. In pups receiving vehicle and fed by dams on a normal diet, trabecular bone volume, osteoblast number, type 1 collagen–positive area, and mineral apposition rate, as well as the expression of bone-formation-related genes, all were reduced significantly in Pth–/– pups compared with WT pups and were decreased even more dramatically in Pth–/–CaR–/– pups. These parameters were increased in WT and Pth–/– pups but not in Pth–/–CaR–/– pups fed by dams on a high-calcium diet compared with pups fed by dams on a normal diet. These parameters also were increased in WT, Pth–/–, and Pth–/–CaR–/– pups following exogenous PTH treatment; however, the percentage increase was less in Pth–/–CaR–/– pups than in WT and Pth–/– pups. In vehicle-treated pups fed by dams on either the normal or high-calcium diet and in PTH-treated pups fed by dams on a normal diet, the number and surfaces of osteoclasts and the ratio of RANKL/OPG were reduced significantly in Pth–/– pups and less significantly in Pth–/–CaR–/– pups compared with WT pups. These parameters were further reduced significantly in WT and Pth–/– pups from dams fed a high-calcium diet but did not decrease significantly in similarly treated Pth–/–CaR–/– pups, and they increased significantly in PTH-treated pups compared with vehicle-treated, genotype-matched pups fed by dams on the normal diet. These results indicate that in neonates, the CaR mediates alterations in bone turnover in response to changes in dietary calcium and modulates PTH-stimulated bone turnover. © 2011 American Society for Bone and Mineral Research.

Shu, Lei; Ji, Ji; Zhu, Qi; Cao, Guofan; Karaplis, Andrew; Pollak, Martin R; Brown, Edward; Goltzman, David; Miao, Dengshun



1,25 dihydroxyvitamin D and dexamethasone decrease in vivo Walker carcinoma growth, but not parathyroid hormone related protein secretion.  


Parathyroid hormone related protein (PTHrP) is produced by several breast cancers. 1,25 dihydroxyvitamin D (1,25[OH]2D) and Dexamethasone (DEX) have been shown to decrease PTHrP mRNA expression in several cell lines. We therefore tested the in vivo effect of both steroids on PTHrP secretion and tumor development of the Walker carcinoma (WC). WC cells were injected subcutaneously in Fisher rats which were simultaneously treated with either vehicle, or 1,25(OH)2D (0.5 micrograms/kg/d) or DEX (2 mg/kg/d). After 7 days, tumor weight was significantly decreased in the 2 treated-groups as compared to the control group. Vehicle treated-rats developed hypercalcemia, which was also observed in rats treated with 1,25(OH)2D; by contrast, the plasma calcium was significantly decreased in the DEX-treated group compared to vehicle-treated rats. In a dose-effect experiment, this dose of 1,25(OH)2D induced marked hypercalcemia in rats not implanted with WC, but was required to decrease the tumor weight in implanted rats. In both 1,25(OH)2D and DEX-treated groups, plasma PTHrP levels were significantly decreased, but there was a similar correlation between PTHrP plasma level and tumor weight in the three groups. Indeed, the cytosolic PTHrP content/mg tumor was identical in the 3 groups. By contrast, the PTHrP/Actin mRNA in the tumor was significantly decreased in the 1,25(OH)2D group, comparatively to the vehicle and DEX groups. Our results show that Dexamethasone and 1,25(OH)2D decrease WC tumor development in vivo, but do not change the PTHrP secretion by the remaining tumor although steady state PTHrP mRNA content level is decreased by 1,25(OH)2D. PMID:8557238

Cohen-Solal, M E; Bouizar, Z; Denne, M A; Graulet, A M; Gueris, J; Bracq, S; Jullienne, A; de Vernejoul, M C



The calcium-sensing receptor mediates bone turnover induced by dietary calcium and parathyroid hormone in neonates.  


We have investigated, in neonates, whether the calcium-sensing receptor (CaR) mediates the effects of dietary calcium on bone turnover and/or modulates parathyroid hormone (PTH)-induced bone turnover. Wild-type (WT) pups and pups with targeted deletion of the Pth (Pth(-/-)) gene or of both Pth and CaR (Pth(-/-)CaR(-/-)) genes were nursed by dams on a normal or high-calcium diet. Pups nursed by dams on a normal diet received daily injections of vehicle or of PTH(1-34) (80?µg/kg) for 2 weeks starting from 1 week of age. In pups receiving vehicle and fed by dams on a normal diet, trabecular bone volume, osteoblast number, type 1 collagen-positive area, and mineral apposition rate, as well as the expression of bone-formation-related genes, all were reduced significantly in Pth(-/-) pups compared with WT pups and were decreased even more dramatically in Pth(-/-)CaR(-/-) pups. These parameters were increased in WT and Pth(-/-) pups but not in Pth(-/-)CaR(-/-) pups fed by dams on a high-calcium diet compared with pups fed by dams on a normal diet. These parameters also were increased in WT, Pth(-/-), and Pth(-/-)CaR(-/-) pups following exogenous PTH treatment; however, the percentage increase was less in Pth(-/-)CaR(-/-) pups than in WT and Pth(-/-) pups. In vehicle-treated pups fed by dams on either the normal or high-calcium diet and in PTH-treated pups fed by dams on a normal diet, the number and surfaces of osteoclasts and the ratio of RANKL/OPG were reduced significantly in Pth(-/-) pups and less significantly in Pth(-/-)CaR(-/-) pups compared with WT pups. These parameters were further reduced significantly in WT and Pth(-/-) pups from dams fed a high-calcium diet but did not decrease significantly in similarly treated Pth(-/-)CaR(-/-) pups, and they increased significantly in PTH-treated pups compared with vehicle-treated, genotype-matched pups fed by dams on the normal diet. These results indicate that in neonates, the CaR mediates alterations in bone turnover in response to changes in dietary calcium and modulates PTH-stimulated bone turnover. PMID:21542007

Shu, Lei; Ji, Ji; Zhu, Qi; Cao, Guofan; Karaplis, Andrew; Pollak, Martin R; Brown, Edward; Goltzman, David; Miao, Dengshun



Is low plasma 25-(OH)vitamin D a major risk factor for hyperparathyroidism and Looser's zones independent of calcitriol?  

Microsoft Academic Search

Is low plasma 25-(OH)vitamin D a major risk factor for hyperparathyroidism and Looser's zones independent of calcitriol?BackgroundRecent reports suggest that calcitriol might not be the sole active metabolite of vitamin D and that plasma concentrations of 25-(OH)vitamin D (25OHD) are often abnormally low in hemodialysis patients. We have therefore evaluated plasma 25OHD as a risk factor for parathyroid hormone (PTH)

Abderhaman Ghazali; Patrice Fardellone; André Pruna; Ahcene Atik; Jean-Michel Achard; Roxana Oprisiu; Michel Brazier; Alex Remond; Philippe Morinière; Michèle Garabedian; John Eastwood; Albert Fournier



Effects of electromagnetic stimuli on bone and bone cells in vitro: Inhibition of responses to parathyroid hormone by low-energy low-frequency fields  

PubMed Central

Low-energy electromagnetic fields pulsed at frequencies of 10-90 Hz significantly increase healing of chronic fracture nonunions in man. These fields are effective at tissue current levels several orders of magnitude lower than those required for transmembrane depolarization of normal cells. We have examined the effects of two clinically used pulsed electromagnetic fields on cultures of the osteoblast-like mouse bone cell line MMB-1. Both fields significantly reduced cellular production of cAMP in response to parathyroid hormone and osteoclast activating factor. Neither basal nor fluoride-activated levels of adenylate cyclase were altered in membranes from cells cultured in the fields; however, the same membrane preparations exhibited markedly inhibited responses to parathyroid hormone. The fields blocked the inhibitory effects of the hormone on collagen synthesis by MMB-1 cells. However, there was no effect on the inhibition of collagen synthesis by 1,25-dihydroxyvitamin D3, which is believed to act primarily by a nuclear, rather than by a membrane-dependent, mechanism. No significant differences were noted between effects of the two fields, one generating continuous pulse trains (72 Hz) and the other generating recurrent bursts (15 Hz) of shorter pulses. We hypothesize that these field effects are mediated primarily at the plasma membrane of osteoblasts, either by interference with hormone-receptor interactions or by blocking of receptor-cyclase coupling in the membrane. These responses occurred with induced extracellular fields of 1 mV/cm or less, even though transmembrane potential gradients are typically 105 V/cm.

Luben, Richard A.; Cain, Christopher D.; Chen, Monica Chi-Yun; Rosen, David M.; Adey, W. Ross



Nonfunctional parathyroid carcinoma.  


A 65-year-old female patient was admitted to our hospital presenting with a superior mediastinal big mass that was elastic, hard, and painless. Laboratory data including serum calcium level and thyroid and parathyroid hormonal functions revealed no abnormalities. Further examination consisting of computed tomography, magnetic resonance imaging, and ultrasonography demonstrated that it was a solid tumor extending into the superior mediastinum. Technetium (Tc-99) sestamibi scan revealed a hypofunctioning focus in that area. The preoperative diagnosis was a thyroid tumor or a metastatic lymph node. Parathyroid carcinoma was suspected on intraoperative frozen pathological examination. The tumor was successfully removed with left thyroid lobectomy, and neck node dissection was performed. Macroscopically, it appeared as a dark reddish solid tumor, and the cut surface presented opalescence. Immunohistology confirmed that there was proliferation of tumor cells with positive chromogranin A staining. Thus, the tumor was diagnosed as parathyroid carcinoma histopathologically despite a lack of clinical evidence for hyperparathyroidism. This patient has been followed with no evidence of recurrence, a normal serum calcium 4 years after surgery, and postoperative radiotherapy. This report describes a case of nonfunctional parathyroid carcinoma with a massive mass that technetium (Tc-99) sestamibi scan failed to detect, and we showed negative immunostaining for parathyroid hormone (PTH) (N). PMID:20224881

Nakamura, Yosuke; Kataoka, Hideyuki; Sakoda, Takema; Horie, Yasushi; Kitano, Hiroya





Vitamins are substances that your body needs to grow and develop normally. There are 13 vitamins your body needs. They are vitamins A, C, D, E, K and the B vitamins (thiamine, riboflavin, niacin, pantothenic acid, biotin, vitamin B- ...


Direct upregulation of parathyroid calcium-sensing receptor and vitamin D receptor by calcimimetics in uremic rats.  


To investigate whether the effect of the calcimimetic AMG 641 and calcitriol on CaSR and VDR expression could be separated from their ability to reduce parathyroid cell proliferation, five-sixth nephrectomized (5/6 Nx) rats received vehicle, AMG 641, calcitriol, or AMG 641+calcitriol either daily for 13 days (long-term protocol) or in a single dose (short-term protocol). In the long-term protocol, AMG 641, calcitriol, and their combination significantly reduced the percentage of proliferating parathyroid cells. Proliferation was uncontrolled in the short-term protocol. A significant increase in CaSR mRNA (% vs. beta-actin) was detected in rats treated with both calcitriol (1.60 +/- 0.30) and AMG 641 (1.66 +/- 0.25) for 13 days (P = 0.01 vs. 5/6 Nx+vehicle, 0.89 +/- 0.09); and there was a further increase when both drugs were administered simultaneously (2.46 +/- 0.33). In the short-term protocol, only rats receiving AMG 641 alone (2.01 +/- 0.33, P < 0.001) showed increased expression of CaSR mRNA, whereas the combination (1.81 +/- 0.20) produced no additional benefit. AMG 641 also increased CaSR mRNA expression in vitro. Changes in VDR mRNA paralleled those of CaSR mRNA. In the long-term treatment, both AMG 641 (0.87 +/- 0.14) and calcitriol (0.99 +/- 0.12) increased VDR mRNA (P < 0.05 vs. 5/6 Nx+vehicle, 0.49 +/- 0.10), and the increase was more accentuated when the drugs were combined (1.49 +/- 0.45). In the short-term protocol, only treatment with AMG 641, alone (1.52 +/- 0.41) or combined with calcitriol (1.86 +/- 0.24), increased VDR mRNA. In conclusion, our results demonstrate an acute increase in CaSR mRNA and VDR mRNA in the parathyroid glands of uremic rats treated with AMG 641, in which cell proliferation was uncontrolled, thus supporting a direct effect of calcimimetics on CaSR and VDR expression by hyperplastic parathyroid cells. PMID:19091789

Mendoza, Francisco J; Lopez, Ignacio; Canalejo, Rocio; Almaden, Yolanda; Martin, David; Aguilera-Tejero, Escolastico; Rodriguez, Mariano



The Women's Health Initiative: Hormone Therapy and Calcium/Vitamin D Supplementation Trials.  


The Women's Health Initiative (WHI) was a large and complex study focused on strategies for the prevention and control of common chronic diseases of postmenopausal women. The WHI included 3 randomized controlled trials: the Hormone Therapy (HT) Trials, the Diet Modification Trial, and the Calcium/Vitamin D (CaD) Trial. Conjugated equine estrogen with or without a progestin significantly decreased hip, clinical vertebral, and all fractures. Once the intervention was stopped, the fracture benefit dissipated. However, estrogen plus progestin was associated with more risks than benefits and use of hormone therapy solely for the prevention of osteoporosis is not recommended. The CaD trial found no overall benefit for fracture reduction except in adherent women and women taking supplements for 5 or more years. Overall, the common practice of taking calcium and vitamin D supplementation with possible benefits on hip and positive evidence on bone mineral density and few risks is reasonable. PMID:23842639

Cauley, Jane A



Daily transient decreases in plasma parathyroid hormone levels induced by the calcimimetic NPS R-568 slows the rate of bone loss but does not increase bone mass in ovariectomized rats  

Microsoft Academic Search

Daily parathyroid hormone (PTH) injections that transiently increase plasma PTH levels within the physiological range increase bone mass in osteopenic, ovariectomized (ovx) rats. This study tested the hypothesis that repeated transient decreases in plasma PTH levels from normal, induced by the daily oral administration of the calcimimetic NPS R-568, would induce an anabolic effect in bone of ovx rats with

M. A Miller; J Fox



The influence of pyrophosphate, condensed phosphates, phosphonates and other phosphate compounds on the dissolution of hydroxyapatite in vitro and on bone resorption induced by parathyroid hormone in tissue culture and in thyroparathyroidectomised rats  

Microsoft Academic Search

Earlier studies have shown that inorganic pyrophosphate (PPi) inhibits the dissolution of hydroxyapatite crystalsin vitro and it has been suggested that PPi might be a physiological regulator of bone resorption. In this study PP1 and other phosphate compounds have been tested for their ability to inhibit bone resorption induced by parathyroid hormone in mouse calvaria and to inhibit the rise

R. G. G. Russell; R. C. Mühlbauer; S. Bisaz; D. A. Williams; H. Fleisch



Parathyroid hormone(1–34) mediates proliferative and apoptotic signaling in human periodontal ligament cells in vitro via protein kinase C-dependent and protein kinase A-dependent pathways  

Microsoft Academic Search

Periodontal ligament (PDL) cells exhibit several osteoblastic traits and are parathyroid hormone (PTH)-responsive providing evidence for a role of these cells in dental hard-tissue repair. To examine the hypothesis that PDL cells respond to PTH stimulation with changes in proliferation and apoptotic signaling through independent but convergent signaling pathways, PDL cells were cultured from human bicuspids obtained from six patients.

S. Lossdörfer; W. Götz; B. Rath-Deschner; A. Jäger



Effect of glutaurine on vitamin A and prednisolone treated thymus cultures.  


The hormone of the parathyroid gland, Glutaurine (gamma-L-glutamyl-taurine) exerts on rat thymus cultures an effect synergistic with vitamin A and antagonistic to prednisolone. When applied in itself, it increased the vitality and macrophage reaction of thymus cultures. PMID:747133

Feuer, L; Török, O; Csaba, G



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

SciTech Connect

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.

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



Effect of switching hepatic enzyme-inducer antiepileptic drug to levetiracetam on bone mineral density, 25 hydroxyvitamin D, and parathyroid hormone in young adult patients with epilepsy.  


We sought to determine the effect of changing phenytoin therapy on bone mineral density (BMD) and 25-hydroxyvitamin D in patients with epilepsy. Of the 90 patients, 54 patients had switched to levetiracetam, 19 patients had stopped, and 17 patients continued taking phenytoin. We proposed a 2-year period to examine 25-hydroxyvitamin D, parathyroid hormone, and BMD. The patients who switched or stopped phenytoin showed a significant increase in BMD of the lumbar spine and left femur, and in 25-hydroxyvitamin D. In contrast, those who continued phenytoin had a significant decrease in BMD at both sites and in 25-hydroxyvitamin D. Patients who were taken off phenytoin and those switching to levetiracetam did not show a significant difference in BMD, 25-hydroxyvitamin D, parathyroid, or calcium at follow-up. Compared with those who continued phenytoin, the BMD was significantly higher in patients switching to levetiracetam and those who stopped using phenytoin. Switching medications may be necessary in some cases to avoid low BMD. PMID:23586623

Phabphal, Kanitpong; Geater, Alan; Limapichat, Kitti; Sathirapanya, Pornchai; Setthawatcharawanich, Suwanna; Leelawattana, Rattana



Hypovitaminosis D and vitamin D deficiency in exclusively breast-feeding infants and their mothers in summer: A justification for vitamin D supplementation of breast-feeding infants  

Microsoft Academic Search

Objective To determine the prevalence of hypovitaminosis D in exclusively breast-feeding infants and their mothers in a community where maternal sunshine exposure is low. Study design Serum levels of calcium, phosphate, alkaline phosphatase, 25-hydroxy vitamin D (25-OHD), and intact parathyroid hormone were measured in 90 unsupplemented healthy term breast-feeding Arab\\/South Asian infants and their mothers in summer. Maternal dietary vitamin

Adekunle Dawodu; Mukesh Agarwal; Moshaddeque Hossain; Jose Kochiyil; Reem Zayed



Switching of G-protein Usage by the Calcium-sensing Receptor Reverses Its Effect on Parathyroid Hormone-related Protein Secretion in Normal Versus Malignant Breast Cells*  

PubMed Central

The calcium-sensing receptor (CaR) is a G-protein-coupled receptor that signals in response to extracellular calcium and regulates parathyroid hormone secretion. The CaR is also expressed on normal mammary epithelial cells (MMECs), where it has been shown to inhibit secretion of parathyroid hormone-related protein (PTHrP) and participate in the regulation of calcium and bone metabolism during lactation. In contrast to normal breast cells, the CaR has been reported to stimulate PTHrP production by breast cancer cells. In this study, we confirmed that the CaR inhibits PTHrP production by MMECs but stimulates PTHrP production by Comma-D cells (immortalized murine mammary cells) and MCF-7 human breast cancer cells. We found that changes in intracellular cAMP, but not phospholipase C or MAPK signaling, correlated with the opposing effects of the CaR on PTHrP production. Pharmacologic stimulation of cAMP accumulation increased PTHrP production by normal and transformed breast cells. Inhibition of protein kinase A activity mimicked the effects of CaR activation on inhibiting PTHrP secretion by MMECs and blocked the effects of the CaR on stimulating PTHrP production in Comma-D and MCF-7 cells. We found that the CaR coupled to G?i in MMECs but coupled to G?s in Comma-D and MCF-7 cells. Thus, the opposing effects of the CaR on PTHrP production are because of alternate G-protein coupling of the receptor in normal versus transformed breast cells. Because PTHrP contributes to hypercalcemia and bone metastases, switching of G-protein usage by the CaR may contribute to the pathogenesis of breast cancer.

Mamillapalli, Ramanaiah; VanHouten, Joshua; Zawalich, Walter; Wysolmerski, John



Switching of G-protein usage by the calcium-sensing receptor reverses its effect on parathyroid hormone-related protein secretion in normal versus malignant breast cells.  


The calcium-sensing receptor (CaR) is a G-protein-coupled receptor that signals in response to extracellular calcium and regulates parathyroid hormone secretion. The CaR is also expressed on normal mammary epithelial cells (MMECs), where it has been shown to inhibit secretion of parathyroid hormone-related protein (PTHrP) and participate in the regulation of calcium and bone metabolism during lactation. In contrast to normal breast cells, the CaR has been reported to stimulate PTHrP production by breast cancer cells. In this study, we confirmed that the CaR inhibits PTHrP production by MMECs but stimulates PTHrP production by Comma-D cells (immortalized murine mammary cells) and MCF-7 human breast cancer cells. We found that changes in intracellular cAMP, but not phospholipase C or MAPK signaling, correlated with the opposing effects of the CaR on PTHrP production. Pharmacologic stimulation of cAMP accumulation increased PTHrP production by normal and transformed breast cells. Inhibition of protein kinase A activity mimicked the effects of CaR activation on inhibiting PTHrP secretion by MMECs and blocked the effects of the CaR on stimulating PTHrP production in Comma-D and MCF-7 cells. We found that the CaR coupled to Galphai in MMECs but coupled to Galphas in Comma-D and MCF-7 cells. Thus, the opposing effects of the CaR on PTHrP production are because of alternate G-protein coupling of the receptor in normal versus transformed breast cells. Because PTHrP contributes to hypercalcemia and bone metastases, switching of G-protein usage by the CaR may contribute to the pathogenesis of breast cancer. PMID:18621740

Mamillapalli, Ramanaiah; VanHouten, Joshua; Zawalich, Walter; Wysolmerski, John



Calcification Inhibitors and Wnt Signaling Proteins Are Implicated in Bovine Artery Smooth Muscle Cell Calcification in the Presence of Phosphate and Vitamin D Sterols  

Microsoft Academic Search

Administration of active vitamin D sterols to treat secondary hyperparathyroidism in patients with chronic kidney disease\\u000a receiving dialysis has been associated with elevated serum calcium and phosphorus levels, which may lead to increased risk\\u000a of vascular calcification. However, calcimimetics, by binding to the parathyroid gland calcium-sensing receptors, reduce serum\\u000a parathyroid hormone, calcium, phosphorus, and the calcium-phosphorus product. Using cultured bovine

V. Shalhoub; E. Shatzen; C. Henley; M. Boedigheimer; J. McNinch; R. Manoukian; M. Damore; D. Fitzpatrick; K. Haas; B. Twomey; P. Kiaei; S. Ward; D. L. Lacey; D. Martin



Management and surgical treatment of parathyroid crisis secondary to parathyroid tumors: report of four cases.  


Parathyroid crisis, also known as a parathyroid storm, is a rare and serious complication of primary hyperparathyroidism. Four cases are reported here in which patients presented to hospital with general complaints due to hypercalcemia secondary to hyperparathyroidism. Blood test results upon admission showed high levels of serum calcium and parathyroid hormone, and medical treatment initiated to lower the calcium level was ineffective. After relevant investigations, each patient underwent surgical exploration of the parathyroid glands, followed by excision of a pathological parathyroid tumor. There was a prompt decrease in parathyroid hormone level immediately after surgery. Histology reports revealed that patients had parathyroid adenoma. All patients recovered after surgery, with serum calcium levels restored back to normal and with resolution of all symptoms of hypercalcemia. This report illustrates how often this disease is initially misdiagnosed, and how prompt appropriate surgical treatment provides the best outcome for the patient. PMID:23754908

Ameerudden, Shakil; He, Xianghui



Sex and age modify biochemical and skeletal manifestations of chronic hyperparathyroidism by altering target organ responses to Ca2+ and parathyroid hormone in mice.  


We studied mice with or without heterozygous deletion of the Casr in the parathyroid gland (PTG) [(PTG) CaSR(+/-)] to delineate effects of age and sex on manifestations of hyperparathyroidism (HPT). In control mice, aging induced a left-shift in the Ca(2+) /parathyroid hormone (PTH) set point accompanied by increased PTG CaSR expression along with lowered serum Ca(2+) and mildly increased PTH levels, suggesting adaptive responses of PTGs to aging-induced changes in mineral homeostasis. The aging effects on Ca(2+) /PTH set point and CaSR expression were significantly blunted in (PTG) CaSR(+/-) mice, who showed instead progressively elevated PTH levels with age, especially in 12-month-old females. These 12-month-old knockout mice demonstrated resistance to their high PTH levels in that serum 1,25-dihydroxyvitamin D (1,25-D) levels and RNA expression of renal Cyp27b1 and expression of genes involved in Ca(2+) transport in kidney and intestine were unresponsive to the rising PTH levels. Such changes may promote negative Ca(2+) balance, which further exacerbate the HPT. Skeletal responses to HPT were age-, sex-, and site-dependent. In control mice of either sex, trabecular bone in the distal femur decreased whereas cortical bone in the tibiofibular junction increased with age. In male (PTG) CaSR(+/-) mice, anabolic actions of the elevated PTH levels seemed to protect against trabecular bone loss at ? 3 months of age at the expense of cortical bone loss. In contrast, HPT produced catabolic effects on trabecular bone and anabolic effects on cortical bone in 3-month-old females; but these effects reversed by 12 months, preserving trabecular bone in aging mice. We demonstrate that the CaSR plays a central role in the adaptive responses of parathyroid function to age-induced changes in mineral metabolism and in target organ responses to calciotropic hormones. Restraining the ability of the PTG to upregulate CaSRs by heterozygous gene deletion contributes to biochemical and skeletal manifestations of HPT, especially in aging females. PMID:23239173

Cheng, Zhiqiang; Liang, Nathan; Chen, Tsui-Hua; Li, Alfred; Santa Maria, Christian; You, Michael; Ho, Hanson; Song, Fuqing; Bikle, Daniel; Tu, Chialing; Shoback, Dolores; Chang, Wenhan



Vitamin D insufficiency and effect of cholecalciferol in children with chronic kidney disease  

Microsoft Academic Search

Vitamin D insufficiency is common in patients with chronic kidney disease (CKD) and may contribute to mineral bone disease.\\u000a In a prospective interventional study, we estimated the prevalence of vitamin D insufficiency (serum 25-hydroxyvitamin D3\\u000a [25OHD] < 30 ng\\/ml), and examined the effect of high-dose (600,000 IU) cholecalciferol supplementation after 6 weeks on serum\\u000a 25OHD and parathyroid hormone (PTH) levels in children with

Pankaj Hari; Nandita Gupta; Smriti Hari; Ashima Gulati; Puneet Mahajan; Arvind Bagga



Successful treatment of vitamin D unresponsive hypoparathyroidism with multipulse subcutaneous infusion of teriparatide  

Microsoft Academic Search

Objective: Hypoparathyroidism is usually controlled with calcium and vitamin-D supplements; in very few cases this treatment fails and teriparatide may be an alternative. We report the first case of hypoparathyroidism refractory to vitamin-D therapy requiring multipulse teriparatide treatment. Case report: A 53 year-old woman presented severe hypocalcemia and hypomagnesemia after thyroidectomy. Preoperatively, mild hypercalciuria was detected with parathyroid hormone (PTH)

Manel Puig-Domingo; Gonzalo Diaz; Joanna Nicolau; Cristian Fernandez; Sergio Rueda; Irene Halperin




PubMed Central

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.

Stein, Donald G.; Cekic, Milos M.



Impaired vitamin D metabolism in CKD.  


Vitamin D metabolism consists of both production and catabolism, which are enzymatically driven and highly regulated. Renal vitamin D metabolism requires filtration and tubular reabsorption of 25-hydroxyvitamin D and is regulated by parathyroid hormone, fibroblast growth factor-23, and 1,25-dihydroxyvitamin D. In chronic kidney disease, renal production of 1,25-dihydroxyvitamin D from 25-hydroxyvitamin D is reduced. In addition, pharmacokinetic studies and epidemiologic studies of 24,25-dihydroxyvitamin D, the most abundant product of 25-hydroxyvitamin D catabolism by CYP24A1, suggest that vitamin D catabolism also is reduced. New insights into the mechanisms and regulation of vitamin D metabolism may lead to novel approaches to assess and treat impaired vitamin D metabolism in chronic kidney disease. PMID:23465502

Bosworth, Cortney; de Boer, Ian H



Phenytoin induced vitamin d deficiency presenting as proximal muscle weakness  

Microsoft Academic Search

A 6-year-old girl presented with proximal muscle weakness of lower limbs. She was receiving phenytoin for epilepsy for 2 years.\\u000a Serum phenytoin level was within therapeutic range. Serum 25(OH) vitamin D was low (5ng\\/mL) and serum parathyroid hormone\\u000a level was high. After administration of oral vitamin D, muscle weakness improved and vitamin D level increased to 39.11ng\\/mL.\\u000a Proximal muscle weakness

M. M. A. Faridi; Anju Aggarwal



Biphasic hypercalcemia in severe rhabdomyolysis: serial analysis of PTH and vitamin D metabolites. A case report and literature review  

Microsoft Academic Search

Calcemic fluxes with hypocalcemia leading to hypercalcemia in acute rhabdomyolisis are poorly understood. Analyses in the literature of the factors modulating the blood calcium level include 2, possibly 3 systems. Conflicting results implicate the parathyroid hormone and vitamin D metabolites, but additional contribution from skeletal and muscle calcium ion deposition and dissolution have been cited in some cases, potentially even

Sarju M. Shrestha; Jacqueline L. Berry; Michael Davies; Francis W. Ballardie



Parathyroid cancer.  


Parathyroid cancer is an uncommon malignancy and rare cause of primary hyperparathyroidism (HPT) with a high morbidity and patient death in advanced cases usually resulting from intractable hypercalcemia. Inactivation of the HRPT2/CDC73 gene, encoding the putative tumor-suppressor protein parafibromin and discovered in the context of the hyperparathyroidism-jaw tumor (HPT-JT) syndrome, is a common, somatic event in most parathyroid cancers. Approximately 25% of patients with apparently sporadic parathyroid cancer carry germline HRPT2/CDC73 mutation. Germline DNA analysis for HRPT2/CDC73 mutation is recommended in all patients with parathyroid cancer because of the potential benefit for first-degree relatives, who should nevertheless undergo serum calcium screening. The histopathologic diagnosis of parathyroid cancer is nonspecific unless vascular, lymphatic, capsular, or soft tissue invasion is seen, or metastases are clinically evident. Immunohistochemical analysis of parathyroid tumors for loss of parafibromin expression offers promise as a diagnostic tool. En bloc tumor resection offers the highest chance of cure in patients with suspected parathyroid carcinoma. No adjuvant chemotherapy regimen has yet proven effective, and the role of local adjuvant radiotherapy is being evaluated. Metastatic disease can be palliated with surgical debulking. Medical therapy with the calcimimetic cinacalcet and bisphosphonates can ameliorate hypercalcemia in patients with inoperable disease. PMID:21167377

Sharretts, John M; Kebebew, Electron; Simonds, William F



Parathyroid Cancer  

PubMed Central

Parathyroid cancer is an uncommon malignancy and rare cause of primary hyperparathyroidism with a high morbidity and patient death in advanced cases usually resulting from intractable hypercalcemia. Inactivation of the HRPT2/CDC73 gene, encoding the putative tumor suppressor protein parafibromin and discovered in the context of the hyperparathyroidism-jaw tumor syndrome (HPT-JT), is a common, somatic genetic event in most parathyroid cancers. Some 25% of patients with apparently sporadic parathyroid cancer carry germline HRPT2/CDC73 mutation. Germline DNA analysis for HRPT2/CDC73 mutation is recommended in all patients with parathyroid cancer because of the potential benefit for offspring and other first-degree relatives. The histopathologic diagnosis of parathyroid cancer is non-specific unless vascular, lymphatic, capsular or soft tissue invasion are seen, or metastases are clinically evident. Immunohistochemical analysis of parathyroid tumors for loss of parafibromin expression offers promise as a diagnostic tool. En bloc tumor resection offers the highest chance of cure in patients with suspected parathyroid carcinoma. No adjuvant chemotherapy regimen has yet proven effective, and the role of local adjuvant radiotherapy is being evaluated. Metastatic disease can be palliated with surgical debulking. Medical therapy with the calcimimetic cinacalcet and bisphosphonates can ameliorate hypercalcemia in patients with inoperable disease.

Sharretts, John M.; Kebebew, Electron



Influence of parathyroid mass on the regulation of PTH secretion  

Microsoft Academic Search

In advanced uremia, parathyroid hormone (PTH) levels should be controlled at a moderately elevated level in order to promote normal bone turnover. As such, a certain degree of parathyroid gland (PG) hyperplasia has to be accepted. No convincing evidence of apoptosis or of involution of PG hyperplasia exists. However, even considerable parathyroid hyperplasia can be controlled when the functional demand

E Lewin; K Olgaard





... and Nutrition Nutrition basics Proteins Carbohydrates Fats Vitamins Minerals Water How to eat for health Special food ... Bone_Health/Nutrition/vitamin_a.asp Vitamin and Mineral Supplement Fact Sheets - This website links to fact ...


Effect of vitamin K 2 and growth hormone on the long bones in hypophysectomized young rats: a bone histomorphometry study  

Microsoft Academic Search

The purpose of the present study was to determine whether vitamin K2 and growth hormone (GH) had an additive effect on the long bones in hypophysectomized young rats. Forty-eight female Sprague–Dawley\\u000a rats (6 weeks old) were assigned to the following five groups by the stratified weight randomization method: intact controls,\\u000a hypophysectomy (HX) alone, HX + vitamin K2 (30?mg\\/kg, p.o., daily),

Jun Iwamoto; Tsuyoshi Takeda; Yoshihiro Sato; James K. Yeh



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.  


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

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



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

PubMed Central

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

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



Decreases in Parathyroid Gland Volume after Cinacalcet Treatment in Hemodialysis Patients with Secondary Hyperparathyroidism  

Microsoft Academic Search

Background\\/Aim: Cinacalcet, an allosteric modulator of the calcium-sensing receptor, effectively reduces serum parathyroid hormone (PTH). It was examined whether a regression of parathyroid glands in hemodialysis patients with secondary hyperparathyroidism was induced by cinacalcet treatment. Methods: Ultrasonography of the parathyroid glands was performed to examine the changes in the parathyroid gland volumes after cinacalcet treatment in 58 patients. Results: After

Mitsuru Ichii; Eiji Ishimura; Senji Okuno; Hidenori Chou; Yoko Kato; Naoki Tsuboniwa; Kyoko Nagasue; Kiyoshi Maekawa; Tomoyuki Yamakawa; Masaaki Inaba; Yoshiki Nishizawa



Peripheral Bone Mass is Not Affected by Winter Vitamin D Deficiency in Children and Young Adults from Ushuaia  

Microsoft Academic Search

.   Low vitamin D levels in elderly people are associated with reduced bone mass, secondary hyperparathyroidism, and increased\\u000a fracture risk. Its effect on the growing skeleton is not well known. The aim of this study was to evaluate the possible influence\\u000a of chronic winter vitamin D deficiency and higher winter parathyroid hormone (PTH) levels on bone mass in prepubertal children

M. B. Oliveri; A. Wittich; C. Mautalen; A. Chaperon; A. Kizlansky



Black bear parathyroid hormone has greater anabolic effects on trabecular bone in dystrophin-deficient mice than in wild type mice.  


Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disease that has deleterious consequences in muscle and bone, leading to decreased mobility, progressive osteoporosis, and premature death. Patients with DMD experience a higher-than-average fracture rate, particularly in the proximal and distal femur and proximal tibia. The dystrophin-deficient mdx mouse is a model of DMD that demonstrates muscle degeneration and fibrosis and osteoporosis. Parathyroid hormone, an effective anabolic agent for post-menopausal and glucocorticoid-induced osteoporosis, has not been explored for DMD. Black bear parathyroid hormone (bbPTH) has been implicated in the maintenance of bone properties during extended periods of disuse (hibernation). We cloned bbPTH and found 9 amino acid residue differences from human PTH. Apoptosis was mitigated and cAMP was activated by bbPTH in osteoblast cultures. We administered 28nmol/kg of bbPTH 1-84 to 4-week old male mdx and wild type mice via daily (5×/week) subcutaneous injection for 6 weeks. Vehicle-treated mdx mice had 44% lower trabecular bone volume fraction than wild type mice. No changes were found in femoral cortical bone geometry or mechanical properties with bbPTH treatment in wild type mice, and only medio-lateral moment of inertia changed with bbPTH treatment in mdx femurs. However, ?CT analyses of the trabecular regions of the distal femur and proximal tibia showed marked increases in bone volume fraction with bbPTH treatment, with a greater anabolic response (7-fold increase) in mdx mice than wild type mice (2-fold increase). Trabecular number increased in mdx long bone, but not wild type bone. Additionally, greater osteoblast area and decreased osteoclast area were observed with bbPTH treatment in mdx mice. The heightened response to PTH in mdx bone compared to wild type suggests a link between dystrophin deficiency, altered calcium signaling, and bone. These findings support further investigation of PTH as an anabolic treatment for DMD-induced osteoporosis. PMID:22584007

Gray, Sarah K; McGee-Lawrence, Meghan E; Sanders, Jennifer L; Condon, Keith W; Tsai, Chung-Jui; Donahue, Seth W



In Vitro & In Vivo Effect of Parathyroid Hormone Analogue (1-14) Containing ?-amino-iso-butyric Acid Residue (Aib)1,3  

PubMed Central

Firstly, parathyroid hormone (1-14) [PTH (1-14)] analogue containing various ?-amino-iso-butyric acid residue (Aib) was synthesized by exchanging the 1st and 3rd Ala residues of alpha carbon of PTH (1-14). This analogue revealed to have the quite tight and stable ?-helical structure using the nuclear magnetic resonance (NMR) analysis. The biological activities of these analogues were examined using a cAMP-generating assay in LLC-PK1 cell lines stably transfected with the wild- type human PTH1 receptor. Only the PTH analogue substituted with methyl moiety without acetylation showed significant cAMP generating action with 15.0 ± 3.414 of EC50. Then, we used an ovariectomized rat model system to compare the in vivo effects of parathyroid hormone analogue with that of PTH (1-84). Daily subcutaneous administration of the unacetylated Aib1,3PTH (1-14) for 5 weeks in 30 nM/kg subcutaneously with positive control group receiving PTH (1-84) with 8 nM/kg were performed. However, there was no significant change in spinal or femoral bone mineral density assessed by dual x-ray absorptiometry (DXA) in the Aib1,3PTH (1-14) group where definite increase of these parameters shown in the PTH (1-84) group (p < 0.001). Assessment of bone strength was evaluated with no significant differences among all groups. It was quite disappointing to see the actual discrepancies between the result of significant pharmacokinetic potency and the in vivo clinical effect of the Aib1,3PTH (1-14). However, there are several limitations to mention, such as the short duration of treatment, matter of dosage, and insufficient effect of tight ?-helical structures with absence of C-terminus. In conclusion, our findings suggest that unacetylated Aib1,3PTH (1-14) did not exhibit any anabolic effects at the bones of ovariectomized rats.

Rhee, Yumie; Lee, Weontae; Lee, Eun Jin; Ma, Suhyun; Park, So Young



Vitamin D Status During Puberty in French Healthy Male Adolescents  

Microsoft Academic Search

:   The vitamin D status was determined on one to four occasions either after summer (September–October) or after winter (March–April)\\u000a in 175 male adolescents (13–17 years), resulting in 394 measurements of serum 25-hydroxyvitamin D (25(OH)D) and intact parathyroid\\u000a hormone (iPTH). The subjects lived in a rural area to the north of Paris (49? N). After summer the 25(OH)D concentration was

J. Guillemant; P. Taupin; H. T. Le; N. Taright; A. Allemandou; G. Pérès; S. Guillemant



Substernal oxyphil parathyroid adenoma producing PTHrP with hypercalcemia and normal PTH level  

PubMed Central

Background Parathyroid adenoma is the most common cause of primary hyperparathyroidism. Preoperative serum calcium and intact-parathyroid hormone levels are the most useful diagnostic parameters that allow differentiating primary hyperparathyroidism from non-parathyroid-dependent hypercalcemia. Parathyroidectomy is the definitive treatment for primary hyperparathyroidism. Approximately 5% of patients who underwent parathyroidectomy present with persistent or recurrent hyperparathyroidism due to ectopic localization of the adenoma. Functioning oxyphil parathyroid adenoma is an uncommon histological form, seldom causing primary hyperparathyroidism. Parathyroid adenoma with hypercalcemia exhibiting normal parathyroid hormone level is rare. An incidence of 5% to 33% has been documented in the literature; no etiologic explanation has been given. In 1987, parathyroid-hormone-related peptide was isolated as a causative factor of humeral hypercalcemia of malignancy. The presence of parathyroid-hormone-related peptide in parathyroid tissue under normal and pathological conditions has been described in the literature; however, its role in causing hyperparathyroidism has not yet been defined. Case presentation We present a case of persistent hypercalcemia with a normal level of intact-parathyroid hormone due to a substernal parathyroid adenoma, treated with radioguided parathyroidectomy. The final histological diagnosis was oxyphil adenoma, positive for parathyroid-hormone-related peptide antigens. Conclusion In clinical practice, this atypical biochemical presentation of primary hyperparathyroidism should be considered in the differential diagnosis of hypercalcemia. The parathyroid-hormone-related peptide should be considered not only in the presence of malignancy.

Gurrado, Angela; Marzullo, Andrea; Lissidini, Germana; Lippolis, Agostino; Rubini, Domenico; Lastilla, Gaetano; Testini, Mario



Treatment of secondary hyperparathyroidism in CKD patients with cinacalcet and/or vitamin D derivatives.  


The discovery of the calcium-sensing receptor (CaR) 15 yr ago was rapidly followed by the development of drugs modulating its activity, the so-called calcimimetics (increasing the CaR signal) and calcilytics (decreasing the CaR signal). The indication for calcimimetics is treatment of primary and secondary hyperparathyroidism, whereas calcilytics have potential for treatment of osteoporosis. A large number of clinical studies has shown that cinacalcet, the only presently available calcimimetic, effectively reduces serum parathyroid hormone in dialysis patients with secondary hyperparathyroidism. In contrast to the effect of active vitamin D derivatives, it simultaneously decreases serum calcium and phosphorus. Experimental studies showed a concomitant decrease in parathyroid hyperplasia. In the treatment of secondary hyperparathyroidism of dialysis patients, important questions remain unresolved, for example, whether there are reasons to prefer calcimimetics to active vitamin D derivatives and whether combined administration offers advantages compared with calcimimetics or active vitamin D given in isolation. For lowering parathyroid hormone, available evidence from recent studies suggests that combination therapy should be preferred to single drug treatment because of less side-effects and greater efficacy in controlling parathyroid overfunction. Future randomized controlled trial must answer whether calcimimetics impact on cardiovascular events or survival and whether in this respect there are differences between vitamin D sterols and calcimimetics. PMID:19056615

Drüeke, Tilman B; Ritz, Eberhard



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

PubMed Central

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

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



Parathyroid Hormone-Related Protein (PTHrP): A Key Regulator of Life/Death Decisions by Tumor Cells with Potential Clinical Applications  

PubMed Central

Parathyroid hormone-related protein (PTHrP), classically regarded as the mediator of the humoral hypercalcemia of malignancy syndrome, is a polyhormone that undergoes proteolytic processing into smaller bioactive forms. These bioactive forms comprise an N-terminal-as well as midregion-and C-terminal peptides, which have been shown to regulate various biological events, such as survival, proliferation and differentiation, in diverse cell model systems, both normal and pathological. A number of experimental data have demonstrated that PTHrP is also able to modulate tumor-relevant phenotypic expressions, thereby playing a role in early and advanced tumorigenesis, and in the response to treatment. In particular, interest has mainly been focused on the effects of PTHrP on cell proliferation/apoptosis, migration and invasion, which are the main roles involved in cancer development in vivo. The objective of this review is to discuss collectively the literature data on the molecular and biochemical basis of the mechanisms underlying the different, and sometimes opposite, effects exerted by PTHrP on various neoplastic cytotypes, with some final comments on both present and potential utilization of PTHrP as a target for anti-cancer therapy.

Luparello, Claudio



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

SciTech Connect

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.

Kream, B.E.; Petersen, D.N.; Raisz, L.G. (Univ. of Connecticut Health Center, Farmington (USA))



Osteoporosis-like changes in Walker carcinoma 256-bearing rats, not accompanied with hypercalcemia or parathyroid hormone-related protein production.  


Walker carcinoma 256 (W256) was reported to induce hypercalcemia dependent on bone metastasis and/or parathyroid hormone-related protein (PTHrP) in the rat, providing a model of the humoral hypercalcemia of malignancy. In this study, after the subcutaneous inoculation of cells of the W256/S line, which is maintained in this laboratory, into young female Wistar Imamichi rats (6 weeks old), serum calcium and phosphorus levels changed only within the control range, whereas serum alkaline phosphatase activity and urinary calcium level significantly increased and urinary phosphorus decreased during the tumor growth, resulting in hypercalciuria and hypophosphaturia. W256/S did not express PTHrP-mRNA, whereas LLC-W256 cells did express it. Serum PTHrP level was not changed in W256/S-bearing rats. Osteoporosis-like changes, bone weight loss, low contents of bone calcium and phosphorus, and a decrease in the bone mineral density (BMD), were observed in the femur 14 days after the tumor inoculation. There was a pronounced decrease in the serum 17 beta-estradiol level during the tumor growth. The reduction of BMD of femurs in W256/S-bearing rats was significantly inhibited by treatment with salmon calcitonin or 17 beta-estradiol. On the basis of these results, W256/S carcinoma-bearing rats seem to be a useful model for osteoporosis of hypoovarianism. PMID:7540609

Waki, Y; Miyamoto, K; Kasugai, S; Ohya, K



Hypercalcemia in childhood acute lymphoblastic leukemia: frequent implication of parathyroid hormone-related peptide and E2A-HLF from translocation 17;19.  


Hypercalcemia is relatively rare but clinically important complication in childhood leukemic patients. To clarify the clinical characteristics, mechanisms of hypercalcemia, response to management for hypercalcemia, incidence of t(17;19) and final outcome of childhood acute lymphoblastic leukemia (ALL) accompanied by hypercalcemia, clinical data of 22 cases of childhood ALL accompanied by hypercalcemia (>12 mg/dl) reported in Japan from 1990 to 2005 were retrospectively analyzed. Eleven patients were 10 years and older. Twenty patients had low white blood cell count (<20 x 10(9)/l), 15 showed hemoglobin> or =8 g/dl and 14 showed platelet count > or =100 x 10(9)/l. Parathyroid hormone-related peptide (PTHrP)-mediated hypercalcemia was confirmed in 11 of the 16 patients in whom elevated-serum level or positive immunohistochemistry of PTHrP was observed. Hypercalcemia and accompanying renal insufficiency resolved quickly, particularly in patients treated with bisphosphonate. t(17;19) or add(19)(p13) was detected in five patients among 17 patients in whom karyotypic data were available, and the presence of E2A-HLF was confirmed in these five patients. All five patients with t(17;19)-ALL relapsed very early. Excluding the t(17;19)-ALL patients, the final outcome of ALL accompanied by hypercalcemia was similar to that of all childhood ALL patients, indicating that the development of hypercalcemia itself is not a poor prognostic factor. PMID:17183364

Inukai, T; Hirose, K; Inaba, T; Kurosawa, H; Hama, A; Inada, H; Chin, M; Nagatoshi, Y; Ohtsuka, Y; Oda, M; Goto, H; Endo, M; Morimoto, A; Imaizumi, M; Kawamura, N; Miyajima, Y; Ohtake, M; Miyaji, R; Saito, M; Tawa, A; Yanai, F; Goi, K; Nakazawa, S; Sugita, K



Interaction of a farnesylated protein with renal type IIa Na/Pi co-transporter in response to parathyroid hormone and dietary phosphate.  

PubMed Central

Treatment with PTH (parathyroid hormone) or a high-P(i) diet causes internalization of the type IIa sodium-dependent phosphate (Na/P(i) IIa) co-transporter from the apical membrane and its degradation in the lysosome. A dibasic amino acid motif (KR) in the third intracellular loop of the co-transporter is essential for protein's PTH-induced retrieval. To elucidate the mechanism of internalization of Na/P(i) IIa, we identified the interacting protein for the endocytic motif by yeast two-hybrid screening. We found a strong interaction of the Na/P(i) IIa co-transporter with a small protein known as the PEX19 (human peroxisomal farnesylated protein; PxF, Pex19p). PEX19 can bind to the KR motif, but not to a mutant with this motif replaced with NI residues. PEX19 is highly expressed in mouse and rat kidney. Western blot analysis indicates that PEX19 is located in the cytosolic and brush-border membrane fractions (microvilli and the subapical component). Overexpression of PEX19 stimulated the endocytosis of the Na/P(i) IIa co-transporter in opossum kidney cells in the absence of PTH. In conclusion, the present study indicates that PEX19 may be actively involved in controlling the internalization and trafficking of the Na/P(i) IIa co-transporter.

Ito, Mikiko; Iidawa, Sachi; Izuka, Michiyo; Haito, Sakiko; Segawa, Hiroko; Kuwahata, Masashi; Ohkido, Ichiro; Ohno, Hiroshi; Miyamoto, Ken-Ichi



Parathyroid hormone PTH(1-34) increases the volume, mineral content, and mechanical properties of regenerated mineralizing tissue after distraction osteogenesis in rabbits  

PubMed Central

Background and purpose Parathyroid hormone (PTH) has attracted considerable interest as a bone anabolic agent. Recently, it has been suggested that PTH can also enhance bone repair after fracture and distraction osteogenesis. We analyzed bone density and strength of the newly regenerated mineralized tissue after intermittent treatment with PTH in rabbits, which undergo Haversian bone remodeling similar to that in humans. Methods 72 New Zealand White rabbits underwent tibial mid-diaphyseal osteotomy and the callus was distracted 1 mm/day for 10 days. The rabbits were divided into 3 groups, which received injections of PTH 25 µg/kg/day for 30 days, saline for 10 days and PTH 25 µg/kg/day for 20 days, or saline for 30 days. At the end of the study, the rabbits were killed and the bone density was evaluated with DEXA. The mechanical bone strength was determined by use of a 3-point bending test. Results In the 2 PTH-treated groups the regenerate callus ultimate load was 33% and 30% higher, absorbed energy was 100% and 65% higher, BMC was 61% and 60% higher, and callus tissue volume was 179% and 197% higher than for the control group. Interpretation We found that treatment with PTH during distraction osteogenesis resulted in substantially higher mineralized tissue volume, mineral content, and bending strength. This suggests that treatment with PTH may benefit new bone formation during distraction osteogenesis and could form a basis for clinical application of this therapy in humans.



AU-rich elements in the 3'-UTR regulate the stability of the 141 amino acid isoform of parathyroid hormone-related protein mRNA.  


We demonstrated previously that parathyroid hormone-related protein (PTHrP) 1-141 mRNA is the least stable of three isoforms and is the only isoform that is stabilized by TGF-?. In order to understand how PTHrP mRNA is stabilized by TGF-?, we first sought to elucidate the mechanism(s) that are responsible for the instability of PTHrP isoform 1-141 mRNA. The 3'-UTR of isoform 1-141 contains four AU-rich elements (AREs), which are known to mediate mRNA degradation. We utilized a luciferase reporter system to test whether these four AREs are responsible for the short half-life of PTHrP 1-141 mRNA. Our results demonstrated that ARE elements in the 3'-UTR of PTHrP 1-141 mRNA play a significant role in regulation of the stability of the mRNA. It is known that AREs mediate their effects on mRNA stability through a number of ARE-binding proteins that recruit the exosome, a complex of exonucleases that degrades the mRNA. We identified tristetraproline (TTP) as an RNA-binding protein that may be involved in ARE-mediated degradation of PTHrP 1-141 mRNA. PMID:22960231

Luchin, Alexander I; Nadella, Murali V P; Thudi, Nanda K; Dirksen, Wessel P; Gulati, Parul; Fernandez, Soledad A; Rosol, Thomas J



Dietary boron supplementation enhanced the action of estrogen, but not that of parathyroid hormone, to improve trabecular bone quality in ovariectomized rats.  


This study investigated whether boron would enhance the ability of 17beta-estradiol (E2) or parathyroid hormone (PTH) to improve bone quality in ovariectomized OVX rats. Adult OVX rats were treated for 5 wk with vehicle, boron (5 ppm as boric acid), E2 (30 microg/kg/d, sc), PTH (60 microg/kg/d, sc), or a combination of boron and E2 or PTH, respectively. The E2 treatment corrected many adverse effects of OVX on bone quality, increased bone Ca, P, and Mg contents, and decreased trabecular plate separation. Dietary boron supplementation had no effects on these bone parameters in OVX rats. When OVX rats were treated with boron and E2 together, trabecular bone volume (Tb.BS/TV) and plate density were increased significantly more than that caused by E2 alone. The boron and E2 combination also increased trabecular bone surface (Tb.BV/TV) and decreased trabecular plate separation in OVX rats. In contrast, whereas daily PTH injection also increased bone Ca, Mg, and P contents, Tb.BV/TV, Tb.BS/TV, trabecular plate density and thickness, and decreased trabecular plate separation in OVX rats, the combination of boron and PTH had no additional improvement in bone quality over that achieved by PTH alone. In summary, this study shows for the first time that boron enhanced the action of E2, but not that of PTH, to improve trabecular bone quality in OVX rats. PMID:11697760

Sheng, M H; Taper, L J; Veit, H; Qian, H; Ritchey, S J; Lau, K H



Parathyroid hormone and lipopolysaccharide induce murine osteoblast-like cells to secrete a cytokine indistinguishable from granulocyte-macrophage colony-stimulating factor.  

PubMed Central

Osteoblasts are the cells responsible for the secretion of collagen and ultimately the formation of new bone. These cells have also been shown to regulate osteoclast activity by the secretion of cytokines, which remain to be defined. In an attempt to identify these unknown cytokines, we have induced primary murine osteoblasts with two bone active agents, parathyroid hormone (PTH) and lipopolysaccharide (LPS) and analyzed the conditioned media (CM) for the presence of specific cytokines. Analysis of the CM was accomplished by functional, biochemical, and serological techniques. The data indicate that both PTH and LPS are capable of inducing the osteoblasts to secrete a cytokine, which by all of the techniques used, is indistinguishable from granulocyte-macrophage colony-stimulating factor (GM-CSF). Secretion of GM-CSF is not constitutive and requires active induction. Production of the cytokine is dependent on the dose of PTH or LPS added. It has been demonstrated that the addition of GM-CSF to bone marrow cultures results in the formation of increased numbers of osteoclasts. Therefore, these data suggest that osteoblasts not only participate in bone remodeling by formation of new matrix but may regulate osteoclast activity indirectly by their ability to regulate hematopoiesis. Images

Horowitz, M C; Coleman, D L; Flood, P M; Kupper, T S; Jilka, R L



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

PubMed Central

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-?1. 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.

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



Antagonist Minigenes Identify Genes Regulated by Parathyroid Hormone Through G Protein-Selective and G Protein Co-regulated Mechanisms in Osteoblastic Cells  

PubMed Central

Parathyroid hormone (PTH) is the major hormone regulating bone remodeling. Binding of PTH to the PTH1 receptor (PTH1R), a heterotrimeric G protein coupled receptor (GPCR), can potentially trigger multiple signal transduction pathways mediated through several different G proteins. In this study, we employed G protein antagonist minigenes inhibiting G?s, G?q or G?12 to selectively dissect out which of these G proteins were responsible for effects of PTH(1–34) in targeted signaling and osteogenesis arrays consisting of 159 genes. Among the 32 genes significantly regulated by 24 hr PTH treatment in UMR-106 osteoblastic cells, 9 genes were exclusively regulated through Gs, 6 genes were solely mediated through Gq, and 3 genes were only controlled through G12. Such findings support the concept that there is some absolute specificity in downstream responses initiated at the G protein level following binding of PTH to the PTH1R. On the other hand, 6 PTH-regulated genes were regulated by both Gs and Gq, 3 genes were regulated by both Gs and G12, and 3 genes were controlled by Gs, Gq and G12. These findings indicate potential overlapping or sequential interactions among different G protein-mediated pathways. In addition, two PTH-regulated genes were not regulated through any of the G proteins examined, suggesting additional signaling mechanisms may be involved. Selectivity was largely maintained over a 2 – 48 hour time period. The minigene effects were mimicked by downstream inhibitors. The dissection of the differential effects of multiple G protein pathways on gene regulation provides a more complete understanding of PTH signaling in osteoblastic cells.

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



Parathyroid carcinoma.  


Parathyroid carcinoma is a rare cause of hypercalcaemia due to primary hyperparathyroidism. Ninety five percent of parathyroid carcinomas are functional tumours. Surgery is the only potential curative treatment. This is a case of a 53 years lady, who presented with pathological fracture of femur, hypercalcaemia, deranged renal functions, change in voice, difficulty in swallowing and markedly raised parathormone levels. Doppler ultrasound localized an irregular mass at right lower gland. SESTAMIBI scan showed probability of adenoma in the region of right lower thyroid pole. Intra-operatively, tumour was found stuck to esophagus and right recurrent laryngeal nerve passing through it. Enlarged parathyroid gland was removed in toto along with the recurrent laryngeal nerve, right thyroid lobe and its isthmus. PMID:23217487

Gauhar, Tooba Mahmud; Shahzad, Noman; Mahmud, Tayyaba; Khwaja, Muhammad Azim



[Pathophysiology and classitication of parathyroidism].  


Hypoparathyroidism is characterized by decreased actions of parathyroid hormone (PTH) either by reduced secretion of or resistance to PTH. The understanding in the pathogenesis of hypoparathyroidism has been greatly increased by recent findings in genetic abnormalities of patients with hypoparathyroidism. A new classification of hypoparathyroidism based upon these genetic abnormalities is proposed, and a diagnostic approach to patients with hypoparathyroidism is summarized. PMID:17660612

Endo, Itsuro; Matsumoto, Toshio; Fukumoto, Seiji



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

PubMed Central

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.

Luong, Khanh vinh quoc; Nguyen, Lan Thi Hoang



Autoregulation in the parathyroid glands by PTH\\/PTHrP receptor ligands in normal and uremic rats  

Microsoft Academic Search

Autoregulation in the parathyroid glands by PTH\\/PTHrP receptor ligands in normal and uremic rats.BackgroundThe secretion of parathyroid hormone (PTH) from the parathyroid glands might be regulated by autocrine\\/paracrine factors. We have previously shown that N-terminal parathyroid hormone-related protein (PTHrP) enhanced the secretory PTH response to low calcium in vivo and in vitro in rat parathyroid glands. N-terminal PTHrP fragments are

Ewa Lewin; Bartolome Garfia; Yolanda Almaden; Mariano Rodriguez; Klaus Olgaard



Distinct Calcium Channel Isoforms Mediate Parathyroid Hormone and Chlorothiazide-stimulated Calcium Entry in Transporting Epithelial Cells  

Microsoft Academic Search

.   Some cells express multiple calcium channel isoforms that are likely to have distinct functions. The present study used molecular\\u000a cloning and antisense techniques to identify calcium channel isoforms mediating calcium entry in mouse distal convoluted tubule\\u000a (DCT) cells. The DCT is the major site of hormone- and diuretic-regulated calcium transport in the kidney. Cellular calcium\\u000a absorption involves entry through

E. L. R. Barry; F. A. Gesek; A. S. L. Yu; J. Lytton; P. A. Friedman



Regulation of 1,25-dihydroxyvitamin D3 receptor gene expression by 1,25-dihydroxyvitamin D3 in the parathyroid in vivo.  

PubMed Central

1,25-Dihydroxyvitamin D3 (1,25(OH)2D3 dramatically decreases parathyroid hormone (PTH) gene transcription. We have now studied the effect of 1,25(OH)2D3 on the 1,25(OH)2D receptor (VDR) in the parathyroid in vivo. Rats were injected with 1,25(OH)2D3 and the parathyroid-thyroid tissue analyzed for PTHmRNA and VDRmRNA. 1,25(OH)2D3 (50 and 100 pmol ip) decreased PTHmRNA at 6 h with a maximum at 48 h (less than 4% of basal), whereas VDRmRNA was increased only after 6 h with a 1.7-fold increase at 24 h. VDRmRNA levels peaked at 25 pmol 1,25(OH)2D3 with a twofold increase. Serum calcium did not affect VDRmRNA. Parathyroid VDRmRNA ran at 2.2 and 4.4 kb, whereas duodenum VDRmRNA had a single band, all of which increased after 1,25(OH)2D3. Weanling rats on a vitamin D-deficient diet for 3 wk had a more intense 2.2-kb transcript, whereas vitamin D-replete rats had a more intense 4.4-kb band. Dispersed parathyroid-thyroid cells were separated by a flow cytometry (FACS) into a parathyroid cell peak containing PTHmRNA and a second peak with cells positive for thyro-globulin mRNA and calcitonin mRNA. VDRmRNA was concentrated in the parathyroid cell peak. In situ hybridization of parathyroid-thyroid and duodenum for VDRmRNA showed its localization to the parathyroid cells and the duodenal mucosa. Therefore, the VDRmRNA in the parathyroid-thyroid tissue represents predominantly parathyroid cell and not C-cell VDRmRNA which is also a 1,25(OH)2D3 target organ. The increased VDR gene expression in the parathyroid cell would amplify the effect of 1,25(OH)2D3 to decrease PTH gene transcription. Images

Naveh-Many, T; Marx, R; Keshet, E; Pike, J W; Silver, J



Parathyroid cancer  


... people older than 30. The cause of parathyroid cancer is unknown. People with a genetic condition called multiple endocrine neoplasia type I have an increased risk for this disease. People who had head or neck radiation may also be at increased risk. Such ...


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


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

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



Relationship between vitamin D deficiency and cardiovascular disease  

PubMed Central

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.

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



Relationship Between Disease Activity and Serum Levels of Vitamin D Metabolites and Parathyroid Hormone in Ankylosing Spondylitis  

Microsoft Academic Search

:   Vertebral fractures due to osteoporosis are a common but frequently unrecognized complication of ankylosing spondylitis (AS)\\u000a and various factors may contribute to the development of osteoporosis in AS. It is known that inflammatory activity in rheumatic\\u000a disease (i.e., proinflammatory cytokines) itself plays a possible role in the pathophysiology of bone loss. 1,25-Dihydroxyvitamin\\u000a D3 (1,25(OH)2D3) seems to be another possible

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



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?  


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 PMID:24002093

Havens, Peter L; 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; Mulligan, Kathleen



Effects of different dosages of parathyroid hormone-related protein 1-34 on the bone metabolism of the ovariectomized rat model of osteoporosis.  


Intermittent and low-dose parathyroid hormone (PTH) injection to stimulate bone formation has been used in the treatment of osteoporosis. The N-terminal fragment 1-34 of PTH is quite similar in structure and function to N-terminal PTH-related protein (PTHrP). PTH(1-34) and PTHrP also share a coreceptor, the PTH/PTHrP receptor. Therefore, some studies have suggested that PTHrP could effectively stimulate bone formation, similar to PTH. We used an ovariectomized (OVX) rat model of osteoporosis to study the effects of PTHrP(1-34) on bone metabolism by measuring bone mineral density (BMD), bone histomorphometrics, and biomechanical parameters. We found that subcutaneous injection of PTHrP(1-34) (40 or 80 ?g/kg body weight every day) in OVX rats increased lumbar and femoral BMD, improved bone biomechanical properties, enhanced bone strength, and promoted bone formation. We selected 40 ?g/kg as the preferred therapeutic dose of PTHrP(1-34) and investigated the effects of frequency of treatment (per 1, 2, 3, or 7 days) on bone metabolism in OVX rats. We found that injection of PTHrP(1-34) once per day or every other day significantly improved the BMD and strength of OVX rats. Serum calcium and phosphate levels in all treated rats did not vary significantly from control rats. Based on our results, intermittent low-dose PTHrP(1-34) injection promoted bone formation in OVX rats, suggesting a high potential for therapeutic use in osteoporosis patients. PMID:23807531

Xu, Jin; Rong, Haiqin; Ji, Hong; Wang, Dong; Wang, Jie; Zhang, Wenwen; Zhang, Yanling



Effect of Human Parathyroid Hormone on Hematopoietic Progenitor Cells in NOD/SCID Mice Co-Transplanted with Human Cord Blood Mononuclear Cells and Mesenchymal Stem Cells  

PubMed Central

Purpose We evaluated the effect of human parathyroid hormone (hPTH) on the engraftment and/or in vivo expansion of hematopoietic stem cells in an umbilical cord blood (UCB)-xenotransplantation model. In addition, we assessed its effect on the expression of cell adhesion molecules. Materials and Methods Female NOD/SCID mice received sublethal total body irradiation with a single dose of 250 cGy. Eighteen to 24 hours after irradiation, 1×107 human UCB-derived mononuclear cells (MNCs) and 5×106 human UCB-derived mesenchymal stem cells (MSCs) were infused via the tail vein. Mice were randomly divided into three groups: Group 1 mice received MNCs only, Group 2 received MNCs only and were then treated with hPTH, Group 3 mice received MNCs and MSCs, and were treated with hPTH. Results Engraftment was achieved in all the mice. Bone marrow cellularity was approximately 20% in Group 1, but 70-80% in the hPTH treated groups. Transplantation of MNCs together with MSCs had no additional effect on bone marrow cellularity. However, the proportion of human CD13 and CD33 myeloid progenitor cells was higher in Group 3, while the proportion of human CD34 did not differ significantly between the three groups. The proportion of CXCR4 cells in Group 3 was larger than in Groups 1 and 2 but without statistical significance. Conclusion We have demonstrated a positive effect of hPTH on stem cell proliferation and a possible synergistic effect of MSCs and hPTH on the proportion of human hematopoietic progenitor cells, in a xenotransplantation model. Clinical trials of the use of hPTH after stem cell transplantation should be considered.

Lim, Yeon-Jung; Hwang, Kyoujung; Kim, Miyeon; Cho, Youl-Hee; Lee, Jong-Hwa



Loss of cancellous bone mass and connectivity in ovariectomized rats can be restored by combined treatment with parathyroid hormone and estradiol.  

PubMed Central

To evaluate the potential use of a combination of antiresorption and bone formation-promoting agents as a treatment for postmenopausal osteoporosis, we examined the effects of combined and separate administration of estrogen (17 beta-estradiol, 30 micrograms/kg per d, s.c.) and parathyroid hormone (rPTH [1-34], 40 micrograms/kg per d, s.c.) on the proximal tibia of ovariectomized (Ovx) rats. The treatments lasted for 4 wk and were initiated 1, 3, and 5 wk after surgery. Ovx resulted in rapid loss of cancellous bone volume (Cn-BV/TV) as well as trabecular connectivity, as determined by two dimensional strut analysis. When administered in a preventive mode, treatment beginning 1 wk post-Ovx, estrogen or PTH treatment alone preserved Cn-BV/TV and trabecular connectivity, and combined estrogen and PTH treatment caused a 40% increment in Cn-BV/TV while maintaining comparable trabecular connectivity with that seen in the Sham-operated animals. When administered in a curative mode to rats with established osteoporosis, treatments beginning 3 or 5 wk post-Ovx, estrogen or PTH treatment alone prevented further loss of connectivity and Cn-BV/TV, whereas the combined treatment resulted in as much as a 300% improvement in one of the parameters of trabecular connectivity, node to node strut length, and a 106% increase in Cn-BV/TV, with respect to the bone status at the initiation of treatment. The beneficial effects of this combined treatment derive from estrogen's ability to prevent accelerated bone resorption and, simultaneously, PTH's promotion of bone formation. These data demonstrate, in an animal model, that therapies can be devised to cure the skeletal defects associated with established osteoporosis.

Shen, V; Dempster, D W; Birchman, R; Xu, R; Lindsay, R



Collagen-targeting parathyroid hormone-related peptide promotes collagen binding and in vitro chondrogenesis in bone marrow-derived MSCs.  


Parathyroid hormone-related peptide (PTHrP) is an important inductive factor during chondrogenesis of mesenchymal stem cells (MSCs). PTHrP induces chondrogenesis and suppresses hypertrophy, yet the lack of an efficient delivery system limits its use for cartilage tissue engineering in clinical application. In this study, a peptide of 7 amino acids was first used to engineer PTHrP to construct a collagen-targeting system. This peptide functioned as a collagen-binding domain (CBD) to specially target the PTHrP to collagen. ELISA assay was used to determine the collagen-binding ability of CBD-PTHrP. The effect of CBD-PTHrP on chondrogenesis was measured by an in vitro pellet assay in bone marrow-derived MSCs (BM-MSCs). As expected, the CBD peptide promoted the binding of CBD-PTHrP to collagen when compared to NAT-PTHrP. Furthermore, the recombinant protein CBD-PTHrP induced the expression of COL2A1 and Sox-9, inhibited the expression of COL1A1 at the mRNA and protein levels as effectively as NAT-PTHrP. Safranin-O and immunohistochemistry for collagen types ?, ?, ? and Sox-9 generally paralleled qRT-PCR and western blotting findings with minor variations. In conclusion, our study demonstrated that CBD-PTHrP is a collagen-targeting system and promotes in vitro chondrogenesis in BM-MSCs. We suggest that this is an efficient delivery system for cartilage tissue engineering in clinical application. PMID:23254644

Wu, Xiao-Cheng; Huang, Bo; Wang, Jian; Li, Chang-Qing; Zhou, Yue



Genistein ameliorates parathyroid hormone-induced epithelial-to-mesenchymal transition and inhibits expression of connective tissue growth factor in human renal proximal tubular cells  

PubMed Central

Introduction Genistein, a soybean and soy-based product, has been reported to inhibit the growth of a wide range of cancer cells, but there is no evidence concerning its treatment of chronic kidney disease. The aim was to investigate whether genistein has potential to inhibit parathyroid hormone (PTH)-induced renal interstitial fibrosis. Material and methods Using human renal tubular epithelial HK-2 cells, ?-smooth muscle actin (?-SMA) was assessed by using immunofluorescence detection. ?-Smooth muscle actin, E-cadherin and connective tissue growth factor (CTGF) were measured by Western blot analysis. The promoter activity of the CTGF gene was examined by the luciferase reporter assay. Results When cells were treated with PTH (0.1 nM) for 48 h, ?-SMA protein expression was induced significantly, the protein expression of E-cadherin decreased substantially, and the promoter activity of the CTGF gene as well as its mRNA and protein expression levels increased (p < 0.01). Interestingly, genistein effectively inhibited PTH-induced ?-SMA expression, restored E-cadherin expression, decreased mRNA and protein expression of CTGF, and suppressed the promoter activity of CTGF in a dose-dependent manner. Conclusions Genistein has the ability to block the biomarker for renal transdifferentiation and epithelial-to-mesenchymal transition, ?-SMA, following PTH treatment and inhibit CTGF expression in human renal tubular epithelial cells; these might be important modes of actions that contribute to genistein anti-fibrogenic effects and may have great implications for its potential in clinical treatment of renal interstitial fibrosis.

Guo, Yunshan; Zhang, Aiping; Ding, Yaohai; Wang, Yanxia



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

PubMed Central

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-?. 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 ?-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.

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



Transcriptomic and proteomic analyses in bone tumor cells: Deciphering parathyroid hormone-related protein regulation of the cell cycle and apoptosis.  


Giant cell tumor of bone (GCT) is an aggressive skeletal tumor characterized by local bone destruction, high recurrence rates, and metastatic potential. Previous works in our laboratory, including functional assays, have shown that neutralization of parathyroid hormone-related protein (PTHrP) in the cell environment inhibits cell proliferation and induces cell death in GCT stromal cells, indicating a role for PTHrP in cell propagation and survival. The objective of this study was to investigate the global gene and protein expression patterns of GCT cells in order to identify the underlying pathways and mechanisms of neoplastic proliferation provided by PTHrP in the bone microenvironment. Primary stromal cell cultures from 10 patients with GCT were used in this study. Cells were exposed to optimized concentrations of either PTHrP peptide or anti-PTHrP neutralizing antiserum and were analyzed with both cDNA microarray and proteomic microarray assays in triplicate. Hierarchical clustering and principal component analyses confirmed that counteraction of PTHrP in GCT stromal cells results in a clear-cut gene expression pattern distinct from all other treatment groups and the control cell line human fetal osteoblast (hFOB). Multiple bioinformatics tools were used to analyze changes in gene/protein expression and identify important gene ontologies and pathways common to this anti-PTHrP-induced regulatory gene network. PTHrP neutralization interferes with multiple cell survival and apoptosis signaling pathways by triggering both death receptors and cell cycle-mediated apoptosis, particularly via the caspase pathway, TRAIL pathway, JAK-STAT signaling pathway, and cyclin E/CDK2-associated G1/S cell cycle progression. These findings indicate that