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

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.     

Effects of pravastatin and cholestyramine on circulating levels of parathyroid hormone and vitamin D metabolites

The subjects were 40 hypercholesterolemic patients (mean age, 58 years) receiving a low-fat diet and randomly assigned to treatment with placebo for eight weeks or 40 or 80 mg of pravastatin, 24 gm of cholestyramine, or 40 mg of pravastatin plus 24 gm of cholestyramine daily for 24 weeks. After eight weeks of active treatment, levels of total and low-density lipoprotein cholesterol were significantly reduced and the decline was maintained for the remaining 16 weeks. Parathyroid hormone levels and levels of the vitamin D metabolites 1,25(OH)2D3 and 25(OH)D3 did not change during treatment. The results indicate that 24 weeks of treatment with pravastatin and cholestyramine does not affect calcium metabolism.     

Reversible resistance to the renal action of parathyroid hormone in human vitamin D deficiency

1. The response to exogenous parathyroid hormone (PTH) was tested in normal subjects and patients with osteomalacia due to vitamin D deficiency; 200 MRC units of bovine PTH were administered intravenously. 2. The rise in plasma adenosine 3':5'-cyclic monophosphate (cyclic AMP) and the increase in urinary excretion of cyclic AMP were reduced in the patients with vitamin D deficiency. After treatment with vitamin D the responses returned to normal. 3. It is suggested that this reversible resistance is due to the secondary hyperparathyroidism associated with vitamin D deficiency.     

Canine renal receptors for parathyroid hormone. Down-regulation in vivo by exogenous parathyroid hormone.

Chronic elevation of circulating parathyroid hormone (PTH) is associated with decreased target cell responsiveness to PTH. To study the subcellular mechanism of this phenomenon we evaluated PTH receptors and adenylate cyclase activity in renal cortical membranes prepared before and after infusion of bovine parathyroid gland extract (PTE) into thyroparathyroidectomized dogs. PTE infusion resulted in a 53% decrease in the number of high-affinity receptors (P less than 0.01) associated with a 66% decrease in PTH-stimulated adenylate cyclase (P less than 0.01) relative to paired base-line values. Both the equilibrium constant of dissociation (KD) for PTH binding and the concentration of PTH that caused half-maximal stimulation of adenylate cyclase were in the range of 1 to 4 nM, and were unaffected by the PTE infusion. Responsiveness of the renal adenylate cyclase to sodium fluoride was 88% of base-line values. Infusion of the PTE vehicle alone did not affect PTH receptor number or blunt the adenylate cyclase response to PTH. Pretreatment of the membranes made after PTE infusion with guanosine triphosphate (GTP), which is known to produce dissociation of receptor-bound PTH, failed to restore either receptor number or PTH-stimulated adenylate cyclase. This finding was not due to a lack of efficacy of the GTP pretreatment, because identical GTP pretreatment restored PTH binding to base-line values in membranes partially occupied by incubation with PTH in vitro. Thus, simple residual occupancy of PTH receptors by the infused hormone did not appear to account for the observed receptor loss. The results of this study suggest that target cell resistance to PTH in patients with hyperparathyroidism might occur, at least in part, due to down-regulation of PTH receptors by circulating hormone.     

Effects of ACE gene polymorphism on vitamin D therapy according to parathyroid hormone level in patients on hemodialysis

Medical management is still far from optimal in secondary hyperparathyroidism. This may be explained, at least in part, by genetic differences. The aim of this study was to evaluate the association of genetic influences of angiotensinconverting enzyme (ACE) gene polymorphisms with response to vitamin D therapy among patients on hemodialysis (HD). Eighty-two patients (female/male, 34/48; mean age, 47.5±15.3 y; HD duration time, 76.6±33.2 mo) with endstage renal disease who were on maintenance HD were included in the study. Five-year retrospective demographic, clinical, laboratory, and treatment data (5-y cumulative doses of phosphate-binding drugs and oral and intravenous cumulative doses of active vitamin D) were retrieved from patients’ hospital records. ACE gene polymorphisms of patients were documented and were used to group patients as follows: The insertion/deletion polymorphism group (I/D) consisted of (1) group non-DD (n=43), who had the DI or II allele, and (2) group DD (n=39), who had the DD allele. Patients with the DD allele (group DD) of ACE gene polymorphism had (1) significantly elevated mean 5-y intact parathyroid hormone levels when compared with the non-DD group (P=.009), and (2) significantly elevated oral and intravenous 5-y cumulative doses of vitamin D. Oral and intravenous 5-y cumulative doses of vitamin D used in group DD patients were significantly higher than those in group I patients (P=.038 and P=.037, respectively). Knowledge of genetic differences among patients on HD may be useful to the clinician in planning treatment strategy. ACE gene polymorphism may have an effect on hyperparathyroidism, as is seen in patients on HD. Patients from this group who have resistant hyperparathyroidism may be candidates for ACE inhibitor therapy     

Vasodilation of the rat mesenteric vasculature by parathyroid hormone

The isolated, perfused rat mesenteric vascular bed was used as a sensitive model of resistance vessel dynamics to evaluate the vascular actions of parathyroid hormone (PTH). Periarterial sympathetic nerve stimulation (PNS) was carried out at 8 Hz, 2 msec in pulse duration (supramaximal voltage) for 30 sec. The pressor response to PNS was decreased in a dose-dependent fashion by synthetic bovine PTH(1-34). Reduction of the PNS response was greater than 30% at 30 nM PTH. The concentration of PTH required to produce a half-maximal (ED50) decrease in PNS-induced tone was 4 nM. The phosphodiesterase inhibitor, methylisobutylxanthine, at 300 nM did not alter the PNS response when given alone, but potentiated PTH action. Isoproterenol (1 microM) decreased the PNS response by only 20%. Propranolol (1 microM) inhibited the effect of isoproterenol on the PNS response, but not that of PTH. The inhibitory analog of PTH, bPTH(7-34), blocked PTH action completely only at 30- to 50-fold higher concentrations than that of PTH. PTH also decreased the pressor response to norepinephrine infusion, similar to the effects on PNS. Again, bPTH(7-34) blocked the actions of PTH on norepinephrine vasoconstriction. These findings indicate that PTH has greater efficacy and potency for reducing PNS pressor activity in the mesenteric vasculature than isoproterenol and demonstrate that PTH has significant vascular effects at nanomolar concentrations.     

Parathyroid hormone-related protein, parathyroid hormone, and vitamin D in hypercalcemia of malignancy

The pathogenesis of cancer-associated hypercalcemia is not yet completely understood. In the majority of cancer patients, hypercalcemia appears to be a consequence of the tumor production of parathyroid hormone (PTH)-related protein (PTHrP). However, patients with humoral hypercalcemia of malignancy, in contrast to those with primary hyperparathyroidism, have an uncoupled bone turnover, and they usually have low circulating levels of 1,25(OH)₂D₃. We performed a case-control study to assess the relationship of plasma PTHrP, PTH and 1,25(OH)₂D₃ with hypercalcemia in cancer patients with a variety of tumors. Sixty of these patients had hypercalcemia, and 45 were normocalcemic. We measured PTHrP and PTH by immunoradiometric assay (Nichols), and 1,25(OH)₂D₃ by radioreceptor assay (Nichols), in plasma in both groups of cancer patients. Using a logistic regression analysis, we found that the higher PTHrP in plasma, the higher association with hypercalcemia occurred in these patients. In addition, the decreased plasma levels of PTH and 1,25(OH)₂D₃ in the majority of cancer patients were found to be significantly associated with hypercalcemia. Our results indicate that the combined determination of PTH, PTHrP and 1,25(OH)₂D₃ in plasma represents a more comprehensive approach to the investigation of hypercalcemia in cancer patients. Our data also support the role of PTHrP as a humoral factor responsible for hypercalcemia in these patients.     

甲状旁腺素、维生素D受体、雌激素受体基因多态对糖尿病患者骨密度的影响

目的探讨甲状旁腺素(PTH)基因多态与中国北方汉族人糖尿病患者骨密度的关系。分析维生素D受体(VDR)、雌激素受体(ER)基因多态性对PTH基因多态性与骨密度、骨量减少及骨质疏松关系的影响。方法运用PCR-RFLP技术检测1型糖尿病(T1DM)组54例、2型糖尿病(T2DM)组104例、健康对照(CON)组102例的中国北方汉族人PTH基因多态性。结果甲状旁腺素基因型和等位基因分布频率在T1DM组、T2DM组与CON组间差异无统计学意义(P0.05);DM患者Bb/bb基因型者发生骨量减少/骨质疏松的相对危险度增加(OR=2.8684)。联合VDR基因多态分析,Bbaa基因型组糖尿病患者并发骨量减少/骨质疏松的相对危险度增高(OR=4.3125);联合ER基因多态分析,bPxx基因型骨量减少/骨质疏松的相对危险度也增高(OR=4.0);联合分析PTH、VDR、ER基因型,同时存在3个或4个易感基因型者伴有骨量减少或骨质疏松,相对危险度增加(OR=5.5385)。结论糖尿病患者PTH基因多态性(BST B1位点)可能是预测骨量减少、骨质疏松易感性的遗传标志。联合VDR、ER基因多态有助于识别DM患者发生骨质疏松的高危人群。     

Reversal of skeletal resistance to parathyroid hormone in uremia by vitamin D metabolites: evidence for the requirement of 1,25(OH)2D3 and 24,25(OH)2D3.

This study evaluates the role of vitamin D metabolites in the genesis of the skeletal resistance to the calcemic action of PTH in uremia. The changes in serum calcium after infusion of 2 U of PTE per kilogram per hour for 8 hr were evaluated in thyroparathyroidectomized dogs before and after 1 and 3 days of acute uremia produced by bilateral nephrectomy. The animals received vitamin D metabolites during the 3 days of uremia. Supplementation of 0.68 microgram/day 1,25(OH)2D3 and 24R,25(OH)2D3 restored the calcemic response to PTE to normal. This is in contrast to only partial correction of the response to PTE by 1,25(OH)2D3 alone. Administration of 1.36 microgram/day 24R,25(OH)2D3 did not improve the calcemic response to PTE. The results indicate that (1) both 1,25(OH)2D3 and 24R,25(OH)2D3 are necessary for the complete reversal of the impaired calcemic response to PTE, (2) this effect is not due to the increase in the amount of the dihydroxylated compounds of vitamin D, since equivalent amounts of these compounds in the form of 24R,25(OH)2D3 alone had no effect, and (3) the better effect of the combination of 1,25(OH)2D3 and 24R,25(OH)2D3 is most probably due to an interaction between these two metabolites of vitamin D permitting an intact calcemic action of PTH.     

Correlations among serum calcium, vitamin D and parathyroid hormone levels in the elderly in southern Taiwan

This study correlates serum vitamin D levels to related hormones and dietary intakes among 57 elderly Chinese above the age of 65 who were living in the same community in rural Southern Taiwan (Pingtung) and who had no conditions or drug intake known to interfere with the metabolism of vitamin D. Demographic characteristics, past medical history, medications, and dietary intake were collected via questionnaires. Venous blood samples were collected for analyses of serum 25-hydroxyvitamin D (25(OH)D), parathyroid hormone (PTH) and calcium levels. Our results showed subjects in this study to have normal mean values of serum 25(OH)D, PTH and calcium levels. The mean serum 25(OH)D level was 36.21 (+/- 6.37) ng/ml, the mean serum PTH level 29.24 (+/- 18.62) pg/ml and the mean serum calcium level 9.14 (+/- 0.52) mg/dl. While the mean serum 25(OH)D and calcium values were not found to be significantly different between men and women, the mean serum PTH level was significantly higher in women (33.42 +/- 20.00 pg/ml) than in men (23.07 +/- 14.66 pg/ml) (p <.05), and serum PTH levels were significantly negatively correlated to serum calcium (r = -.33, p <.05) but not 25(OH)D (r = -.21). A higher intake of calcium was significantly associated with higher serum calcium levels (r =.29, p <.05), but not with serum 25(OH)D levels. Results from this study suggested that the elderly people living in Pingtung, a particularly sunny region, had normal serum 25(OH)D levels. The fact that the elderly women studied had higher serum PTH levels and that these levels were negatively correlated to serum calcium levels suggests that a higher PTH level in the elderly women may be related to susceptibility for osteoporosis. In an effort to provide optimal nursing care for the elderly by minimizing hip fractures and related morbidity, further nursing studies are needed to study the effects of the environment, dietary intake and bone metabolism.     

The metabolism of labeled parathyroid hormone. VI. Effects of vitamin D status.

Labeled 125I-PTH with full biological activity was utilized to investigate the interrelationship between vitamin D and parathyroid hormone (PTH) function. The distribution of labeled PTH was studied in rats and chickens on diets containing various amounts of vitamin D and calcium. The effects of vitamin D deficiency were found to be minor. There was a slightly delayed (10--30%) blood clearance of the hormone and a smaller deposition in the liver (20--30%) in the D-deficient animals. Deposition in bone and kidney appeared to be essentially normal. It is concluded that any failure of PTH to evoke a bone response in the deficient animal is not due to the failure of binding of hormone at the target organ.     

The interactions of thiazide diuretics with parathyroid hormone and vitamin D: Studies in patients with hypoparathyroidism

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.     

Effects of active vitamin D3 and parathyroid hormone on the serum osteocalcin in idiopathic hypoparathyroidism and pseudohypoparathyroidism.

Serum osteocalcin was measured in patients with idiopathic hypoparathyroidism or pseudohypoparathyroidism, before or during the treatment with active vitamin D3 (1,25(OH)2D3 or 1 alpha OHD3). Serum osteocalcin and plasma 1,25(OH)2D were decreased in 11 patients with idiopathic hypoparathyroidism before treatment (2.8 +/- 1.27 ng/ml, P less than 0.001 and 14.3 +/- 4.27 pg/ml, P less than 0.001, respectively). In 24 patients with idiopathic hypoparathyroidism during the treatment, serum osteocalcin and plasma 1,25(OH)2D were within the normal range (4.5 +/- 0.74 ng/ml and 25.7 +/- 5.69 pg/ml, respectively). In five patients with pseudohypoparathyroidism before treatment, plasma 1,25(OH)2D was decreased (15.6 +/- 10.6 pg/ml, P less than 0.001) but serum osteocalcin was normal (7.8 +/- 1.66 ng/ml). In nine patients with pseudohypoparathyroidism during the treatment with active vitamin D3, serum osteocalcin and plasma 1,25(OH)2D were normal (6.8 +/- 1.47 ng/ml and 27.2 +/- 6.0 pg/ml, respectively). Serum PTH in pseudohypoparathyroidism was increased before treatment (0.70 +/- 0.34 ng/ml, P less than 0.05) and was normal during the treatment (0.50 +/- 0.13 ng/ml). In idiopathic hypoparathyroidism, the active vitamin D3 increased serum osteocalcin without PTH. In pseudohypoparathyroidism, PTH may increase serum osteocalcin or modulate the effect of active vitamin D3 on serum osteocalcin.