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

Delmez, James A.; Tindira, Carol A.; Grooms, Patricia; Dusso, Adriana; Windus, David W.; Slatopolsky, Eduardo

doi:10.1172/jci114022

Cited by 258 publications

(86 citation statements)

References 29 publications

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“…PTH and D3 are major hormones controlling extracellular fluid calcium concentrations, and interplay between the two hormones is complex. Previous work showed that D3 can downregulate PTH gene expression in the parathyroids (6,7,43). Given that bone is a major site of action of both PTH and D3, it was interesting to determine if D3 modulated the expression of PTHR in bone.…”

Section: Resultsmentioning

confidence: 99%

“…D3 also stimulates bone resorption and calcium release from bone and enhances calcium absorption in the intestine (3)(4)(5). D3 has been shown to downregulate expression of PTH in the parathyroid glands (6,7), whereas PTH promotes formation of active D3 by stimulating expression of 1α-hydroxylase activity in the kidney, converting the inactive 25-hydroxy precursor to the active 1α,25-dihydroxy form of D3 (8). PTH-related peptide (PTHrP) was first identified as a factor that mimics the action of PTH when overexpressed by a number of tumors (9)(10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Amizuka

Kwan²,

Goltzman³

et al. 1999

J. Clin. Invest.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Amizuka

Kwan²,

Goltzman³

et al. 1999

J. Clin. Invest.

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“…An important question is whether there are reasons to prefer one to the other, and whether combined administration offers advantages compared with each drug (or drug class) given in isolation. Potential arguments for the latter approach, which has been proposed by Levi and Silver (17), may be the findings that active vitamin D increases Ca ϩϩ sensitivity of the parathyroid (46) and that the CaR is regulated by vitamin D but not by calcium (47). In terms of PTH control, the efficacy of the two drug classes can be considered equal, although a recent meta-analysis cast some doubt on the consistent efficacy of vitamin D compounds in reducing PTH levels in patients with CKD (48).…”

Section: Role Of Cinacalcet and Vitamin D Derivatives In The Managemementioning

confidence: 99%

Treatment of Secondary Hyperparathyroidism in CKD Patients with Cinacalcet and/or Vitamin D Derivatives

Drüeke¹,

Ritz²

2009

Clinical Journal of the American Society of Nephrology

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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.

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“…A substantial reduction in the expression of the Ca ϩϩ -sensing receptor (CaR) protein and mRNA has been demonstrated in hyperplastic parathyroid glands from uremic patients (6,7). 1,25(OH) 2 D 3 dramatically decreases PTH gene transcription (8), and it has been proposed that this sterol also influences the sensitivity of the parathyroid cells to Ca ϩϩ (9). Changes in the vitamin D receptor (VDR) concentration of the parathyroids would allow for a modulation of the effect of 1,25(OH) 2 D 3 .…”

mentioning

confidence: 99%

Persistent Downregulation of Calcium-Sensing Receptor mRNA in Rat Parathyroids when Severe Secondary Hyperparathyroidism Is Reversed by an Isogenic Kidney Transplantation

Lewin¹,

Garfia

Recio

et al. 2002

Journal of the American Society of Nephrology

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Abstract. Experimental severe secondary hyperparathyroidism (HPT) is reversed within 1 wk after reversal of uremia by an isogenic kidney transplantation (KT) in the uremic rats. Abnormal parathyroid hormone (PTH) secretion in uremia is related to downregulation of CaR and vitamin D receptor (VDR) in the parathyroid glands (PG). The aim of this investigation was to examine the expression of CaR and VDR genes after reversal of uremia and HPT in KT rats. 5/6 nephrectomized rats were kept on a normal or high-phosphorus (hP) diet for 8 wk to induce severe HPT (n ϭ 8 in each group). In another group of seven uremic hP rats, uremia was reversed by an isogenic KT and PG were harvested within 1 wk posttransplant. Plasma urea, creatinine, total calcium, phosphorus, and PTH levels were measured. Parathyroid CaR and VDR mRNA were measured by quantitative PCR. Uremic hP rats had significantly elevated levels of creatinine, urea, and phosphorus (P Ͻ 0.001) and developed significant hypocalcemia (plasma calcium 1.83 Ϯ 0.2 mmol/L; P Ͻ 0.001) compared with normal control rats. After KT, the levels were normalized from day 3 to 7: creatinine from 0.117 Ϯ 0.016 to 0.050 Ϯ 0.002 mmol/L; urea from 23 Ϯ 4 to 7 Ϯ 0.3 mmol/L; phosphorus from 3.9 Ϯ 0.6 to 1.5 Ϯ 0.06 mmol/L; calcium from 1.8 Ϯ 0.2 to 2.5 Ϯ 0.02 mmol/L. Plasma PTH levels fell from 849 Ϯ 224 to a normal level of 38 Ϯ 9 pg/ml (P Ͻ 0.01). In uremic rats on a standard diet, CaR mRNA was similar to that of normal control rats, whereas VDR mRNA was significantly decreased. In uremic rats kept on hP diet, CaR mRNA was significantly decreased to 26 Ϯ 7% of control rats (P ϭ 0.01) and VDR mRNA reduced to 36 Ϯ 11% (P Ͻ 0.01). In KT, previously hP uremic rats, both CaR mRNA and VDR mRNA remained severely reduced (CaR, 39 Ϯ 7%; VDR, 9 Ϯ 3%; P Ͻ 0.01) compared with normal rats. In conclusion, circulating plasma PTH levels normalized rapidly after KT, despite persisting downregulation of CaR and VDR gene expression. This indicates that upregulation of CaR mRNA and VDR mRNA is not necessary to induce the rapid normalization of PTH secretion from hyperplastic parathyroid glands.In chronic uremia, the parathyroid gland (PG) function is abnormal, resulting in an increase in parathyroid hormone (PTH) biosynthesis and secretion and parathyroid cell hyperplasia (1,2,3). The molecular basis for the abnormal PTH secretion still remains partly obscure. It presumably involves dysfunction of the mechanism by which the parathyroid cells sense changes in plasma calcium (4). PG from patients with severe secondary or tertiary hyperparathyroidism (HPT) have an elevated set-point for Ca ϩϩ in vitro (5). A substantial reduction in the expression of the Ca ϩϩ -sensing receptor (CaR) protein and mRNA has been demonstrated in hyperplastic parathyroid glands from uremic patients (6,7). 1,25(OH) 2 D 3 dramatically decreases PTH gene transcription (8), and it has been proposed that this sterol also influences the sensitivity of the parathyroid cells to Ca ϩϩ (9). Changes in the vitamin D receptor (VDR) concent...

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

Cited by 258 publications

References 29 publications

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

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

Treatment of Secondary Hyperparathyroidism in CKD Patients with Cinacalcet and/or Vitamin D Derivatives

Persistent Downregulation of Calcium-Sensing Receptor mRNA in Rat Parathyroids when Severe Secondary Hyperparathyroidism Is Reversed by an Isogenic Kidney Transplantation

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