Destabilization of parathyroid hormone mRNA by extracellular Ca2+ and the calcimimetic R-568 in parathyroid cells: role of cytosolic Ca and requirement for gene transcription

Ritter, Cynthia S.; Pande, Sangeeta; Krits, Irina; Slatopolsky, Eduardo; Brown, Alex

doi:10.1677/jme-07-0085

Cited by 29 publications

(14 citation statements)

References 28 publications

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“…1, a 2-day treatment with 1a,25(OH) 2 D 3 reduced PTH secretion by over 90%. The slow rate of suppression is consistent with a transcriptional repression and relatively long half-life of Pth mRNA (Ritter et al 2008). Note that the reduction in PTH continued for 24 h after washout of the 1a,25(OH) 2 D 3 .…”

Section: Characterization Of Cultured Mouse Tptgssupporting

confidence: 64%

Direct Suppression of PTH Gene Expression by the Vitamin D Prohormones Doxercalciferol and Calcidiol Requires the Vitamin D Receptor

Ritter¹,

Brown²

2010

Journal of Molecular Endocrinology

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Vitamin D compounds regulate PTH at the transcriptional level, presumably via binding to the vitamin D receptor (VDR), but the exact mechanism is presently unclear. We recently reported that the several vitamin D prohormones with low VDR affinity suppressed PTH, even when their activation was inhibited, raising the possibility that their actions may be VDR independent. To test this hypothesis, we developed a novel organ culture that allowed the assessment of activities of the prohormones on PTH release from wild-type and VDR-null thyroparathyroid explants. The cultures remained viable with respect to PTH release for at least 2 weeks. Full suppression of PTH by the native vitamin D hormone, 1a,25-dihydroxyvitamin D 3 [1a,25 (OH) 2 D 3 ], required 2 days, consistent with a transcriptional mechanism, and was reversible, indicating that reduced PTH was not attributable to cell death. Inhibition of PTH release by 1a,25 (OH) 2 D 3 and two prohormones, 25-hydroxyvitamin D 3 and 1a-hydroxyvitamin D 2 , was observed in explants from wild-type mice but not in those from VDR-null mice. These findings 1) are the first direct demonstration of the role of the VDR in regulation of PTH by 1a,25(OH) 2 D 3 , 2) confirm that the suppressive actions of the vitamin D prohormones are mediated by the VDR, and 3) introduce a novel organ culture model that allows the ex vivo study of the function of parathyroid glands from transgenic animals.

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Section: Characterization Of Cultured Mouse Tptgssupporting

confidence: 64%

Direct Suppression of PTH Gene Expression by the Vitamin D Prohormones Doxercalciferol and Calcidiol Requires the Vitamin D Receptor

Ritter¹,

Brown²

2010

Journal of Molecular Endocrinology

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“…The absence of kidney function results in an extended terminal half life for AMG 416, indicating that the kidney is a major clearance organ for the peptide [5]. In contrast, the half-life of cinacalcet is independent of kidney function [11], as the main route of clearance is through hepatic mechanisms [12]. Consistent with the animal data and modeling PK studies, IV administration of AMG 416 to hemodialysis patients with SHPT resulted in dose-dependent, sustained control of PTH throughout the interdialytic period [6].…”

Section: Discussionmentioning

confidence: 99%

Comparison of AMG 416 and cinacalcet in rodent models of uremia

et al. 2014

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BackgroundAMG 416 is a novel peptide agonist of the calcium-sensing receptor (CaSR). This report describes the activity of AMG 416 in two different rodent models of uremia, compared in each case to cinacalcet, an approved therapeutic for secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease on dialysis.MethodsAMG 416 was administered as a single intravenous (IV) bolus in a severe, acute model of renal insufficiency (the “1K1C” model) and plasma parathyroid hormone (PTH) and serum calcium levels were monitored for 24 hours. In a chronic, less severe model of renal dysfunction, the 5/6 nephrectomy (5/6 Nx) model, AMG 416 was administered as a once-daily IV bolus for 28 days. Both studies included a control (vehicle) group and a comparison cinacalcet group (po dosing at 30 mg/kg and 10 mg/kg for the 1K1C and 5/6 Nx studies, respectively).ResultsAdministration of AMG 416 by IV bolus injection into rats with acute renal dysfunction (1K1C model) resulted in a sustained reduction in plasma PTH from the initial elevated values. Following a single IV bolus (0.5 mg/kg), AMG 416 caused a substantial drop in PTH levels which remained approximately 50% below their initial level at 24 hrs. In the same model, oral treatment with cinacalcet (30 mg/kg) resulted in an acute drop in PTH which almost returned to the starting level by 24 hours after dosing. In the 5/6 Nx chronic uremia model, daily IV dosing of AMG 416 over 4 weeks (1 mg/kg) resulted in a sustained reduction in PTH, with approximately 50% of the initial level observed 48 hours post treatment throughout the study. Cinacalcet treatment (10 mg/kg) in the same model resulted in acutely lowered plasma PTH levels which returned to placebo levels by 24 hours post-dose. Consistent with the reductions in plasma PTH, reductions in serum calcium were observed in both AMG 416- and cinacalcet-treated animals.ConclusionsAs a long-acting CaSR agonist suitable for administration by the IV route, AMG 416 is a potential new therapy for the treatment of CKD patients with SHPT receiving hemodialysis.

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“…There are recent data showing that CaR signaling decreases the level of PTH mRNA produced in parathyroid cells, suggesting an additional means by which the receptor limits the level of circulating PTH [52]. CaR-regulated reduction of PTH mRNA levels has been shown to require gene transcription and an increase in cytosolic calcium levels [53]. CaR is negatively regulate the proliferation of parathyroid cells based on the evidence of greater parathyroid hyperplasia associated with decreased CaR function, as seen in patients with neonatal severe hyperparathyroidism, or reduced expression in parathyroid adenomas [54].…”

Section: The Regulation Of Pth Synthesis and Secretionmentioning

confidence: 99%

An Update on the Structure of the Parathyroid Gland

Chen¹,

Senda²,

Emura³

et al. 2013

Open Anat J

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Abstract:The parathyroid glands hold a special place in human anatomy, since they were the last major organ to be recognized by humans. The glands are recognized in all vertebrate animals higher than fish, and are derived from the pharyngeal pouches. The molecular signaling pathways that are involved in determining the differentiation of the glands are being elucidated. Studies in mice have demonstrated that the transcription factor encoded by Glial cells missing 2 (Gcm2) is a key regulator of parathyroid development. Recent studies indicate that the tetrapod parathyroid glands and the gills of fish are evolutionarily related structures, and that the parathyroid glands likely come into being as a result of the transformation of the gills during tetrapod evolution. The parathyroid chief cells play a central role in calcium homeostasis by sensing changes in extracellular calcium and releasing parathyroid hormone (PTH) to correct or maintain normal blood calcium levels. Chief cells undergo morphologic changes corresponding to different stages of the secretory cycle. Parathyroid oxyphil cells derived from chief cells as aging or some metabolic derangements, have the potential to produce PTH, PTH-related protein, and calcitriol. The existence of water-clear cells is confirmed in some kinds of animals, which may represent hyperfunction of the parathyroid gland. The presence of water-clear cell is associated with parathyroid hyperplasia or parathyroid adenoma. The molecular regulation of PTH synthesis and release indicates that parathyroid cells detect changes of the extracellular calcium levels by calcium-sensing receptor, which plays a central role in regulating PTH secretion.

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Destabilization of parathyroid hormone mRNA by extracellular Ca2+ and the calcimimetic R-568 in parathyroid cells: role of cytosolic Ca and requirement for gene transcription

Cited by 29 publications

References 28 publications

Direct Suppression of PTH Gene Expression by the Vitamin D Prohormones Doxercalciferol and Calcidiol Requires the Vitamin D Receptor

Direct Suppression of PTH Gene Expression by the Vitamin D Prohormones Doxercalciferol and Calcidiol Requires the Vitamin D Receptor

Comparison of AMG 416 and cinacalcet in rodent models of uremia

An Update on the Structure of the Parathyroid Gland

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