Improved Screening Test for Idiopathic Infantile Hypercalcemia Confirms Residual Levels of Serum 24,25-(OH)2D3 in Affected Patients

Kaufmann, Martin; Morse, Nicole Erin; Molloy, Billy J.; Cooper, Donald P.; Schlingmann, Karl Peter; Molin, Arnaud; Kottler, Marie Laure; Gallagher, J. Christopher; Armas, Laura A.G.; Jones, Glenville

doi:10.1002/jbmr.3135

Cited by 55 publications

(56 citation statements)

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“…The effects of further decreases in Cyp24a1 expression were even more striking in M1-IKO, M1/M21-DIKO, and Cyp27b1-null mice, wherein 24,25(OH) 2 D 3 levels decreased rapidly to below the limits of detection (loss of synthesis) while 25(OH)D 3 levels continued to rise almost exponentially (loss of catabolism); the ratio of the two metabolites also continued to Cyp27b1-null mice all increased to well above 500. The results in the Cyp24a1-null mouse confirm a recent similar measurement in the same mutant mouse strain, a study that also included several humans with inactivating CYP24A1 mutations characteristic of idiopathic infantile hypercalcemia (13,39,40). Collectively, these results suggest that an additional role for renal Cyp24a1 may be to modulate actively the circulating levels of 25(OH)D 3 via degradation.…”

Section: The Role Of Cyp24a1 In the Regulation Of Circulating 25(oh)dsupporting

confidence: 84%

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A chromatin-based mechanism controls differential regulation of the cytochrome P450 gene Cyp24a1 in renal and non-renal tissues

Meyer

Lee

Carlson

et al. 2019

Journal of Biological Chemistry

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Edited by Joel M. GottesfeldCytochrome P450 family 27 subfamily B member 1 (CYP27B1) and CYP24A1 function to maintain physiological levels of 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) in the kidney. Renal Cyp27b1 and Cyp24a1 expression levels are transcriptionally regulated in a highly reciprocal manner by parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), and 1,25(OH) 2 D 3 . In contrast, Cyp24a1 regulation in nonrenal target cells (NRTCs) is limited to induction by 1,25(OH) 2 D 3 . Herein, we used ChIP-Seq analyses of mouse tissues to identify regulatory regions within the Cyp24a1 gene locus. We found an extended region downstream of Cyp24a1 containing a cluster of sites, termed C24-DS1, binding PTH-sensitive cAMP-responsive element-binding protein (CREB) and a cluster termed C24-DS2 binding the vitamin D receptor (VDR). VDR-occupied sites were present in both the kidney and NRTCs, but pCREB sites were occupied only in the kidney. We deleted each segment in the mouse and observed that although the overt phenotypes of both cluster deletions were unremarkable, RNA analysis in the C24-DS1-deleted strain revealed a loss of basal renal Cyp24a1 expression, total resistance to FGF23 and PTH regulation, and secondary suppression of renal Cyp27b1; 1,25(OH) 2 D 3 induction remained unaffected in all tissues. In contrast, loss of the VDR cluster in the C24-DS2-deleted strain did not affect 1,25(OH) 2 D 3 induction of renal Cyp24a1 expression yet reduced but did not eliminate Cyp24a1 responses in NRTCs. We conclude that a chromatin-based mechanism differentially regulates Cyp24a1 in the kidney and NRTCs and is essential for the specific functions of Cyp24a1 in these two tissue types.

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Section: The Role Of Cyp24a1 In the Regulation Of Circulating 25(oh)dsupporting

confidence: 84%

“…Serum 25(OH)D 3 , 24,25(OH) 2 D 3 , 1,25(OH) 2 D 3 , and 1,24,25(OH) 3 D 3 were quantified by LC-MS/MS using previously published methods (15,39,40), as recently reported (7).…”

Section: Quantification Of Serum Vitamin D Metabolitesmentioning

confidence: 99%

A chromatin-based mechanism controls differential regulation of the cytochrome P450 gene Cyp24a1 in renal and non-renal tissues

Meyer

Lee

Carlson

et al. 2019

Journal of Biological Chemistry

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“…Circulating FGF‐23 and α‐klotho was measured in duplicate using an ELISA (FGF‐23: Kainos Laboratories, Tokyo, Japan; Immutopics Inc.; α‐klotho: Immuno‐Biological Laboratories Co., Fujioka, Japan). Serum 1,25(OH) 2 ‐D 3 were measured by LC‐MS/MS …”

Section: Methodsmentioning

confidence: 99%

“…Serum 1,25(OH) 2 -D 3 were measured by LC-MS/MS. (16,17) Analyses Text values are represented as mean AE SD. Figure…”

Section: Human Methodsmentioning

confidence: 99%

Impaired Phosphate Tolerance Revealed With an Acute Oral Challenge

Turner

White

Hopman

et al. 2017

Journal of Bone and Mineral Research

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Elevated serum phosphate is consistently linked with cardiovascular disease (CVD) events and mortality in the setting of normal and impaired kidney function. However, serum phosphate does not often exceed the upper limit of normal until glomerular filtration rate (GFR) falls below 30 mL/min/m 2 . It was hypothesized that the response to an oral, bioavailable phosphate load will unmask impaired phosphate tolerance, a maladaptation not revealed by baseline serum phosphate concentrations. In this study, rats with varying kidney function as well as normo-phosphatemic human subjects, with inulin-measured GFR (13.2 to 128.3mL/min), received an oral phosphate load. Hormonal and urinary responses were evaluated over 2 hours. Results revealed that the more rapid elevation of serum phosphate was associated with subjects and rats with higher levels of kidney function, greater responsiveness to acute changes in parathyroid hormone (PTH), and significantly more urinary phosphate at 2 hours. In humans, increases in urinary phosphate to creatinine ratio did not correlate with baseline serum phosphate concentrations but did correlate strongly to early increase of serum phosphate. The blunted rise in serum phosphate in rats with CKD was not the result of altered absorption. This result suggests acute tissue deposition may be altered in the setting of kidney function impairment. Early recognition of impaired phosphate tolerance could translate to important interventions, such as dietary phosphate restriction or phosphate binders, being initiated at much higher levels of kidney function than is current practice.

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“…The ethanol eluate was evaporated to dryness and derivatized with 4-[2-(3,4-dihydro-6,7-dimethoxy-4-methyl-3-oxo-2-quinoxalinyl)ethyl]-3H-1,2,4-triazole-3.5-(4H)-dione (DMEQ-TAD) as described previously. The sample was re-dissolved in 50 l of mobile phase consisting of 50:50 (% by volume) methanol/water, and 35 l (110-l eq of serum) was injected into the LC-MS/MS system as described previously (68 …”

Section: Blood Chemistrymentioning

confidence: 99%

A kidney-specific genetic control module in mice governs endocrine regulation of the cytochrome P450 gene Cyp27b1 essential for vitamin D3 activation

Meyer

Benkusky

Kaufmann

et al. 2017

Journal of Biological Chemistry

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127

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The vitamin D endocrine system regulates mineral homeostasis through its activities in the intestine, kidney, and bone. Terminal activation of vitamin D 3 to its hormonal form, 1␣,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ), occurs in the kidney via the cytochrome P450 enzyme CYP27B1. Despite its importance in vitamin D metabolism, the molecular mechanisms underlying the regulation of the gene for this enzyme, Cyp27b1, are unknown. Here, we identified a kidney-specific control module governed by a renal cell-specific chromatin structure located distal to Cyp27b1 that mediates unique basal and parathyroid hormone (PTH)-, fibroblast growth factor 23 (FGF23)-, and 1,25(OH) 2 D 3 -mediated regulation of Cyp27b1 expression. Selective genomic deletion of key components within this module in mice resulted in loss of either PTH induction or FGF23 and 1,25(OH) 2 D 3 suppression of Cyp27b1 gene expression; the former loss caused a debilitating skeletal phenotype, whereas the latter conferred a quasi-normal bone mineral phenotype through compensatory homeostatic mechanisms involving Cyp24a1. We found that Cyp27b1 is also expressed at low levels in non-renal cells, in which transcription was modulated exclusively by inflammatory factors via a process that was unaffected by deletion of the kidney-specific module. These results reveal that differential regulation of Cyp27b1 expression represents a mechanism whereby 1,25(OH) 2 D 3 can fulfill separate functional roles, first in the kidney to control mineral homeostasis and second in extra-renal cells to regulate target genes linked to specific biological responses. Furthermore, we conclude that these mouse models open new avenues for the study of vitamin D metabolism and its involvement in therapeutic strategies for human health and disease.The vitamin D endocrine system serves to regulate mineral homeostasis through its actions in the intestine, kidney, and bone (1). Vitamin D 3 itself is sequentially activated via two specific chemical modifications that occur first in the liver by CYP2R1 to 25(OH)D 3 2 and then in the kidney by CYP27B1 to 1␣,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ), the active hormonal form of the vitamin (2). Blood levels of 1,25(OH) 2 D 3 are also determined by rates of catabolism that represent the primary function of CYP24A1 in the kidney (3). CYP27B1 is also expressed at low levels in many non-renal target cells (NRTCs), particularly those of skin and the immune system, where local production of 1,25(OH) 2 D 3 has been suggested to preferentially influence the many pleiotropic, non-calcemic functions of 1,25(OH) 2 D 3 (4, 5). Neither the mechanisms nor the overall biological impact of these non-renal cellular sources of 1,25(OH) 2 D 3 are clear, particularly in the context of circulating 1,25(OH) 2 D 3 , which is believed to be derived exclusively from the kidney. Despite these uncertainties, the regulated expression of Cyp27b1 and Cyp24a1 is well-recognized as central to the overall biological activity of the vitamin D endocrine system.Cyp27b1 expressi...

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Improved Screening Test for Idiopathic Infantile Hypercalcemia Confirms Residual Levels of Serum 24,25-(OH)2D3 in Affected Patients

Cited by 55 publications

References 24 publications

A chromatin-based mechanism controls differential regulation of the cytochrome P450 gene Cyp24a1 in renal and non-renal tissues

A chromatin-based mechanism controls differential regulation of the cytochrome P450 gene Cyp24a1 in renal and non-renal tissues

Impaired Phosphate Tolerance Revealed With an Acute Oral Challenge

A kidney-specific genetic control module in mice governs endocrine regulation of the cytochrome P450 gene Cyp27b1 essential for vitamin D3 activation

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