Regulation of Metabolism of 25-Hydroxycholecalciferol by Kidney Tissue in vitro by Dietary Calcium

Omdahl, John L.; Gray, Richard W.; Boyle, I. T.; Knutson, Joyce C.; DeLuca, Hector F.

doi:10.1038/newbio237063a0

Cited by 156 publications

(59 citation statements)

References 9 publications

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“…This is supported by the increased concentrations of renal cyp27B1 mRNA in sost KO mice compared with WT mice. This enzyme is regulated by PTH, FGF-23, and by the concentration of serum P (24,(26)(27)(28)(29)(30)(31). In sost KO mice, FGF-23 concentrations are reduced compared with those found in WT mice.…”

Section: Discussionmentioning

confidence: 89%

Sclerostin alters serum vitamin D metabolite and fibroblast growth factor 23 concentrations and the urinary excretion of calcium

Ryan¹,

Ketha²,

McNulty³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

118

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Inactivating mutations of the SOST (sclerostin) gene are associated with overgrowth and sclerosis of the skeleton. To determine mechanisms by which increased amounts of calcium and phosphorus are accreted to enable enhanced bone mineralization in the absence of sclerostin, we measured concentrations of calciotropic and phosphaturic hormones, and urine and serum calcium and inorganic phosphorus in mice in which the sclerostin (sost) gene was replaced by the β-D-galactosidase (lacZ) gene in the germ line. Knockout (KO) (sost −/− ) mice had increased bone mineral density and content, increased cortical and trabecular bone thickness, and greater net bone formation as a result of increased osteoblast and decreased osteoclast surfaces compared with wild-type (WT) mice. β-Galactosidase activity was detected in osteocytes of sost KO mice but was undetectable in WT mice. Eight-week-old, male sost KO mice had increased serum 1α,25-dihydroxyvitamin D, decreased 24,25-dihydroxyvitamin D, decreased intact fibroblast growth factor 23, and elevated inorganic phosphorus concentrations compared with age-matched WT mice. 25-Hydroxyvitamin D 1α-hydroxylase cytochrome P450 (cyp27B1) mRNA was increased in kidneys of sost KO mice compared with WT mice. Treatment of cultured proximal tubule cells with mouse recombinant sclerostin decreased cyp27B1 mRNA transcripts. Urinary calcium and renal fractional excretion of calcium were decreased in sost KO mice compared with WT mice. Sost KO and WT mice had similar serum calcium and parathyroid hormone concentrations. The data show that sclerostin not only alters bone mineralization, but also influences mineral metabolism by altering concentrations of hormones that regulate mineral accretion.S clerostin, an osteocyte-derived, secreted, cystine-knot protein inhibits bone formation by interacting with and altering the activity of bone morphogenetic proteins (BMPs), low-density lipoprotein-receptor-related protein 5 (LRP 5/6), cysteine-rich protein 61, the receptor tyrosine kinase v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (erb B3), among other proteins (1-12). Inactivating mutations in the human sclerostin gene (SOST) are associated with sclerosteosis (Mendelian Inheritance in Man, MIM 269500) or van Buchem disease (MIM 239100) (6), both of which are characterized by progressive overgrowth and sclerosis of the axial and appendicular skeleton and an increase in bone mineral density (6,13,14). These results are supported by data from sost knockout mice, which have markedly increased bone density (15-17).The physiological adaptations that occur in human sclerosteosis and mouse models of the disease that permit the increased accretion of calcium (Ca) and phosphorus (P) required for bone formation are unknown. For example, it is unknown whether sclerostin influences vitamin D metabolite concentrations, the concentrations of phosphaturic peptides such as fibroblast growth factor 23 (FGF-23), and the renal handling of calcium and phosphorus. It is important to understand the adaptations ...

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Section: Discussionmentioning

confidence: 89%

Sclerostin alters serum vitamin D metabolite and fibroblast growth factor 23 concentrations and the urinary excretion of calcium

Ryan¹,

Ketha²,

McNulty³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

118

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“…The need to defi ne the enzyme in biochemical terms became urgent as soon as it became apparent that the 25-hydroxyvitamin D-1 ␣ -hydroxylase was a central regulatory axis of the calcium and phosphate homeostatic systems, subject to upregulation by parathyroid hormone (PTH), low Ca 2+ , and low PO 4 3-levels ( 1,61,62 ). It was quickly recognized that serum 1,25-(OH) 2 D 3 was predominantly made in the kidney ( 3,63 ), with a PTH-regulated form located in the proximal convoluted tubule and a calcitonin-regulated form in the proximal straight tubule (64)(65)(66)(67).…”

Section: -Hydroxyvitamin D-1 ␣ -Hydroxylase (Cyp27b1)mentioning

confidence: 99%

Cytochrome P450-mediated metabolism of vitamin D

Jones

Prosser

Kaufmann

2014

Journal of Lipid Research

384

292

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signal transduction system, the DBP-knockout mouse is normocalcemic and exhibits normal tissue distribution of vitamin D metabolites and vitamin D action despite exhibiting very low blood levels of 1,25-(OH) 2 D 3 . This unexpected phenotype raised questions about DBP's exact role: essential transporter or buffer against toxicity ( 7,8 ). Work performed on the 25-hydroxylases over the past four decades in humans and a variety of animal species has revealed that several cytochrome P450 enzymes 2 (CYP), such as CYP2R1, CYP27A1, CYP3A4, CYP2D25, and perhaps others, are capable of 25-hydroxylation of vitamin D 3 or related compounds. These CYPs can be referred to as vitamin D 3 -25-hydroxylases, and it is CYP2R1 that is emerging as the physiologically relevant enzyme ( 9 ). On the other hand, there is no ambiguity over the second step of 1 ␣ -hydroxylation or the 25-OH-D 3 -1 ␣ -hydroxylase enzyme responsible, which is carried by a single cytochrome P450 2 named CYP27B1 ( 10-12 ). The inactivation of vitamin D is carried out by the mitochondrial enzyme, 25-hydroxyvitamin D 3 -24-hydroxylase, fi rst described in the early 1970s and initially believed to be involved solely in the renal 24-hydroxylation of 25-OH-D 3 ( 13 ). Work performed over the last 35 years has shown that 24-hydroxylase enzyme activity is the result of CYP24A1 ( 5, 14 ). CYP24A1 catalyzes the conversion of both 25-OH-D 3 and 1,25-(OH) 2 D 3 into a series of 24-and 23-hydroxylated products targeted for excretion along well-established pathways culminating in the water-soluble biliary metabolite calcitroic acid or a 26,23-lactone.This article assembles the most currently pertinent literature on the activating and inactivating enzymes of vitamin D metabolism and highlights protein structure and enzymatic properties, crystal structures, gene organization, and The activation of vitamin D 3 is accomplished by sequential steps of 25-hydroxylation to produce the main circulating form, 25-hydroxyvitamin D (25-OH-D 3 ), followed by 1 ␣ -hydroxylation to the hormonal form, 1 ␣ ,25-dihydroxyvitamin D 3 (1,25-(OH) 2 D 3 ) ( 1 ) ( Fig. 1 ). The initial step of 25-hydroxylation occurs in the liver ( 2 ), and the second step occurs both in the kidney and extrarenal sites ( 3, 4 ). The fat-soluble vitamin D and its metabolites are transported from one tissue to another on the vitamin D-binding protein (DBP), which shows different affi nity for the individual metabolites ( 5 ). The cell-surface receptor megalin-cubilin is thought to facilitate the endocytosis of a DBP-bound 25-OH-D 3 into a number of cell types, especially kidney cells ( 6 ). While it is widely believed that DBP is an essential component of the vitamin D

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“…The work from DeLuca's laboratory suggested a dominant role for calcium at first (9,10), then, more recently, for phosphate (11) in the long-term regulation of 250HD3 la-hydroxylase activity. It is not clear from their reports that much consideration was given to the interaction of calcium and phosphate in the regulation of 1,25 (OH)2Da production.…”

Section: Introductionmentioning

confidence: 99%

“…25-Hydroxyvitamin Ds (25OHDs) la-hydroxylase, the enzyme that produces 1,25(OH)2D8 from 25OHDa, is found exclusively in kidney mitochondria (8). Studies carried out in vivo have indicated that the rate of 1,25 (OH)2D8 production is regulated by changes in the plasma concentrations of calcium (9,10), phosphate (11), parathyroid hormone (12)(13)(14), and calcitonin (15). These studies have employed intact animals.…”

Section: Introductionmentioning

confidence: 99%

The ionic control of 1,25-dihydroxyvitamin D3 production in isolated chick renal tubules.

Bikle¹,

Rasmussen²

1975

J. Clin. Invest.

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A B S T R A C T Isolated renal tubules prepared from vitamin D-deficient chicks catalyze the la-hydroxylation of 25-hydroxyvitamin D8 (250HDs) in vitro. The effect of calcium and phosphate on the rate of synthesis of the product, 1,25-dihydroxyvitamin Da (1,25 (OH)2Ds), was studied at two levels: the long-term effects of various dietary calcium and phosphate contents on the ability of the tubules to produce 1,25 (OH)2Ds, and the acute effects of different calcium and phosphate concentrations in the incubation medium on the rate of synthesis of 1,25 (OH)2Ds by the tubules.Manipulation of dietary calcium and phosphate sufficient to produce marked changes in the concentration of calcium and phosphate in the serum led to altered rates of 1,25 (OH)2D8 synthesis by the isolated renal tubules.The renal tubules isolated from chicks raised on a vitamin D-deficient diet containing 0.43% calcium and 0.3% P as inorganic phosphate showed the highest rate of synthesis of 1,25 (OH)2Ds. Diets containing more or less of either calcium or phosphate produced chicks whose renal tubules had a slower rate of 1,25 (OH)2D8 production.The calcium, phosphate, and hydrogen ion content of the incubation medium were manipulated to determine the possible factors concerned with the immediate regulation of 1,25 (OH)2Ds production. A calcium concentration of 0.5-1.0 mM was necessary for optimal enzymatic activity. Concentrations of calcium greater than this optimal concentration inhibited 1,25 (OH)2D8 production if phosphate was also present, and this inhibition was more pronounced as the phosphate concentration was increased. The stimulation of 1,25 (OH)2Ds production by calcium was less at pH 6.7 than at 7.4. Raising the phosphate concentration from 0 to 6 mM in the absence of calcium also stimulated the rate of synthesis of 1,25-

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Regulation of Metabolism of 25-Hydroxycholecalciferol by Kidney Tissue in vitro by Dietary Calcium

Cited by 156 publications

References 9 publications

Sclerostin alters serum vitamin D metabolite and fibroblast growth factor 23 concentrations and the urinary excretion of calcium

Sclerostin alters serum vitamin D metabolite and fibroblast growth factor 23 concentrations and the urinary excretion of calcium

Cytochrome P450-mediated metabolism of vitamin D

The ionic control of 1,25-dihydroxyvitamin D3 production in isolated chick renal tubules.

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