Control of 25-Hydroxycholecalciferol Metabolism by Parathyroid Glands

Garabédian, M; Holick, Michael F.; DeLuca, Hector F.; Boyle, I. T.

doi:10.1073/pnas.69.7.1673

Cited by 615 publications

(221 citation statements)

References 24 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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“…While experiments to test this postulate have not been performed. nevertheless there is available recent evidence wvhich indicates that while TCT does, in fact, inhibit the conversion of 25HCC to 1,25DHCC, on the other hand, PTH and cAMP enhance this reaction (49,50). However, if 1,25DHCC must be further mnetabolized before the kidney-active derivative is formed (25), this hypothesis would have to be reevaluated.…”

Section: Discussionmentioning

confidence: 99%

Study of the Renal Tubular Interactions of Thyrocalcitonin, Cyclic Adenosine 3′, 5′ -Monophosphate, 25-Hydroxycholecalciferol, and Calcium Ion

Puschett¹,

Beck²,

Jelonek³

et al. 1974

J. Clin. Invest.

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A B S T R A C T Acute clearance studies were performed in thyroparathyroidectomized animals to determine the actions and interactions of thyrocalcitonin (TCT), cyclic adenosine 3'5'-monophosphate (cAMP), 25-hydroxycholecalciferol (25HCC), and calcium ion on the reabsorption of phosphate, calcium, sodium, and potassium by the kidney. The infusion of 25HCC in a dosage of 60 U/h to moderately saline-expanded animals (2.5% body weight) induced a fall in the excretion of all of the ions under study after 90-120 min similar to that observed in previous experiments from this laboratory. Mean decrements in fractional excretion were: phosphate, 42.0% (P < 0.005); calcium, 25.0% (P < 0.005); sodium, 23.4% (P < 0.001); and potassium, 14.7% (P < 0.005). The superimposition of either porcine or salmon TCT (1-100 MRC U/h for 2 h) resulted in no further alterations in electrolyte excretion. However, the infusion of TCT during steady-state saline expansion, before the administration of 25HCC, obviated the renal transport effects of the vitamin D metabolite. Both in the latter studies, as well as those in whiicl similar doses of TCT were given to hydropenic animnals, the hormone itself failed to induce any consistent alteration in electrolyte excretion. Cyclic AMP (50 mg/h) caused an increase in the excretion of phosphate, sodium, and potassium and no change in calcium excretion. Like TCT, the nucleotide blocked the action of 25HCC on the kidney. Raising the mean level of serum ultrafilterable calcium to 3.02±0.25 mEq/liter from 1.62±0

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“…In conditions of low serum calcium, the calcium-sensing receptor of the parathyroid gland stimulates PTH secretion (1). PTH increases circulating levels of 1,25(OH) 2 D 3 by increasing expression of the renal 25-hydroxyvitamin D 3 -1␣-hydroxylase (1␣-hydroxylase) gene (2,3), which encodes the enzyme responsible for the production of the vitamin D hormone. 1,25(OH) 2 D 3 exerts the biological actions of vitamin D by binding to the vitamin D receptor (VDR), a steroid͞thyroid hormone nuclear receptor, and regulating the transcription of target genes.…”

mentioning

confidence: 99%

Parathyroid hormone decreases renal vitamin D receptor expressionin vivo

Healy

Vanhooke²,

Prahl³

et al. 2005

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

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The vitamin D receptor (VDR) is a nuclear transcription factor responsible for mediating the biological activities of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. Renal and parathyroid gland VDR content is an important factor in calcium homeostasis, vitamin D metabolism, and the treatment of secondary hyperparathyroidism and renal osteodystrophy. In these tissues, VDR expression is highly regulated by the calcium and vitamin D status. Although 1,25(OH)2D3 up-regulates VDR expression, hypocalcemia and vitamin D deficiency result in drastically reduced expression of the receptor. The generation of 25-hydroxyvitamin D3-1␣-hydroxylase-null mice, which are incapable of endogenously producing 1,25(OH)2D3, has allowed us to investigate the influence of parathyroid hormone (PTH) on VDR expression independent of PTHmediated increases in 1,25(OH)2D3. Administration of human PTH (1-34) (110 g͞kg per day) for 48 h reduced renal VDR levels from 515 to 435 fmol͞mg protein (15%, P < 0.03) in wild-type mice. In the 25-hydroxyvitamin D3-1␣-hydroxylase-null mice, PTH administration strongly reduced renal VDR levels, from 555 to 394 fmol͞mg protein (29%, P < 0.001). These results demonstrate that PTH is a potent down-regulator of VDR expression in vivo. The biological response to 1,25(OH) 2 D 3 is directly related to the VDR content of target tissues (6, 7). Thus, the regulation of receptor expression is a critical determinant of hormone activity. The VDR has been shown to be developmentally regulated, expressed in a tissue-specific manner, and regulated by a variety of physiological factors and hormones (8). It is well established that 1,25(OH) 2 D 3 can stimulate receptor expression in the kidney and parathyroid gland while having minimal influence on intestinal VDR expression (9-13). Several studies also have noted a positive correlation between calcium and VDR expression. Hypocalcemia induced by dietary calcium restriction dramatically reduces renal VDR levels and prevents 1,25(OH) 2 D 3 from increasing VDR expression (14-16). Reduced dietary calcium also has been associated with diminished VDR mRNA in avian and rat parathyroid gland (11,12). If left untreated, renal failure with subsequent vitamin D deficiency and hypocalcemia will lead to a decrease in parathyroid gland VDR content and the development of vitamin D resistance (17, 18). The molecular trigger responsible for the hypocalcemia-mediated decline in renal and parathyroid gland VDR content is heretofore unknown.PTH expression is inversely related to serum calcium values (19). Because hypocalcemic animals have high circulating levels of PTH and reduced renal and parathyroid gland VDR expression, we hypothesized that PTH may down-regulate VDR expression. Previous investigations into PTH-mediated regulation of VDR expression yielded mixed results. A PTH-mediated increase of VDR and VDR mRNA was reported in osteoblastlike UMR-106 cells (20, 21), whereas a PTH-mediated decrease in VDR and its transcript was reported in ROS 17͞2.8 osteoblast cells (22). In vivo, osmotic PTH adm...

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Control of 25-Hydroxycholecalciferol Metabolism by Parathyroid Glands

Cited by 615 publications

References 24 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

Study of the Renal Tubular Interactions of Thyrocalcitonin, Cyclic Adenosine 3′, 5′ -Monophosphate, 25-Hydroxycholecalciferol, and Calcium Ion

Parathyroid hormone decreases renal vitamin D receptor expressionin vivo

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