scholarly journals FGF23 gene regulation by 1,25-dihydroxyvitamin D: opposing effects in adipocytes and osteocytes

2015 ◽  
Vol 226 (3) ◽  
pp. 155-166 ◽  
Author(s):  
Ichiro Kaneko ◽  
Rimpi K Saini ◽  
Kristin P Griffin ◽  
G Kerr Whitfield ◽  
Mark R Haussler ◽  
...  
Keyword(s):  
Leptin Receptor ◽  
Fibroblast Growth Factor 23 ◽  
K562 Cells ◽  
Proximal Promoter ◽  
Luciferase Reporter ◽  
Surface Acting ◽  
Reporter Construct ◽  
Dihydroxyvitamin D ◽  
1,25 Dihydroxyvitamin D ◽  
High Calcium

In a closed endocrine loop, 1,25-dihydroxyvitamin D3 (1,25D) induces the expression of fibroblast growth factor 23 (FGF23) in bone, with the phosphaturic peptide in turn acting at kidney to feedback repress CYP27B1 and induce CYP24A1 to limit the levels of 1,25D. In 3T3-L1 differentiated adipocytes, 1,25D represses FGF23 and leptin expression and induces C/EBPβ, but does not affect leptin receptor transcription. Conversely, in UMR-106 osteoblast-like cells, FGF23 mRNA concentrations are upregulated by 1,25D, an effect that is blunted by lysophosphatidic acid, a cell-surface acting ligand. Progressive truncation of the mouse FGF23 proximal promoter linked in luciferase reporter constructs reveals a 1,25D-responsive region between −400 and −200 bp. A 0.6 kb fragment of the mouse FGF23 promoter, linked in a reporter construct, responds to 1,25D with a fourfold enhancement of transcription in transfected K562 cells. Mutation of either an ETS1 site at −346 bp, or an adjacent candidate vitamin D receptor (VDR)/Nurr1-element, in the 0.6 kb reporter construct reduces the transcriptional activity elicited by 1,25D to a level that is not significantly different from a minimal promoter. This composite ETS1–VDR/Nurr1 cis-element may function as a switch between induction (osteocytes) and repression (adipocytes) of FGF23, depending on the cellular setting of transcription factors. Moreover, experiments demonstrate that a 1 kb mouse FGF23 promoter–reporter construct, transfected into MC3T3-E1 osteoblast-like cells, responds to a high calcium challenge with a statistically significant 1.7- to 2.0-fold enhancement of transcription. Thus, the FGF23 proximal promoter harbors cis elements that drive responsiveness to 1,25D and calcium, agents that induce FGF23 to curtail the pathologic consequences of their excess.

scholarly journals Fibroblast growth factor 23 inhibits extrarenal synthesis of 1,25-dihydroxyvitamin D in human monocytes

2012 ◽  
Vol 28 (1) ◽  
pp. 46-55 ◽  
Author(s):  
Justine Bacchetta ◽  
Jessica L Sea ◽  
Rene F Chun ◽  
Thomas S Lisse ◽  
Katherine Wesseling-Perry ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor 23 ◽  
Fibroblast Growth ◽  
Human Monocytes ◽  
Dihydroxyvitamin D ◽  
1,25 Dihydroxyvitamin D

Disorders of phosphate metabolism

2019 ◽  
Vol 72 (11) ◽  
pp. 741-747 ◽  
Author(s):  
Jenny Leung ◽  
Martin Crook
Keyword(s):  
Fibroblast Growth Factor 23 ◽  
The Body ◽  
Plasma Phosphate ◽  
Phosphate Homeostasis ◽  
Organic Form ◽  
Dihydroxyvitamin D ◽  
1,25 Dihydroxyvitamin D ◽  
Renal Tubular Reabsorption ◽  
Renal Tubular ◽  
Storage Pools

Phosphate in both inorganic and organic form is essential for several functions in the body. Plasma phosphate level is maintained by a complex interaction between intestinal absorption, renal tubular reabsorption, and the transcellular movement of phosphate between intracellular fluid and bone storage pools. This homeostasis is regulated by several hormones, principally the parathyroid hormone, 1,25-dihydroxyvitamin D and fibroblast growth factor 23. Abnormalities in phosphate regulation can lead to serious and fatal complications. In this review phosphate homeostasis and the aetiology, pathophysiology, clinical features, investigation and management of hypophosphataemia and hyperphosphataemia will be discussed.

scholarly journals The Receptor-Dependent Actions of 1,25-Dihydroxyvitamin D Are Required for Normal Growth Plate Maturation in NPt2a Knockout Mice

Endocrinology ◽  
2010 ◽  
Vol 151 (10) ◽  
pp. 4607-4612 ◽  
Author(s):  
Susanne U. Miedlich ◽  
Eric D. Zhu ◽  
Yves Sabbagh ◽  
Marie B. Demay
Keyword(s):  
Vitamin D ◽  
Growth Plate ◽  
Fibroblast Growth Factor 23 ◽  
Normal Growth ◽  
Chondrocyte Apoptosis ◽  
Apoptotic Pathway ◽  
Dihydroxyvitamin D ◽  
1,25 Dihydroxyvitamin D ◽  
Hypertrophic Chondrocyte

Rickets is a growth plate abnormality observed in growing animals and humans. Rachitic expansion of the hypertrophic chondrocyte layer of the growth plate, in the setting of hypophosphatemia, is due to impaired apoptosis of these cells. Rickets is observed in humans and mice with X-linked hypophosphatemia that is associated with renal phosphate wasting secondary to elevated levels of fibroblast growth factor-23. Rickets is also seen in settings of impaired vitamin D action, due to elevated PTH levels that increase renal phosphate excretion. However, mice with hypophosphatemia secondary to ablation of the renal sodium-dependent phosphate transport protein 2a (Npt2a), have not been reported to develop rickets. Because activation of the mitochondrial apoptotic pathway by phosphate is required for hypertrophic chondrocyte apoptosis in vivo, investigations were undertaken to address this paradox. Analyses of the Npt2a null growth plate demonstrate expansion of the hypertrophic chondrocyte layer at 2 wk of age, with resolution of this abnormality by 5 wk of age. This is temporally associated with an increase in circulating levels of 1,25-dihydroxyvitamin D. To address whether the receptor-dependent actions of this steroid hormone are required for normalization of the growth plate phenotype, the Npt2a null mice were mated with mice lacking the vitamin D receptor or were rendered vitamin D deficient. These studies demonstrate that the receptor-dependent actions of 1,25-dihydroxyvitamin D are required for maintenance of a normal growth plate phenotype in the Npt2a null mice.

scholarly journals 1,25-Dihydroxyvitamin D Maintains Brush Border Membrane NaPi2a and Attenuates Phosphaturia in Hyp Mice

Endocrinology ◽  
2019 ◽  
Vol 160 (10) ◽  
pp. 2204-2214 ◽  
Author(s):  
Janaina S Martins ◽  
Eva S Liu ◽  
W Bruce Sneddon ◽  
Peter A Friedman ◽  
Marie B Demay
Keyword(s):  
Brush Border ◽  
Hormonal Regulation ◽  
Fibroblast Growth Factor 23 ◽  
Term Treatment ◽  
Scaffolding Protein ◽  
Phosphate Reabsorption ◽  
Dihydroxyvitamin D ◽  
Protein Levels ◽  
1,25 Dihydroxyvitamin D ◽  
Long Term Treatment

Abstract Phosphate homeostasis is critical for many cellular processes and is tightly regulated. The sodium-dependent phosphate cotransporter, NaPi2a, is the major regulator of urinary phosphate reabsorption in the renal proximal tubule. Its activity is dependent upon its brush border localization that is regulated by fibroblast growth factor 23 (FGF23) and PTH. High levels of FGF23, as are seen in the Hyp mouse model of human X-linked hypophosphatemia, lead to renal phosphate wasting. Long-term treatment of Hyp mice with 1,25-dihydroxyvitamin D (1,25D) or 1,25D analogues has been shown to improve renal phosphate wasting in the setting of increased FGF23 mRNA expression. Studies were undertaken to define the cellular and molecular basis for this apparent FGF23 resistance. 1,25D increased FGF23 protein levels in the cortical bone and circulation of Hyp mice but did not impair FGF23 cleavage. 1,25D attenuated urinary phosphate wasting as early as one hour postadministration, without suppressing FGF23 receptor/coreceptor expression. Although 1,25D treatment induced expression of early growth response 1, an early FGF23 responsive gene required for its phosphaturic effects, it paradoxically enhanced renal phosphate reabsorption and NaPi2a protein expression in renal brush border membranes (BBMs) within one hour. The Na-H+ exchange regulatory factor 1 (NHERF1) is a scaffolding protein thought to anchor NaPi2a to the BBM. Although 1,25D did not alter NHERF1 protein levels acutely, it enhanced NHERF1-NaPi2a interactions in Hyp mice. 1,25D also prevented the decrease in NHERF1/NaPi2a interactions in PTH-treated wild-type mice. Thus, these investigations identify a novel role for 1,25D in the hormonal regulation of renal phosphate handling.

scholarly journals SAT-356 Reversible Suppression of Serum 1,25-Dihydroxyvitamin D in Williams Syndrome

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Michael Yuri Torchinsky ◽  
Eric Bugaieski
Keyword(s):  
Alkaline Phosphatase ◽  
Williams Syndrome ◽  
Serum Calcium ◽  
Calcium Content ◽  
Dietary Calcium ◽  
Dietary Calcium Intake ◽  
Dihydroxyvitamin D ◽  
1,25 Dihydroxyvitamin D ◽  
High Calcium ◽  
Medullary Nephrocalcinosis

Abstract Background: Hypercalcemia has been reported in 5% to 50% of patients with Williams syndrome; however, observations about the role of 1,25-dihydroxyvitamin D in hypercalcemia related to Williams syndrome have been contradictory. Objective: The objective was to investigate the mineral metabolism in an 11-month-old patient with Williams-Beuren syndrome who had hypercalcemia, hypercalciuria and nephrocalcinosis. Methods: We reviewed test results in an 11-month-old infant with Williams syndrome who developed hypercalcemia following excessive dietary calcium intake that was two to three times higher than recommended for age because he continued receiving a premature formula with high calcium content from birth. Results: Our patient presented with feeding difficulties, daily vomiting, weight loss, and constipation. He had serum total calcium 14.8 mg/dL, phosphorus 4.0 mg/dL, PTH <4 pg/mL, 1,25-dihydroxyvitamin D <8 pg/mL, 25-hydroxyvitamin D 29 ng/mL, PTH-related peptide 3.7 pmoL/L (expected <4.2), alkaline phosphatase 118 U/L, beta-crosslaps 1257 pg/mL, and urinary calcium/creatinine ratio 1.19. XR Skeletal Survey revealed increased bone density in the metaphyseal regions, in particular, above the knee, distal radius and ulna that may result from hypercalcemia; no evidence of rickets, osteoporosis or congenital osteodystrophy was seen. Renal ultrasound revealed increased echogenicity of the renal medullary pyramids consistent with medullary nephrocalcinosis. Hypercalcemia and hypercalciuria were initially treated with IV fluids and Furosemide IV, and resolved only after Pamidronate 0.5 mg/kg/dose IV x 2 doses. After serum calcium normalized, the patient’s symptoms resolved, PTH recovered to 18 pg/mL (expected 10 - 65), and 1,25-dihydroxyvitamin D increased to 27 pg/mL (expected 24 - 86). Chromosomal micro-array analysis showed a 1.9 megabase deletion at 7q11.23 that overlapped the Williams syndrome critical region including the ELN gene, consistent with diagnosis of Williams syndrome. Serum calcium remained normal with dietary calcium restriction using a low-calcium formula and complementary foods. Conclusions: PTH-independent hypercalcemia in our patient with Williams syndrome was due to calcium overload resulting from dietary calcium excess in addition to possibly enhanced intestinal calcium absorption. Serum 1,25-dihydroxyvitamin D was undetectable and returned to normal only with resumption of PTH secretion required for its synthesis after hypercalcemia resolved. The balance between bone formation and resorption was shifted to resorption possibly to remove skeletal calcium excess, based on normal alkaline phosphatase (marker of osteoblast activity) and high collagen beta-crosslaps (marker of osteoclast activity). A premature formula with high calcium content should be switched to a full-term formula when risk for rickets of prematurity clears.

Phosphate homeostasis and genetic mutations of familial hypophosphatemic rickets

2015 ◽  
Vol 28 (9-10) ◽  
Author(s):  
Nurul Nadirah Razali ◽  
Ting Tzer Hwu ◽  
Karuppiah Thilakavathy
Keyword(s):  
Autosomal Recessive ◽  
Autosomal Dominant ◽  
Fibroblast Growth Factor 23 ◽  
Hypophosphatemic Rickets ◽  
Genetic Mutations ◽  
Renal Tubules ◽  
Phosphate Homeostasis ◽  
Tooth Structure ◽  
Dihydroxyvitamin D ◽  
1,25 Dihydroxyvitamin D

AbstractHypophosphatemic rickets (HR) is a syndrome of hypophosphatemia and rickets that resembles vitamin D deficiency, which is caused by malfunction of renal tubules in phosphate reabsorption. Phosphate is an essential mineral, which is important for bone and tooth structure. It is regulated by parathyroid hormone, 1,25-dihydroxyvitamin D and fibroblast-growth-factor 23 (FGF23). X-linked hypophosphatemia (XLH), autosomal dominant HR (ADHR), and autosomal recessive HR (ARHR) are examples of hereditary forms of HR, which are mainly caused by mutations in the phosphate regulating endopeptidase homolog, X-linked (

scholarly journals Transactivation of the Progesterone Receptor Gene in Granulosa Cells: Evidence that Sp1/Sp3 Binding Sites in the Proximal Promoter Play a Key Role in Luteinizing Hormone Inducibility

2003 ◽  
Vol 17 (3) ◽  
pp. 436-449 ◽  
Author(s):  
Venkataraman Sriraman ◽  
S. Chidananda Sharma ◽  
JoAnne S. Richards
Keyword(s):  
Progesterone Receptor ◽  
Granulosa Cells ◽  
Binding Sites ◽  
Primary Cultures ◽  
Regulatory Elements ◽  
Proximal Promoter ◽  
Luciferase Reporter ◽  
Reporter Construct ◽  
Reporter Activity ◽  
Distal Promoter

Abstract LH induction of the progesterone receptor (PR) in granulosa cells is a central event in ovulation. To identify critical regions of the mouse PR promoter that confer LH inducibility in granulosa cells, a mouse PR promoter (−384/+680) genomic fragment was ligated to a luciferase reporter construct and transfected into primary cultures of granulosa cells. Forskolin/phorbol myristate (PMA) induced PR promoter-luciferase reporter activity in granulosa cells greater than 15-fold. A deletion construct comprised only of the distal promoter alone (−348/+64) was inactive. Conversely, deletion constructs eliminating putative distal promoter-regulatory elements that bind Sp1, nuclear factor Y, and GATA-4 as well as the transcription start site (+1) failed to reduce forskolin/PMA activation of reporter activity. Additional 5′-deletions identified a minimal promoter region (+420/+680) sufficient to bestow cAMP responsiveness approximately 8- to 10-fold. Two GC-rich regions Sp1(A)[+440/+461] and Sp1(B) [+473/+490] bound Sp1/Sp3. Site-directed mutagenesis of Sp1(A) and Sp1(B) reduced activity of the proximal (+357/+680) promoter reporter construct approximately 50% and 99%, respectively. When the same Sp1(B) mutation was introduced into the intact promoter (−145/+680), forskolin/PMA induction of promoter activity was reduced by 70–80%. When the distal GC box as well as the proximal Sp1(B) site were both mutated in the context of the intact promoter, inducibility of the transgene was even more severely reduced. The importance of these Sp1/Sp3 binding regions was confirmed in human MCF-7 cells and Drosophila SL2 cells. Collectively, these results indicate that the Sp1/Sp3 binding sites within the mouse PR proximal promoter are essential for transactivation of the gene by agonists in granulosa cells. The molecular mechanisms by which LH activates Sp1/Sp3 at this region within the PR gene remain unknown but do not involve changes in the binding of Sp1/Sp3 to the critical GC boxes. Rather, Sp1/Sp3 appear to recruit other factors to the promoter.

scholarly journals Gene-by-Diet Interactions Affect Serum 1,25-Dihydroxyvitamin D Levels in Male BXD Recombinant Inbred Mice

Endocrinology ◽  
2015 ◽  
Vol 157 (2) ◽  
pp. 470-481 ◽  
Author(s):  
James C. Fleet ◽  
Rebecca A. Replogle ◽  
Perla Reyes-Fernandez ◽  
Libo Wang ◽  
Min Zhang ◽  
...  
Keyword(s):  
Recombinant Inbred ◽  
Inbred Mice ◽  
Recombinant Inbred Lines ◽  
Fibroblast Growth Factor 23 ◽  
Inbred Lines ◽  
Narrow Sense Heritability ◽  
Natural Genetic Variation ◽  
Dihydroxyvitamin D ◽  
1,25 Dihydroxyvitamin D ◽  
Basal Serum

Abstract 1,25-Dihydroxyvitamin D (1,25[OH]2D) regulates calcium (Ca), phosphate, and bone metabolism. Serum 1,25(OH)2D levels are reduced by low vitamin D status and high fibroblast growth factor 23 (FGF23) levels and increased by low Ca intake and high PTH levels. Natural genetic variation controls serum 25-hydroxyvitamin D (25[OH]D) levels, but it is unclear how it controls serum 1,25(OH)2D or the response of serum 1,25(OH)2D levels to dietary Ca restriction (RCR). Male mice from 11 inbred lines and from 51 BXD recombinant inbred lines were fed diets with either 0.5% (basal) or 0.25% Ca from 4 to 12 weeks of age (n = 8 per line per diet). Significant variation among the lines was found in basal serum 1,25(OH)2D and in the RCR as well as basal serum 25(OH)D and FGF23 levels. 1,25(OH)2D was not correlated to 25(OH)D but was negatively correlated to FGF23 (r = −0.5). Narrow sense heritability of 1,25(OH)2D was 0.67 on the 0.5% Ca diet, 0.66 on the 0.25% Ca diet, and 0.59 for the RCR, indicating a strong genetic control of serum 1,25(OH)2D. Genetic mapping revealed many loci controlling 1,25(OH)2D (seven loci) and the RCR (three loci) as well as 25(OH)D (four loci) and FGF23 (two loci); a locus on chromosome 18 controlled both 1,25(OH)2D and FGF23. Candidate genes underlying loci include the following: Ets1 (1,25[OH]2D), Elac1 (FGF23 and 1,25[OH]2D), Tbc1d15 (RCR), Plekha8 and Lyplal1 (25[OH]D), and Trim35 (FGF23). This report is the first to reveal that serum 1,25(OH)2D levels are controlled by multiple genetic factors and that some of these genetic loci interact with the dietary environment.

Circulating Levels of Dickkopf-Related Protein 1 Decrease as Measured GFR Declines and Are Associated with PTH Levels

2020 ◽  
Vol 51 (11) ◽  
pp. 871-880
Author(s):  
Corey M. Forster ◽  
Christine A. White ◽  
Mandy E. Turner ◽  
Patrick A. Norman ◽  
Emilie C. Ward ◽  
...  
Keyword(s):  
Bone Disease ◽  
Mineral Metabolism ◽  
Early Stage ◽  
Fibroblast Growth Factor 23 ◽  
Vitamin D Metabolites ◽  
Related Protein ◽  
Clinical Indicators ◽  
Dihydroxyvitamin D ◽  
1,25 Dihydroxyvitamin D ◽  
Fgf 23

<b><i>Background:</i></b> The Wnt/β-catenin pathway has been implicated in the development of adynamic bone disease in early-stage chronic kidney disease (CKD). Dickkopf-related protein 1 (DKK1) and sclerostin are antagonists of the Wnt/β-catenin pathway yet have not been widely used as clinical indicators of bone disease. This study characterized levels of DKK1, sclerostin, and other biomarkers of mineral metabolism in participants across a spectrum of inulin-measured glomerular filtration rate (GFR). <b><i>Methods:</i></b> GFR was measured by urinary inulin clearance (mGFR) in 90 participants. Blood samples were obtained for measurement of circulating DKK1, sclerostin, fibroblast growth factor 23 (FGF-23), parathyroid hormone (PTH), calcium, phosphate, α-klotho, and vitamin D metabolites including 25-hydroxyvitamin D<sub>3</sub> and 1,25-dihydroxyvitamin D<sub>3</sub>. Spearman correlations and linear regressions were used where appropriate to examine the associations between measured values. <b><i>Results:</i></b> The median [IQR] age was 64 years [53.0–71.0], and the median [IQR] mGFR was 32.6 [21.7–60.6] mL/min. DKK1 decreased (<i>r</i> = 0.6, <i>p</i> &#x3c; 0.001) and sclerostin increased (<i>r</i> = −0.4, <i>p</i> &#x3c; 0.001) as kidney function declined, and both were associated with phosphate, PTH, FGF-23, and 1,25-dihydroxyvitamin D<sub>3</sub> in the unadjusted analysis. After adjustment for age and mGFR, DKK1 remained significantly associated with PTH. <b><i>Conclusion:</i></b> The results of this study demonstrate opposing trends in Wnt/β-catenin pathway inhibitors, DKK1 and sclerostin, as mGFR declines. Unlike sclerostin, DKK1 levels decreased significantly as mGFR declined and was independently associated with PTH. Future studies should determine whether measurement of Wnt signaling inhibitors may be useful in predicting bone histomorphometric findings and important clinical outcomes in patients with CKD.

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