Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Reviews in Endocrine and Metabolic Disorders
Published in: Reviews in Endocrine and Metabolic Disorders 1/2012

01-03-2012

The role of vitamin D in the FGF23, klotho, and phosphate bone-kidney endocrine axis

Authors: Mark R. Haussler, G. Kerr Whitfield, Ichiro Kaneko, Ryan Forster, Rimpi Saini, Jui-Cheng Hsieh, Carol A. Haussler, Peter W. Jurutka

Published in: Reviews in Endocrine and Metabolic Disorders | Issue 1/2012

Login to get access

Abstract

1,25-dihydroxyvitamin D (1,25D), through association with the nuclear vitamin D receptor (VDR), exerts control over a novel endocrine axis consisting of the bone-derived hormone FGF23, and the kidney-expressed klotho, CYP27B1, and CYP24A1 genes, which together prevent hyperphosphatemia/ectopic calcification and govern the levels of 1,25D to maintain bone mineral integrity while promoting optimal function of other vital tissues. When occupied by 1,25D, VDR interacts with RXR to form a heterodimer that binds to VDREs in the region of genes directly controlled by 1,25D (e.g., FGF23, klotho, Npt2c, CYP27B1 and CYP24A1). By recruiting complexes of comodulators, activated VDR initiates a series of events that induces or represses the transcription of genes encoding proteins such as: the osteocyte-derived hormone, FGF23; the renal anti-senescence factor and protein co-receptor for FGF23, klotho; other mediators of phosphate transport including Npt2a/c; and vitamin D hormone metabolic enzymes, CYP27B1 and CYP24A1. The mechanism whereby osteocytes are triggered to release FGF23 is yet to be fully defined, but 1,25D, phosphate, and leptin appear to play major roles. The kidney responds to FGF23 to elicit CYP24A1-catalyzed detoxification of the 1,25D hormone while also repressing both Npt2a/c to mediate phosphate elimination and CYP27B1 to limit de novo 1,25D synthesis. Comprehension of these skeletal and renal actions of 1,25D should facilitate the development of novel mimetics to prevent ectopic calcification, chronic renal and vascular disease, and promote healthful aging.
Literature
1.
Bergwitz C, Juppner H. Regulation of phosphate homeostasis by PTH, vitamin D, and FGF23. Annu Rev Med. 2010;61:91–104.PubMedCrossRef
2.
Kolek OI, Hines ER, Jones MD, Lesueur LK, Lipko MA, Kiela PR, et al. 1{alpha},25-Dihydroxyvitamin D3 upregulates FGF23 gene expression in bone: the final link in a renal-gastrointestinal-skeletal axis that controls phosphate transport. Am J Physiol Gastrointest Liver Physiol. 2005;289(6):G1036–42.PubMedCrossRef
3.
Saito H, Maeda A, Ohtomo S, Hirata M, Kusano K, Kato S, et al. Circulating FGF-23 is regulated by 1alpha,25-dihydroxyvitamin D3 and phosphorus in vivo. J Biol Chem. 2005;280(4):2543–9.PubMedCrossRef
4.
Liu S, Tang W, Zhou J, Stubbs JR, Luo Q, Pi M, et al. Fibroblast growth factor 23 is a counter-regulatory phosphaturic hormone for vitamin D. J Am Soc Nephrol. 2006;17(5):1305–15.PubMedCrossRef
5.
Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature. 1997;390(6655):45–51.PubMedCrossRef
6.
Kiela PR, Ghishan FK. Recent advances in the renal-skeletal-gut axis that controls phosphate homeostasis. Lab Invest. 2009;89(1):7–14.PubMedCrossRef
7.
Shimada T, Hasegawa H, Yamazaki Y, Muto T, Hino R, Takeuchi Y, et al. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res. 2004;19(3):429–35.PubMedCrossRef
8.
Shimada T, Kakitani M, Yamazaki Y, Hasegawa H, Takeuchi Y, Fujita T, et al. Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J Clin Invest. 2004;113(4):561–8.PubMed
9.
Haussler MR, Haussler CA, Bartik L, Whitfield GK, Hsieh JC, Slater S, et al. Vitamin D receptor: molecular signaling and actions of nutritional ligands in disease prevention. Nutr Rev. 2008;66(10 Suppl 2):S98–S112.PubMedCrossRef
10.
Haussler MR, Haussler CA, Whitfield GK, Hsieh JC, Thompson PD, Barthel TK, et al. The nuclear vitamin D receptor controls the expression of genes encoding factors which feed the “Fountain of Youth” to mediate healthful aging. J Steroid Biochem Mol Biol. 2010;121:88–97.PubMedCrossRef
11.
Ben-Dov IZ, Galitzer H, Lavi-Moshayoff V, Goetz R, Kuro-o M, Mohammadi M, et al. The parathyroid is a target organ for FGF23 in rats. J Clin Invest. 2007;117(12):4003–8.PubMed
12.
Razzaque MS. The FGF23-Klotho axis: endocrine regulation of phosphate homeostasis. Nat Rev Endocrinol. 2009;5(11):611–9.PubMedCrossRef
13.
Gattineni J, Twombley K, Goetz R, Mohammadi M, Baum M. Regulation of serum 1,25(OH)2Vitamin D3 levels by fibroblast growth factor 23 is mediated by FGF receptors 3 and 4. Am J Physiol Renal Physiol. 2011;301(2):F371–7.PubMedCrossRef
14.
Perwad F, Zhang MY, Tenenhouse HS, Portale AA. Fibroblast growth factor 23 impairs phosphorus and vitamin D metabolism in vivo and suppresses 25-hydroxyvitamin D-1alpha-hydroxylase expression in vitro. Am J Physiol Renal Physiol. 2007;293(5):F1577–83.PubMedCrossRef
15.
Fukuda T, Kanomata K, Nojima J, Urakawa I, Suzawa T, Imada M, et al. FGF23 induces expression of two isoforms of NAB2, which are corepressors of Egr-1. Biochem Biophys Res Commun. 2007;353(1):147–51.PubMedCrossRef
16.
Eswarakumar VP, Lax I, Schlessinger J. Cellular signaling by fibroblast growth factor receptors. Cytokine Growth Factor Rev. 2005;16(2):139–49.PubMedCrossRef
17.
Hesse M, Frohlich LF, Zeitz U, Lanske B, Erben RG. Ablation of vitamin D signaling rescues bone, mineral, and glucose homeostasis in Fgf-23 deficient mice. Matrix Biol. 2007;26(2):75–84.PubMedCrossRef
18.
Renkema KY, Alexander RT, Bindels RJ, Hoenderop JG. Calcium and phosphate homeostasis: concerted interplay of new regulators. Ann Med. 2008;40(2):82–91.PubMedCrossRef
19.
Yuan B, Takaiwa M, Clemens TL, Feng JQ, Kumar R, Rowe PS, et al. Aberrant Phex function in osteoblasts and osteocytes alone underlies murine X-linked hypophosphatemia. J Clin Invest. 2008;118(2):722–34.PubMed
20.
Fukumoto S. Fibroblast growth factor (FGF) 23 works as a phosphate-regulating hormone and is involved in the pathogenesis of several disorders of phosphate metabolism. Rinsho Byori. 2007;55(6):555–9.PubMed
21.
Yu X, Sabbagh Y, Davis SI, Demay MB, White KE. Genetic dissection of phosphate- and vitamin D-mediated regulation of circulating Fgf23 concentrations. Bone. 2005;36(6):971–7.PubMedCrossRef
22.
Kim TH, Abdullaev ZK, Smith AD, Ching KA, Loukinov DI, Green RD, et al. Analysis of the vertebrate insulator protein CTCF-binding sites in the human genome. Cell. 2007;128(6):1231–45.PubMedCrossRef
23.
Barski A, Cuddapah S, Cui K, Roh TY, Schones DE, Wang Z, et al. High-resolution profiling of histone methylations in the human genome. Cell. 2007;129(4):823–37.PubMedCrossRef
24.
Pike JW, Meyer MB, Martowicz ML, Bishop KA, Lee SM, Nerenz RD, et al. Emerging regulatory paradigms for control of gene expression by 1,25-dihydroxyvitamin D(3). J Steroid Biochem Mol Biol. 2010;121:130–5.PubMedCrossRef
25.
Masuyama R, Stockmans I, Torrekens S, Van Looveren R, Maes C, Carmeliet P, et al. Vitamin D receptor in chondrocytes promotes osteoclastogenesis and regulates FGF23 production in osteoblasts. J Clin Invest. 2006;116(12):3150–9.PubMedCrossRef
26.
Hsieh A, Gurevich M, Mathern D, Kaczmarska MJ, Haussler CA, Whitfield GK, et al. Identification of cEts1 and STAT1 as potential primary targets in the secondary gene regulation of the human fibroblast growth factor-23 gene by 1,25-dihydroxyvitamin D3. J Bone Miner Res. 2007;22:S402.
27.
Ito M, Sakai Y, Furumoto M, Segawa H, Haito S, Yamanaka S, et al. Vitamin D and phosphate regulate fibroblast growth factor-23 in K-562 cells. Am J Physiol Endocrinol Metab. 2005;288(6):E1101–9.PubMedCrossRef
28.
Juppner H, Wolf M, Salusky IB. FGF-23: more than a regulator of renal phosphate handling? J Bone Miner Res. 2010;25(10):2091–7.PubMedCrossRef
29.
Fukumoto S. FGF23: phosphate metabolism and beyond. IBMS BoneKEy. 2010;7(8):268–78.CrossRef
30.
Miedlich SU, Zhu ED, Sabbagh Y, Demay MB. The receptor-dependent actions of 1,25-dihydroxyvitamin D are required for normal growth plate maturation in NPt2a knockout mice. Endocrinology. 2010;151(10):4607–12.PubMedCrossRef
31.
Tsuji K, Maeda T, Kawane T, Matsunuma A, Horiuchi N. Leptin stimulates fibroblast growth factor 23 expression in bone and suppresses renal 1alpha,25-dihydroxyvitamin D3 synthesis in leptin-deficient mice. J Bone Miner Res. 2010;25(8):1711–23.PubMedCrossRef
32.
Durant L, Watford WT, Ramos HL, Laurence A, Vahedi G, Wei L, et al. Diverse targets of the transcription factor STAT3 contribute to T cell pathogenicity and homeostasis. Immunity. 2010;32(5):605–15.PubMedCrossRef
33.
Farrow EG, Davis SI, Ward LM, Summers LJ, Bubbear JS, Keen R, et al. Molecular analysis of DMP1 mutants causing autosomal recessive hypophosphatemic rickets. Bone. 2009;44(2):287–94.PubMedCrossRef
34.
Martin A, Liu S, David V, Li H, Karydis A, Feng JQ, et al. Bone proteins PHEX and DMP1 regulate fibroblastic growth factor Fgf23 expression in osteocytes through a common pathway involving FGF receptor (FGFR) signaling. FASEB J. 2011;25(8):2551–62.PubMedCrossRef
35.
Ichikawa S, Imel EA, Kreiter ML, Yu X, Mackenzie DS, Sorenson AH, et al. A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis. J Clin Invest. 2007;117(9):2684–91.PubMedCrossRef
36.
37.
Chen CD, Podvin S, Gillespie E, Leeman SE, Abraham CR. Insulin stimulates the cleavage and release of the extracellular domain of Klotho by ADAM10 and ADAM17. Proc Natl Acad Sci USA. 2007;104(50):19796–801.PubMedCrossRef
38.
Matsumura Y, Aizawa H, Shiraki-Iida T, Nagai R, Kuro-o M, Nabeshima Y. Identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein. Biochem Biophys Res Commun. 1998;242(3):626–30.PubMedCrossRef
39.
Thurston RD, Larmonier CB, Majewski PM, Ramalingam R, Midura-Kiela M, Laubitz D, et al. Tumor necrosis factor and interferon-gamma down-regulate Klotho in mice with colitis. Gastroenterology. 2010;138(4):1384–94. 94 e1-2.PubMedCrossRef
40.
Quarles LD. Endocrine functions of bone in mineral metabolism regulation. J Clin Invest. 2008;118(12):3820–8.PubMedCrossRef
41.
Tsujikawa H, Kurotaki Y, Fujimori T, Fukuda K, Nabeshima Y. Klotho, a gene related to a syndrome resembling human premature aging, functions in a negative regulatory circuit of vitamin D endocrine system. Mol Endocrinol. 2003;17(12):2393–403.PubMedCrossRef
42.
Barthel TK, Mathern DR, Whitfield GK, Haussler CA, Hopper IV HA, Hsieh JC, et al. 1,25-Dihydroxyvitamin D3/VDR-mediated induction of FGF23 as well as transcriptional control of other bone anabolic and catabolic genes that orchestrate the regulation of phosphate and calcium mineral metabolism. J Steroid Biochem Mol Biol. 2007;103(3–5):381–8.PubMedCrossRef
43.
Bartik L, Whitfield GK, Kaczmarska M, Lowmiller CL, Moffet EW, Furmick JK, et al. Curcumin: a novel nutritionally derived ligand of the vitamin D receptor with implications for colon cancer chemoprevention. J Nutr Biochem. 2010;21:1153–61.PubMedCrossRef
44.
Bishop KA, Meyer MB, Pike JW. A novel distal enhancer mediates cytokine induction of mouse RANKl gene expression. Mol Endocrinol. 2009;23(12):2095–110.PubMedCrossRef
45.
Keisala T, Minasyan A, Lou YR, Zou J, Kalueff AV, Pyykko I, et al. Premature aging in vitamin D receptor mutant mice. J Steroid Biochem Mol Biol. 2009;115(3–5):91–7.PubMedCrossRef
46.
Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP. 1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system. J Clin Invest. 2002;110(2):229–38.PubMed
47.
Nagai R, Saito Y, Ohyama Y, Aizawa H, Suga T, Nakamura T, et al. Endothelial dysfunction in the klotho mouse and downregulation of klotho gene expression in various animal models of vascular and metabolic diseases. Cell Mol Life Sci. 2000;57(5):738–46.PubMedCrossRef
48.
Saito Y, Yamagishi T, Nakamura T, Ohyama Y, Aizawa H, Suga T, et al. Klotho protein protects against endothelial dysfunction. Biochem Biophys Res Commun. 1998;248(2):324–9.PubMedCrossRef
49.
Mitani H, Ishizaka N, Aizawa T, Ohno M, Usui S, Suzuki T, et al. In vivo klotho gene transfer ameliorates angiotensin II-induced renal damage. Hypertension. 2002;39(4):838–43.PubMedCrossRef
50.
Katai K, Miyamoto K, Kishida S, Segawa H, Nii T, Tanaka H, et al. Regulation of intestinal Na+−dependent phosphate co-transporters by a low-phosphate diet and 1,25-dihydroxyvitamin D3. Biochem J. 1999;343(Pt 3):705–12.PubMedCrossRef
51.
Taketani Y, Segawa H, Chikamori M, Morita K, Tanaka K, Kido S, et al. Regulation of type II renal Na+-dependent inorganic phosphate transporters by 1,25-dihydroxyvitamin D3. Identification of a vitamin D-responsive element in the human NAPi-3 gene. J Biol Chem. 1998;273(23):14575–81.PubMedCrossRef
52.
Masuda M, Yamamoto H, Kozai M, Tanaka S, Ishiguro M, Takei Y, et al. Regulation of renal sodium-dependent phosphate co-transporter genes (Npt2a and Npt2c) by all-trans-retinoic acid and its receptors. Biochem J. 2010;429(3):583–92.PubMedCrossRef
53.
Segawa H, Onitsuka A, Kuwahata M, Hanabusa E, Furutani J, Kaneko I, et al. Type IIc sodium-dependent phosphate transporter regulates calcium metabolism. J Am Soc Nephrol. 2009;20(1):104–13.PubMedCrossRef
54.
Lorenz-Depiereux B, Benet-Pages A, Eckstein G, Tenenbaum-Rakover Y, Wagenstaller J, Tiosano D, et al. Hereditary hypophosphatemic rickets with hypercalciuria is caused by mutations in the sodium-phosphate cotransporter gene SLC34A3. Am J Hum Genet. 2006;78(2):193–201.PubMedCrossRef
55.
Cha SK, Hu MC, Kurosu H, Kuro-o M, Moe O, Huang CL. Regulation of renal outer medullary potassium channel and renal K(+) excretion by Klotho. Mol Pharmacol. 2009;76(1):38–46.PubMedCrossRef
56.
Wu X, Li Y. Role of FGF19 induced FGFR4 activation in the regulation of glucose homeostasis. Aging (Albany NY). 2009;1(12):1023–7.
57.
Kurosu H, Kuro-o M. The Klotho gene family and the endocrine fibroblast growth factors. Curr Opin Nephrol Hypertens. 2008;17(4):368–72.PubMedCrossRef
58.
Shardell M, Hicks GE, Miller RR, Kritchevsky S, Andersen D, Bandinelli S, et al. Association of low vitamin D levels with the frailty syndrome in men and women. J Gerontol A Biol Sci Med Sci. 2009;64(1):69–75.PubMedCrossRef
59.
Ensrud KE, Ewing SK, Fredman L, Hochberg MC, Cauley JA, Hillier TA, et al. Circulating 25-hydroxyvitamin D levels and frailty status in older women. J Clin Endocrinol Metab. 2010;95(12):5266–73.PubMedCrossRef
60.
Tuohimaa P, Tenkanen L, Ahonen M, Lumme S, Jellum E, Hallmans G, et al. Both high and low levels of blood vitamin D are associated with a higher prostate cancer risk: a longitudinal, nested case-control study in the Nordic countries. Int J Cancer. 2004;108(1):104–8.PubMedCrossRef
61.
Manson JE, Mayne ST, Clinton SK. Vitamin D and prevention of cancer–ready for prime time? New Engl J Med. 2011;364(15):1385–7.PubMedCrossRef
62.
Wang TJ, Pencina MJ, Booth SL, Jacques PF, Ingelsson E, Lanier K, et al. Vitamin D deficiency and risk of cardiovascular disease. Circulation. 2008;117(4):503–11.PubMedCrossRef
63.
Watson KE, Abrolat ML, Malone LL, Hoeg JM, Doherty T, Detrano R, et al. Active serum vitamin D levels are inversely correlated with coronary calcification. Circulation. 1997;96(6):1755–60.PubMed
64.
Ohnishi M, Razzaque MS. Dietary and genetic evidence for phosphate toxicity accelerating mammalian aging. FASEB J. 2010;24(9):3562–71.PubMedCrossRef
65.
Takemura A, Iijima K, Ota H, Son BK, Ito Y, Ogawa S, et al. Sirtuin 1 retards hyperphosphatemia-induced calcification of vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2011;31(9):2054–62.
66.
Yoshizawa T, Handa Y, Uematsu Y, Takeda S, Sekine K, Yoshihara Y, et al. Mice lacking the vitamin D receptor exhibit impaired bone formation, uterine hypoplasia and growth retardation after weaning. Nat Genet. 1997;16(4):391–6.PubMedCrossRef
Metadata
Title
The role of vitamin D in the FGF23, klotho, and phosphate bone-kidney endocrine axis
Authors
Mark R. Haussler
G. Kerr Whitfield
Ichiro Kaneko
Ryan Forster
Rimpi Saini
Jui-Cheng Hsieh
Carol A. Haussler
Peter W. Jurutka
Publication date
01-03-2012
Publisher
Springer US
Published in
Reviews in Endocrine and Metabolic Disorders / Issue 1/2012
Print ISSN: 1389-9155
Electronic ISSN: 1573-2606
DOI
https://doi.org/10.1007/s11154-011-9199-8

Other articles of this Issue 1/2012

Reviews in Endocrine and Metabolic Disorders 1/2012 Go to the issue

Announcement

Letter from the Editors

ReviewPaper

Mechanism of action of 1,25-dihydroxyvitamin D3 on intestinal calcium absorption

ReviewPaper

Mechanism of action of vitamin D and the vitamin D receptor in colorectal cancer prevention and treatment

ReviewPaper

Vitamin D and the skin: Physiology and pathophysiology

ReviewPaper

Regulation of target gene expression by the vitamin D receptor - an update on mechanisms

Erratum

Erratum to: Clinical and molecular genetics of neonatal diabetes due to mutations in the insulin gene
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits