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

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

Research output: Contribution to journalArticle

69 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)57-69
Number of pages13
JournalReviews in Endocrine and Metabolic Disorders
Volume13
Issue number1
DOIs
StatePublished - Mar 2012

Fingerprint

Vitamin D
25-Hydroxyvitamin D3 1-alpha-Hydroxylase
Phosphates
Kidney
Bone and Bones
Calcitriol Receptors
Hormones
Osteocytes
Hyperphosphatemia
1,25-dihydroxyvitamin D
Leptin
Chronic Renal Insufficiency
Vascular Diseases
Genes
Minerals
Proteins
Vitamin D3 24-Hydroxylase
Enzymes

Keywords

  • 1,25-dihydroxyvitamin D hormone
  • Autosomal dominant hypophosphatemic rickets
  • Phosphate homeostasis
  • Retinoid X receptor
  • Tumor-induced osteomalacia
  • Tumoral calcinosis
  • Vitamin D receptor
  • X-linked hypophosphatemic rickets

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

The role of vitamin D in the FGF23, klotho, and phosphate bone-kidney endocrine axis. / Haussler, Mark R.; Whitfield, G. Kerr; Kaneko, Ichiro; Forster, Ryan; Saini, Rimpi; Hsieh, Jui Cheng; Haussler, Carol A.; Jurutka, Peter.

In: Reviews in Endocrine and Metabolic Disorders, Vol. 13, No. 1, 03.2012, p. 57-69.

Research output: Contribution to journalArticle

Haussler, MR, Whitfield, GK, Kaneko, I, Forster, R, Saini, R, Hsieh, JC, Haussler, CA & Jurutka, P 2012, 'The role of vitamin D in the FGF23, klotho, and phosphate bone-kidney endocrine axis', Reviews in Endocrine and Metabolic Disorders, vol. 13, no. 1, pp. 57-69. https://doi.org/10.1007/s11154-011-9199-8
Haussler, Mark R. ; Whitfield, G. Kerr ; Kaneko, Ichiro ; Forster, Ryan ; Saini, Rimpi ; Hsieh, Jui Cheng ; Haussler, Carol A. ; Jurutka, Peter. / The role of vitamin D in the FGF23, klotho, and phosphate bone-kidney endocrine axis. In: Reviews in Endocrine and Metabolic Disorders. 2012 ; Vol. 13, No. 1. pp. 57-69.
@article{b5f7b07bcc2542abb67f51dc84d4fdac,
title = "The role of vitamin D in the FGF23, klotho, and phosphate bone-kidney endocrine axis",
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.",
keywords = "1,25-dihydroxyvitamin D hormone, Autosomal dominant hypophosphatemic rickets, Phosphate homeostasis, Retinoid X receptor, Tumor-induced osteomalacia, Tumoral calcinosis, Vitamin D receptor, X-linked hypophosphatemic rickets",
author = "Haussler, {Mark R.} and Whitfield, {G. Kerr} and Ichiro Kaneko and Ryan Forster and Rimpi Saini and Hsieh, {Jui Cheng} and Haussler, {Carol A.} and Peter Jurutka",
year = "2012",
month = "3",
doi = "10.1007/s11154-011-9199-8",
language = "English (US)",
volume = "13",
pages = "57--69",
journal = "Reviews in Endocrine and Metabolic Disorders",
issn = "1389-9155",
publisher = "Springer Netherlands",
number = "1",

}

TY - JOUR

T1 - The role of vitamin D in the FGF23, klotho, and phosphate bone-kidney endocrine axis

AU - Haussler, Mark R.

AU - Whitfield, G. Kerr

AU - Kaneko, Ichiro

AU - Forster, Ryan

AU - Saini, Rimpi

AU - Hsieh, Jui Cheng

AU - Haussler, Carol A.

AU - Jurutka, Peter

PY - 2012/3

Y1 - 2012/3

N2 - 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.

AB - 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.

KW - 1,25-dihydroxyvitamin D hormone

KW - Autosomal dominant hypophosphatemic rickets

KW - Phosphate homeostasis

KW - Retinoid X receptor

KW - Tumor-induced osteomalacia

KW - Tumoral calcinosis

KW - Vitamin D receptor

KW - X-linked hypophosphatemic rickets

UR - http://www.scopus.com/inward/record.url?scp=84858128980&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84858128980&partnerID=8YFLogxK

U2 - 10.1007/s11154-011-9199-8

DO - 10.1007/s11154-011-9199-8

M3 - Article

VL - 13

SP - 57

EP - 69

JO - Reviews in Endocrine and Metabolic Disorders

JF - Reviews in Endocrine and Metabolic Disorders

SN - 1389-9155

IS - 1

ER -