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Erythropoietin stimulates fibroblast growth factor 23 (FGF23) in mice and men


Daryadel, Arezoo; Bettoni, Carla; Haider, Thomas; Imenez Silva, Pedro H; Schnitzbauer, Udo; Pastor-Arroyo, Eva Maria; Wenger, Roland H; Gassmann, Max; Wagner, Carsten A (2018). Erythropoietin stimulates fibroblast growth factor 23 (FGF23) in mice and men. Pflügers Archiv : European Journal of Physiology, 470(10):1569-1582.

Abstract

Fibroblast growth factor 23 (FGF23) is a major endocrine regulator of phosphate and 1,25 (OH)2 vitamin D3 metabolism and is mainly produced by osteocytes. Its production is upregulated by a variety of factors including 1,25 (OH)2 vitamin D3, high dietary phosphate intake, and parathyroid hormone (PTH). Recently, iron deficiency and hypoxia have been suggested as additional regulators of FGF23 and a role of erythropoietin (EPO) was shown. However, the regulation of FGF23 by EPO and the impact on phosphate and 1,25(OH)2 vitamin D3 are not completely understood. Here, we demonstrate that acute administration of recombinant human EPO (rhEPO) to healthy humans increases the C-terminal fragment of FGF23 (C-terminal FGF23) but not intact FGF23 (iFGF23). In mice, rhEPO stimulates acutely (24 h) C-terminal FGF23 but iFGF23 only after 4 days without effects on PTH and plasma phosphate. 1,25 (OH)2 D3 levels and αklotho expression in the kidney decrease after 4 days. rhEPO induced FGF23 mRNA in bone marrow but not in bone, with increased staining of FGF23 in CD71+ erythroid precursors in bone marrow. Chronic elevation of EPO in transgenic mice increases iFGF23. Finally, acute injections of recombinant FGF23 reduced renal EPO mRNA expression. Our data demonstrate stimulation of FGF23 levels in mice which impacts mostly on 1,25 (OH)2 vitamin D3 levels and metabolism. In humans, EPO is mostly associated with the C-terminal fragment of FGF23; in mice, EPO has a time-dependent effect on both FGF23 forms. EPO and FGF23 may form a feedback loop controlling and linking erythropoiesis and mineral metabolism.

Abstract

Fibroblast growth factor 23 (FGF23) is a major endocrine regulator of phosphate and 1,25 (OH)2 vitamin D3 metabolism and is mainly produced by osteocytes. Its production is upregulated by a variety of factors including 1,25 (OH)2 vitamin D3, high dietary phosphate intake, and parathyroid hormone (PTH). Recently, iron deficiency and hypoxia have been suggested as additional regulators of FGF23 and a role of erythropoietin (EPO) was shown. However, the regulation of FGF23 by EPO and the impact on phosphate and 1,25(OH)2 vitamin D3 are not completely understood. Here, we demonstrate that acute administration of recombinant human EPO (rhEPO) to healthy humans increases the C-terminal fragment of FGF23 (C-terminal FGF23) but not intact FGF23 (iFGF23). In mice, rhEPO stimulates acutely (24 h) C-terminal FGF23 but iFGF23 only after 4 days without effects on PTH and plasma phosphate. 1,25 (OH)2 D3 levels and αklotho expression in the kidney decrease after 4 days. rhEPO induced FGF23 mRNA in bone marrow but not in bone, with increased staining of FGF23 in CD71+ erythroid precursors in bone marrow. Chronic elevation of EPO in transgenic mice increases iFGF23. Finally, acute injections of recombinant FGF23 reduced renal EPO mRNA expression. Our data demonstrate stimulation of FGF23 levels in mice which impacts mostly on 1,25 (OH)2 vitamin D3 levels and metabolism. In humans, EPO is mostly associated with the C-terminal fragment of FGF23; in mice, EPO has a time-dependent effect on both FGF23 forms. EPO and FGF23 may form a feedback loop controlling and linking erythropoiesis and mineral metabolism.

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Contributors:National Center of Competence in Research NCCR Kidney.Ch, Zürich, Switzerland
Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology

04 Faculty of Medicine > Center for Integrative Human Physiology
05 Vetsuisse Faculty > Institute of Veterinary Physiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Uncontrolled Keywords:Bone, Erythropoietin, FGF23, Kidney, Mineral metabolism, Vitamin D3
Language:English
Date:2 July 2018
Deposited On:25 Jul 2018 15:26
Last Modified:14 Sep 2018 01:01
Publisher:Springer
ISSN:0031-6768
OA Status:Closed
Publisher DOI:https://doi.org/10.1007/s00424-018-2171-7
PubMed ID:29961920
Project Information:
  • : FunderSNSF
  • : Grant ID31003A_176125
  • : Project TitleMolecular mechanisms of mammalian phosphate sensing and homeostatic control
  • : FunderSNSF
  • : Grant ID31003A_165679
  • : Project TitleHydroxylation-dependent functions of OTUB1 in oxygen physiology
  • : FunderSNSF
  • : Grant ID31003A_156481
  • : Project TitleReduced incidence of cancer at high altitude: analyzing the impact of hypoxia on tumor development
  • : FunderNational Center for Competence in Research NCCR Kidney.Ch
  • : Grant ID
  • : Project Title

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