Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, PCB137

Poster Communications

Erythropoietin stimulates Fibroblast Growth Factor 23 (FGF23) in mice and men

A. Daryadel1,3, T. Haider2, P. Imenez Silva1,3, U. Schnitzbauer1,3, C. Bettoni1,3, E. M. Pastor Arroyo1,3, R. Wenger1,3, M. Gassmann2, C. A. Wagner1,3

1. Institute of Physiology, Zürich, Switzerland. 2. Institute of Veterinary Physiology, Zürich, Switzerland. 3. National Center of Competence in Research NCCR Kidney.CH, Zürich, Switzerland.

Introduction: 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 up-regulated 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. Therefore, we aimed to investigate the regulatory effect of EPO via FGF23 on phosphate and 1,25 (OH)2 vitamin D3 metabolism. Methods: Blood samples were collected from healthy 32 subjects (EPOPERF-Project, a randomized double-blinded, placebo-controlled, crossover clinical trial (, identifier code: NCT01889056) at 24 hours post treatment with a single high dose of recombinant erythropoietin (rhEPO). Additionally, C57BL/6 male mice were injected daily with rhEPO for 24 hours or 4days. Plasma intact FGF23 (iFGF23), C-terminal FGF23 fragment (cFGF23), PTH and 1,25 (OH)2 D3 levels were measured by Elisa and radioimmunoassay respectively. Abundance of FGF23 in bone marrow cells was analyzed by real time PCR and immunostaining assays. Furthermore, renal EPO mRNA levels were assessed by real time PCR and NaPiIIa and α-klotho protein expression were tested by western blot. Results: We demonstrate that acute administration of rhEPO to healthy humans increased the cFGF23, but not iFGF23. In mice, rhEPO stimulated acutely (24 hrs) cFGF23 but iFGF23 only after 4 days without effects on PTH and plasma phosphate. Systemic 1,25 (OH)2 D3 levels and α-klotho and NaPiIIa expression in kidney decreased 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 (Tg6) increased iFGF23. Finally, acute injections of recombinant FGF23 reduced renal EPO mRNA expression. Conclusion: 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 caused elevation of cFGF23, 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.

Where applicable, experiments conform with Society ethical requirements