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.
Similar content being viewed by others
References
Agoro R, Montagna A, Goetz R, Aligbe O, Singh G, Coe LM, Mohammadi M, Rivella S, Sitara D (2018) Inhibition of fibroblast growth factor 23 (FGF23) signaling rescues renal anemia. FASEB J:fj201700667R. doi:https://doi.org/10.1096/fj.201700667R
Bhattacharyya N, Chong WH, Gafni RI, Collins MT (2012) Fibroblast growth factor 23: state of the field and future directions. Trends Endocrinol Metab 23:610–618. https://doi.org/10.1016/j.tem.2012.07.002
Chen G, Liu Y, Goetz R, Fu L, Jayaraman S, Hu MC, Moe OW, Liang G, Li X, Mohammadi M (2018) Alpha-klotho is a non-enzymatic molecular scaffold for FGF23 hormone signalling. Nature 553:461–466. https://doi.org/10.1038/nature25451
Clinkenbeard EL, Farrow EG, Summers LJ, Cass TA, Roberts JL, Bayt CA, Lahm T, Albrecht M, Allen MR, Peacock M, White KE (2014) Neonatal iron deficiency causes abnormal phosphate metabolism by elevating FGF23 in normal and ADHR mice. J Bone Miner Res 29:361–369. https://doi.org/10.1002/jbmr.2049
Clinkenbeard EL, Hanudel MR, Stayrook KR, Appaiah HN, Farrow EG, Cass TA, Summers LJ, Ip CS, Hum JM, Thomas JC, Ivan M, Richine BM, Chan RJ, Clemens TL, Schipani E, Sabbagh Y, Xu L, Srour EF, Alvarez MB, Kacena MA, Salusky IB, Ganz T, Nemeth E, White KE (2017) Erythropoietin stimulates murine and human fibroblast growth factor-23, revealing novel roles for bone and bone marrow. Haematologica 102:e427–e430. https://doi.org/10.3324/haematol.2017.167882
Clinkenbeard EL, White KE (2017) Heritable and acquired disorders of phosphate metabolism: etiologies involving FGF23 and current therapeutics. Bone. https://doi.org/10.1016/j.bone.2017.01.034
Coe LM, Madathil SV, Casu C, Lanske B, Rivella S, Sitara D (2014) FGF-23 is a negative regulator of prenatal and postnatal erythropoiesis. J Biol Chem 289:9795–9810. https://doi.org/10.1074/jbc.M113.527150
Custer M, Lötscher M, Biber J, Murer H, Kaissling B (1994) Expression of Na-Pi cotransport in rat kidney: localization by RT-PCR and immunohistochemistry. Am J Phys 266:F767–F774
Daryadel A, Bourgeois S, Figueiredo MF, Gomes Moreira A, Kampik NB, Oberli L, Mohebbi N, Lu X, Meima ME, Danser AH, Wagner CA (2016) Colocalization of the (pro)renin receptor/Atp6ap2 with H+-ATPases in mouse kidney but prorenin does not acutely regulate intercalated cell H+-ATPase activity. PLoS One 11:e0147831. https://doi.org/10.1371/journal.pone.0147831. PONE-D-15-01396 [pii]
Daryadel A, Grifone RF, Simon HU, Yousefi S (2006) Apoptotic neutrophils release macrophage migration inhibitory factor upon stimulation with tumor necrosis factor-alpha. J Biol Chem 281:27653–27661. https://doi.org/10.1074/jbc.M604051200
David V, Martin A, Isakova T, Spaulding C, Qi L, Ramirez V, Zumbrennen-Bullough KB, Sun CC, Lin HY, Babitt JL, Wolf M (2016) Inflammation and functional iron deficiency regulate fibroblast growth factor 23 production. Kidney Int 89:135–146. https://doi.org/10.1038/ki.2015.290
Flamme I, Ellinghaus P, Urrego D, Kruger T (2017) FGF23 expression in rodents is directly induced via erythropoietin after inhibition of hypoxia inducible factor proline hydroxylase. PLoS One 12:e0186979. https://doi.org/10.1371/journal.pone.0186979
Gammella E, Diaz V, Recalcati S, Buratti P, Samaja M, Dey S, Noguchi CT, Gassmann M, Cairo G (2015) Erythropoietin's inhibiting impact on hepcidin expression occurs indirectly. Am J Physiol Regul Integr Comp Physiol 308:R330–R335. https://doi.org/10.1152/ajpregu.00410.2014
Goetz R, Nakada Y, Hu MC, Kurosu H, Wang L, Nakatani T, Shi M, Eliseenkova AV, Razzaque MS, Moe OW, Kuro-o M, Mohammadi M (2010) Isolated C-terminal tail of FGF23 alleviates hypophosphatemia by inhibiting FGF23-FGFR-klotho complex formation. Proc Natl Acad Sci U S A 107:407–412. https://doi.org/10.1073/pnas.0902006107
Goldberg MA, Gaut CC, Bunn HF (1991) Erythropoietin mRNA levels are governed by both the rate of gene transcription and posttranscriptional events. Blood 77:271–277
Hiram-Bab S, Liron T, Deshet-Unger N, Mittelman M, Gassmann M, Rauner M, Franke K, Wielockx B, Neumann D, Gabet Y (2015) Erythropoietin directly stimulates osteoclast precursors and induces bone loss. FASEB J 29:1890–1900. https://doi.org/10.1096/fj.14-259085
Hu MC, Shiizaki K, Kuro-o M, Moe OW (2013) Fibroblast growth factor 23 and klotho: physiology and pathophysiology of an endocrine network of mineral metabolism. Annu Rev Physiol 75:503–533. https://doi.org/10.1146/annurev-physiol-030212-183727
Ito N, Wijenayaka AR, Prideaux M, Kogawa M, Ormsby RT, Evdokiou A, Bonewald LF, Findlay DM, Atkins GJ (2015) Regulation of FGF23 expression in IDG-SW3 osteocytes and human bone by pro-inflammatory stimuli. Mol Cell Endocrinol 399:208–218. https://doi.org/10.1016/j.mce.2014.10.007
Kurt B, Gerl K, Karger C, Schwarzensteiner I, Kurtz A (2015) Chronic hypoxia-inducible transcription factor-2 activation stably transforms juxtaglomerular renin cells into fibroblast-like cells in vivo. J Am Soc Nephrol 26:587–596. https://doi.org/10.1681/ASN.2013111152
Lindberg K, Amin R, Moe OW, Hu MC, Erben RG, Ostman Wernerson A, Lanske B, Olauson H, Larsson TE (2014) The kidney is the principal organ mediating klotho effects. J Am Soc Nephrol 25:2169–2175. https://doi.org/10.1681/ASN.2013111209
Liu S, Zhou J, Tang W, Jiang X, Rowe DW, Quarles LD (2006) Pathogenic role of Fgf23 in Hyp mice. Am J Physiol Endocrinol Metab 291:E38–E49
Martin A, David V, Quarles LD (2012) Regulation and function of the FGF23/klotho endocrine pathways. Physiol Rev 92:131–155. https://doi.org/10.1152/physrev.00002.2011
Masuda Y, Ohta H, Morita Y, Nakayama Y, Miyake A, Itoh N, Konishi M (2015) Expression of Fgf23 in activated dendritic cells and macrophages in response to immunological stimuli in mice. Biol Pharm Bull 38:687–693. https://doi.org/10.1248/bpb.b14-00276
McGary EC, Rondon IJ, Beckman BS (1997) Post-transcriptional regulation of erythropoietin mRNA stability by erythropoietin mRNA-binding protein. J Biol Chem 272:8628–8634
Mehta R, Cai X, Hodakowski A, Lee J, Leonard M, Ricardo A, Chen J, Hamm L, Sondheimer J, Dobre M, David V, Yang W, Go A, Kusek JW, Feldman H, Wolf M, Isakova T (2017) Fibroblast growth factor 23 and anemia in the chronic renal insufficiency cohort study. Clin J Am Soc Nephrol 12:1795–1803. https://doi.org/10.2215/CJN.03950417
Rabadi S, Udo I, Leaf DE, Waikar SS, Christov M (2018) Acute blood loss stimulates fibroblast growth factor 23 production. Am J Physiol Renal Physiol 314:F132–F139. https://doi.org/10.1152/ajprenal.00081.2017
Rauner M, Franke K, Murray M, Singh RP, Hiram-Bab S, Platzbecker U, Gassmann M, Socolovsky M, Neumann D, Gabet Y, Chavakis T, Hofbauer LC, Wielockx B (2016) Increased EPO levels are associated with bone loss in mice lacking PHD2 in EPO-producing cells. J Bone Miner Res 31:1877–1887. https://doi.org/10.1002/jbmr.2857
Ruschitzka FT, Wenger RH, Stallmach T, Quaschning T, de Wit C, Wagner K, Labugger R, Kelm M, Noll G, Rulicke T, Shaw S, Lindberg RL, Rodenwaldt B, Lutz H, Bauer C, Luscher TF, Gassmann M (2000) Nitric oxide prevents cardiovascular disease and determines survival in polyglobulic mice overexpressing erythropoietin. Proc Natl Acad Sci U S A 97:11609–11613. https://doi.org/10.1073/pnas.97.21.11609. 97/21/11609 [pii]
Shiozawa Y, Jung Y, Ziegler AM, Pedersen EA, Wang J, Wang Z, Song J, Lee CH, Sud S, Pienta KJ, Krebsbach PH, Taichman RS (2010) Erythropoietin couples hematopoiesis with bone formation. PLoS One 5:e10853. https://doi.org/10.1371/journal.pone.0010853
Takenaka T, Watanabe Y, Inoue T, Miyazaki T, Suzuki H (2013) Fibroblast growth factor 23 enhances renal klotho abundance. Pflugers Arch 465:935–943. https://doi.org/10.1007/s00424-013-1226-z
Toro L, Barrientos V, Leon P, Rojas M, Gonzalez M, Gonzalez-Ibanez A, Illanes S, Sugikawa K, Abarzua N, Bascunan C, Arcos K, Fuentealba C, Tong AM, Elorza AA, Pinto ME, Alzamora R, Romero C, Michea L (2018) Erythropoietin induces bone marrow and plasma fibroblast growth factor 23 during acute kidney injury. Kidney Int 93:1131–1141. https://doi.org/10.1016/j.kint.2017.11.018
Vogel J, Gassmann M (2011) Erythropoietic and non-erythropoietic functions of erythropoietin in mouse models. J Physiol 589:1259–1264. https://doi.org/10.1113/jphysiol.2010.196147
Wolf M, Koch TA, Bregman DB (2013) Effects of iron deficiency anemia and its treatment on fibroblast growth factor 23 and phosphate homeostasis in women. J Bone Miner Res 28:1793–1803. https://doi.org/10.1002/jbmr.1923
Wu K, Zhou K, Wang Y, Zhou Y, Tian N, Wu Y, Chen D, Zhang D, Wang X, Xu H, Zhang X (2016) Stabilization of HIF-1alpha by FG-4592 promotes functional recovery and neural protection in experimental spinal cord injury. Brain Res 1632:19–26. https://doi.org/10.1016/j.brainres.2015.12.017
Zhang B, Umbach AT, Chen H, Yan J, Fakhri H, Fajol A, Salker MS, Spichtig D, Daryadel A, Wagner CA, Foller M, Lang F (2016) Up-regulation of FGF23 release by aldosterone. Biochem Biophys Res Commun 470:384–390. https://doi.org/10.1016/j.bbrc.2016.01.034
Zhang B, Yan J, Umbach AT, Fakhri H, Fajol A, Schmidt S, Salker MS, Chen H, Alexander D, Spichtig D, Daryadel A, Wagner CA, Foller M, Lang F (2016) NFkappaB-sensitive Orai1 expression in the regulation of FGF23 release. J Mol Med (Berl) 94:557–566. https://doi.org/10.1007/s00109-015-1370-3. 10.1007/s00109-015-1370-3 [pii]
Funding
This study has been supported by the Swiss National Science Foundation (SNSF) through the National Center for Competence in Research NCCR Kidney.CH and the SNSF funded projects 31003A_176125 to C.A.W., 31003A_165679 to R.H.W., and 31003A_156481 to M.G.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Supplementary table 1
(PDF 14 kb)
Rights and permissions
About this article
Cite this article
Daryadel, A., Bettoni, C., Haider, T. et al. Erythropoietin stimulates fibroblast growth factor 23 (FGF23) in mice and men. Pflugers Arch - Eur J Physiol 470, 1569–1582 (2018). https://doi.org/10.1007/s00424-018-2171-7
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00424-018-2171-7