Non-renal-Related Mechanisms of FGF23 Pathophysiology

Current Osteoporosis Reports

Volumn 16, Issue 6, 2018, Pages 724-729

  Hanudel, Mark R ^a   Laster, Marciana ^a   Salusky, Isidro B ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

Anemia; Chronic kidney disease; CKD mineral and bone disorder; Fibroblast growth factor 23; Iron

Indexed keywords

ERYTHROPOIETIN; FIBROBLAST GROWTH FACTOR 23; IRON; FIBROBLAST GROWTH FACTOR;

ANEMIA; CHRONIC KIDNEY FAILURE; COMORBIDITY; CYTOKINE PRODUCTION; HUMAN; INFLAMMATION; IRON DEFICIENCY; NONHUMAN; PATHOPHYSIOLOGY; PROTEIN METABOLISM; REVIEW; BONE; COMPLICATION; METABOLIC BONE DISEASE; METABOLISM;

BONE AND BONES; BONE DISEASES, METABOLIC; FIBROBLAST GROWTH FACTORS; HUMANS; RENAL INSUFFICIENCY, CHRONIC;

EID: 85055702147     PISSN: 15441873     EISSN: 15442241     Source Type: Journal    
DOI: 10.1007/s11914-018-0492-2     Document Type: Review

References (65)

1. 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. 10.1172/jci19081
2. Gattineni J, Bates C, Twombley K, Dwarakanath V, Robinson ML, Goetz R, et al. FGF23 decreases renal NaPi-2a and NaPi-2c expression and induces hypophosphatemia in vivo predominantly via FGF receptor 1. Am J Physiol Ren Physiol. 2009;297(2):F282–91. 10.1152/ajprenal.90742.2008
3. Bai XY, Miao D, Goltzman D, Karaplis AC. The autosomal dominant hypophosphatemic rickets R176Q mutation in fibroblast growth factor 23 resists proteolytic cleavage and enhances in vivo biological potency. J Biol Chem. 2003;278(11):9843–9. 10.1074/jbc.M210490200
4. 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. 10.1359/jbmr.0301264
5. Christakos S, Dhawan P, Verstuyf A, Verlinden L, Carmeliet G. Vitamin D: Metabolism, molecular mechanism of action, and pleiotropic effects. Physiol Rev. 2016;96(1):365–408. 10.1152/physrev.00014.2015
6. Pereira RC, Juppner H, Azucena-Serrano CE, Yadin O, Salusky IB, Wesseling-Perry K. Patterns of FGF-23, DMP1, and MEPE expression in patients with chronic kidney disease. Bone. 2009;45(6):1161–8. 10.1016/j.bone.2009.08.008
7. Isakova T, Wahl P, Vargas GS, Gutierrez OM, Scialla J, Xie H, et al. Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease. Kidney Int. 2011;79(12):1370–8. 10.1038/ki.2011.47
8. Larsson T, Nisbeth U, Ljunggren O, Juppner H, Jonsson KB. Circulating concentration of FGF-23 increases as renal function declines in patients with chronic kidney disease, but does not change in response to variation in phosphate intake in healthy volunteers. Kidney Int. 2003;64(6):2272–9. 10.1046/j.1523-1755.2003.00328.x
9. Gutierrez O, Isakova T, Rhee E, Shah A, Holmes J, Collerone G, et al. Fibroblast growth factor-23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease. J Am Soc Nephrol. 2005;16(7):2205–15. 10.1681/asn.2005010052
10. Portale AA, Wolf M, Juppner H, Messinger S, Kumar J, Wesseling-Perry K, et al. Disordered FGF23 and mineral metabolism in children with CKD. Clin J Am Soc Nephrol. 2014;9(2):344–53. 10.2215/cjn.05840513
11. Faul C, Amaral AP, Oskouei B, Hu MC, Sloan A, Isakova T, et al. FGF23 induces left ventricular hypertrophy. J Clin Invest. 2011;121(11):4393–408. 10.1172/jci46122
12. Gutierrez OM, Januzzi JL, Isakova T, Laliberte K, Smith K, Collerone G, et al. Fibroblast growth factor 23 and left ventricular hypertrophy in chronic kidney disease. Circulation. 2009;119(19):2545–52. 10.1161/circulationaha.108.844506
13. Mitsnefes MM, Betoko A, Schneider MF, Salusky IB, Wolf MS, Juppner H, et al. FGF23 and left ventricular hypertrophy in children with CKD. Clin J Am Soc Nephrol. 2018;13(1):45–52. 10.2215/cjn.02110217
14. Dai B, David V, Martin A, Huang J, Li H, Jiao Y, et al. A comparative transcriptome analysis identifying FGF23 regulated genes in the kidney of a mouse CKD model. PLoS One. 2012;7(9):e44161. 10.1371/journal.pone.0044161
15. Smith ER, Holt SG, Hewitson TD. FGF23 activates injury-primed renal fibroblasts via FGFR4-dependent signalling and enhancement of TGF-beta autoinduction. Int J Biochem Cell Biol. 2017;92:63–78. 10.1016/j.biocel.2017.09.009
16. Fliser D, Kollerits B, Neyer U, Ankerst DP, Lhotta K, Lingenhel A, et al. Fibroblast growth factor 23 (FGF23) predicts progression of chronic kidney disease: the Mild to Moderate Kidney Disease (MMKD) Study. J Am Soc Nephrol. 2007;18(9):2600–8. 10.1681/asn.2006080936
17. Isakova T, Xie H, Yang W, Xie D, Anderson AH, Scialla J, et al. Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease. JAMA. 2011;305(23):2432–9. 10.1001/jama.2011.826
18. Portale AA, Wolf MS, Messinger S, Perwad F, Juppner H, Warady BA, et al. Fibroblast growth factor 23 and risk of CKD progression in children. Clin J Am Soc Nephrol. 2016;11(11):1989–98. 10.2215/cjn.02110216
19. Rossaint J, Oehmichen J, Van Aken H, Reuter S, Pavenstadt HJ, Meersch M, et al. FGF23 signaling impairs neutrophil recruitment and host defense during CKD. J Clin Invest. 2016;126(3):962–74. 10.1172/jci83470
20. Chonchol M, Greene T, Zhang Y, Hoofnagle AN, Cheung AK. Low vitamin D and high fibroblast growth factor 23 serum levels associate with infectious and cardiac deaths in the HEMO study. J Am Soc Nephrol. 2016;27(1):227–37. 10.1681/asn.2014101009
21. Gutierrez OM, Mannstadt M, Isakova T, Rauh-Hain JA, Tamez H, Shah A, et al. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med. 2008;359(6):584–92. 10.1056/NEJMoa0706130
22. Komaba H, Fukagawa M. The role of FGF23 in CKD--with or without Klotho. Nat Rev Nephrol. 2012;8(8):484–90. 10.1038/nrneph.2012.116
23. Tagliabracci VS, Engel JL, Wiley SE, Xiao J, Gonzalez DJ, Nidumanda Appaiah H, et al. Dynamic regulation of FGF23 by Fam20C phosphorylation, GalNAc-T3 glycosylation, and furin proteolysis. Proc Natl Acad Sci U S A. 2014;111(15):5520–5. 10.1073/pnas.1402218111
24. Yamamoto H, Ramos-Molina B, Lick AN, Prideaux M, Albornoz V, Bonewald L, et al. Posttranslational processing of FGF23 in osteocytes during the osteoblast to osteocyte transition. Bone. 2016;84:120–30. 10.1016/j.bone.2015.12.055
25. Wolf M, White KE. Coupling fibroblast growth factor 23 production and cleavage: iron deficiency, rickets, and kidney disease. Curr Opin Nephrol Hypertens. 2014;23(4):411–9. 10.1097/01.mnh.0000447020.74593.6f
26. Shimada T, Urakawa I, Isakova T, Yamazaki Y, Epstein M, Wesseling-Perry K, et al. Circulating fibroblast growth factor 23 in patients with end-stage renal disease treated by peritoneal dialysis is intact and biologically active. J Clin Endocrinol Metab. 2010;95(2):578–85. 10.1210/jc.2009-1603
27. Smith ER, Cai MM, McMahon LP, Holt SG. Biological variability of plasma intact and C-terminal FGF23 measurements. J Clin Endocrinol Metab. 2012;97(9):3357–65. 10.1210/jc.2012-1811
28. 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. 10.1074/jbc.M408903200
29. Antoniucci DM, Yamashita T, Portale AA. Dietary phosphorus regulates serum fibroblast growth factor-23 concentrations in healthy men. J Clin Endocrinol Metab. 2006;91(8):3144–9. 10.1210/jc.2006-0021
30. Wesseling-Perry K, Pereira RC, Sahney S, Gales B, Wang HJ, Elashoff R, et al. Calcitriol and doxercalciferol are equivalent in controlling bone turnover, suppressing parathyroid hormone, and increasing fibroblast growth factor-23 in secondary hyperparathyroidism. Kidney Int. 2011;79(1):112–9. 10.1038/ki.2010.352
31. Lavi-Moshayoff V, Wasserman G, Meir T, Silver J, Naveh-Many T. PTH increases FGF23 gene expression and mediates the high-FGF23 levels of experimental kidney failure: a bone parathyroid feedback loop. Am J Physiol Ren Physiol. 2010;299(4):F882–9. 10.1152/ajprenal.00360.2010
32. Lopez I, Rodriguez-Ortiz ME, Almaden Y, Guerrero F, de Oca AM, Pineda C, et al. Direct and indirect effects of parathyroid hormone on circulating levels of fibroblast growth factor 23 in vivo. Kidney Int. 2011;80(5):475–82. 10.1038/ki.2011.107
33. Shimada T, Yamazaki Y, Takahashi M, Hasegawa H, Urakawa I, Oshima T, et al. Vitamin D receptor-independent FGF23 actions in regulating phosphate and vitamin D metabolism. Am J Physiol Ren Physiol. 2005;289(5):F1088–95. 10.1152/ajprenal.00474.2004
34. Hu MC, Kuro-o M, Moe OW. Klotho and chronic kidney disease. Contrib Nephrol. 2013;180:47–63. 10.1159/000346778
35. Farrow EG, Yu X, Summers LJ, Davis SI, Fleet JC, Allen MR, et al. Iron deficiency drives an autosomal dominant hypophosphatemic rickets (ADHR) phenotype in fibroblast growth factor-23 (Fgf23) knock-in mice. Proc Natl Acad Sci U S A. 2011;108(46):E1146–55. 10.1073/pnas.1110905108
36. Clinkenbeard EL, Farrow EG, Summers LJ, Cass TA, Roberts JL, Bayt CA, et al. Neonatal iron deficiency causes abnormal phosphate metabolism by elevating FGF23 in normal and ADHR mice. J Bone Miner Res. 2014;29(2):361–9. 10.1002/jbmr.2049
37. • David V, Martin A, Isakova T, Spaulding C, Qi L, Ramirez V, et al. Inflammation and functional iron deficiency regulate fibroblast growth factor 23 production. Kidney Int. 2016;89(1):135–46. 10.1038/ki.2015.290 This study demonstrates the effects of iron deficiency and inflammation on FGF23 production and metabolism
38. Hanudel MR, Chua K, Rappaport M, Gabayan V, Valore E, Goltzman D, et al. Effects of dietary iron intake and chronic kidney disease on fibroblast growth factor 23 metabolism in wild-type and hepcidin knockout mice. Am J Physiol Ren Physiol. 2016;311(6):F1369–f77. 10.1152/ajprenal.00281.2016
39. Durham BH, Joseph F, Bailey LM, Fraser WD. The association of circulating ferritin with serum concentrations of fibroblast growth factor-23 measured by three commercial assays. Ann Clin Biochem. 2007;44(Pt 5):463–6. 10.1258/000456307781646102
40. Imel EA, Peacock M, Gray AK, Padgett LR, Hui SL, Econs MJ. Iron modifies plasma FGF23 differently in autosomal dominant hypophosphatemic rickets and healthy humans. J Clin Endocrinol Metab. 2011;96(11):3541–9. 10.1210/jc.2011-1239
41. Wolf M, Koch TA, Bregman DB. Effects of iron deficiency anemia and its treatment on fibroblast growth factor 23 and phosphate homeostasis in women. J Bone Miner Res. 2013;28(8):1793–803. 10.1002/jbmr.1923
42. Ali FN, Josefson J, Mendez AJ, Mestan K, Wolf M. Cord blood ferritin and fibroblast growth Factor-23 levels in neonates. J Clin Endocrinol Metab. 2016;101(4):1673–9. 10.1210/jc.2015-3709
43. Imel EA, Liu Z, McQueen AK, Acton D, Acton A, Padgett LR, et al. Serum fibroblast growth factor 23, serum iron and bone mineral density in premenopausal women. Bone. 2016;86:98–105. 10.1016/j.bone.2016.03.005
44. Lewerin C, Ljunggren O, Nilsson-Ehle H, Karlsson MK, Herlitz H, Lorentzon M, et al. Low serum iron is associated with high serum intact FGF23 in elderly men: the Swedish MrOS study. Bone. 2017;98:1–8. 10.1016/j.bone.2017.02.005
45. Zhang Q, Doucet M, Tomlinson RE, Han X, Quarles LD, Collins MT, et al. The hypoxia-inducible factor-1alpha activates ectopic production of fibroblast growth factor 23 in tumor-induced osteomalacia. Bone Res. 2016;4:16011. 10.1038/boneres.2016.11
46. Hanudel MR, Wesseling-Perry K, Gales B, Ramos G, Campbell V, Ethridge K, et al. Effects of acute kidney injury and chronic hypoxemia on fibroblast growth factor 23 levels in pediatric cardiac surgery patients. Pediatr Nephrol. 2016;31(4):661–9. 10.1007/s00467-015-3257-5
47. McMahon S, Grondin F, McDonald PP, Richard DE, Dubois CM. Hypoxia-enhanced expression of the proprotein convertase furin is mediated by hypoxia-inducible factor-1: impact on the bioactivation of proproteins. J Biol Chem. 2005;280(8):6561–9. 10.1074/jbc.M413248200
48. Silvestri L, Pagani A, Camaschella C. Furin-mediated release of soluble hemojuvelin: a new link between hypoxia and iron homeostasis. Blood. 2008;111(2):924–31. 10.1182/blood-2007-07-100677
49. Munoz Mendoza J, Isakova T, Ricardo AC, Xie H, Navaneethan SD, Anderson AH, et al. Fibroblast growth factor 23 and inflammation in CKD. Clin J Am Soc Nephrol. 2012;7(7):1155–62. 10.2215/cjn.13281211
50. Hanks LJ, Casazza K, Judd SE, Jenny NS, Gutierrez OM. Associations of fibroblast growth factor-23 with markers of inflammation, insulin resistance and obesity in adults. PLoS One. 2015;10(3):e0122885. 10.1371/journal.pone.0122885
51. Ito N, Wijenayaka AR, Prideaux M, Kogawa M, Ormsby RT, Evdokiou A, et al. Regulation of FGF23 expression in IDG-SW3 osteocytes and human bone by pro-inflammatory stimuli. Mol Cell Endocrinol. 2015;399:208–18. 10.1016/j.mce.2014.10.007
52. Durlacher-Betzer K, Hassan A, Levi R, Axelrod J, Silver J, Naveh-Many T. Interleukin-6 contributes to the increase in fibroblast growth factor 23 expression in acute and chronic kidney disease. Kidney Int. 2018;94:315–25. 10.1016/j.kint.2018.02.026
53. Ganz T. Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood. 2003;102(3):783–8. 10.1182/blood-2003-03-0672
54. Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 2004;306(5704):2090–3. 10.1126/science.1104742
55. Clinkenbeard EL, Hanudel MR, Stayrook KR, Appaiah HN, Farrow EG, Cass TA, et al. Erythropoietin stimulates murine and human fibroblast growth factor-23, revealing novel roles for bone and bone marrow. Haematologica. 2017;102(11):e427–e30. 10.3324/haematol.2017.167882
56. Rabadi S, Udo I, Leaf DE, Waikar SS, Christov M. Acute blood loss stimulates fibroblast growth factor 23 production. Am J Physiol Ren Physiol. 2018;314(1):F132–f9. 10.1152/ajprenal.00081.2017
57. Flamme I, Ellinghaus P, Urrego D, Kruger T. FGF23 expression in rodents is directly induced via erythropoietin after inhibition of hypoxia inducible factor proline hydroxylase. PLoS One. 2017;12(10):e0186979. 10.1371/journal.pone.0186979
58. Toro L, Barrientos V, Leon P, Rojas M, Gonzalez M, Gonzalez-Ibanez A, et al. Erythropoietin induces bone marrow and plasma fibroblast growth factor 23 during acute kidney injury. Kidney Int. 2018;93(5):1131–41. 10.1016/j.kint.2017.11.018
59. Daryadel A, Bettoni C, Haider T, Imenez Silva PH, Schnitzbauer U, Pastor-Arroyo EM, et al. Erythropoietin stimulates fibroblast growth factor 23 (FGF23) in mice and men. Pflugers Arch. 2018;470:1569–82. 10.1007/s00424-018-2171-7
60. Hanudel MR, Eisenga MF, Rappaport M, Chua K, Qiao B, Jung G, et al. Effects of erythropoietin on fibroblast growth factor 23 in mice and humans. Nephrol Dial Transplant. 2018. 10.1093/ndt/gfy189
61. Artunc F, Risler T. Serum erythropoietin concentrations and responses to anaemia in patients with or without chronic kidney disease. Nephrol Dial Transplant. 2007;22(10):2900–8. 10.1093/ndt/gfm316
62. • Coe LM, Madathil SV, Casu C, Lanske B, Rivella S, Sitara D. FGF-23 is a negative regulator of prenatal and postnatal erythropoiesis. J Biol Chem. 2014;289(14):9795–810. 10.1074/jbc.M113.527150 This study demonstrates how FGF23 may inhibit aspects of erythropoiesis
63. Agoro R, Montagna A, Goetz R, Aligbe O, Singh G, Coe LM, et al. Inhibition of fibroblast growth factor 23 (FGF23) signaling rescues renal anemia. FASEB J. 2018. 10.1096/fj.201700667R
64. Mehta R, Cai X, Hodakowski A, Lee J, Leonard M, Ricardo A, et al. Fibroblast growth factor 23 and anemia in the chronic renal insufficiency cohort study. Clin J Am Soc Nephrol. 2017;12(11):1795–803. 10.2215/cjn.03950417
65. Singh S, Grabner A, Yanucil C, Schramm K, Czaya B, Krick S, et al. Fibroblast growth factor 23 directly targets hepatocytes to promote inflammation in chronic kidney disease. Kidney Int. 2016;90(5):985–96. 10.1016/j.kint.2016.05.019