Fibroblast growth factor 23 explained

Fibroblast growth factor 23 (FGF-23) is a protein and member of the fibroblast growth factor (FGF) family which participates in the regulation of phosphate in plasma and vitamin D metabolism. In humans it is encoded by the gene. FGF-23 decreases reabsorption of phosphate in the kidney. Mutations in FGF23 can lead to its increased activity, resulting in autosomal dominant hypophosphatemic rickets.

Description

Fibroblast growth factor 23 (FGF23) is a protein which in humans is encoded by the gene.^[1] FGF23 is a member of the fibroblast growth factor (FGF) family which participates in phosphate and vitamin D metabolism and regulation.^[2]

Function

FGF23´s main function is to regulate the phosphate concentration in plasma. It does this by decreasing reabsorption of phosphate in the kidney, which means phosphate is excreted in urine. FGF23 is secreted by osteocytes in response to increased calcitriol and phosphate.^{[3] [4] [5]} FGF23 acts on the kidneys by decreasing the expression of NPT2, a sodium-phosphate cotransporter in the proximal tubule.^[6]

FGF23 may also suppress 1-alpha-hydroxylase, reducing its ability to activate vitamin D and subsequently impairing calcium absorption.^{[7] [8]}

Genetics

In humans FGF23 is encoded by the gene, which is located on chromosome 12 and is composed of three exons. The gene was identified by its mutations associated with autosomal dominant hypophosphatemic rickets.^[9]

Clinical significance

Mutations in FGF23, which render the protein resistant to proteolytic cleavage, lead to its increased activity and to renal phosphate loss, in the human disease autosomal dominant hypophosphatemic rickets.

FGF23 can also be overproduced by some types of tumors, such as the benign mesenchymal neoplasm phosphaturic mesenchymal tumor causing tumor-induced osteomalacia, a paraneoplastic syndrome.^{[10] [11]}

Loss of FGF23 activity is thought to lead to increased phosphate levels and the clinical syndrome of familial tumor calcinosis. Mice lacking either FGF23 or the klotho enzyme age prematurely due to hyperphosphatemia.^[12]

Over-expression of FGF23 has been associated with cardiovascular disease in chronic kidney disease including cardiomyocyte hypertrophy, vascular calcification, stroke, and endothelial dysfunction.^[13]

FGF23 expression and cleavage is promoted by iron deficiency and inflammation.^[14]

FGF23 is associated with at least 7 non-nutritional diseases of hypophosphatemia: aside from autosomal dominant hypophosphatemic rickets, X-linked hypophosphatemia, autosomal recessive hypophosphatemic rickets type 1, 2, and 3, Tumor-induced osteomalacia and Hypophosphatemic rickets with hypercalciuria.^[13]

History

Prior to its discovery in 2000, it was hypothesized that a protein existed which performed the functions subsequently shown for FGF23. This putative protein was known as phosphatonin.^[15] Several types of effects were described including impairment of sodium dependent phosphate transport in both intestinal and renal brush border membrane vesicles, inhibition of production of calcitriol, stimulation of breakdown of calcitriol, and inhibition of production/secretion of parathyroid hormone.

References

Further reading

• Kiela PR, Ghishan FK . Recent advances in the renal-skeletal-gut axis that controls phosphate homeostasis . Laboratory Investigation; A Journal of Technical Methods and Pathology . 89 . 1 . 7–14 . January 2009 . 19029978 . 4292907 . 10.1038/labinvest.2008.114 .
• Silve C, Beck L . Is FGF23 the long sought after phosphaturic factor phosphatonin? . Nephrology, Dialysis, Transplantation . 17 . 6 . 958–61 . June 2002 . 12032180 . 10.1093/ndt/17.6.958 .
• Quarles LD . FGF23, PHEX, and MEPE regulation of phosphate homeostasis and skeletal mineralization . American Journal of Physiology. Endocrinology and Metabolism . 285 . 1 . E1-9 . July 2003 . 12791601 . 10.1152/ajpendo.00016.2003 .
• Fukagawa M, Nii-Kono T, Kazama JJ . Role of fibroblast growth factor 23 in health and in chronic kidney disease . Current Opinion in Nephrology and Hypertension . 14 . 4 . 325–9 . July 2005 . 15930999 . 10.1097/01.mnh.0000172717.49476.80 . 23555353 .
• Imel EA, Econs MJ . Fibroblast growth factor 23: roles in health and disease . Journal of the American Society of Nephrology . 16 . 9 . 2565–75 . September 2005 . 16033853 . 10.1681/ASN.2005050573 . 8612881 .
• Liu S, Quarles LD . How fibroblast growth factor 23 works . Journal of the American Society of Nephrology . 18 . 6 . 1637–47 . June 2007 . 17494882 . 10.1681/ASN.2007010068 . free .
• White KE, Evans WE, O'Riordan JL, Speer MC, Econs MJ, Lorenz-Depiereux B, Grabowski M, Meitinger T, Strom TM . 6 . ADHR Consortium . Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23 . Nature Genetics . 26 . 3 . 345–348 . November 2000 . 11062477 . 10.1038/81664 . 38870810 .
• White KE, Jonsson KB, Carn G, Hampson G, Spector TD, Mannstadt M, Lorenz-Depiereux B, Miyauchi A, Yang IM, Ljunggren O, Meitinger T, Strom TM, Jüppner H, Econs MJ . 6 . The autosomal dominant hypophosphatemic rickets (ADHR) gene is a secreted polypeptide overexpressed by tumors that cause phosphate wasting . The Journal of Clinical Endocrinology and Metabolism . 86 . 2 . 497–500 . February 2001 . 11157998 . 10.1210/jcem.86.2.7408 . free .
• Shimada T, Mizutani S, Muto T, Yoneya T, Hino R, Takeda S, Takeuchi Y, Fujita T, Fukumoto S, Yamashita T . 6 . Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia . Proceedings of the National Academy of Sciences of the United States of America . 98 . 11 . 6500–5 . May 2001 . 11344269 . 33497 . 10.1073/pnas.101545198 . 2001PNAS...98.6500S . free .
• Bowe AE, Finnegan R, Jan de Beur SM, Cho J, Levine MA, Kumar R, Schiavi SC . FGF-23 inhibits renal tubular phosphate transport and is a PHEX substrate . Biochemical and Biophysical Research Communications . 284 . 4 . 977–81 . June 2001 . 11409890 . 10.1006/bbrc.2001.5084 .
• White KE, Carn G, Lorenz-Depiereux B, Benet-Pages A, Strom TM, Econs MJ . Autosomal-dominant hypophosphatemic rickets (ADHR) mutations stabilize FGF-23 . Kidney International . 60 . 6 . 2079–86 . December 2001 . 11737582 . 10.1046/j.1523-1755.2001.00064.x . free .
• Kruse K, Woelfel D, Strom TM, Storm TM . Loss of renal phosphate wasting in a child with autosomal dominant hypophosphatemic rickets caused by a FGF23 mutation . Hormone Research . 55 . 6 . 305–8 . 2002 . 11805436 . 10.1159/000050018 . 46748089 .
• Yamashita T, Konishi M, Miyake A, Inui K, Itoh N . Fibroblast growth factor (FGF)-23 inhibits renal phosphate reabsorption by activation of the mitogen-activated protein kinase pathway . The Journal of Biological Chemistry . 277 . 31 . 28265–70 . August 2002 . 12032146 . 10.1074/jbc.M202527200 . free .
• Saito H, Kusano K, Kinosaki M, Ito H, Hirata M, Segawa H, Miyamoto K, Fukushima N . 6 . Human fibroblast growth factor-23 mutants suppress Na+-dependent phosphate co-transport activity and 1alpha,25-dihydroxyvitamin D3 production . The Journal of Biological Chemistry . 278 . 4 . 2206–11 . January 2003 . 12419819 . 10.1074/jbc.M207872200 . free .
• 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 . The Journal of Biological Chemistry . 278 . 11 . 9843–9 . March 2003 . 12519781 . 10.1074/jbc.M210490200 . free .
• Larsson T, Zahradnik R, Lavigne J, Ljunggren O, Jüppner H, Jonsson KB . Immunohistochemical detection of FGF-23 protein in tumors that cause oncogenic osteomalacia . European Journal of Endocrinology . 148 . 2 . 269–76 . February 2003 . 12590648 . 10.1530/eje.0.1480269 . free .
• Campos M, Couture C, Hirata IY, Juliano MA, Loisel TP, Crine P, Juliano L, Boileau G, Carmona AK . 6 . Human recombinant endopeptidase PHEX has a strict S1' specificity for acidic residues and cleaves peptides derived from fibroblast growth factor-23 and matrix extracellular phosphoglycoprotein . The Biochemical Journal . 373 . Pt 1 . 271–9 . July 2003 . 12678920 . 1223479 . 10.1042/BJ20030287 .

Notes and References

1. Yamashita T, Yoshioka M, Itoh N . Identification of a novel fibroblast growth factor, FGF-23, preferentially expressed in the ventrolateral thalamic nucleus of the brain . Biochemical and Biophysical Research Communications . 277 . 2 . 494–8 . October 2000 . 11032749 . 10.1006/bbrc.2000.3696 .
2. Fukumoto S . Physiological regulation and disorders of phosphate metabolism--pivotal role of fibroblast growth factor 23 . Internal Medicine . 47 . 5 . 337–43 . 2008 . 18310961 . 10.2169/internalmedicine.47.0730 . free .
3. Dance A . Fun facts about bones: More than just scaffolding . Knowable Magazine . 23 February 2022 . 10.1146/knowable-022222-1. 247095495 . free . 8 March 2022.
4. Robling AG, Bonewald LF . The Osteocyte: New Insights . Annual Review of Physiology . 82 . 1 . 485–506 . February 2020 . 32040934 . 10.1146/annurev-physiol-021119-034332 . 8274561 .
5. Cha SK, Ortega B, Kurosu H, Rosenblatt KP, Kuro-O M, Huang CL . Removal of sialic acid involving Klotho causes cell-surface retention of TRPV5 channel via binding to galectin-1 . Proceedings of the National Academy of Sciences of the United States of America . 105 . 28 . 9805–9810 . July 2008 . 18606998 . 2474477 . 10.1073/pnas.0803223105 . free . 2008PNAS..105.9805C .
6. Jüppner H . Phosphate and FGF-23 . Kidney International. Supplement . 79 . 121 . S24–S27 . April 2011 . 21346724 . 3257051 . 10.1038/ki.2011.27 .
7. Perwad F, Zhang MY, Tenenhouse HS, Portale AA . Fibroblast growth factor 23 impairs phosphorus and vitamin D metabolism in vivo and suppresses 25-hydroxyvitamin D-1alpha-hydroxylase expression in vitro . American Journal of Physiology. Renal Physiology . 293 . 5 . F1577-83 . November 2007 . 17699549 . 10.1152/ajprenal.00463.2006 . 20559055 .
8. Rodríguez-Ortiz ME, Rodríguez M . FGF23 as a calciotropic hormone . F1000Research . 4 . 1472 . 2015 . 27081473 . 4815615 . 10.12688/f1000research.7189.1 . free .
9. Web site: Entrez Gene: FGF23 fibroblast growth factor 23.
10. Zadik Y, Nitzan DW . Tumor induced osteomalacia: a forgotten paraneoplastic syndrome? . Oral Oncology . 48 . 2 . e9–10 . February 2012 . 21985764 . 10.1016/j.oraloncology.2011.09.011 .
11. Green D, Mohorianu I, Piec I, Turner J, Beadsmoore C, Toms A, Ball R, Nolan J, McNamara I, Dalmay T, Fraser WD . 6 . MicroRNA expression in a phosphaturic mesenchymal tumour . Bone Reports . 7 . 63–69 . December 2017 . 28932769 . 10.1016/j.bonr.2017.09.001 . 5596358 . free .
12. Huang CL . Regulation of ion channels by secreted Klotho: mechanisms and implications . Kidney International . 77 . 10 . 855–60 . May 2010 . 20375979 . 10.1038/ki.2010.73 . free .
13. Beck-Nielsen . Signe Sparre . Mughal . Zulf . Haffner . Dieter . Nilsson . Ola . Levtchenko . Elena . Ariceta . Gema . de Lucas Collantes . Carmen . Schnabel . Dirk . Jandhyala . Ravi . Mäkitie . Outi . 2019-02-26 . FGF23 and its role in X-linked hypophosphatemia-related morbidity . Orphanet Journal of Rare Diseases . 14 . 1 . 58 . 10.1186/s13023-019-1014-8 . 1750-1172 . 6390548 . 30808384 . free .
14. David . Valentin . Martin . Aline . Isakova . Tamara . Spaulding . Christina . Qi . Lixin . Ramirez . Veronica . Zumbrennen-Bullough . Kimberly . Sun . Chia Chi . Lin . Herbert . Babitt . Jodie . Wolf . Myles . 2016-01-04 . Inflammation and functional iron deficiency regulate fibroblast growth factor 23 production . Kidney International . 89 . 1 . 135–146 . 10.1038/ki.2015.290 . 0085-2538 . 4854810 . 26535997 . free .
15. Strewler GJ . FGF23, hypophosphatemia, and rickets: has phosphatonin been found? . Proceedings of the National Academy of Sciences of the United States of America . 98 . 11 . 5945–6 . May 2001 . 11371627 . 33399 . 10.1073/pnas.11154898 . free .