View source for Fibroblast growth factor 23

{{Short description|Protein found in humans}}
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'''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 [[Coding region|encode]]d by the {{gene|FGF23}} [[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|FGF23}} [[gene]].<ref name="pmid11032749">{{cite journal | vauthors = Yamashita T, Yoshioka M, Itoh N | title = Identification of a novel fibroblast growth factor, FGF-23, preferentially expressed in the ventrolateral thalamic nucleus of the brain | journal = Biochemical and Biophysical Research Communications | volume = 277 | issue = 2 | pages = 494–498 | date = October 2000 | pmid = 11032749 | doi = 10.1006/bbrc.2000.3696 }}</ref> FGF23 is a member of the [[fibroblast growth factor]] (FGF) family which participates in [[phosphate]] and [[vitamin D]] metabolism and regulation.<ref name="pmid18310961">{{cite journal | vauthors = Fukumoto S | title = Physiological regulation and disorders of phosphate metabolism--pivotal role of fibroblast growth factor 23 | journal = Internal Medicine | volume = 47 | issue = 5 | pages = 337–343 | year = 2008 | pmid = 18310961 | doi = 10.2169/internalmedicine.47.0730 | doi-access = free }}</ref><ref name="pmid17699549" />

== 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 [[osteocyte]]s in response to increased [[calcitriol]] and phosphate.<ref name="Dance">{{cite journal | vauthors = Dance A |title=Fun facts about bones: More than just scaffolding |journal=Knowable Magazine |date=23 February 2022 |doi=10.1146/knowable-022222-1|s2cid=247095495 |doi-access=free |url=https://knowablemagazine.org/article/health-disease/2022/fun-facts-about-bones-more-just-scaffolding |access-date=8 March 2022|url-access=subscription }}</ref><ref name="Robling">{{cite journal | vauthors = Robling AG, Bonewald LF | title = The Osteocyte: New Insights | journal = Annual Review of Physiology | volume = 82 | issue = 1 | pages = 485–506 | date = February 2020 | pmid = 32040934 | pmc = 8274561 | doi = 10.1146/annurev-physiol-021119-034332 }}</ref><ref name="pmid18606998">{{cite journal | vauthors = Cha SK, Ortega B, Kurosu H, Rosenblatt KP, Kuro-O M, Huang CL | title = Removal of sialic acid involving Klotho causes cell-surface retention of TRPV5 channel via binding to galectin-1 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 28 | pages = 9805–9810 | date = July 2008 | pmid = 18606998 | pmc = 2474477 | doi = 10.1073/pnas.0803223105 | doi-access = free | bibcode = 2008PNAS..105.9805C }}</ref><ref>{{cite book | vauthors = Brown RB, Razzaque MS | chapter = Chapter 31 - Endocrine Regulation of Phosphate Homeostasis |date= January 2018 | title = Textbook of Nephro-Endocrinology | edition = Second |pages=539–548 | veditors = Singh AK, Williams GH |publisher=Academic Press |language=en |doi=10.1016/b978-0-12-803247-3.00032-5 |isbn=978-0-12-803247-3  |hdl=10012/15679 |s2cid=102827267 |hdl-access=free }}</ref> FGF23 acts on the kidneys by decreasing the expression of NPT2, a [[sodium/phosphate cotransporter|sodium-phosphate cotransporter]] in the [[proximal tubule]].<ref name="pmid21346724">{{cite journal | vauthors = Jüppner H | title = Phosphate and FGF-23 | journal = Kidney International. Supplement | volume = 79 | issue = 121 | pages = S24–S27 | date = April 2011 | pmid = 21346724 | pmc = 3257051 | doi = 10.1038/ki.2011.27 }}</ref>

FGF23 may also suppress [[25-Hydroxyvitamin D3 1-alpha-hydroxylase|1-alpha-hydroxylase]], reducing its ability to activate [[vitamin D]] and subsequently impairing calcium absorption.<ref name="pmid17699549">{{cite journal | vauthors = Perwad F, Zhang MY, Tenenhouse HS, Portale AA | title = Fibroblast growth factor 23 impairs phosphorus and vitamin D metabolism in vivo and suppresses 25-hydroxyvitamin D-1alpha-hydroxylase expression in vitro | journal = American Journal of Physiology. Renal Physiology | volume = 293 | issue = 5 | pages = F1577–F1583 | date = November 2007 | pmid = 17699549 | doi = 10.1152/ajprenal.00463.2006 | s2cid = 20559055 }}</ref><ref name="pmid27081473">{{cite journal | vauthors = Rodríguez-Ortiz ME, Rodríguez M | title = FGF23 as a calciotropic hormone | journal = F1000Research | volume = 4 | pages = 1472 | year = 2015 | pmid = 27081473 | pmc = 4815615 | doi = 10.12688/f1000research.7189.1 | doi-access = free }}</ref>

==Genetics==
In humans FGF23 is encoded by the {{gene|FGF23}} [[gene]], which is located on [[chromosome 12]] and is composed of three [[exon]]s. The gene was identified by its mutations associated with [[autosomal dominant hypophosphatemic rickets]].<ref name="entrez">{{cite web | title = Entrez Gene: FGF23 fibroblast growth factor 23| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=8074}}</ref>

== Clinical significance ==

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

FGF23 can also be overproduced by some types of [[tumor]]s, such as the [[benign]] [[mesenchymal]] neoplasm [[phosphaturic mesenchymal tumor]] causing [[tumor-induced osteomalacia]], a [[paraneoplastic syndrome]].<ref name="TIO">{{cite journal | vauthors = Zadik Y, Nitzan DW | title = Tumor induced osteomalacia: a forgotten paraneoplastic syndrome? | journal = Oral Oncology | volume = 48 | issue = 2 | pages = e9-10 | date = February 2012 | pmid = 21985764 | doi = 10.1016/j.oraloncology.2011.09.011 }}</ref><ref name="pmid28932769">{{cite journal | vauthors = Green D, Mohorianu I, Piec I, Turner J, Beadsmoore C, Toms A, Ball R, Nolan J, McNamara I, Dalmay T, Fraser WD | title = MicroRNA expression in a phosphaturic mesenchymal tumour | journal = Bone Reports | volume = 7 | pages = 63–69 | date = December 2017 | pmid = 28932769 | pmc = 5596358 | doi = 10.1016/j.bonr.2017.09.001 | doi-access = free }}</ref>

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 (biology)|klotho]] enzyme age prematurely due to [[hyperphosphatemia]].<ref name="pmid20375979">{{cite journal | vauthors = Huang CL | title = Regulation of ion channels by secreted Klotho: mechanisms and implications | journal = Kidney International | volume = 77 | issue = 10 | pages = 855–860 | date = May 2010 | pmid = 20375979 | doi = 10.1038/ki.2010.73 | doi-access = free }}</ref>

Over-expression of FGF23 has been associated with cardiovascular disease in chronic kidney disease including cardiomyocyte hypertrophy, vascular calcification, stroke, and endothelial dysfunction.<ref name="Beck-Nielsen">{{cite journal | vauthors = Beck-Nielsen SS, Mughal Z, Haffner D, Nilsson O, Levtchenko E, Ariceta G, de Lucas Collantes C, Schnabel D, Jandhyala R, Mäkitie O | title = FGF23 and its role in X-linked hypophosphatemia-related morbidity | journal = Orphanet Journal of Rare Diseases | volume = 14 | issue = 1 | pages = 58 | date = February 2019 | pmid = 30808384 | pmc = 6390548 | doi = 10.1186/s13023-019-1014-8 | doi-access = free }}</ref>

FGF23 expression and cleavage is promoted by [[iron deficiency]] and inflammation.<ref name= "David">{{cite journal | vauthors = David V, Martin A, Isakova T, Spaulding C, Qi L, Ramirez V, Zumbrennen-Bullough KB, Sun CC, Lin HY, Babitt JL, Wolf M | title = Inflammation and functional iron deficiency regulate fibroblast growth factor 23 production | journal = Kidney International | volume = 89 | issue = 1 | pages = 135–146 | date = January 2016 | pmid = 26535997 | pmc = 4854810 | doi = 10.1038/ki.2015.290 | doi-access = free }}</ref>

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.<ref name="Beck-Nielsen"/>

==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.<ref>{{cite journal | vauthors = Strewler GJ | title = FGF23, hypophosphatemia, and rickets: has phosphatonin been found? | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 11 | pages = 5945–5946 | date = May 2001 | pmid = 11371627 | pmc = 33399 | doi = 10.1073/pnas.11154898 | doi-access = free }}</ref>  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 ==
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== Further reading ==
{{refbegin | 2}}
* {{cite journal | vauthors = Kiela PR, Ghishan FK | title = Recent advances in the renal-skeletal-gut axis that controls phosphate homeostasis | journal = Laboratory Investigation; A Journal of Technical Methods and Pathology | volume = 89 | issue = 1 | pages = 7–14 | date = January 2009 | pmid = 19029978 | pmc = 4292907 | doi = 10.1038/labinvest.2008.114 }}
* {{cite journal | vauthors = Silve C, Beck L | title = Is FGF23 the long sought after phosphaturic factor phosphatonin? | journal = Nephrology, Dialysis, Transplantation | volume = 17 | issue = 6 | pages = 958–961 | date = June 2002 | pmid = 12032180 | doi = 10.1093/ndt/17.6.958 | doi-access =  }}
* {{cite journal | vauthors = Quarles LD | title = FGF23, PHEX, and MEPE regulation of phosphate homeostasis and skeletal mineralization | journal = American Journal of Physiology. Endocrinology and Metabolism | volume = 285 | issue = 1 | pages = E1–E9 | date = July 2003 | pmid = 12791601 | doi = 10.1152/ajpendo.00016.2003 }}
* {{cite journal | vauthors = Fukagawa M, Nii-Kono T, Kazama JJ | title = Role of fibroblast growth factor 23 in health and in chronic kidney disease | journal = Current Opinion in Nephrology and Hypertension | volume = 14 | issue = 4 | pages = 325–329 | date = July 2005 | pmid = 15930999 | doi = 10.1097/01.mnh.0000172717.49476.80 | s2cid = 23555353 }}
* {{cite journal | vauthors = Imel EA, Econs MJ | title = Fibroblast growth factor 23: roles in health and disease | journal = Journal of the American Society of Nephrology | volume = 16 | issue = 9 | pages = 2565–2575 | date = September 2005 | pmid = 16033853 | doi = 10.1681/ASN.2005050573 | s2cid = 8612881 | doi-access =  }}
* {{cite journal | vauthors = Liu S, Quarles LD | title = How fibroblast growth factor 23 works | journal = Journal of the American Society of Nephrology | volume = 18 | issue = 6 | pages = 1637–1647 | date = June 2007 | pmid = 17494882 | doi = 10.1681/ASN.2007010068 | doi-access = free }}
* {{cite journal | title = Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23 | journal = Nature Genetics | volume = 26 | issue = 3 | pages = 345–348 | date = November 2000 | pmid = 11062477 | doi = 10.1038/81664 | collaboration = ADHR Consortium | s2cid = 38870810 | vauthors = White KE, Evans WE, O'Riordan JL, Speer MC, Econs MJ, Lorenz-Depiereux B, Grabowski M, Meitinger T, Strom TM }}
* {{cite journal | vauthors = 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 | title = The autosomal dominant hypophosphatemic rickets (ADHR) gene is a secreted polypeptide overexpressed by tumors that cause phosphate wasting | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 86 | issue = 2 | pages = 497–500 | date = February 2001 | pmid = 11157998 | doi = 10.1210/jcem.86.2.7408 | doi-access = free }}
* {{cite journal | vauthors = Shimada T, Mizutani S, Muto T, Yoneya T, Hino R, Takeda S, Takeuchi Y, Fujita T, Fukumoto S, Yamashita T | title = Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 11 | pages = 6500–6505 | date = May 2001 | pmid = 11344269 | pmc = 33497 | doi = 10.1073/pnas.101545198 | doi-access = free | bibcode = 2001PNAS...98.6500S }}
* {{cite journal | vauthors = Bowe AE, Finnegan R, Jan de Beur SM, Cho J, Levine MA, Kumar R, Schiavi SC | title = FGF-23 inhibits renal tubular phosphate transport and is a PHEX substrate | journal = Biochemical and Biophysical Research Communications | volume = 284 | issue = 4 | pages = 977–981 | date = June 2001 | pmid = 11409890 | doi = 10.1006/bbrc.2001.5084 }}
* {{cite journal | vauthors = White KE, Carn G, Lorenz-Depiereux B, Benet-Pages A, Strom TM, Econs MJ | title = Autosomal-dominant hypophosphatemic rickets (ADHR) mutations stabilize FGF-23 | journal = Kidney International | volume = 60 | issue = 6 | pages = 2079–2086 | date = December 2001 | pmid = 11737582 | doi = 10.1046/j.1523-1755.2001.00064.x | doi-access = free }}
* {{cite journal | vauthors = Kruse K, Woelfel D, Strom TM | title = Loss of renal phosphate wasting in a child with autosomal dominant hypophosphatemic rickets caused by a FGF23 mutation | journal = Hormone Research | volume = 55 | issue = 6 | pages = 305–308 | year = 2002 | pmid = 11805436 | doi = 10.1159/000050018 | doi-broken-date = 1 November 2024 | s2cid = 46748089 }}
* {{cite journal | vauthors = Yamashita T, Konishi M, Miyake A, Inui K, Itoh N | title = Fibroblast growth factor (FGF)-23 inhibits renal phosphate reabsorption by activation of the mitogen-activated protein kinase pathway | journal = The Journal of Biological Chemistry | volume = 277 | issue = 31 | pages = 28265–28270 | date = August 2002 | pmid = 12032146 | doi = 10.1074/jbc.M202527200 | doi-access = free }}
* {{cite journal | vauthors = Saito H, Kusano K, Kinosaki M, Ito H, Hirata M, Segawa H, Miyamoto K, Fukushima N | title = Human fibroblast growth factor-23 mutants suppress Na+-dependent phosphate co-transport activity and 1alpha,25-dihydroxyvitamin D3 production | journal = The Journal of Biological Chemistry | volume = 278 | issue = 4 | pages = 2206–2211 | date = January 2003 | pmid = 12419819 | doi = 10.1074/jbc.M207872200 | doi-access = free }}
* {{cite journal | vauthors = Bai XY, Miao D, Goltzman D, Karaplis AC | title = The autosomal dominant hypophosphatemic rickets R176Q mutation in fibroblast growth factor 23 resists proteolytic cleavage and enhances in vivo biological potency | journal = The Journal of Biological Chemistry | volume = 278 | issue = 11 | pages = 9843–9849 | date = March 2003 | pmid = 12519781 | doi = 10.1074/jbc.M210490200 | doi-access = free }}
* {{cite journal | vauthors = Larsson T, Zahradnik R, Lavigne J, Ljunggren O, Jüppner H, Jonsson KB | title = Immunohistochemical detection of FGF-23 protein in tumors that cause oncogenic osteomalacia | journal = European Journal of Endocrinology | volume = 148 | issue = 2 | pages = 269–276 | date = February 2003 | pmid = 12590648 | doi = 10.1530/eje.0.1480269 | doi-access = free }}
* {{cite journal | vauthors = Campos M, Couture C, Hirata IY, Juliano MA, Loisel TP, Crine P, Juliano L, Boileau G, Carmona AK | title = 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 | journal = The Biochemical Journal | volume = 373 | issue = Pt 1 | pages = 271–279 | date = July 2003 | pmid = 12678920 | pmc = 1223479 | doi = 10.1042/BJ20030287 }}
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[[Category:Fibroblast growth factor]]