fibroblast growth factor 23

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|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.{{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 }} FGF23 is a member of the fibroblast growth factor (FGF) family which participates in phosphate and vitamin D metabolism and regulation.{{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 }}

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.{{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}}{{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 }}{{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 }}{{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 }} FGF23 acts on the kidneys by decreasing the expression of NPT2, a sodium-phosphate cotransporter in the proximal tubule.{{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 }}

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

Genetics

In humans FGF23 is encoded by the {{gene|FGF23}} 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.{{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}}

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.{{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 }}{{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 }}

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.{{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 }}

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

FGF23 expression and cleavage is promoted by iron deficiency and inflammation.{{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 }}

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.

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.{{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 }} 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.