FGF18 explained

Fibroblast growth factor 18 (FGF-18) is a protein that is encoded by the FGF18 gene in humans.^{[1] [2] [3]} The protein was first discovered in 1998, when two newly-identified murine genes Fgf17 and Fgf18 were described and confirmed as being closely related by sequence homology to Fgf8.^[4] The three proteins were eventually grouped into the FGF8 subfamily, which contains several of the endocrine FGF superfamily members FGF8, FGF17, and FGF18.^[5] Subsequent studies identified FGF18's role in promoting chondrogenesis,^[6] and an apparent specific activity for the generation of the hyaline cartilage in articular joints.^[7]

The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell survival activities, and are involved in a variety of biological processes, including embryonic development, cell growth, morphogenesis, and tissue repair. It has been shown in vitro that this protein is able to induce neurite outgrowth in PC12 cells.^[8]

Function

FGF18 signals through fibroblast growth factor receptor (FGFR) family, preferentially binding FGFR 3c (followed by 4△, 2c, 1c, and finally 3b),^[9] signaling via FGFR3 promotes generation of cartilage (chondrogenesis).^[10] FGF18 and has been shown to cause thickening of cartilage in a murine model of osteoarthritis,^[11] and the recombinant version of it (sprifermin) is in a clinical trial as a potential treatment for osteoarthritis (OA). Recent findings from a placebo-controlled randomized clinical study demonstrate the potential of FGF18 to reduce the rate of progression to joint replacement surgery^[12] and delay progression of OA-related pain (WOMAC).^[13] Another study suggested the ability of FGF18 to inhibit intravertebral disc degeneration in a rabbit model of the disease.

Studies of the similar proteins in mouse and chick suggested that this protein is a pleiotropic growth factor that stimulates proliferation in a number of tissues, most notably the liver and small intestine. Knockout studies of the similar gene in mice implied the role of this protein in regulating proliferation and differentiation of midline cerebellar structures.

FGF18 appears to be a pleiotropic factor, expressed in a broad range of tissues and organs; the highest level of FGF18 expression were confirmed in the right ventricle interventricular septum of the heart.^[14] The role of FGF18 in the heart appears to be associated with protection from stress-induced pathological cardiac hypertrophy via the induction of survival or regenerative signals.^[15] Similarly, studies confirmed that overexpression of FGF18 in the liver was able to attenuate liver fibrosis following chemically-induced injury.^[16]

Studies of FGF18 in relation to oncology have shown both decreased levels^[17] and increased levels^[18] of FGF18 in a number of cancer types and stages, however, FGF18 does not appear to be causative or prognostic^[19] and long-term clinical studies of the FGF18 analog, sprifermin, have demonstrated an excellent safety profile with no reported oncogenic effects.^[20]

Further reading

• Haque T, Nakada S, Hamdy RC . A review of FGF18: Its expression, signaling pathways and possible functions during embryogenesis and post-natal development . Histol. Histopathol. . 22 . 1 . 97–105 . 2007 . 17128416 .
• Hu MC, Wang YP, Qiu WR . Human fibroblast growth factor-18 stimulates fibroblast cell proliferation and is mapped to chromosome 14p11 . Oncogene . 18 . 16 . 2635–42 . 1999 . 10353607 . 10.1038/sj.onc.1202616 . 32973576 .
• Xu J, Liu Z, Ornitz DM . Temporal and spatial gradients of Fgf8 and Fgf17 regulate proliferation and differentiation of midline cerebellar structures . Development . 127 . 9 . 1833–43 . 2000 . 10.1242/dev.127.9.1833 . 10751172 .
• Hartley JL, Temple GF, Brasch MA . DNA Cloning Using In Vitro Site-Specific Recombination . Genome Res. . 10 . 11 . 1788–95 . 2001 . 11076863 . 10.1101/gr.143000 . 310948 .
• Whitmore TE . Assignment of fibroblast growth factor 18 (FGF18) to human chromosome 5q34 by use of radiation hybrid mapping and fluorescence in situ hybridization . Cytogenet. Cell Genet. . 90 . 3–4 . 231–3 . 2001 . 11124520 . 10.1159/000056775 . Maurer MF . Sexson S . Raymond . F. . Conklin . D. . Deisher . T.A. . 84820296 .
• Simpson JC . Systematic subcellular localization of novel proteins identified by large-scale cDNA sequencing . EMBO Rep. . 1 . 3 . 287–92 . 2001 . 11256614 . 10.1093/embo-reports/kvd058 . 1083732 . Wellenreuther R . Poustka A . Pepperkok . R . Wiemann . S .
• Strausberg RL . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences . Proc. Natl. Acad. Sci. U.S.A. . 99 . 26 . 16899–903 . 2003 . 12477932 . 10.1073/pnas.242603899 . 139241 . Feingold EA . Grouse LH . Derge . JG . Klausner . RD . Collins . FS . Wagner . L . Shenmen . CM . Schuler . GD . 2002PNAS...9916899M . free .
• Clark HF . The Secreted Protein Discovery Initiative (SPDI), a Large-Scale Effort to Identify Novel Human Secreted and Transmembrane Proteins: A Bioinformatics Assessment . Genome Res. . 13 . 10 . 2265–70 . 2003 . 12975309 . 10.1101/gr.1293003 . 403697 . Gurney AL . Abaya E . Baker . K . Baldwin . D . Brush . J . Chen . J . Chow . B . Chui . C .
• Popovici C, Conchonaud F, Birnbaum D, Roubin R . Functional phylogeny relates LET-756 to fibroblast growth factor 9 . J. Biol. Chem. . 279 . 38 . 40146–52 . 2004 . 15199049 . 10.1074/jbc.M405795200 . free .
• Gerhard DS . The Status, Quality, and Expansion of the NIH Full-Length cDNA Project: The Mammalian Gene Collection (MGC) . Genome Res. . 14 . 10B . 2121–7 . 2004 . 15489334 . 10.1101/gr.2596504 . 528928 . Wagner L . Feingold EA . Shenmen . CM . Grouse . LH . Schuler . G . Klein . SL . Old . S . Rasooly . R .
• Wiemann S . From ORFeome to Biology: A Functional Genomics Pipeline . Genome Res. . 14 . 10B . 2136–44 . 2004 . 15489336 . 10.1101/gr.2576704 . 528930 . Arlt D . Huber W . Wellenreuther . R . Schleeger . S . Mehrle . A . Bechtel . S . Sauermann . M . Korf . U .
• Cormier S, Leroy C, Delezoide AL, Silve C . Expression of fibroblast growth factors 18 and 23 during human embryonic and fetal development . Gene Expr. Patterns . 5 . 4 . 569–73 . 2005 . 15749088 . 10.1016/j.modgep.2004.10.008 .
• Antoine M . Expression pattern of fibroblast growth factors (FGFs), their receptors and antagonists in primary endothelial cells and vascular smooth muscle cells . Growth Factors . 23 . 2 . 87–95 . 2005 . 16019430 . 10.1080/08977190500096004 . Wirz W . Tag CG . Mavituna . M. . Emans . N. . Korff . T. . Stoldt . V. . Gressner . A. M. . Kiefer . P. . 27380246 .
• Mehrle A . The LIFEdb database in 2006 . Nucleic Acids Res. . 34 . Database issue . D415–8 . 2006 . 16381901 . 10.1093/nar/gkj139 . 1347501 . Rosenfelder H . Schupp I . Del Val . C . Arlt . D . Hahne . F . Bechtel . S . Simpson . J . Hofmann . O .
• Antoine M . Fibroblast growth factor 16 and 18 are expressed in human cardiovascular tissues and induce on endothelial cells migration but not proliferation . Biochem. Biophys. Res. Commun. . 346 . 1 . 224–33 . 2006 . 16756958 . 10.1016/j.bbrc.2006.05.105 . Wirz W . Tag CG . Gressner . A.M. . Wycislo . M. . Müller . R. . Kiefer . P. .
• Riley BM . Impaired FGF signaling contributes to cleft lip and palate . Proc. Natl. Acad. Sci. U.S.A. . 104 . 11 . 4512–7 . 2007 . 17360555 . 10.1073/pnas.0607956104 . 1810508 . Mansilla MA . Ma J . Daack-Hirsch . S. . Maher . B. S. . Raffensperger . L. M. . Russo . E. T. . Vieira . A. R. . Dode . C. . 2007PNAS..104.4512R . free .

Notes and References

1. Ohbayashi N, Hoshikawa M, Kimura S, Yamasaki M, Fukui S, Itoh N . Structure and expression of the mRNA encoding a novel fibroblast growth factor, FGF-18 . J Biol Chem . 273 . 29 . 18161–4 . Aug 1998 . 9660775 . 10.1074/jbc.273.29.18161 . free .
2. Hu MC, Qiu WR, Wang YP, Hill D, Ring BD, Scully S, Bolon B, DeRose M, Luethy R, Simonet WS, Arakawa T, Danilenko DM . FGF-18, a Novel Member of the Fibroblast Growth Factor Family, Stimulates Hepatic and Intestinal Proliferation . Mol Cell Biol . 18 . 10 . 6063–74 . Nov 1998 . 9742123 . 109192 . 10.1128/MCB.18.10.6063.
3. Web site: Entrez Gene: FGF18 fibroblast growth factor 18.
4. Maruoka . Y. . Ohbayashi . N. . Hoshikawa . M. . Itoh . N. . Hogan . B. L. . Furuta . Y. . June 1998 . Comparison of the expression of three highly related genes, Fgf8, Fgf17 and Fgf18, in the mouse embryo . Mechanisms of Development . 74 . 1–2 . 175–177 . 10.1016/s0925-4773(98)00061-6 . 0925-4773 . 9651520. 18400935 . free .
5. Itoh . Nobuyuki . Ornitz . David M. . November 2004 . Evolution of the Fgf and Fgfr gene families . Trends in Genetics . 20 . 11 . 563–569 . 10.1016/j.tig.2004.08.007 . 0168-9525 . 15475116.
6. Moore . E. E. . Bendele . A. M. . Thompson . D. L. . Littau . A. . Waggie . K. S. . Reardon . B. . Ellsworth . J. L. . July 2005 . Fibroblast growth factor-18 stimulates chondrogenesis and cartilage repair in a rat model of injury-induced osteoarthritis . Osteoarthritis and Cartilage . 13 . 7 . 623–631 . 10.1016/j.joca.2005.03.003 . 1063-4584 . 15896984. free .
7. Hollander . Judith M. . Goraltchouk . Alex . Rawal . Miraj . Liu . Jingshu . Luppino . Francesco . Zeng . Li . Seregin . Alexey . 2023-03-06 . Adeno-Associated Virus-Delivered Fibroblast Growth Factor 18 Gene Therapy Promotes Cartilage Anabolism . Cartilage . 14 . 4 . 492–505 . 10.1177/19476035231158774 . 1947-6043 . 36879540. 257376179 . free . 10807742 .
8. Ohbayashi . N. . Hoshikawa . M. . Kimura . S. . Yamasaki . M. . Fukui . S. . Itoh . N. . 1998-07-17 . Structure and expression of the mRNA encoding a novel fibroblast growth factor, FGF-18 . The Journal of Biological Chemistry . 273 . 29 . 18161–18164 . 10.1074/jbc.273.29.18161 . 0021-9258 . 9660775 . free .
9. Ornitz . David M. . Itoh . Nobuyuki . 2015 . The Fibroblast Growth Factor signaling pathway . Wiley Interdisciplinary Reviews. Developmental Biology . 4 . 3 . 215–266 . 10.1002/wdev.176 . 1759-7692 . 4393358 . 25772309.
10. Davidson . D. . Blanc . A. . Filion . D. . Wang . H. . Plut . P. . Pfeffer . G. . Buschmann . M. D. . Henderson . J. E. . 10.1074/jbc.M410148200 . Fibroblast Growth Factor (FGF) 18 Signals through FGF Receptor 3 to Promote Chondrogenesis . Journal of Biological Chemistry . 280 . 21 . 20509–20515 . 2005 . 15781473. free .
11. Moore . E. . Bendele . A. . Thompson . D. . Littau . A. . Waggie . K. . Reardon . B. . Ellsworth . J. . 10.1016/j.joca.2005.03.003 . Fibroblast growth factor-18 stimulates chondrogenesis and cartilage repair in a rat model of injury-induced osteoarthritis . Osteoarthritis and Cartilage . 13 . 7 . 623–631 . 2005 . 15896984. free .
12. Eckstein . Felix . Hochberg . Marc C. . Guehring . Hans . Moreau . Flavie . Ona . Victor . Bihlet . Asger Reinstrup . Byrjalsen . Inger . Andersen . Jeppe Ragnar . Daelken . Benjamin . Guenther . Oliver . Ladel . Christoph . Michaelis . Martin . Conaghan . Philip G. . August 2021 . Long-term structural and symptomatic effects of intra-articular sprifermin in patients with knee osteoarthritis: 5-year results from the FORWARD study . Annals of the Rheumatic Diseases . 80 . 8 . 1062–1069 . 10.1136/annrheumdis-2020-219181 . 1468-2060 . 8292562 . 33962962.
13. Conaghan . P. G. . Katz . N. . Hunter . D. . Guermazi . A. . Hochberg . M. . Somberg . K. . Clive . J. . Johnson . M. . Goel . N. . 2023-06-01 . Pos1348 Effects of Sprifermin on a Novel Outcome of Osteoarthritis Symptom Progression: Post-Hoc Analysis of the Forward Randomized Trial . Annals of the Rheumatic Diseases . en . 82 . Suppl 1 . 1025–1026 . 10.1136/annrheumdis-2023-eular.2454 . 0003-4967. free .
14. Web site: Genevisible: O76093 . Jul 22, 2023 . Genevisible.
15. Web site: fgf18 heart - Search Results - PubMed . 2023-07-22 . PubMed . en.
16. Tong . Gaozan . Chen . Xixi . Lee . Jongsuk . Fan . Junfu . Li . Santie . Zhu . Kunxuan . Hu . Zijing . Mei . Lin . Sui . Yanru . Dong . Yonggan . Chen . Rui . Jin . Zhouxiang . Zhou . Bin . Li . Xiaokun . Wang . Xu . April 2022 . Fibroblast growth factor 18 attenuates liver fibrosis and HSCs activation via the SMO-LATS1-YAP pathway . Pharmacological Research . 178 . 106139 . 10.1016/j.phrs.2022.106139 . 1096-1186 . 35202822. 247030847 .
17. Mosleh . Berta . Schelch . Karin . Mohr . Thomas . Klikovits . Thomas . Wagner . Christina . Ratzinger . Lukas . Dong . Yawen . Sinn . Katharina . Ries . Alexander . Berger . Walter . Grasl-Kraupp . Bettina . Hoetzenecker . Konrad . Laszlo . Viktoria . Dome . Balazs . Hegedus . Balazs . 2023-06-21 . Circulating FGF18 is decreased in pleural mesothelioma but not correlated with disease prognosis . Thoracic Cancer . 14 . 22 . 2177–2186 . 10.1111/1759-7714.15004 . 1759-7714 . 37340889. 10396789 . 259210554 .
18. Flannery . Clare A. . Fleming . Andrew G. . Choe . Gina H. . Naqvi . Hanyia . Zhang . Margaret . Sharma . Anu . Taylor . Hugh S. . October 2016 . Endometrial Cancer-Associated FGF18 Expression Is Reduced by Bazedoxifene in Human Endometrial Stromal Cells In Vitro and in Murine Endometrium . Endocrinology . 157 . 10 . 3699–3708 . 10.1210/en.2016-1233 . 1945-7170 . 5045514 . 27267714.
19. Web site: Expression of FGF18 in cancer - Summary - The Human Protein Atlas . 2023-07-22 . www.proteinatlas.org.
20. Eckstein . Felix . Hochberg . Marc C. . Guehring . Hans . Moreau . Flavie . Ona . Victor . Bihlet . Asger Reinstrup . Byrjalsen . Inger . Andersen . Jeppe Ragnar . Daelken . Benjamin . Guenther . Oliver . Ladel . Christoph . Michaelis . Martin . Conaghan . Philip G. . August 2021 . Long-term structural and symptomatic effects of intra-articular sprifermin in patients with knee osteoarthritis: 5-year results from the FORWARD study . Annals of the Rheumatic Diseases . 80 . 8 . 1062–1069 . 10.1136/annrheumdis-2020-219181 . 1468-2060 . 8292562 . 33962962.