FGF18

Fibroblast growth factor 18 (FGF18) is a protein that is encoded by the Fgf18 gene in humans.[5][6][7] 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.[8] The three proteins were eventually grouped into the FGF8 subfamily, which contains several of the endocrine FGF superfamily members FGF8, FGF17, and FGF18.[9] Subsequent studies identified FGF18's role in promoting chondrogenesis,[10] and an apparent specific activity for the generation of the hyaline cartilage in articular joints.[11]

FGF18
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesFGF18, FGF-18, ZFGF5, fibroblast growth factor 18
External IDsOMIM: 603726 MGI: 1277980 HomoloGene: 2867 GeneCards: FGF18
Orthologs
SpeciesHumanMouse
Entrez

8817

14172

Ensembl

ENSG00000156427

ENSMUSG00000057967

UniProt

O76093

O89101

RefSeq (mRNA)

NM_033649
NM_003862

NM_008005

RefSeq (protein)

NP_003853

NP_032031

Location (UCSC)Chr 5: 171.42 – 171.46 MbChr 11: 33.07 – 33.1 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.[12]

Function

FGF18 signals through fibroblast growth factor receptor (FGFR) family, preferentially binding FGFR 3c (followed by 4△, 2c, 1c, and finally 3b),[13] signaling via FGFR3 promotes generation of cartilage (chondrogenesis).[14] FGF18 and has been shown to cause thickening of cartilage in a murine model of osteoarthritis,[15] and the recombinant version of it (sprifermin) is in a clinical trial as a potential treatment for osteoarthritis (OA).[16] Recent findings from a placebo-controlled randomized clinical study demonstrate the potential of FGF18 to reduce the rate of progression to joint replacement surgery[17] and delay progression of OA-related pain (WOMAC).[18] 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.[7]

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.[19] 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.[20] Similarly, studies confirmed that overexpression of FGF18 in the liver was able to attenuate liver fibrosis following chemically-induced injury.[21]

Studies of FGF18 in relation to oncology have shown both decreased levels[22] and increased levels[23] of FGF18 in a number of cancer types and stages, however, FGF18 does not appear to be causative or prognostic[24] and long-term clinical studies of the FGF18 analog, sprifermin, have demonstrated an excellent safety profile with no reported oncogenic effects.[25]

References
  1. GRCh38: Ensembl release 89: ENSG00000156427 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000057967 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Ohbayashi N, Hoshikawa M, Kimura S, Yamasaki M, Fukui S, Itoh N (Aug 1998). "Structure and expression of the mRNA encoding a novel fibroblast growth factor, FGF-18". J Biol Chem. 273 (29): 18161–4. doi:10.1074/jbc.273.29.18161. PMID 9660775.
  6. Hu MC, Qiu WR, Wang YP, Hill D, Ring BD, Scully S, Bolon B, DeRose M, Luethy R, Simonet WS, Arakawa T, Danilenko DM (Nov 1998). "FGF-18, a Novel Member of the Fibroblast Growth Factor Family, Stimulates Hepatic and Intestinal Proliferation". Mol Cell Biol. 18 (10): 6063–74. doi:10.1128/MCB.18.10.6063. PMC 109192. PMID 9742123.
  7. "Entrez Gene: FGF18 fibroblast growth factor 18".
  8. 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. doi:10.1016/s0925-4773(98)00061-6. ISSN 0925-4773. PMID 9651520. S2CID 18400935.
  9. Itoh, Nobuyuki; Ornitz, David M. (November 2004). "Evolution of the Fgf and Fgfr gene families". Trends in Genetics. 20 (11): 563–569. doi:10.1016/j.tig.2004.08.007. ISSN 0168-9525. PMID 15475116.
  10. 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. doi:10.1016/j.joca.2005.03.003. ISSN 1063-4584. PMID 15896984.
  11. 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: 19476035231158774. doi:10.1177/19476035231158774. ISSN 1947-6043. PMID 36879540. S2CID 257376179.
  12. 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. doi:10.1074/jbc.273.29.18161. ISSN 0021-9258. PMID 9660775.
  13. Ornitz, David M.; Itoh, Nobuyuki (2015). "The Fibroblast Growth Factor signaling pathway". Wiley Interdisciplinary Reviews. Developmental Biology. 4 (3): 215–266. doi:10.1002/wdev.176. ISSN 1759-7692. PMC 4393358. PMID 25772309.
  14. Davidson, D.; Blanc, A.; Filion, D.; Wang, H.; Plut, P.; Pfeffer, G.; Buschmann, M. D.; Henderson, J. E. (2005). "Fibroblast Growth Factor (FGF) 18 Signals through FGF Receptor 3 to Promote Chondrogenesis". Journal of Biological Chemistry. 280 (21): 20509–20515. doi:10.1074/jbc.M410148200. PMID 15781473.
  15. Moore, E.; Bendele, A.; Thompson, D.; Littau, A.; Waggie, K.; Reardon, B.; Ellsworth, J. (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. doi:10.1016/j.joca.2005.03.003. PMID 15896984.
  16. Merck Announces Collaboration With Nordic Bioscience for Sprifermin in Osteoarthritis of the Knee, retrieved 2013-04-02
  17. 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. doi:10.1136/annrheumdis-2020-219181. ISSN 1468-2060. PMC 8292562. PMID 33962962.
  18. 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. 82 (Suppl 1): 1025–1026. doi:10.1136/annrheumdis-2023-eular.2454. ISSN 0003-4967.
  19. "Genevisible: O76093". Genevisible. Retrieved Jul 22, 2023.
  20. "fgf18 heart - Search Results - PubMed". PubMed. Retrieved 2023-07-22.
  21. 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. doi:10.1016/j.phrs.2022.106139. ISSN 1096-1186. PMID 35202822. S2CID 247030847.
  22. 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. doi:10.1111/1759-7714.15004. ISSN 1759-7714. PMC 10396789. PMID 37340889. S2CID 259210554.
  23. 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. doi:10.1210/en.2016-1233. ISSN 1945-7170. PMC 5045514. PMID 27267714.
  24. "Expression of FGF18 in cancer - Summary - The Human Protein Atlas". www.proteinatlas.org. Retrieved 2023-07-22.
  25. 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. doi:10.1136/annrheumdis-2020-219181. ISSN 1468-2060. PMC 8292562. PMID 33962962.

Further reading
  • Overview of all the structural information available in the PDB for UniProt: O76093 (Fibroblast growth factor 18) at the PDBe-KB.
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