FGF18

Last updated
FGF18
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases FGF18 , FGF-18, ZFGF5, fibroblast growth factor 18
External IDs OMIM: 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 Mb Chr 11: 33.07 – 33.1 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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]

Contents

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]

Related Research Articles

<span class="mw-page-title-main">Paracrine signaling</span> Form of localized cell signaling

In cellular biology, paracrine signaling is a form of cell signaling, a type of cellular communication in which a cell produces a signal to induce changes in nearby cells, altering the behaviour of those cells. Signaling molecules known as paracrine factors diffuse over a relatively short distance, as opposed to cell signaling by endocrine factors, hormones which travel considerably longer distances via the circulatory system; juxtacrine interactions; and autocrine signaling. Cells that produce paracrine factors secrete them into the immediate extracellular environment. Factors then travel to nearby cells in which the gradient of factor received determines the outcome. However, the exact distance that paracrine factors can travel is not certain.

<span class="mw-page-title-main">Hyaline cartilage</span> Type of cartilage in animals

Hyaline cartilage is the glass-like (hyaline) and translucent cartilage found on many joint surfaces. It is also most commonly found in the ribs, nose, larynx, and trachea. Hyaline cartilage is pearl-gray in color, with a firm consistency and has a considerable amount of collagen. It contains no nerves or blood vessels, and its structure is relatively simple.

<span class="mw-page-title-main">Chondrocyte</span> Cell that makes up cartilage

Chondrocytes are the only cells found in healthy cartilage. They produce and maintain the cartilaginous matrix, which consists mainly of collagen and proteoglycans. Although the word chondroblast is commonly used to describe an immature chondrocyte, the term is imprecise, since the progenitor of chondrocytes can differentiate into various cell types, including osteoblasts.

<span class="mw-page-title-main">Basic fibroblast growth factor</span> Growth factor and signaling protein otherwise known as FGF2

Fibroblast growth factor 2, also known as basic fibroblast growth factor (bFGF) and FGF-β, is a growth factor and signaling protein encoded by the FGF2 gene. It binds to and exerts effects via specific fibroblast growth factor receptor (FGFR) proteins, themselves a family of closely related molecules. Fibroblast growth factor protein was first purified in 1975; soon thereafter three variants were isolated: 'basic FGF' (FGF2); Heparin-binding growth factor-2; and Endothelial cell growth factor-2. Gene sequencing revealed that this group is the same FGF2 protein and is a member of a family of FGF proteins.

Fibroblast growth factors (FGF) are a family of cell signalling proteins produced by macrophages; they are involved in a wide variety of processes, most notably as crucial elements for normal development in animal cells. Any irregularities in their function lead to a range of developmental defects. These growth factors typically act as systemic or locally circulating molecules of extracellular origin that activate cell surface receptors. A defining property of FGFs is that they bind to heparin and to heparan sulfate. Thus, some are sequestered in the extracellular matrix of tissues that contains heparan sulfate proteoglycans and are released locally upon injury or tissue remodeling.

<span class="mw-page-title-main">FGF3</span> Protein-coding gene in humans

INT-2 proto-oncogene protein also known as FGF-3 is a protein that in humans is encoded by the FGF3 gene.

<span class="mw-page-title-main">Perlecan</span>

Perlecan (PLC) also known as basement membrane-specific heparan sulfate proteoglycan core protein (HSPG) or heparan sulfate proteoglycan 2 (HSPG2), is a protein that in humans is encoded by the HSPG2 gene. The HSPG2 gene codes for a 4,391 amino acid protein with a molecular weight of 468,829. It is one of the largest known proteins. The name perlecan comes from its appearance as a "string of pearls" in rotary shadowed images.

The fibroblast growth factor receptors (FGFR) are, as their name implies, receptors that bind to members of the fibroblast growth factor (FGF) family of proteins. Some of these receptors are involved in pathological conditions. For example, a point mutation in FGFR3 can lead to achondroplasia.

<span class="mw-page-title-main">Limb development</span>

Limb development in vertebrates is an area of active research in both developmental and evolutionary biology, with much of the latter work focused on the transition from fin to limb.

<span class="mw-page-title-main">Syndecan-4</span> Protein-coding gene in the species Homo sapiens

Syndecan-4 is a protein that in humans is encoded by the SDC4 gene. Syndecan-4 is one of the four vertebrate syndecans and has a molecular weight of ~20 kDa. Syndecans are the best-characterized plasma membrane proteoglycans. Their intracellular domain of membrane-spanning core protein interacts with actin cytoskeleton and signaling molecules in the cell cortex. Syndecans are normally found on the cell surface of fibroblasts and epithelial cells. Syndecans interact with fibronectin on the cell surface, cytoskeletal and signaling proteins inside the cell to modulate the function of integrin in cell-matrix adhesion. Also, syndecans bind to FGFs and bring them to the FGF receptor on the same cell. As a co-receptor or regulator, mutated certain proteoglycans could cause severe developmental defects, like disordered distribution or inactivation of signaling molecules.

<span class="mw-page-title-main">FGF7</span> Protein-coding gene in the species Homo sapiens

Keratinocyte growth factor is a protein that in humans is encoded by the FGF7 gene.

<span class="mw-page-title-main">FGF10</span> Protein-coding gene in the species Homo sapiens

Fibroblast growth factor 10 is a protein that in humans is encoded by the FGF10 gene.

<span class="mw-page-title-main">Fibroblast growth factor 8</span> Protein-coding gene in the species Homo sapiens

Fibroblast growth factor 8(FGF-8) is a protein that in humans is encoded by the FGF8 gene.

<span class="mw-page-title-main">FGF9</span> Protein-coding gene in the species Homo sapiens

Glia-activating factor is a protein that in humans is encoded by the FGF9 gene.

<span class="mw-page-title-main">FGF4</span> Fibroblast growth factor gene

Fibroblast growth factor 4 is a protein that in humans is encoded by the FGF4 gene.

<span class="mw-page-title-main">FGF5</span> Mammalian protein found in Homo sapiens

Fibroblast growth factor 5 is a protein that in humans is encoded by the FGF5 gene.

<span class="mw-page-title-main">Fibroblast growth factor receptor-like 1</span> Protein found in humans

Fibroblast growth factor receptor-like 1 is a protein that in humans is encoded by the FGFRL1 gene.

<span class="mw-page-title-main">FGF17</span> Protein-coding gene in the species Homo sapiens

Fibroblast growth factor 17 is a protein that in humans is encoded by the FGF17 gene.

Fibroblast growth factor 16 is a protein which in humans is encoded by the FGF16 gene.

Sprifermin (INN), is a recombinant human fibroblast growth factor 18 (rhFGF18) analog, which is under development by TrialSpark for the treatment of osteoarthritis. FGF18 and sprifermin act via the Fibroblast Growth Factor Receptor (FGFR) family, with preferential activity via FGFR3c.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000156427 - Ensembl, May 2017
  2. 1 2 3 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. 1 2 "Entrez Gene: FGF18 fibroblast growth factor 18".
  8. ↑ Maruoka Y, Ohbayashi N, Hoshikawa M, Itoh N, Hogan BL, 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 N, Ornitz DM (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 EE, Bendele AM, Thompson DL, Littau A, Waggie KS, Reardon B, Ellsworth JL (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 JM, Goraltchouk A, Rawal M, Liu J, Luppino F, Zeng L, Seregin A (2023-03-06). "Adeno-Associated Virus-Delivered Fibroblast Growth Factor 18 Gene Therapy Promotes Cartilage Anabolism". Cartilage. 14 (4): 492–505. 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 DM, Itoh N (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 MD, Henderson JE (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 F, Hochberg MC, Guehring H, Moreau F, Ona V, Bihlet AR, Byrjalsen I, Andersen JR, Daelken B, Guenther O, Ladel C, Michaelis M, Conaghan PG (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 PG, 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 G, Chen X, Lee J, Fan J, Li S, Zhu K, Hu Z, Mei L, Sui Y, Dong Y, Chen R, Jin Z, Zhou B, Li X, Wang X (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 B, Schelch K, Mohr T, Klikovits T, Wagner C, Ratzinger L, Dong Y, Sinn K, Ries A, Berger W, Grasl-Kraupp B, Hoetzenecker K, Laszlo V, Dome B, Hegedus B (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 CA, Fleming AG, Choe GH, Naqvi H, Zhang M, Sharma A, Taylor HS (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 F, Hochberg MC, Guehring H, Moreau F, Ona V, Bihlet AR, Byrjalsen I, Andersen JR, Daelken B, Guenther O, Ladel C, Michaelis M, Conaghan PG (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.

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