The FGF family: biology, pathophysiology and therapy

Key Points

  • Fibroblast growth factors (FGFs) signal through FGF receptor tyrosine kinases to regulate a wide range of biological processes during development and adulthood.

  • FGF receptors (FGFRs) are involved in the pathogenesis of cancer and skeletal disorders. Experiments in model systems have shown that FGFR-specific inhibitors may be valuable in treating multiple myeloma, bladder and endometrial cancers.

  • FGF1, FGF2 and FGF4 have been studied in clinical trials for the treatment of cardiovascular disease. The results of most of these trials have been unclear. However, some promising prospects remain. In particular, plasmids encoding FGF1 have shown potential in treating peripheral ischaemia.

  • Recombinant FGF7 is Food and Drug Administration approved for the treatment of chemoradiation-induced oral mucositis. Research into the application of FGF7 to treat conditions such as graft-versus-host disease is ongoing.

  • FGF18 increases cartilage formation in rats and may be useful in treating osteoarthritis.

  • The endocrine FGF19 subfamily holds the greatest promise for therapeutic development. These ligands circulate throughout the body owing to weak affinity for HSGAG (heparan sulphate glycosaminoglycan), and they require α-klotho–β-klotho proteins as cofactors for their activity. The α-klotho–β-klotho proteins also determine the target-tissue specificity of FGF19 subfamily ligands.

  • FGF19 negatively regulates bile acid synthesis and recombinant FGF19 increases the metabolic rate of mice. Unfortunately, FGF19 transgenic mice develop hepatocellular carcinomas, and this side effect may impede the pharmaceutical development of FGF19.

  • FGF21 is a mediator of the fasting response that increases glucose uptake, improves insulin sensitivity and reduces serum glucagon and triglyceride levels.

  • In contrast to FGF19, FGF21 is not mitogenic, and FGF21 administration leads to neither oedema nor hypoglycaemia, which are two common side effects of agents that modulate metabolic disorders. FGF21 thus shows great potential for treating type 2 diabetes.

  • FGF23 reduces renal phosphate reabsorption and downregulates vitamin D activation. FGF23 is broadly implicated in human disease, including autosomal-dominant hypophosphataemic rickets, tumour-induced osteomalacia, familial tumoral calcinosis and end-stage kidney disease. Neutralizing antibodies against FGF23 have shown efficacy in model systems and demonstrate the clinical potential of FGF23-specific therapies.

Abstract

The family of fibroblast growth factors (FGFs) regulates a plethora of developmental processes, including brain patterning, branching morphogenesis and limb development. Several mitogenic, cytoprotective and angiogenic therapeutic applications of FGFs are already being explored, and the recent discovery of the crucial roles of the endocrine-acting FGF19 subfamily in bile acid, glucose and phosphate homeostasis has sparked renewed interest in the pharmacological potential of this family. This Review discusses traditional applications of recombinant FGFs and small-molecule FGF receptor kinase inhibitors in the treatment of cancer and cardiovascular disease and their emerging potential in the treatment of metabolic syndrome and hypophosphataemic diseases.

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Figure 1: Structural features of fibroblast growth factors (FGFs).
Figure 2: Structural features of fibroblast growth factor receptors (FGFRs).
Figure 3: Fibroblast growth factor receptor (FGFR) signalling.
Figure 4: The physiology of fibroblast growth factor 19 (FGF19), FGF21 and FGF23.

References

  1. 1

    Itoh, N. & Ornitz, D. M. Evolution of the Fgf and Fgfr gene families. Trends Genet. 20, 563–569 (2004).

    CAS  Google Scholar 

  2. 2

    Olsen, S. K. et al. Fibroblast growth factor (FGF) homologous factors share structural but not functional homology with FGFs. J. Biol. Chem. 278, 34226–34236 (2003).

    CAS  PubMed  Google Scholar 

  3. 3

    Fu, L. et al. Fibroblast growth factor19 increases metabolic rate and reverses dietary and leptin-deficient diabetes. Endocrinology 145, 2594–2603 (2004).

    CAS  Google Scholar 

  4. 4

    Kharitonenkov, A. et al. FGF-21 as a novel metabolic regulator. J. Clin. Invest. 115, 1627–1635 (2005). The first paper to describe the metabolic profile of FGF21 in mice and rats.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5

    Razzaque, M. S. & Lanske, B. The emerging role of the fibroblast growth factor-23-klotho axis in renal regulation of phosphate homeostasis. J. Endocrinol. 194, 1–10 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Tomlinson, E. et al. Transgenic mice expressing human fibroblast growth factor-19 display increased metabolic rate and decreased adiposity. Endocrinology 143, 1741–1747 (2002). Initiated interest in FGF19 as a metabolic regulator by detailing the phenotype of FGF19 transgenic mice.

    CAS  Google Scholar 

  7. 7

    White, K. E. et al. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nature Genet. 26, 345–348 (2000). This study showed that an FGF23 mutation caused ADHR, which began to unravel the physiology of FGF23.

    CAS  Google Scholar 

  8. 8

    Milunsky, J. M., Zhao, G., Maher, T. A., Colby, R. & Everman, D. B. LADD syndrome is caused by FGF10 mutations. Clin. Genet. 69, 349–354 (2006).

    CAS  PubMed  Google Scholar 

  9. 9

    Tekin, M. et al. Homozygous mutations in fibroblast growth factor 3 are associated with a new form of syndromic deafness characterized by inner ear agenesis, microtia, and microdontia. Am. J. Hum. Genet. 80, 338–344 (2007).

    CAS  PubMed  Google Scholar 

  10. 10

    Falardeau, J. et al. Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice. J. Clin. Invest. 118, 2822–2831 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Revest, J. M., DeMoerlooze, L. & Dickson, C. Fibroblast growth factor 9 secretion is mediated by a non-cleaved amino-terminal signal sequence. J. Biol. Chem. 275, 8083–8090 (2000).

    CAS  PubMed  Google Scholar 

  12. 12

    Nickel, W. Unconventional secretory routes: direct protein export across the plasma membrane of mammalian cells. Traffic 6, 607–614 (2005).

    CAS  PubMed  Google Scholar 

  13. 13

    Mohammadi, M., Olsen, S. K. & Ibrahimi, O. A. Structural basis for fibroblast growth factor receptor activation. Cytokine Growth Factor Rev. 16, 107–137 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Goetz, R. et al. Molecular insights into the klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members. Mol. Cell. Biol. 27, 3417–3428 (2007). Elucidates the structural rationale for the reduced binding of the FGF19 subfamily to heparan sulphate.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Wang, F., Kan, M., Yan, G., Xu, J. & McKeehan, W. L. Alternately spliced NH2-terminal immunoglobulin-like loop I in the ectodomain of the fibroblast growth factor (FGF) receptor 1 lowers affinity for both heparin and FGF-1. J. Biol. Chem. 270, 10231–10235 (1995).

    CAS  PubMed  Google Scholar 

  16. 16

    Johnson, D. E., Lu, J., Chen, H., Werner, S. & Williams, L. T. The human fibroblast growth factor receptor genes: a common structural arrangement underlies the mechanisms for generating receptor forms that differ in their third immunoglobulin domain. Mol. Cell. Biol. 11, 4627–4634 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Ornitz, D. M. et al. Heparin is required for cell-free binding of basic fibroblast growth factor to a soluble receptor and for mitogenesis in whole cells. Mol. Cell. Biol. 12, 240–247 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Schlessinger, J. et al. Crystal structure of a ternary FGF–FGFR–heparin complex reveals a dual role for heparin in FGFR binding and dimerization. Mol. Cell 6, 743–750 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Yayon, A., Klagsbrun, M., Esko, J. D., Leder, P. & Ornitz, D. M. Cell surface, heparin-like molecules are required for binding of basic fibroblast growth factor to its high affinity receptor. Cell 64, 841–848 (1991).

    CAS  PubMed  Google Scholar 

  20. 20

    Mohammadi, M. et al. Identification of six novel autophosphorylation sites on fibroblast growth factor receptor 1 and elucidation of their importance in receptor activation and signal transduction. Mol. Cell. Biol. 16, 977–989 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Dailey, L., Ambrosetti, D., Mansukhani, A. & Basilico, C. Mechanisms underlying differential responses to FGF signaling. Cytokine Growth Factor Rev. 16, 233–247 (2005).

    CAS  Google Scholar 

  22. 22

    Wiedlocha, A. & Sorensen, V. Signaling, internalization, and intracellular activity of fibroblast growth factor. Curr. Top. Microbiol. Immunol. 286, 45–79 (2004).

    CAS  PubMed  Google Scholar 

  23. 23

    Orr-Urtreger, A. et al. Developmental localization of the splicing alternatives of fibroblast growth factor receptor-2 (FGFR2). Dev. Biol. 158, 475–486 (1993).

    CAS  PubMed  Google Scholar 

  24. 24

    Grose, R. & Dickson, C. Fibroblast growth factor signaling in tumorigenesis. Cytokine Growth Factor Rev. 16, 179–186 (2005).

    CAS  PubMed  Google Scholar 

  25. 25

    Ibrahimi, O. A. et al. Analysis of mutations in fibroblast growth factor (FGF) and a pathogenic mutation in FGF receptor (FGFR) provides direct evidence for the symmetric two-end model for FGFR dimerization. Mol. Cell. Biol. 25, 671–684 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Hacker, U., Nybakken, K. & Perrimon, N. Heparan sulphate proteoglycans: the sweet side of development. Nature Rev. Mol. Cell Biol. 6, 530–541 (2005).

    Google Scholar 

  27. 27

    Wu, D. Q., Kan, M. K., Sato, G. H., Okamoto, T. & Sato, J. D. Characterization and molecular cloning of a putative binding protein for heparin-binding growth factors. J. Biol. Chem. 266, 16778–16785 (1991).

    CAS  PubMed  Google Scholar 

  28. 28

    Aigner, A. et al. An FGF-binding protein (FGF-BP) exerts its biological function by parallel paracrine stimulation of tumor cell and endothelial cell proliferation through FGF-2 release. Int. J. Cancer 92, 510–517 (2001).

    CAS  PubMed  Google Scholar 

  29. 29

    Tassi, E. et al. Enhancement of fibroblast growth factor (FGF) activity by an FGF-binding protein. J. Biol. Chem. 276, 40247–40253 (2001).

    CAS  PubMed  Google Scholar 

  30. 30

    Abuharbeid, S., Czubayko, F. & Aigner, A. The fibroblast growth factor-binding protein FGF-BP. Int. J. Biochem. Cell Biol. 38, 1463–1468 (2006).

    CAS  PubMed  Google Scholar 

  31. 31

    Bottcher, R. T., Pollet, N., Delius, H. & Niehrs, C. The transmembrane protein XFLRT3 forms a complex with FGF receptors and promotes FGF signalling. Nature Cell Biol. 6, 38–44 (2004).

    PubMed  Google Scholar 

  32. 32

    Hacohen, N., Kramer, S., Sutherland, D., Hiromi, Y. & Krasnow, M. A. sprouty encodes a novel antagonist of FGF signaling that patterns apical branching of the Drosophila airways. Cell 92, 253–263 (1998).

    CAS  PubMed  Google Scholar 

  33. 33

    Cabrita, M. A. & Christofori, G. Sprouty proteins, masterminds of receptor tyrosine kinase signaling. Angiogenesis 11, 53–62 (2008).

    CAS  Google Scholar 

  34. 34

    Tsang, M. & Dawid, I. B. Promotion and attenuation of FGF signaling through the Ras-MAPK pathway. Sci. STKE 228, pe17 (2004).

    Google Scholar 

  35. 35

    Ibrahimi, O. A. et al. Structural basis for fibroblast growth factor receptor 2 activation in Apert syndrome. Proc. Natl Acad. Sci. USA 98, 7182–7187 (2001).

    CAS  PubMed  Google Scholar 

  36. 36

    Dode, C. et al. Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome. Nature Genet. 33, 463–465 (2003).

    CAS  PubMed  Google Scholar 

  37. 37

    Muenke, M. et al. A common mutation in the fibroblast growth factor receptor 1 gene in Pfeiffer syndrome. Nature Genet. 8, 269–274 (1994).

    CAS  PubMed  Google Scholar 

  38. 38

    Rand, V. et al. Sequence survey of receptor tyrosine kinases reveals mutations in glioblastomas. Proc. Natl Acad. Sci. USA 102, 14344–14349 (2005).

    CAS  PubMed  Google Scholar 

  39. 39

    Giri, D., Ropiquet, F. & Ittmann, M. Alterations in expression of basic fibroblast growth factor (FGF) 2 and its receptor FGFR-1 in human prostate cancer. Clin. Cancer Res. 5, 1063–1071 (1999).

    CAS  PubMed  Google Scholar 

  40. 40

    Cross, N. C. & Reiter, A. Fibroblast growth factor receptor and platelet-derived growth factor receptor abnormalities in eosinophilic myeloproliferative disorders. Acta Haematol. 119, 199–206 (2008).

    CAS  PubMed  Google Scholar 

  41. 41

    Kan, S. H. et al. Genomic screening of fibroblast growth-factor receptor 2 reveals a wide spectrum of mutations in patients with syndromic craniosynostosis. Am. J. Hum. Genet. 70, 472–486 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Chen, H. et al. A molecular brake in the kinase hinge region regulates the activity of receptor tyrosine kinases. Mol. Cell 27, 717–730 (2007).

    PubMed  PubMed Central  Google Scholar 

  43. 43

    Dutt, A. et al. Drug-sensitive FGFR2 mutations in endometrial carcinoma. Proc. Natl Acad. Sci. USA 105, 8713–8717 (2008).

    CAS  Google Scholar 

  44. 44

    Pollock, P. M. et al. Frequent activating FGFR2 mutations in endometrial carcinomas parallel germline mutations associated with craniosynostosis and skeletal dysplasia syndromes. Oncogene 26, 7158–7162 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Neilson, K. M. & Friesel, R. E. Constitutive activation of fibroblast growth factor receptor-2 by a point mutation associated with Crouzon syndrome. J. Biol. Chem. 270, 26037–26040 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Ibrahimi, O. A. et al. Biochemical analysis of pathogenic ligand-dependent FGFR2 mutations suggests distinct pathophysiological mechanisms for craniofacial and limb abnormalities. Hum. Mol. Genet. 13, 2313–2324 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Raybaud, C. & Di Rocco, C. Brain malformation in syndromic craniosynostoses, a primary disorder of white matter: a review. Childs Nerv. Syst. 23, 1379–1388 (2007).

    PubMed  Google Scholar 

  48. 48

    Tanimoto, Y. et al. A soluble form of fibroblast growth factor receptor 2 (FGFR2) with S252W mutation acts as an efficient inhibitor for the enhanced osteoblastic differentiation caused by FGFR2 activation in Apert syndrome. J. Biol. Chem. 279, 45926–45934 (2004).

    CAS  PubMed  Google Scholar 

  49. 49

    Antoniou, A. C. et al. Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers. Am. J. Hum. Genet. 82, 937–948 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Webster, M. K. & Donoghue, D. J. FGFR activation in skeletal disorders: too much of a good thing. Trends Genet. 13, 178–182 (1997).

    CAS  Google Scholar 

  51. 51

    Naski, M. C., Wang, Q., Xu, J. & Ornitz, D. M. Graded activation of fibroblast growth factor receptor 3 by mutations causing achondroplasia and thanatophoric dysplasia. Nature Genet. 13, 233–237 (1996).

    CAS  PubMed  Google Scholar 

  52. 52

    Passos-Bueno, M. R. et al. Clinical spectrum of fibroblast growth factor receptor mutations. Hum. Mutat. 14, 115–125 (1999).

    CAS  PubMed  Google Scholar 

  53. 53

    Tavormina, P. L. et al. A novel skeletal dysplasia with developmental delay and acanthosis nigricans is caused by a Lys650Met mutation in the fibroblast growth factor receptor 3 gene. Am. J. Hum. Genet. 64, 722–731 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Rohmann, E. et al. Mutations in different components of FGF signaling in LADD syndrome. Nature Genet. 38, 414–417 (2006).

    CAS  PubMed  Google Scholar 

  55. 55

    Chesi, M. et al. Frequent translocation t(4;14)(p16.3;q32.3) in multiple myeloma is associated with increased expression and activating mutations of fibroblast growth factor receptor 3. Nature Genet. 16, 260–264 (1997).

    CAS  PubMed  Google Scholar 

  56. 56

    Cappellen, D. et al. Frequent activating mutations of FGFR3 in human bladder and cervix carcinomas. Nature Genet. 23, 18–20 (1999).

    CAS  PubMed  Google Scholar 

  57. 57

    Hafner, C., Vogt, T. & Hartmann, A. FGFR3 mutations in benign skin tumors. Cell Cycle 5, 2723–2728 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Logie, A. et al. Activating mutations of the tyrosine kinase receptor FGFR3 are associated with benign skin tumors in mice and humans. Hum. Mol. Genet. 14, 1153–1160 (2005).

    CAS  PubMed  Google Scholar 

  59. 59

    Wang, J., Stockton, D. W. & Ittmann, M. The fibroblast growth factor receptor-4 Arg388 allele is associated with prostate cancer initiation and progression. Clin. Cancer Res. 10, 6169–6178 (2004).

    CAS  PubMed  Google Scholar 

  60. 60

    Streit, S. et al. Involvement of the FGFR4 Arg388 allele in head and neck squamous cell carcinoma. Int. J. Cancer 111, 213–217 (2004).

    CAS  PubMed  Google Scholar 

  61. 61

    Meijer, D. et al. Fibroblast growth factor receptor 4 predicts failure on tamoxifen therapy in patients with recurrent breast cancer. Endocr. Relat. Cancer 15, 101–111 (2008).

    CAS  PubMed  Google Scholar 

  62. 62

    Chow, L. Q. & Eckhardt, S. G. Sunitinib: from rational design to clinical efficacy. J. Clin. Oncol. 25, 884–896 (2007).

    CAS  PubMed  Google Scholar 

  63. 63

    Grand, E. K., Chase, A. J., Heath, C., Rahemtulla, A. & Cross, N. C. Targeting FGFR3 in multiple myeloma: inhibition of t(4;14)-positive cells by SU5402 and PD173074. Leukemia 18, 962–966 (2004).

    CAS  PubMed  Google Scholar 

  64. 64

    Meyer, A. N., McAndrew, C. W. & Donoghue, D. J. Nordihydroguaiaretic acid inhibits an activated fibroblast growth factor receptor 3 mutant and blocks downstream signaling in multiple myeloma cells. Cancer Res. 68, 7362–7370 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    Byron, S. A. et al. Inhibition of activated fibroblast growth factor receptor 2 in endometrial cancer cells induces cell death despite PTEN abrogation. Cancer Res. 68, 6902–6907 (2008).

    CAS  PubMed  Google Scholar 

  66. 66

    Martinez-Torrecuadrada, J. L. et al. Antitumor activity of fibroblast growth factor receptor 3-specific immunotoxins in a xenograft mouse model of bladder carcinoma is mediated by apoptosis. Mol. Cancer Ther. 7, 862–873 (2008).

    CAS  PubMed  Google Scholar 

  67. 67

    Trudel, S. et al. The inhibitory anti-FGFR3 antibody, PRO-001, is cytotoxic to t(4;14) multiple myeloma cells. Blood 107, 4039–4046 (2006).

    CAS  PubMed  Google Scholar 

  68. 68

    Roumiantsev, S. et al. Distinct stem cell myeloproliferative/T lymphoma syndromes induced by ZNF198–FGFR1 and BCR–FGFR1 fusion genes from 8p11 translocations. Cancer Cell 5, 287–298 (2004).

    CAS  PubMed  Google Scholar 

  69. 69

    Miller, D. L., Ortega, S., Bashayan, O., Basch, R. & Basilico, C. Compensation by fibroblast growth factor 1 (FGF1) does not account for the mild phenotypic defects observed in FGF2 null mice. Mol. Cell. Biol. 20, 2260–2268 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    Cuevas, P. et al. Hypotensive activity of fibroblast growth factor. Science 254, 1208–1210 (1991). One of the original papers on FGF1 physiology that helped lay the groundwork for the extensive study of FGF1 and FGF2 in clinical trials.

    CAS  PubMed  Google Scholar 

  71. 71

    Cuevas, P. et al. Correction of hypertension by normalization of endothelial levels of fibroblast growth factor and nitric oxide synthase in spontaneously hypertensive rats. Proc. Natl Acad. Sci. USA 93, 11996–12001 (1996).

    CAS  PubMed  Google Scholar 

  72. 72

    Zhou, M. et al. Fibroblast growth factor 2 control of vascular tone. Nature Med. 4, 201–207 (1998).

    CAS  PubMed  Google Scholar 

  73. 73

    Dono, R., Texido, G., Dussel, R., Ehmke, H. & Zeller, R. Impaired cerebral cortex development and blood pressure regulation in FGF-2-deficient mice. EMBO J. 17, 4213–4225 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Ware, J. A. & Simons, M. Angiogenesis in ischemic heart disease. Nature Med. 3, 158–164 (1997).

    CAS  PubMed  Google Scholar 

  75. 75

    Yanagisawa-Miwa, A. et al. Salvage of infarcted myocardium by angiogenic action of basic fibroblast growth factor. Science 257, 1401–1403 (1992).

    CAS  PubMed  Google Scholar 

  76. 76

    Scholz, D., Cai, W. J. & Schaper, W. Arteriogenesis, a new concept of vascular adaptation in occlusive disease. Angiogenesis 4, 247–257 (2001).

    CAS  PubMed  Google Scholar 

  77. 77

    Fulgham, D. L., Widhalm, S. R., Martin, S. & Coffin, J. D. FGF-2 dependent angiogenesis is a latent phenotype in basic fibroblast growth factor transgenic mice. Endothelium 6, 185–195 (1999).

    CAS  PubMed  Google Scholar 

  78. 78

    Khurana, R. & Simons, M. Insights from angiogenesis trials using fibroblast growth factor for advanced arteriosclerotic disease. Trends Cardiovasc. Med. 13, 116–122 (2003).

    CAS  PubMed  Google Scholar 

  79. 79

    Keller, M., Ruegg, A., Werner, S. & Beer, H. D. Active caspase-1 is a regulator of unconventional protein secretion. Cell 132, 818–831 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80

    Bosse, Y. & Rola-Pleszczynski, M. FGF2 in asthmatic airway-smooth-muscle-cell hyperplasia. Trends Mol. Med. 14, 3–11 (2008).

    CAS  PubMed  Google Scholar 

  81. 81

    Hutley, L. et al. Fibroblast growth factor 1: a key regulator of human adipogenesis. Diabetes 53, 3097–3106 (2004).

    CAS  PubMed  Google Scholar 

  82. 82

    Iwakura, A. et al. Myocardial ischemia enhances the expression of acidic fibroblast growth factor in human pericardial fluid. Heart Vessels 15, 112–116 (2000).

    CAS  PubMed  Google Scholar 

  83. 83

    Uriel, S., Brey, E. M. & Greisler, H. P. Sustained low levels of fibroblast growth factor-1 promote persistent microvascular network formation. Am. J. Surg. 192, 604–609 (2006).

    CAS  PubMed  Google Scholar 

  84. 84

    Cuevas, P. et al. Fibroblast growth factor-1 prevents myocardial apoptosis triggered by ischemia reperfusion injury. Eur. J. Med. Res. 2, 465–468 (1997).

    CAS  PubMed  Google Scholar 

  85. 85

    Schumacher, B., Pecher, P., von Specht, B. U. & Stegmann, T. Induction of neoangiogenesis in ischemic myocardium by human growth factors: first clinical results of a new treatment of coronary heart disease. Circulation 97, 645–650 (1998).

    CAS  PubMed  Google Scholar 

  86. 86

    Comerota, A. J. et al. Naked plasmid DNA encoding fibroblast growth factor type 1 for the treatment of end-stage unreconstructible lower extremity ischemia: preliminary results of a phase I trial. J. Vasc. Surg. 35, 930–936 (2002).

    PubMed  Google Scholar 

  87. 87

    Nikol, S. et al. Therapeutic angiogenesis with intramuscular NV1FGF improves amputation-free survival in patients with critical limb ischemia. Mol. Ther. 16, 972–978 (2008).

    CAS  PubMed  Google Scholar 

  88. 88

    Ruck, A. & Sylven, C. Therapeutic angiogenesis gains a leg to stand on. Mol. Ther. 16, 808–810 (2008).

    PubMed  Google Scholar 

  89. 89

    Cheng, H., Cao, Y. & Olson, L. Spinal cord repair in adult paraplegic rats: partial restoration of hind limb function. Science 273, 510–513 (1996).

    CAS  PubMed  Google Scholar 

  90. 90

    Lin, P. H., Cheng, H., Huang, W. C. & Chuang, T. Y. Spinal cord implantation with acidic fibroblast growth factor as a treatment for root avulsion in obstetric brachial plexus palsy. J. Chin. Med. Assoc. 68, 392–396 (2005).

    PubMed  Google Scholar 

  91. 91

    Lin, P. H., Chuang, T. Y., Liao, K. K., Cheng, H. & Shih, Y. S. Functional recovery of chronic complete idiopathic transverse myelitis after administration of neurotrophic factors. Spinal Cord 44, 254–257 (2006).

    PubMed  Google Scholar 

  92. 92

    Cheng, H., Liao, K. K., Liao, S. F., Chuang, T. Y. & Shih, Y. H. Spinal cord repair with acidic fibroblast growth factor as a treatment for a patient with chronic paraplegia. Spine 29, E284–E288 (2004).

    PubMed  Google Scholar 

  93. 93

    Unger, E. F. et al. Effects of a single intracoronary injection of basic fibroblast growth factor in stable angina pectoris. Am. J. Cardiol. 85, 1414–1419 (2000).

    CAS  PubMed  Google Scholar 

  94. 94

    Laham, R. J. et al. Intracoronary and intravenous administration of basic fibroblast growth factor: myocardial and tissue distribution. Drug Metab. Dispos. 27, 821–826 (1999).

    CAS  PubMed  Google Scholar 

  95. 95

    Simons, M. et al. Pharmacological treatment of coronary artery disease with recombinant fibroblast growth factor-2: double-blind, randomized, controlled clinical trial. Circulation 105, 788–793 (2002).

    CAS  PubMed  Google Scholar 

  96. 96

    Sellke, F. W., Laham, R. J., Edelman, E. R., Pearlman, J. D. & Simons, M. Therapeutic angiogenesis with basic fibroblast growth factor: technique and early results. Ann. Thorac. Surg. 65, 1540–1544 (1998).

    CAS  PubMed  Google Scholar 

  97. 97

    Ruel, M. et al. Long-term effects of surgical angiogenic therapy with fibroblast growth factor 2 protein. J. Thorac. Cardiovasc. Surg. 124, 28–34 (2002).

    CAS  PubMed  Google Scholar 

  98. 98

    Lazarous, D. F. et al. Basic fibroblast growth factor in patients with intermittent claudication: results of a phase I trial. J. Am. Coll. Cardiol. 36, 1239–1244 (2000).

    CAS  PubMed  Google Scholar 

  99. 99

    Lederman, R. J. et al. Therapeutic angiogenesis with recombinant fibroblast growth factor-2 for intermittent claudication (the TRAFFIC study): a randomised trial. Lancet 359, 2053–2058 (2002).

    CAS  PubMed  Google Scholar 

  100. 100

    D'Amato, R. J., Loughnan, M. S., Flynn, E. & Folkman, J. Thalidomide is an inhibitor of angiogenesis. Proc. Natl Acad. Sci. USA 91, 4082–4085 (1994).

    CAS  PubMed  Google Scholar 

  101. 101

    Figg, W. D. et al. A randomized phase II trial of thalidomide, an angiogenesis inhibitor, in patients with androgen-independent prostate cancer. Clin. Cancer Res. 7, 1888–1893 (2001).

    CAS  PubMed  Google Scholar 

  102. 102

    Eisen, T. et al. Continuous low dose Thalidomide: a phase II study in advanced melanoma, renal cell, ovarian and breast cancer. Br. J. Cancer 82, 812–817 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103

    Myers, C. et al. Suramin: a novel growth factor antagonist with activity in hormone-refractory metastatic prostate cancer. J. Clin. Oncol. 10, 881–889 (1992).

    CAS  PubMed  Google Scholar 

  104. 104

    Eisenberger, M. A. et al. Suramin, an active drug for prostate cancer: interim observations in a phase I trial. J. Natl Cancer Inst. 85, 611–621 (1993).

    CAS  PubMed  Google Scholar 

  105. 105

    Motzer, R. J. et al. Phase II trial of suramin in patients with advanced renal cell carcinoma: treatment results, pharmacokinetics, and tumor growth factor expression. Cancer Res. 52, 5775–5779 (1992).

    CAS  PubMed  Google Scholar 

  106. 106

    Walther, M. M., Figg, W. D. & Linehan, W. M. Intravesical suramin: a novel agent for the treatment of superficial transitional-cell carcinoma of the bladder. World J. Urol. 14, S8–S11 (1996).

    PubMed  Google Scholar 

  107. 107

    Danesi, R. et al. Suramin inhibits bFGF-induced endothelial cell proliferation and angiogenesis in the chick chorioallantoic membrane. Br. J. Cancer 68, 932–938 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108

    Zhang, Y., Song, S., Yang, F., Au, J. L. & Wientjes, M. G. Nontoxic doses of suramin enhance activity of doxorubicin in prostate tumors. J. Pharmacol. Exp. Ther. 299, 426–433 (2001).

    CAS  PubMed  Google Scholar 

  109. 109

    Song, S., Wientjes, M. G., Gan, Y. & Au, J. L. Fibroblast growth factors: an epigenetic mechanism of broad spectrum resistance to anticancer drugs. Proc. Natl Acad. Sci. USA 97, 8658–8663 (2000).

    CAS  PubMed  Google Scholar 

  110. 110

    Hawkins, M. J. Clinical trials of antiangiogenic agents. Curr. Opin. Oncol. 7, 90–93 (1995).

    CAS  PubMed  Google Scholar 

  111. 111

    Sasisekharan, R., Shriver, Z., Venkataraman, G. & Narayanasami, U. Roles of heparan-sulphate glycosaminoglycans in cancer. Nature Rev. Cancer 2, 521–528 (2002).

    CAS  Google Scholar 

  112. 112

    Kudchadkar, R., Gonzalez, R. & Lewis, K. D. PI-88: a novel inhibitor of angiogenesis. Expert Opin. Investig. Drugs 17, 1769–1776 (2008).

    CAS  PubMed  Google Scholar 

  113. 113

    Singh, R. K. et al. Interferons alpha and beta down-regulate the expression of basic fibroblast growth factor in human carcinomas. Proc. Natl Acad. Sci. USA 92, 4562–4566 (1995).

    CAS  PubMed  Google Scholar 

  114. 114

    Dinney, C. P. et al. Inhibition of basic fibroblast growth factor expression, angiogenesis, and growth of human bladder carcinoma in mice by systemic interferon-α administration. Cancer Res. 58, 808–814 (1998).

    CAS  PubMed  Google Scholar 

  115. 115

    Wang, Y. & Becker, D. Antisense targeting of basic fibroblast growth factor and fibroblast growth factor receptor-1 in human melanomas blocks intratumoral angiogenesis and tumor growth. Nature Med. 3, 887–893 (1997).

    CAS  PubMed  Google Scholar 

  116. 116

    Presta, M. et al. Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis. Cytokine Growth Factor Rev. 16, 159–178 (2005).

    CAS  PubMed  Google Scholar 

  117. 117

    Kirkwood, J. M. et al. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J. Clin. Oncol. 14, 7–17 (1996).

    CAS  PubMed  Google Scholar 

  118. 118

    Hamm, C., Verma, S., Petrella, T., Bak, K. & Charette, M. Biochemotherapy for the treatment of metastatic malignant melanoma: a systematic review. Cancer Treat. Rev. 34, 145–156 (2008).

    CAS  PubMed  Google Scholar 

  119. 119

    Rayburn, E. R. & Zhang, R. Antisense, RNAi, and gene silencing strategies for therapy: mission possible or impossible? Drug Discov. Today 13, 513–521 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120

    Evans, S. J. et al. Dysregulation of the fibroblast growth factor system in major depression. Proc. Natl Acad. Sci. USA 101, 15506–15511 (2004).

    CAS  PubMed  Google Scholar 

  121. 121

    Turner, C. A., Calvo, N., Frost, D. O., Akil, H. & Watson, S. J. The fibroblast growth factor system is downregulated following social defeat. Neurosci. Lett. 430, 147–150 (2008).

    CAS  PubMed  Google Scholar 

  122. 122

    Turner, C. A., Gula, E. L., Taylor, L. P., Watson, S. J. & Akil, H. Antidepressant-like effects of intracerebroventricular FGF2 in rats. Brain Res. 1224, 63–68 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123

    Ellman, M. B., An, H. S., Muddasani, P. & Im, H. J. Biological impact of the fibroblast growth factor family on articular cartilage and intervertebral disc homeostasis. Gene 420, 82–89 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 124

    Aviles, R. J., Annex, B. H. & Lederman, R. J. Testing clinical therapeutic angiogenesis using basic fibroblast growth factor (FGF-2). Br. J. Pharmacol. 140, 637–646 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125

    Kitamura, M. et al. Periodontal tissue regeneration using fibroblast growth factor-2: randomized controlled phase II clinical trial. PLoS ONE 3, e2611 (2008).

    PubMed  PubMed Central  Google Scholar 

  126. 126

    Sugi, Y. et al. Fibroblast growth factor (FGF)-4 can induce proliferation of cardiac cushion mesenchymal cells during early valve leaflet formation. Dev. Biol. 258, 252–263 (2003).

    CAS  PubMed  Google Scholar 

  127. 127

    Sun, X., Mariani, F. V. & Martin, G. R. Functions of FGF signalling from the apical ectodermal ridge in limb development. Nature 418, 501–508 (2002).

    CAS  PubMed  Google Scholar 

  128. 128

    Feldman, B., Poueymirou, W., Papaioannou, V. E., DeChiara, T. M. & Goldfarb, M. Requirement of FGF-4 for postimplantation mouse development. Science 267, 246–249 (1995).

    CAS  PubMed  Google Scholar 

  129. 129

    Hebert, J. M., Rosenquist, T., Gotz, J. & Martin, G. R. FGF5 as a regulator of the hair growth cycle: evidence from targeted and spontaneous mutations. Cell 78, 1017–1025 (1994).

    CAS  PubMed  Google Scholar 

  130. 130

    Drogemuller, C., Rufenacht, S., Wichert, B. & Leeb, T. Mutations within the FGF5 gene are associated with hair length in cats. Anim. Genet. 38, 218–221 (2007).

    CAS  PubMed  Google Scholar 

  131. 131

    Housley, D. J. & Venta, P. J. The long and the short of it: evidence that FGF5 is a major determinant of canine 'hair'-itability. Anim. Genet. 37, 309–315 (2006).

    CAS  PubMed  Google Scholar 

  132. 132

    Armand, A. S., Laziz, I. & Chanoine, C. FGF6 in myogenesis. Biochim. Biophys. Acta 1763, 773–778 (2006).

    CAS  PubMed  Google Scholar 

  133. 133

    Floss, T., Arnold, H. H. & Braun, T. A role for FGF-6 in skeletal muscle regeneration. Genes Dev. 11, 2040–2051 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. 134

    Flynn, A. & O'Brien, T. Alferminogene tadenovec, an angiogenic FGF4 gene therapy for coronary artery disease. IDrugs 11, 283–293 (2008).

    CAS  PubMed  Google Scholar 

  135. 135

    Grines, C. L. et al. Angiogenic Gene Therapy (AGENT) trial in patients with stable angina pectoris. Circulation 105, 1291–1297 (2002).

    CAS  PubMed  Google Scholar 

  136. 136

    Henry, T. D. et al. Effects of Ad5FGF-4 in patients with angina: an analysis of pooled data from the AGENT-3 and AGENT-4 trials. J. Am. Coll. Cardiol. 50, 1038–1046 (2007).

    CAS  PubMed  Google Scholar 

  137. 137

    Guo, L., Degenstein, L. & Fuchs, E. Keratinocyte growth factor is required for hair development but not for wound healing. Genes Dev. 10, 165–175 (1996).

    CAS  PubMed  Google Scholar 

  138. 138

    Qiao, J. et al. FGF-7 modulates ureteric bud growth and nephron number in the developing kidney. Development 126, 547–554 (1999).

    CAS  PubMed  Google Scholar 

  139. 139

    Werner, S. et al. Large induction of keratinocyte growth factor expression in the dermis during wound healing. Proc. Natl Acad. Sci. USA 89, 6896–6900 (1992).

    CAS  PubMed  Google Scholar 

  140. 140

    Baskin, L. S. et al. Growth factors in bladder wound healing. J. Urol. 157, 2388–2395 (1997).

    CAS  PubMed  Google Scholar 

  141. 141

    Ichimura, T., Finch, P. W., Zhang, G., Kan, M. & Stevens, J. L. Induction of FGF-7 after kidney damage: a possible paracrine mechanism for tubule repair. Am. J. Physiol. 271, F967–F976 (1996).

    CAS  PubMed  Google Scholar 

  142. 142

    Kato, S. & Sekine, K. FGF–FGFR signaling in vertebrate organogenesis. Cell Mol. Biol. (Noisy-le-grand) 45, 631–638 (1999).

    CAS  PubMed  Google Scholar 

  143. 143

    Umemori, H., Linhoff, M. W., Ornitz, D. M. & Sanes, J. R. FGF22 and its close relatives are presynaptic organizing molecules in the mammalian brain. Cell 118, 257–270 (2004).

    CAS  PubMed  Google Scholar 

  144. 144

    Finch, P. W., Pricolo, V., Wu, A. & Finkelstein, S. D. Increased expression of keratinocyte growth factor messenger RNA associated with inflammatory bowel disease. Gastroenterology 110, 441–451 (1996).

    CAS  PubMed  Google Scholar 

  145. 145

    Finch, P. W., Murphy, F., Cardinale, I. & Krueger, J. G. Altered expression of keratinocyte growth factor and its receptor in psoriasis. Am. J. Pathol. 151, 1619–1628 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. 146

    Kovacs, D. et al. Immunohistochemical analysis of keratinocyte growth factor and fibroblast growth factor 10 expression in psoriasis. Exp. Dermatol. 14, 130–137 (2005).

    CAS  PubMed  Google Scholar 

  147. 147

    Thomson, A. A. & Cunha, G. R. Prostatic growth and development are regulated by FGF10. Development 126, 3693–3701 (1999).

    CAS  Google Scholar 

  148. 148

    Yan, G., Fukabori, Y., Nikolaropoulos, S., Wang, F. & McKeehan, W. L. Heparin-binding keratinocyte growth factor is a candidate stromal-to-epithelial-cell andromedin. Mol. Endocrinol. 6, 2123–2128 (1992).

    CAS  PubMed  Google Scholar 

  149. 149

    Spielberger, R. et al. Palifermin for oral mucositis after intensive therapy for hematologic cancers. N. Engl. J. Med. 351, 2590–2598 (2004). The results of this clinical trial helped bring FGF7 into use for the treatment of oral mucositis.

    CAS  Google Scholar 

  150. 150

    Potten, C. S. et al. Cell kinetic studies in the murine ventral tongue epithelium: the effects of repeated exposure to keratinocyte growth factor. Cell Prolif. 35 (Suppl. 1), 22–31 (2002).

    CAS  PubMed  Google Scholar 

  151. 151

    Potten, C. S. et al. Cell kinetic studies in the murine ventral tongue epithelium: mucositis induced by radiation and its protection by pretreatment with keratinocyte growth factor (KGF). Cell Prolif. 35 (Suppl. 1), 32–47 (2002).

    CAS  PubMed  Google Scholar 

  152. 152

    Braun, S. et al. Nrf2 transcription factor, a novel target of keratinocyte growth factor action which regulates gene expression and inflammation in the healing skin wound. Mol. Cell. Biol. 22, 5492–5505 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. 153

    Ellison, C. A. et al. Effect of recombinant human keratinocyte growth factor (rHuKGF) on the immunopathogenesis of intestinal graft-vs-host disease induced without a preconditioning regimen. J. Clin. Immunol. 24, 197–211 (2004).

    CAS  PubMed  Google Scholar 

  154. 154

    Panoskaltsis-Mortari, A. et al. Keratinocyte growth factor facilitates alloengraftment and ameliorates graft-versus-host disease in mice by a mechanism independent of repair of conditioning-induced tissue injury. Blood 96, 4350–4356 (2000).

    CAS  PubMed  Google Scholar 

  155. 155

    Beaven, A. W. & Shea, T. C. The effect of palifermin on chemotherapy and radiation therapy-induced mucositis: a review of the current literature. Support Cancer Ther. 4, 188–197 (2007).

    CAS  PubMed  Google Scholar 

  156. 156

    van der Velden, W. J., Herbers, A. H. & Blijlevens, N. M. Palifermin in allogeneic HSCT: many questions remain. Bone Marrow Transplant. 43, 85–86 (2008).

    PubMed  Google Scholar 

  157. 157

    Werner, S. Keratinocyte growth factor: a unique player in epithelial repair processes. Cytokine Growth Factor Rev. 9, 153–165 (1998).

    CAS  PubMed  Google Scholar 

  158. 158

    Freytes, C. O. et al. Phase I/II randomized trial evaluating the safety and clinical effects of repifermin administered to reduce mucositis in patients undergoing autologous hematopoietic stem cell transplantation. Clin. Cancer Res. 10, 8318–8324 (2004).

    CAS  PubMed  Google Scholar 

  159. 159

    Sandborn, W. J. et al. Repifermin (keratinocyte growth factor-2) for the treatment of active ulcerative colitis: a randomized, double-blind, placebo-controlled, dose-escalation trial. Aliment. Pharmacol. Ther. 17, 1355–1364 (2003).

    CAS  PubMed  Google Scholar 

  160. 160

    Liu, A. & Joyner, A. L. Early anterior/posterior patterning of the midbrain and cerebellum. Annu. Rev. Neurosci. 24, 869–896 (2001).

    CAS  PubMed  Google Scholar 

  161. 161

    O'Leary, D. D., Chou, S. J. & Sahara, S. Area patterning of the mammalian cortex. Neuron 56, 252–269 (2007).

    CAS  PubMed  Google Scholar 

  162. 162

    Meyers, E. N., Lewandoski, M. & Martin, G. R. An Fgf8 mutant allelic series generated by Cre- and Flp-mediated recombination. Nature Genet. 18, 136–141 (1998).

    CAS  PubMed  Google Scholar 

  163. 163

    Xu, J., Liu, Z. & Ornitz, D. M. Temporal and spatial gradients of Fgf8 and Fgf17 regulate proliferation and differentiation of midline cerebellar structures. Development 127, 1833–1843 (2000).

    CAS  PubMed  Google Scholar 

  164. 164

    Liu, Z., Xu, J., Colvin, J. S. & Ornitz, D. M. Coordination of chondrogenesis and osteogenesis by fibroblast growth factor 18. Genes Dev. 16, 859–869 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. 165

    Ohbayashi, N. et al. FGF18 is required for normal cell proliferation and differentiation during osteogenesis and chondrogenesis. Genes Dev. 16, 870–879 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. 166

    Ellsworth, J. L. et al. Fibroblast growth factor-18 is a trophic factor for mature chondrocytes and their progenitors. Osteoarthritis Cartilage 10, 308–320 (2002).

    CAS  PubMed  Google Scholar 

  167. 167

    Moore, E. E. et al. Fibroblast growth factor-18 stimulates chondrogenesis and cartilage repair in a rat model of injury-induced osteoarthritis. Osteoarthritis Cartilage 13, 623–631 (2005).

    CAS  PubMed  Google Scholar 

  168. 168

    Maruyama-Takahashi, K. et al. A neutralizing anti-fibroblast growth factor (FGF) 8 monoclonal antibody shows anti-tumor activity against FGF8b-expressing LNCaP xenografts in androgen-dependent and -independent conditions. Prostate 68, 640–650 (2008).

    CAS  PubMed  Google Scholar 

  169. 169

    Shimada, N. et al. A neutralizing anti-fibroblast growth factor 8 monoclonal antibody shows potent antitumor activity against androgen-dependent mouse mammary tumors in vivo. Clin. Cancer Res. 11, 3897–3904 (2005).

    CAS  PubMed  Google Scholar 

  170. 170

    Colvin, J. S., Green, R. P., Schmahl, J., Capel, B. & Ornitz, D. M. Male-to-female sex reversal in mice lacking fibroblast growth factor 9. Cell 104, 875–889 (2001).

    CAS  PubMed  Google Scholar 

  171. 171

    Colvin, J. S., White, A. C., Pratt, S. J. & Ornitz, D. M. Lung hypoplasia and neonatal death in Fgf9-null mice identify this gene as an essential regulator of lung mesenchyme. Development 128, 2095–2106 (2001).

    CAS  PubMed  Google Scholar 

  172. 172

    Lu, S. Y. et al. FGF-16 is required for embryonic heart development. Biochem. Biophys. Res. Commun. 373, 270–274 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. 173

    van der Walt, J. M. et al. Fibroblast growth factor 20 polymorphisms and haplotypes strongly influence risk of Parkinson disease. Am. J. Hum. Genet. 74, 1121–1127 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. 174

    Wang, G. et al. Variation in the miRNA-433 binding site of FGF20 confers risk for Parkinson disease by overexpression of α-synuclein. Am. J. Hum. Genet. 82, 283–289 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. 175

    Ohmachi, S., Mikami, T., Konishi, M., Miyake, A. & Itoh, N. Preferential neurotrophic activity of fibroblast growth factor-20 for dopaminergic neurons through fibroblast growth factor receptor-1c. J. Neurosci. Res. 72, 436–443 (2003).

    CAS  PubMed  Google Scholar 

  176. 176

    Takagi, Y. et al. Dopaminergic neurons generated from monkey embryonic stem cells function in a Parkinson primate model. J. Clin. Invest. 115, 102–109 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. 177

    Schuster, M. W. et al. Safety and tolerability of velafermin (CG53135–05) in patients receiving high-dose chemotherapy and autologous peripheral blood stem cell transplant. Support Care Cancer 16, 477–483 (2008).

    PubMed  Google Scholar 

  178. 178

    Kuro-o, M. et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 390, 45–51 (1997). The first paper to describe the discovery of αklotho and its role in ageing in mice.

    CAS  Google Scholar 

  179. 179

    Kurosu, H. et al. Suppression of aging in mice by the hormone Klotho. Science 309, 1829–1833 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. 180

    Imura, A. et al. Secreted Klotho protein in sera and CSF: implication for post-translational cleavage in release of Klotho protein from cell membrane. FEBS Lett. 565, 143–147 (2004).

    CAS  PubMed  Google Scholar 

  181. 181

    Nabeshima, Y. The discovery of α-Klotho and FGF23 unveiled new insight into calcium and phosphate homeostasis. Cell. Mol. Life Sci. 65, 3218–3230 (2008).

    CAS  PubMed  Google Scholar 

  182. 182

    Imura, A. et al. α-Klotho as a regulator of calcium homeostasis. Science 316, 1615–1618 (2007).

    CAS  PubMed  Google Scholar 

  183. 183

    Chang, Q. et al. The β-glucuronidase klotho hydrolyzes and activates the TRPV5 channel. Science 310, 490–493 (2005).

    CAS  PubMed  Google Scholar 

  184. 184

    Tsujikawa, H., Kurotaki, Y., Fujimori, T., Fukuda, K. & Nabeshima, Y. Klotho, a gene related to a syndrome resembling human premature aging, functions in a negative regulatory circuit of vitamin D endocrine system. Mol. Endocrinol. 17, 2393–2403 (2003).

    CAS  PubMed  Google Scholar 

  185. 185

    Shimada, T. et al. Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J. Clin. Invest. 113, 561–568 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. 186

    Kurosu, H. et al. Regulation of fibroblast growth factor-23 signaling by klotho. J. Biol. Chem. 281, 6120–6123 (2006). The first evidence that FGF23 requires α-klotho to activate FGFRs.

    CAS  PubMed  PubMed Central  Google Scholar 

  187. 187

    Urakawa, I. et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 444, 770–774 (2006). References 186 and 187 showed, for the first time, that FGF23 requires α-klotho to activate FGFR1c.

    CAS  PubMed  PubMed Central  Google Scholar 

  188. 188

    Ito, S. et al. Impaired negative feedback suppression of bile acid synthesis in mice lacking βKlotho. J. Clin. Invest. 115, 2202–2208 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. 189

    Inagaki, T. et al. Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab. 2, 217–225 (2005).

    CAS  PubMed  Google Scholar 

  190. 190

    Yu, C. et al. Elevated cholesterol metabolism and bile acid synthesis in mice lacking membrane tyrosine kinase receptor FGFR4. J. Biol. Chem. 275, 15482–15489 (2000).

    CAS  Google Scholar 

  191. 191

    Kurosu, H. et al. Tissue-specific expression of βKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21. J. Biol. Chem. 282, 26687–26695 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  192. 192

    Lin, B. C., Wang, M., Blackmore, C. & Desnoyers, L. R. Liver-specific activities of FGF19 require Klotho beta. J. Biol. Chem. 282, 27277–27284 (2007).

    CAS  Google Scholar 

  193. 193

    Wu, X. et al. Co-receptor requirements for fibroblast growth factor-19 signaling. J. Biol. Chem. 282, 29069–29072 (2007).

    CAS  Google Scholar 

  194. 194

    Kharitonenkov, A. et al. FGF-21/FGF-21 receptor interaction and activation is determined by βKlotho. J. Cell. Physiol. 215, 1–7 (2008).

    CAS  Google Scholar 

  195. 195

    Ogawa, Y. et al. βKlotho is required for metabolic activity of fibroblast growth factor 21. Proc. Natl Acad. Sci. USA 104, 7432–7437 (2007).

    CAS  Google Scholar 

  196. 196

    Suzuki, M. et al. βKlotho is required for fibroblast growth factor (FGF) 21 signaling through FGF receptor (FGFR) 1c and FGFR3c. Mol. Endocrinol. 22, 1006–1014 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  197. 197

    Nishimura, T., Utsunomiya, Y., Hoshikawa, M., Ohuchi, H. & Itoh, N. Structure and expression of a novel human FGF, FGF-19, expressed in the fetal brain. Biochim. Biophys. Acta. 1444, 148–151 (1999).

    CAS  PubMed  Google Scholar 

  198. 198

    Xie, M. H. et al. FGF-19, a novel fibroblast growth factor with unique specificity for FGFR4. Cytokine 11, 729–735 (1999).

    CAS  Google Scholar 

  199. 199

    Holt, J. A. et al. Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis. Genes Dev. 17, 1581–1591 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  200. 200

    Lundasen, T., Galman, C., Angelin, B. & Rudling, M. Circulating intestinal fibroblast growth factor 19 has a pronounced diurnal variation and modulates hepatic bile acid synthesis in man. J. Intern. Med. 260, 530–536 (2006). This interesting study revealed that FGF19 is induced following feeding in humans.

    CAS  Google Scholar 

  201. 201

    Choi, M. et al. Identification of a hormonal basis for gallbladder filling. Nature Med. 12, 1253–1255 (2006).

    CAS  PubMed  Google Scholar 

  202. 202

    Harmer, N. J. et al. Towards a resolution of the stoichiometry of the fibroblast growth factor (FGF)–FGF receptor–heparin complex. J. Mol. Biol. 339, 821–834 (2004).

    CAS  PubMed  Google Scholar 

  203. 203

    Dostalova, I. et al. Plasma concentrations of fibroblast growth factors 19 and 21 in patients with anorexia nervosa. J. Clin. Endocrinol. Metab. 93, 3627–3632 (2008).

    CAS  Google Scholar 

  204. 204

    Nicholes, K. et al. A mouse model of hepatocellular carcinoma: ectopic expression of fibroblast growth factor 19 in skeletal muscle of transgenic mice. Am. J. Pathol. 160, 2295–2307 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  205. 205

    Desnoyers, L. R. et al. Targeting FGF19 inhibits tumor growth in colon cancer xenograft and FGF19 transgenic hepatocellular carcinoma models. Oncogene 27, 85–97 (2008).

    CAS  Google Scholar 

  206. 206

    Pai, R. et al. Inhibition of fibroblast growth factor 19 reduces tumor growth by modulating β-catenin signaling. Cancer Res. 68, 5086–5095 (2008).

    CAS  PubMed  Google Scholar 

  207. 207

    Strack, A. M. & Myers, R. W. Modulation of metabolic syndrome by fibroblast growth factor 19 (FGF19)? Endocrinology 145, 2591–2593 (2004).

    CAS  PubMed  Google Scholar 

  208. 208

    Nishimura, T., Nakatake, Y., Konishi, M. & Itoh, N. Identification of a novel FGF, FGF-21, preferentially expressed in the liver. Biochim. Biophys. Acta 1492, 203–206 (2000).

    CAS  Google Scholar 

  209. 209

    Zhang, X. et al. Serum FGF21 levels are increased in obesity and are independently associated with the metabolic syndrome in humans. Diabetes 57, 1246–1253 (2008).

    CAS  Google Scholar 

  210. 210

    Wente, W. et al. Fibroblast growth factor-21 improves pancreatic β-cell function and survival by activation of extracellular signal-regulated kinase 1/2 and Akt signaling pathways. Diabetes 55, 2470–2478 (2006).

    CAS  Google Scholar 

  211. 211

    Izumiya, Y. et al. FGF21 is an Akt-regulated myokine. FEBS Lett. 582, 3805–3810 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  212. 212

    Coskun, T. et al. FGF21 corrects obesity in mice. Endocrinology 149, 6018–6027 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  213. 213

    Xu, J. et al. FGF21 reverses hepatic steatosis, increases energy expenditure and improves insulin sensitivity in diet-induced obese mice. Diabetes 58, 250–259 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  214. 214

    Inagaki, T. et al. Inhibition of growth hormone signaling by the fasting-induced hormone FGF21. Cell Metab. 8, 77–83 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  215. 215

    Badman, M. K. et al. Hepatic fibroblast growth factor 21 is regulated by PPARα and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metab. 5, 426–437 (2007).

    CAS  PubMed  Google Scholar 

  216. 216

    Kharitonenkov, A. et al. The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21. Endocrinology 148, 774–781 (2007).

    CAS  Google Scholar 

  217. 217

    Inagaki, T. et al. Endocrine regulation of the fasting response by PPARα-mediated induction of fibroblast growth factor 21. Cell Metab. 5, 415–425 (2007). References 215 and 217 describe the role of FGF21 in the fasting response.

    CAS  PubMed  Google Scholar 

  218. 218

    Palou, M. et al. Sequential changes in the expression of genes involved in lipid metabolism in adipose tissue and liver in response to fasting. Pflugers Arch. 456, 825–836 (2008).

    CAS  PubMed  Google Scholar 

  219. 219

    Reitman, M. L. FGF21: a missing link in the biology of fasting. Cell Metab. 5, 405–407 (2007).

    CAS  PubMed  Google Scholar 

  220. 220

    Wang, H., Qiang, L. & Farmer, S. R. Identification of a domain within peroxisome proliferator-activated receptor γ regulating expression of a group of genes containing fibroblast growth factor 21 that are selectively repressed by SIRT1 in adipocytes. Mol. Cell. Biol. 28, 188–200 (2008).

    Google Scholar 

  221. 221

    Moyers, J. S. et al. Molecular determinants of FGF-21 activity-synergy and cross-talk with PPARγ signaling. J. Cell. Physiol. 210, 1–6 (2007).

    CAS  PubMed  Google Scholar 

  222. 222

    Arner, P. et al. FGF21 attenuates lipolysis in human adipocytes — a possible link to improved insulin sensitivity. FEBS Lett. 582, 1725–1730 (2008).

    CAS  PubMed  Google Scholar 

  223. 223

    Muise, E. S. et al. Adipose fibroblast growth factor 21 is up-regulated by peroxisome proliferator-activated receptor γ and altered metabolic states. Mol. Pharmacol. 74, 403–412 (2008).

    CAS  Google Scholar 

  224. 224

    Galman, C. et al. The circulating metabolic regulator FGF21 is induced by prolonged fasting and PPARα activation in man. Cell Metab. 8, 169–174 (2008).

    PubMed  Google Scholar 

  225. 225

    Chen, W. W. et al. Circulating FGF-21 levels in normal subjects and in newly diagnose patients with type 2 diabetes mellitus. Exp. Clin. Endocrinol. Diabetes 116, 65–68 (2008).

    CAS  PubMed  Google Scholar 

  226. 226

    Yamashita, T., Yoshioka, M. & Itoh, N. Identification of a novel fibroblast growth factor, FGF-23, preferentially expressed in the ventrolateral thalamic nucleus of the brain. Biochem. Biophys. Res. Commun. 277, 494–498 (2000).

    CAS  Google Scholar 

  227. 227

    Riminucci, M. et al. FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting. J. Clin. Invest. 112, 683–692 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  228. 228

    Liu, S. et al. Regulation of fibroblastic growth factor 23 expression but not degradation by PHEX. J. Biol. Chem. 278, 37419–37426 (2003).

    CAS  Google Scholar 

  229. 229

    Bai, X. Y., Miao, D., Goltzman, D. & Karaplis, A. C. The autosomal dominant hypophosphatemic rickets R176Q mutation in fibroblast growth factor 23 resists proteolytic cleavage and enhances in vivo biological potency. J. Biol. Chem. 278, 9843–9849 (2003).

    CAS  PubMed  Google Scholar 

  230. 230

    Larsson, T. et al. Transgenic mice expressing fibroblast growth factor 23 under the control of the α1(I) collagen promoter exhibit growth retardation, osteomalacia, and disturbed phosphate homeostasis. Endocrinology 145, 3087–3094 (2004).

    CAS  PubMed  Google Scholar 

  231. 231

    Fukumoto, S. Physiological regulation and disorders of phosphate metabolism — pivotal role of fibroblast growth factor 23. Intern. Med. 47, 337–343 (2008).

    PubMed  Google Scholar 

  232. 232

    Saito, H. et al. Human fibroblast growth factor-23 mutants suppress Na+-dependent phosphate co-transport activity and 1α, 25-dihydroxyvitamin D3 production. J. Biol. Chem. 278, 2206–2211 (2003).

    CAS  PubMed  Google Scholar 

  233. 233

    Segawa, H. et al. Effect of hydrolysis-resistant FGF23–R179Q on dietary phosphate regulation of the renal type-II Na/Pi transporter. Pflugers Arch. 446, 585–592 (2003).

    CAS  PubMed  Google Scholar 

  234. 234

    Ben-Dov, I. Z. et al. The parathyroid is a target organ for FGF23 in rats. J. Clin. Invest. 117, 4003–4008 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  235. 235

    Sitara, D. et al. Homozygous ablation of fibroblast growth factor-23 results in hyperphosphatemia and impaired skeletogenesis, and reverses hypophosphatemia in Phex-deficient mice. Matrix Biol. 23, 421–432 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  236. 236

    Hesse, M., Frohlich, L. F., Zeitz, U., Lanske, B. & Erben, R. G. Ablation of vitamin D signaling rescues bone, mineral, and glucose homeostasis in Fgf-23 deficient mice. Matrix Biol. 26, 75–84 (2007).

    CAS  Google Scholar 

  237. 237

    Razzaque, M. S., Sitara, D., Taguchi, T., St-Arnaud, R. & Lanske, B. Premature aging-like phenotype in fibroblast growth factor 23 null mice is a vitamin D-mediated process. FASEB J. 20, 720–722 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  238. 238

    Sitara, D. et al. Genetic ablation of vitamin D activation pathway reverses biochemical and skeletal anomalies in Fgf-23-null animals. Am. J. Pathol. 169, 2161–2170 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  239. 239

    Kuro-o, M. Klotho as a regulator of fibroblast growth factor signaling and phosphate/calcium metabolism. Curr. Opin. Nephrol. Hypertens. 15, 437–441 (2006).

    CAS  PubMed  Google Scholar 

  240. 240

    Inoue, Y. et al. Role of the vitamin D receptor in FGF23 action on phosphate metabolism. Biochem. J. 390, 325–331 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  241. 241

    Medici, D. et al. FGF-23-Klotho signaling stimulates proliferation and prevents vitamin D-induced apoptosis. J. Cell Biol. 182, 459–465 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  242. 242

    A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets. The HYP Consortium. Nature Genet. 11, 130–136 (1995).

  243. 243

    Jonsson, K. B. et al. Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia. N. Engl. J. Med. 348, 1656–1663 (2003).

    CAS  Google Scholar 

  244. 244

    Yamazaki, Y. et al. Increased circulatory level of biologically active full-length FGF-23 in patients with hypophosphatemic rickets/osteomalacia. J. Clin. Endocrinol. Metab. 87, 4957–4960 (2002).

    CAS  Google Scholar 

  245. 245

    Weber, T. J., Liu, S., Indridason, O. S. & Quarles, L. D. Serum FGF23 levels in normal and disordered phosphorus homeostasis. J. Bone Miner. Res. 18, 1227–1234 (2003).

    CAS  PubMed  Google Scholar 

  246. 246

    Shulman, D. I. et al. Tumor-induced rickets: usefulness of MR gradient echo recall imaging for tumor localization. J. Pediatr. 144, 381–385 (2004).

    PubMed  Google Scholar 

  247. 247

    Lyles, K. W. et al. Genetic transmission of tumoral calcinosis: autosomal dominant with variable clinical expressivity. J. Clin. Endocrinol. Metab. 60, 1093–1096 (1985).

    CAS  PubMed  Google Scholar 

  248. 248

    Araya, K. et al. A novel mutation in fibroblast growth factor 23 gene as a cause of tumoral calcinosis. J. Clin. Endocrinol. Metab. 90, 5523–5527 (2005).

    CAS  PubMed  Google Scholar 

  249. 249

    Benet-Pages, A., Orlik, P., Strom, T. M. & Lorenz-Depiereux, B. An FGF23 missense mutation causes familial tumoral calcinosis with hyperphosphatemia. Hum. Mol. Genet. 14, 385–390 (2005).

    CAS  PubMed  Google Scholar 

  250. 250

    Larsson, T. et al. A novel recessive mutation in fibroblast growth factor-23 causes familial tumoral calcinosis. J. Clin. Endocrinol. Metab. 90, 2424–2427 (2005).

    CAS  PubMed  Google Scholar 

  251. 251

    Ichikawa, S. et al. A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis. J. Musculoskelet. Neuronal Interact. 7, 318–319 (2007).

    CAS  PubMed  Google Scholar 

  252. 252

    Shimada, T. et al. Mutant FGF-23 responsible for autosomal dominant hypophosphatemic rickets is resistant to proteolytic cleavage and causes hypophosphatemia in vivo. Endocrinology 143, 3179–3182 (2002).

    CAS  PubMed  Google Scholar 

  253. 253

    Kato, K. et al. Polypeptide GalNAc-transferase T3 and familial tumoral calcinosis. Secretion of fibroblast growth factor 23 requires O-glycosylation. J. Biol. Chem. 281, 18370–18377 (2006).

    CAS  PubMed  Google Scholar 

  254. 254

    Topaz, O. et al. Mutations in GALNT3, encoding a protein involved in O-linked glycosylation, cause familial tumoral calcinosis. Nature Genet. 36, 579–581 (2004).

    CAS  PubMed  Google Scholar 

  255. 255

    Imanishi, Y. et al. FGF-23 in patients with end-stage renal disease on hemodialysis. Kidney Int. 65, 1943–1946 (2004).

    CAS  PubMed  Google Scholar 

  256. 256

    Larsson, T., Nisbeth, U., Ljunggren, O., Juppner, H. & Jonsson, K. B. Circulating concentration of FGF-23 increases as renal function declines in patients with chronic kidney disease, but does not change in response to variation in phosphate intake in healthy volunteers. Kidney Int. 64, 2272–2279 (2003).

    CAS  PubMed  Google Scholar 

  257. 257

    Razzaque, M. S. Does FGF23 toxicity influence the outcome of chronic kidney disease? Nephrol. Dial. Transplant. 24, 4–7 (2009).

    PubMed  Google Scholar 

  258. 258

    Gutierrez, O. M. et al. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N. Engl. J. Med. 359, 584–592 (2008). This study shows a correlation between serum FGF23 levels and chronic kidney disease mortality. This area requires further research, as the role of FGF23 in chronic kidney disease is poorly understood.

    CAS  PubMed  PubMed Central  Google Scholar 

  259. 259

    Nakanishi, S. et al. Serum fibroblast growth factor-23 levels predict the future refractory hyperparathyroidism in dialysis patients. Kidney Int. 67, 1171–1178 (2005).

    CAS  PubMed  Google Scholar 

  260. 260

    Aono Y, et al. The neutralization of FGF-23 ameliorates hypophosphatemia and rickets in Hyp mice. J. Bone Miner. Res. 18, S16 (2003).

    Google Scholar 

  261. 261

    Yamazaki, Y. et al. Anti-FGF23 neutralizing antibodies demonstrate the physiological role and structural features of FGF23. J. Bone Miner. Res. 23, 1509–1518 (2008).

    CAS  Google Scholar 

  262. 262

    Turner, C. A., Akil, H., Watson, S. J. & Evans, S. J. The fibroblast growth factor system and mood disorders. Biol. Psychiatry 59, 1128–1135 (2006).

    CAS  PubMed  Google Scholar 

  263. 263

    Goldfarb, M. Fibroblast growth factor homologous factors: evolution, structure, and function. Cytokine Growth Factor Rev. 16, 215–220 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  264. 264

    Dor, Y. et al. Conditional switching of VEGF provides new insights into adult neovascularization and pro-angiogenic therapy. EMBO J. 21, 1939–1947 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  265. 265

    Bush, M. A. et al. Pharmacokinetics and pharmacodynamics of recombinant FGF-2 in a phase I trial in coronary artery disease. J. Clin. Pharmacol. 41, 378–385 (2001).

    CAS  PubMed  Google Scholar 

  266. 266

    Nugent, M. A. & Edelman, E. R. Kinetics of basic fibroblast growth factor binding to its receptor and heparan sulfate proteoglycan: a mechanism for cooperactivity. Biochemistry 31, 8876–8883 (1992).

    CAS  PubMed  Google Scholar 

  267. 267

    Ortega, S. et al. Conversion of cysteine to serine residues alters the activity, stability, and heparin dependence of acidic fibroblast growth factor. J. Biol. Chem. 266, 5842–5846 (1991).

    CAS  PubMed  Google Scholar 

  268. 268

    Dubey, V. K., Lee, J., Somasundaram, T., Blaber, S. & Blaber, M. Spackling the crack: stabilizing human fibroblast growth factor-1 by targeting the N and C terminus β-strand interactions. J. Mol. Biol. 371, 256–268 (2007).

    CAS  PubMed  Google Scholar 

  269. 269

    Rajanayagam, M. A. et al. Intracoronary basic fibroblast growth factor enhances myocardial collateral perfusion in dogs. J. Am. Coll. Cardiol. 35, 519–526 (2000).

    CAS  PubMed  Google Scholar 

  270. 270

    Lazarous, D. F. et al. Pharmacodynamics of basic fibroblast growth factor: route of administration determines myocardial and systemic distribution. Cardiovasc. Res. 36, 78–85 (1997).

    CAS  PubMed  Google Scholar 

  271. 271

    Post, M. J., Laham, R., Sellke, F. W. & Simons, M. Therapeutic angiogenesis in cardiology using protein formulations. Cardiovasc. Res. 49, 522–531 (2001).

    CAS  PubMed  Google Scholar 

  272. 272

    Yla-Herttuala, S. & Martin, J. F. Cardiovascular gene therapy. Lancet 355, 213–222 (2000).

    CAS  PubMed  Google Scholar 

  273. 273

    Kornowski, R., Fuchs, S., Leon, M. B. & Epstein, S. E. Delivery strategies to achieve therapeutic myocardial angiogenesis. Circulation 101, 454–458 (2000).

    CAS  PubMed  Google Scholar 

  274. 274

    Lee, R. J. et al. VEGF gene delivery to myocardium: deleterious effects of unregulated expression. Circulation 102, 898–901 (2000).

    CAS  PubMed  Google Scholar 

  275. 275

    Celletti, F. L. et al. Vascular endothelial growth factor enhances atherosclerotic plaque progression. Nature Med. 7, 425–429 (2001).

    CAS  PubMed  Google Scholar 

  276. 276

    Simons, M. et al. Clinical trials in coronary angiogenesis: issues, problems, consensus: an expert panel summary. Circulation 102, E73–E86 (2000).

    CAS  PubMed  Google Scholar 

  277. 277

    Presta, M. et al. Heparin derivatives as angiogenesis inhibitors. Curr. Pharm. Des. 9, 553–566 (2003).

    CAS  PubMed  Google Scholar 

  278. 278

    Goetz, R. et al. Crystal structure of a fibroblast growth factor homologous factor defines conserved surface for binding and modulation of voltage-gated sodium channels. J. Biol. Chem. (in the press).

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Acknowledgements

This work was supported by the US National Institutes of Health (NIH) grant R01-DE13686 (to M.M.) and by NIH/NIGMS training grant T32-GM066704-05 (to A.B.).

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Glossary

Autosomal dominant hypophosphataemic rickets

A hereditary disorder of phosphate wasting characterized by rickets, lower extremity deformities and osteomalacia.

Lacrimo-auriculo-dento-digital syndrome

(LADD). A syndrome characterized by abnormalities of the digits and teeth, low-set ears and aplasia of the lacrimal and salivary glands. Mutations in FGFR2 and FGF10 are known to cause LADD.

Kallmann syndrome

This syndrome results from a deficiency of gonadotropin-releasing hormone, which leads to hypogonadism. Mutations in FGFR1c and FGF8 are known to cause Kallmann syndrome.

Oral mucositis

This condition results from injury to the epithelium of the oral cavity and can vary widely in severity. In the worst cases, oral mucositis can lead to ulceration, infection and the need for assisted feeding.

Heparan sulphate glycosaminoglycan

(HSGAG). HSGAGs are long chains of repeating disaccharide units that can be variably sulphated or acetylated, allowing for considerable structural diversity. HSGAGs are located in the extracellular matrix at the surface of every cell, where they modulate the activity of a wide range of growth factors and morphogens.

Exon skipping

A specific type of alternative splicing in which an exon is entirely skipped.

Alternative splicing

This process increases protein diversity by dividing up the primary RNA gene transcript, excluding certain exons, and then reconnecting the transcript. These alternative ribonucleotide sequences are then translated, giving a variety of protein isoforms.

Craniosynostosis

This condition results from the premature closure of sutures of a developing skull before the completion of brain growth. The brain continues to grow in areas of the skull where sutures have not closed, leading to a malformed cranium.

Apert's syndrome

One of the most common craniosynostosis syndromes that exhibits severe syndactyly (digit fusion) of the hands and feet. Apert's syndrome is often associated with visceral abnormalities of the cardiovascular, respiratory and urogenital systems.

Osteoglophonic dysplasia

A bone disorder presenting with dwarfism, vertebral fragility, craniosynostosis and failure to thrive. The term osteoglophonic refers to the 'hollowed out' appearance of the metaphyses in X-rays, which are the growth zones of long bones.

Pfeiffer's syndrome

A craniosynostosis disorder that can also present with polydactyly.

Glioblastoma

An aggressive tumour derived from glial cells that exhibits high levels of neovascularization.

Myeloproliferative syndrome

A progressive disease that can transform into acute leukaemia. Also known as stem cell leukaemia or lymphoma syndrome, it often presents with a T-cell lymphoblastic lymphoma and eosinophilia.

Crouzon's syndrome

A craniosynostosis syndrome presenting with a beaked nose and bulging, excessively separated eyes (exopthalmos and hypertelorism, respectively).

Callosal agenesis

An absence of the corpus callosum, the tissue that connects the two hemispheres of the brain.

Ventriculomegaly

A condition associated with enlarged lateral ventricles in the brain. Ventriculomegaly can have many causes, one of which is callosal agenesis.

Hypochrondroplasia

A mild dwarfism syndrome generally presenting with nearly normal cranial and facial characteristics.

Thanatophoric dysplasia type II

A lethal neonatal skeletal dysplasia associated with a severe cloverleaf-shaped skull deformity.

Severe achondroplasia with developmental delay and acanthosis nigricans syndrome

This dwarfism syndrome is accompanied by substantial neurological disorders and acanthosis nigricans, which involves a hyperpigmentation of the skin.

Nitric oxide

Among its many functions, this small molecule relaxes the smooth muscle surrounding blood vessels.

Brachial plexus

The bundle of nerves located in the axilla (armpit) that descends into the upper limb to provide sensation and motor control.

Chronic transverse myelitis

Inflammation across the width of one segment of the spinal cord that can lead to destruction of myelin and neurological impairment.

Heparin

A highly sulphated heparan sulphate glycosaminoglycan (HSGAG). Although it does not act physiologically on FGF–FGFR signalling, it can substitute for other HSGAGs in experimental studies.

Trophoblast

These cells form the outer layer of the developing embryo and are responsible for its implantation into the endometrium.

Osteomalacia

Demineralization of the bones often associated with a lack of vitamin D.

Secondary hyperparathyroidism

This condition is marked by excessive secretion of parathyroid hormone as a result of low serum calcium levels. It is often seen in patients suffering from kidney disease.

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Beenken, A., Mohammadi, M. The FGF family: biology, pathophysiology and therapy. Nat Rev Drug Discov 8, 235–253 (2009). https://doi.org/10.1038/nrd2792

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