Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Fibroblast growth factor signalling in osteoarthritis and cartilage repair

Nature Reviews Rheumatology volume 16, pages 547–564 (2020)Cite this article

Subjects

Abstract

Regulated fibroblast growth factor (FGF) signalling is a prerequisite for the correct development and homeostasis of articular cartilage, as evidenced by the fact that aberrant FGF signalling contributes to the maldevelopment of joints and to the onset and progression of osteoarthritis. Of the four FGF receptors (FGFRs 1–4), FGFR1 and FGFR3 are strongly implicated in osteoarthritis, and FGFR1 antagonists, as well as agonists of FGFR3, have shown therapeutic efficacy in mouse models of spontaneous and surgically induced osteoarthritis. FGF18, a high affinity ligand for FGFR3, is the only FGF-based drug currently in clinical trials for osteoarthritis. This Review covers the latest advances in our understanding of the molecular mechanisms that regulate FGF signalling during normal joint development and in the pathogenesis of osteoarthritis. Strategies for FGF signalling-based treatment of osteoarthritis and for cartilage repair in animal models and clinical trials are also introduced. An improved understanding of FGF signalling from a structural biology perspective, and of its roles in skeletal development and diseases, could unlock new avenues for discovery of modulators of FGF signalling that can slow or stop the progression of osteoarthritis.

Key points

  • Fibroblast growth factor (FGF) signalling pathways have important roles in the development and homeostasis of articular cartilage.

  • Aberrant FGF activity contributes to joint deformity and to the onset and progression of osteoarthritis.

  • Structural studies have provided important mechanistic insights into the regulation of FGF signalling.

  • Advances in understanding FGF signalling suggest potential approaches to FGF-based therapeutics for the treatment of osteoarthritis and cartilage injury.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Paracrine and endocrine FGFR cell surface signal transduction units.
Fig. 2: The FGF signalling cascade.
Fig. 3: Expression of FGFs and FGFRs during endochondral bone and synovial joint formation.
Fig. 4: FGF signalling in osteoarthritis.

Similar content being viewed by others

References

  1. Huey, D. J., Hu, J. C. & Athanasiou, K. A. Unlike bone, cartilage regeneration remains elusive. Science 338, 917–921 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Zhang, Y. & Jordan, J. M. Epidemiology of osteoarthritis. Clin. Geriatr. Med. 26, 355–369 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Allen, K. D. & Golightly, Y. M. State of the evidence. Curr. Opin. Rheumatol. 27, 276–283 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Wallace, I. J. et al. Knee osteoarthritis has doubled in prevalence since the mid-20th century. Proc. Natl Acad. Sci. USA 114, 9332–9336 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Martel-Pelletier, J. et al. Osteoarthritis. Nat. Rev. Dis. Prim. 2, 16072 (2016).

    Article  PubMed  Google Scholar 

  6. Roemer, F. W. et al. Presence of MRI-detected joint effusion and synovitis increases the risk of cartilage loss in knees without osteoarthritis at 30-month follow-up: the MOST study. Ann. Rheum. Dis. 70, 1804–1809 (2011).

    Article  PubMed  Google Scholar 

  7. Liu-Bryan, R. & Terkeltaub, R. Emerging regulators of the inflammatory process in osteoarthritis. Nat. Rev. Rheumatol. 11, 35–44 (2015).

    Article  CAS  PubMed  Google Scholar 

  8. Hunter, D. J. & Bierma-Zeinstra, S. Osteoarthritis. Lancet 393, 1745–1759 (2019).

    Article  CAS  PubMed  Google Scholar 

  9. Bijlsma, J. W., Berenbaum, F. & Lafeber, F. P. Osteoarthritis: an update with relevance for clinical practice. Lancet 377, 2115–2126 (2011).

    Article  PubMed  Google Scholar 

  10. Kwon, H. et al. Surgical and tissue engineering strategies for articular cartilage and meniscus repair. Nat. Rev. Rheumatol. 15, 550–570 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Tiku, M. L. & Sabaawy, H. E. Cartilage regeneration for treatment of osteoarthritis: a paradigm for nonsurgical intervention. Ther. Adv. Musculoskelet. Dis. 7, 76–87 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Mastbergen, S. C., Saris, D. B. & Lafeber, F. P. Functional articular cartilage repair: here, near, or is the best approach not yet clear? Nat. Rev. Rheumatol. 9, 277–290 (2013).

    Article  CAS  PubMed  Google Scholar 

  13. Chijimatsu, R. & Saito, T. Mechanisms of synovial joint and articular cartilage development. Cell. Mol. Life Sci. 76, 3939–3952 (2019).

    Article  CAS  PubMed  Google Scholar 

  14. Ellman, M. B. et al. Fibroblast growth factor control of cartilage homeostasis. J. Cell. Biochem. 114, 735–742 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Su, N., Jin, M. & Chen, L. Role of FGF/FGFR signaling in skeletal development and homeostasis: learning from mouse models. Bone Res. 2, 14003 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Ornitz, D. M. & Marie, P. J. Fibroblast growth factor signaling in skeletal development and disease. Genes Dev. 29, 1463–1486 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Beenken, A. & Mohammadi, M. The FGF family: biology, pathophysiology and therapy. Nat. Rev. Drug. Discov. 8, 235–253 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Itoh, N. & Ornitz, D. M. Fibroblast growth factors: from molecular evolution to roles in development, metabolism and disease. J. Biochem. 149, 121–130 (2011).

    Article  CAS  PubMed  Google Scholar 

  19. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Belov, A. A. & Mohammadi, M. Molecular mechanisms of fibroblast growth factor signaling in physiology and pathology. Cold Spring Harb. Perspect. Biol. 5, a015958 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Plotnikov, A. N., Schlessinger, J., Hubbard, S. R. & Mohammadi, M. Structural basis for FGF receptor dimerization and activation. Cell 98, 641–650 (1999).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  23. Stauber, D. J., DiGabriele, A. D. & Hendrickson, W. A. Structural interactions of fibroblast growth factor receptor with its ligands. Proc. Natl Acad. Sci. USA 97, 49–54 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kalinina, J. et al. The alternatively spliced acid box region plays a key role in FGF receptor autoinhibition. Structure 20, 77–88 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Olsen, S. K. et al. Insights into the molecular basis for fibroblast growth factor receptor autoinhibition and ligand-binding promiscuity. Proc. Natl Acad. Sci. USA 101, 935–940 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Fantl, W. J., Johnson, D. E. & Williams, L. T. Signalling by receptor tyrosine kinases. Annu. Rev. Biochem. 62, 453–481 (1993).

    Article  CAS  PubMed  Google Scholar 

  27. Givol, D. & Yayon, A. Complexity of FGF receptors: genetic basis for structural diversity and functional specificity. FASEB J. 6, 3362–3369 (1992).

    Article  CAS  PubMed  Google Scholar 

  28. Ornitz, D. M. et al. Receptor specificity of the fibroblast growth factor family. J. Biol. Chem. 271, 15292–15297 (1996).

    Article  CAS  PubMed  Google Scholar 

  29. Zhang, X. et al. Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family. J. Biol. Chem. 281, 15694–15700 (2006).

    Article  CAS  PubMed  Google Scholar 

  30. 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).

    Article  CAS  PubMed  Google Scholar 

  31. Asada, M. et al. Glycosaminoglycan affinity of the complete fibroblast growth factor family. Biochim. Biophys. Acta 1790, 40–48 (2009).

    Article  CAS  PubMed  Google Scholar 

  32. Sarrazin, S., Lamanna, W. C. & Esko, J. D. Heparan sulfate proteoglycans. Cold Spring Harb. Perspect. Biol. 3, a004952 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Goetz, R. et al. Conversion of a paracrine fibroblast growth factor into an endocrine fibroblast growth factor. J. Biol. Chem. 287, 29134–29146 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Goetz, R. & Mohammadi, M. Exploring mechanisms of FGF signalling through the lens of structural biology. Nat. Rev. Mol. Cell Biol. 14, 166–180 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Itoh, N., Ohta, H. & Konishi, M. Endocrine FGFs: evolution, physiology, pathophysiology, and pharmacotherapy. Front. Endocrinol. 6, 154 (2015).

    Article  Google Scholar 

  36. Beenken, A. & Mohammadi, M. The structural biology of the FGF19 subfamily. Adv. Exp. Med. Biol. 728, 1–24 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kurosu, H. et al. Regulation of fibroblast growth factor-23 signaling by klotho. J. Biol. Chem. 281, 6120–6123 (2006).

    Article  CAS  PubMed  Google Scholar 

  38. Urakawa, I. et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 444, 770–774 (2006).

    Article  CAS  PubMed  Google Scholar 

  39. Goetz, R. et al. Isolated C-terminal tail of FGF23 alleviates hypophosphatemia by inhibiting FGF23-FGFR-klotho complex formation. Proc. Natl Acad. Sci. USA 107, 407–412 (2010).

    Article  CAS  PubMed  Google Scholar 

  40. Henrissat, B. & Davies, G. Structural and sequence-based classification of glycoside hydrolases. Curr. Opin. Struct. Biol. 7, 637–644 (1997).

    Article  CAS  PubMed  Google Scholar 

  41. Chen, G. et al. α-Klotho is a non-enzymatic molecular scaffold for FGF23 hormone signalling. Nature 553, 461–466 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. 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).

    Article  CAS  PubMed  Google Scholar 

  44. Makarenkova, H. P. et al. Differential interactions of FGFs with heparan sulfate control gradient formation and branching morphogenesis. Sci. Signal. 2, ra55 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Zinkle, A. & Mohammadi, M. Structural biology of the FGF7 subfamily. Front. Genet. 10, 102 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Huang, Z. et al. Uncoupling the mitogenic and metabolic functions of FGF1 by tuning FGF1-FGF receptor dimer stability. Cell Rep. 20, 1717–1728 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Zinkle, A. & Mohammadi, M. A threshold model for receptor tyrosine kinase signaling specificity and cell fate determination. F1000Research 7, 872 (2018).

    Article  CAS  Google Scholar 

  48. Scotet, E. & Houssaint, E. The choice between alternative IIIb and IIIc exons of the FGFR-3 gene is not strictly tissue-specific. Biochim. Biophys. Acta 1264, 238–242 (1995).

    Article  PubMed  Google Scholar 

  49. Murgue, B., Tsunekawa, S., Rosenberg, I., de Beaumont, M. & Podolsky, D. K. Identification of a novel variant form of fibroblast growth factor receptor 3 (FGFR3 IIIb) in human colonic epithelium. Cancer Res. 54, 5206–5211 (1994).

    CAS  PubMed  Google Scholar 

  50. Plotnikov, A. N., Hubbard, S. R., Schlessinger, J. & Mohammadi, M. Crystal structures of two FGF-FGFR complexes reveal the determinants of ligand-receptor specificity. Cell 101, 413–424 (2000).

    Article  CAS  PubMed  Google Scholar 

  51. Yeh, B. K. et al. Structural basis by which alternative splicing confers specificity in fibroblast growth factor receptors. Proc. Natl Acad. Sci. USA 100, 2266–2271 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Olsen, S. K. et al. Structural basis by which alternative splicing modulates the organizer activity of FGF8 in the brain. Genes Dev. 20, 185–198 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Liu, Y. et al. Regulation of receptor binding specificity of FGF9 by an autoinhibitory homodimerization. Structure 25, 1325–1336.e3 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Ornitz, D. M. & Itoh, N. The fibroblast growth factor signaling pathway. Wiley Interdiscip. Rev. Dev. Biol. 4, 215–266 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Bae, J. H. et al. Asymmetric receptor contact is required for tyrosine autophosphorylation of fibroblast growth factor receptor in living cells. Proc. Natl Acad. Sci. USA 107, 2866–2871 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Chen et al. Molecular basis for receptor tyrosine kinase A-loop tyrosine transphosphorylation. Nat. Chem. Biol. 16, 267–277 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Mohammadi, M., Schlessinger, J. & Hubbard, S. R. Structure of the FGF receptor tyrosine kinase domain reveals a novel autoinhibitory mechanism. Cell 86, 577–587 (1996).

    Article  CAS  PubMed  Google Scholar 

  58. 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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Eswarakumar, V. P., Lax, I. & Schlessinger, J. Cellular signaling by fibroblast growth factor receptors. Cytokine Growth Factor Rev. 16, 139–149 (2005).

    Article  CAS  PubMed  Google Scholar 

  60. Mohammadi, M. et al. A tyrosine-phosphorylated carboxy-terminal peptide of the fibroblast growth factor receptor (Flg) is a binding site for the SH2 domain of phospholipase C-gamma 1. Mol. Cell Biol. 11, 5068–5078 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Peters, K. G., Werner, S., Chen, G. & Williams, L. T. Two FGF receptor genes are differentially expressed in epithelial and mesenchymal tissues during limb formation and organogenesis in the mouse. Development 114, 233–243 (1992).

    CAS  PubMed  Google Scholar 

  62. Newton, A. C. Protein kinase C: structural and spatial regulation by phosphorylation, cofactors, and macromolecular interactions. Chem. Rev. 101, 2353–2364 (2001).

    Article  CAS  PubMed  Google Scholar 

  63. Rosse, C. et al. PKC and the control of localized signal dynamics. Nat. Rev. Mol. Cell Biol. 11, 103–112 (2010).

    Article  CAS  PubMed  Google Scholar 

  64. Igumenova, T. I. Dynamics and membrane interactions of protein kinase C. Biochemistry 54, 4953–4968 (2015).

    Article  CAS  PubMed  Google Scholar 

  65. Turner, N. & Grose, R. Fibroblast growth factor signalling: from development to cancer. Nat. Rev. Cancer 10, 116–129 (2010).

    Article  CAS  PubMed  Google Scholar 

  66. Shin, E. Y. et al. Basic fibroblast growth factor stimulates activation of Rac1 through a p85 βPIX phosphorylation-dependent pathway. J. Biol. Chem. 279, 1994–2004 (2004).

    Article  CAS  PubMed  Google Scholar 

  67. Lee, J. G. & Kay, E. P. FGF-2-induced wound healing in corneal endothelial cells requires Cdc42 activation and Rho inactivation through the phosphatidylinositol 3-kinase pathway. Invest. Ophthalmol. Vis. Sci. 47, 1376–1386 (2006).

    Article  PubMed  Google Scholar 

  68. Schlessinger, J. Phospholipase Cγ activation and phosphoinositide hydrolysis are essential for embryonal development. Proc. Natl Acad. Sci. USA 94, 2798–2799 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Ellis, M. V. et al. Catalytic domain of phosphoinositide-specific phospholipase C (PLC). Mutational analysis of residues within the active site and hydrophobic ridge of PLCδ1. J. Biol. Chem. 273, 11650–11659 (1998).

    Article  CAS  PubMed  Google Scholar 

  70. Kolch, W. et al. Protein kinase Cα activates RAF-1 by direct phosphorylation. Nature 364, 249–252 (1993).

    Article  CAS  PubMed  Google Scholar 

  71. Bunney, T. D. et al. Structural and functional integration of the PLCγ interaction domains critical for regulatory mechanisms and signaling deregulation. Structure 20, 2062–2075 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Hajicek, N., Charpentier, T. H., Rush, J. R., Harden, T. K. & Sondek, J. Autoinhibition and phosphorylation-induced activation of phospholipase C-γ isozymes. Biochemistry 52, 4810–4819 (2013).

    Article  CAS  PubMed  Google Scholar 

  73. Poulin, B., Sekiya, F. & Rhee, S. G. Intramolecular interaction between phosphorylated tyrosine-783 and the C-terminal Src homology 2 domain activates phospholipase C-γ1. Proc. Natl Acad. Sci. USA 102, 4276–4281 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Huang, Z. et al. Two FGF receptor kinase molecules act in concert to recruit and transphosphorylate phospholipase Cγ. Mol. Cell 61, 98–110 (2016).

    Article  CAS  PubMed  Google Scholar 

  75. Wang, J. K., Xu, H., Li, H. C. & Goldfarb, M. Broadly expressed SNT-like proteins link FGF receptor stimulation to activators of Ras. Oncogene 13, 721–729 (1996).

    CAS  PubMed  Google Scholar 

  76. Kouhara, H. et al. A lipid-anchored Grb2-binding protein that links FGF-receptor activation to the Ras/MAPK signaling pathway. Cell 89, 693–702 (1997).

    Article  CAS  PubMed  Google Scholar 

  77. Hadari, Y. R., Kouhara, H., Lax, I. & Schlessinger, J. Binding of Shp2 tyrosine phosphatase to FRS2 is essential for fibroblast growth factor-induced PC12 cell differentiation. Mol. Cell Biol. 18, 3966–3973 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Gotoh, N. Regulation of growth factor signaling by FRS2 family docking/scaffold adaptor proteins. Cancer Sci. 99, 1319–1325 (2008).

    Article  CAS  PubMed  Google Scholar 

  79. Xu, H., Lee, K. W. & Goldfarb, M. Novel recognition motif on fibroblast growth factor receptor mediates direct association and activation of SNT adapter proteins. J. Biol. Chem. 273, 17987–17990 (1998).

    Article  CAS  PubMed  Google Scholar 

  80. Ong, S. H. et al. FRS2 proteins recruit intracellular signaling pathways by binding to diverse targets on fibroblast growth factor and nerve growth factor receptors. Mol. Cell Biol. 20, 979–989 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Cha, J. Y., Maddileti, S., Mitin, N., Harden, T. K. & Der, C. J. Aberrant receptor internalization and enhanced FRS2-dependent signaling contribute to the transforming activity of the fibroblast growth factor receptor 2 IIIb C3 isoform. J. Biol. Chem. 284, 6227–6240 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Dhalluin, C. et al. Structural basis of SNT PTB domain interactions with distinct neurotrophic receptors. Mol. Cell 6, 921–929 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Chardin, P. et al. Human Sos1: a guanine nucleotide exchange factor for Ras that binds to GRB2. Science 260, 1338–1343 (1993).

    Article  CAS  PubMed  Google Scholar 

  84. Li, N. et al. Guanine-nucleotide-releasing factor hSos1 binds to Grb2 and links receptor tyrosine kinases to Ras signalling. Nature 363, 85–88 (1993).

    Article  CAS  PubMed  Google Scholar 

  85. Simon, J. A. & Schreiber, S. L. Grb2 SH3 binding to peptides from Sos: evaluation of a general model for SH3-ligand interactions. Chem. Biol. 2, 53–60 (1995).

    Article  CAS  PubMed  Google Scholar 

  86. Schaeper, U. et al. Coupling of Gab1 to c-Met, Grb2, and Shp2 mediates biological responses. J. Cell Biol. 149, 1419–1432 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Ong, S. H. et al. Stimulation of phosphatidylinositol 3-kinase by fibroblast growth factor receptors is mediated by coordinated recruitment of multiple docking proteins. Proc. Natl Acad. Sci. USA 98, 6074–6079 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Lock, L. S., Royal, I., Naujokas, M. A. & Park, M. Identification of an atypical Grb2 carboxyl-terminal SH3 domain binding site in Gab docking proteins reveals Grb2-dependent and -independent recruitment of Gab1 to receptor tyrosine kinases. J. Biol. Chem. 275, 31536–31545 (2000).

    Article  CAS  PubMed  Google Scholar 

  89. Lamothe, B. et al. The docking protein Gab1 is an essential component of an indirect mechanism for fibroblast growth factor stimulation of the phosphatidylinositol 3-kinase/Akt antiapoptotic pathway. Mol. Cell Biol. 24, 5657–5666 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Rodrigues, G. A., Falasca, M., Zhang, Z., Ong, S. H. & Schlessinger, J. A novel positive feedback loop mediated by the docking protein Gab1 and phosphatidylinositol 3-kinase in epidermal growth factor receptor signaling. Mol. Cell Biol. 20, 1448–1459 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Faes, S. & Dormond, O. PI3K and AKT: unfaithful partners in cancer. Int. J. Mol. Sci. 16, 21138–21152 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Birge, R. B., Kalodimos, C., Inagaki, F. & Tanaka, S. Crk and CrkL adaptor proteins: networks for physiological and pathological signaling. Cell Commun. Signal. 7, 13 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Seo, J. H., Suenaga, A., Hatakeyama, M., Taiji, M. & Imamoto, A. Structural and functional basis of a role for CRKL in a fibroblast growth factor 8-induced feed-forward loop. Mol. Cell Biol. 29, 3076–3087 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Park, T. J. & Curran, T. Essential roles of Crk and CrkL in fibroblast structure and motility. Oncogene 33, 5121–5132 (2014).

    Article  CAS  PubMed  Google Scholar 

  95. Park, T., Koptyra, M. & Curran, T. Fibroblast growth requires CT10 regulator of kinase (Crk) and Crk-like (CrkL). J. Biol. Chem. 291, 26273–26290 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Collins, T. N. et al. Crk proteins transduce FGF signaling to promote lens fiber cell elongation. eLife 7, e32586 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Kao, S., Jaiswal, R. K., Kolch, W. & Landreth, G. E. Identification of the mechanisms regulating the differential activation of the MAPK cascade by epidermal growth factor and nerve growth factor in PC12 cells. J. Biol. Chem. 276, 18169–18177 (2001).

    Article  CAS  PubMed  Google Scholar 

  98. Manser, E., Leung, T., Salihuddin, H., Zhao, Z. S. & Lim, L. A brain serine/threonine protein kinase activated by Cdc42 and Rac1. Nature 367, 40–46 (1994).

    Article  CAS  PubMed  Google Scholar 

  99. Zugasti, O. et al. Raf-MEK-Erk cascade in anoikis is controlled by Rac1 and Cdc42 via Akt. Mol. Cell Biol. 21, 6706–6717 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Lu, W., Gong, D., Bar-Sagi, D. & Cole, P. A. Site-specific incorporation of a phosphotyrosine mimetic reveals a role for tyrosine phosphorylation of SHP-2 in cell signaling. Mol. Cell 8, 759–769 (2001).

    Article  CAS  PubMed  Google Scholar 

  101. Araki, T., Nawa, H. & Neel, B. G. Tyrosyl phosphorylation of Shp2 is required for normal ERK activation in response to some, but not all, growth factors. J. Biol. Chem. 278, 41677–41684 (2003).

    Article  CAS  PubMed  Google Scholar 

  102. Dance, M., Montagner, A., Salles, J. P., Yart, A. & Raynal, P. The molecular functions of Shp2 in the Ras/mitogen-activated protein kinase (ERK1/2) pathway. Cell Signal. 20, 453–459 (2008).

    Article  CAS  PubMed  Google Scholar 

  103. Hanafusa, H., Torii, S., Yasunaga, T. & Nishida, E. Sprouty1 and Sprouty2 provide a control mechanism for the Ras/MAPK signalling pathway. Nat. Cell Biol. 4, 850–858 (2002).

    Article  CAS  PubMed  Google Scholar 

  104. Hanafusa, H., Torii, S., Yasunaga, T., Matsumoto, K. & Nishida, E. Shp2, an SH2-containing protein-tyrosine phosphatase, positively regulates receptor tyrosine kinase signaling by dephosphorylating and inactivating the inhibitor Sprouty. J. Biol. Chem. 279, 22992–22995 (2004).

    Article  CAS  PubMed  Google Scholar 

  105. Ornitz, D. M. & Marie, P. J. Fibroblast growth factors in skeletal development. Curr. Top. Dev. Biol. 133, 195–234 (2019).

    Article  CAS  PubMed  Google Scholar 

  106. Du, X., Xie, Y., Xian, C. J. & Chen, L. Role of FGFs/FGFRs in skeletal development and bone regeneration. J. Cell. Physiol. 227, 3731–3743 (2012).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  108. White, K. E. et al. Mutations that cause osteoglophonic dysplasia define novel roles for FGFR1 in bone elongation. Am. J. Hum. Genet. 76, 361–367 (2005).

    Article  CAS  PubMed  Google Scholar 

  109. Wilkie, A. O. et al. Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome. Nat. Genet. 9, 165–172 (1995).

    Article  CAS  PubMed  Google Scholar 

  110. Meyers, G. A. et al. FGFR2 exon IIIa and IIIc mutations in Crouzon, Jackson-Weiss, and Pfeiffer syndromes: evidence for missense changes, insertions, and a deletion due to alternative RNA splicing. Am. J. Hum. Genet. 58, 491–498 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Park, W. J. et al. Novel FGFR2 mutations in Crouzon and Jackson-Weiss syndromes show allelic heterogeneity and phenotypic variability. Hum. Mol. Genet. 4, 1229–1233 (1995).

    Article  CAS  PubMed  Google Scholar 

  112. Pulleyn, L. J. et al. Spectrum of craniosynostosis phenotypes associated with novel mutations at the fibroblast growth factor receptor 2 locus. Eur. J. Hum. Genet. 4, 283–291 (1996).

    Article  CAS  PubMed  Google Scholar 

  113. Przylepa, K. A. et al. Fibroblast growth factor receptor 2 mutations in Beare-Stevenson cutis gyrata syndrome. Nat. Genet. 13, 492–494 (1996).

    Article  CAS  PubMed  Google Scholar 

  114. Merrill, A. E. et al. Bent bone dysplasia-FGFR2 type, a distinct skeletal disorder, has deficient canonical FGF signaling. Am. J. Hum. Genet. 90, 550–557 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Robertson, S. C. et al. Activating mutations in the extracellular domain of the fibroblast growth factor receptor 2 function by disruption of the disulfide bond in the third immunoglobulin-like domain. Proc. Natl Acad. Sci. USA 95, 4567–4572 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Muenke, M. et al. A unique point mutation in the fibroblast growth factor receptor 3 gene (FGFR3) defines a new craniosynostosis syndrome. Am. J. Hum. Genet. 60, 555–564 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Tavormina, P. L. et al. Thanatophoric dysplasia (types I and II) caused by distinct mutations in fibroblast growth factor receptor 3. Nat. Genet. 9, 321–328 (1995).

    Article  CAS  PubMed  Google Scholar 

  118. Ye, X. et al. Mutation screening of candidate genes in patients with nonsyndromic sagittal craniosynostosis. Plast. Reconstr. Surg. 137, 952–961 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Barroso, E. et al. Mild isolated craniosynostosis due to a novel FGFR3 mutation, p.Ala334Thr. Am. J. Med. Genet. A 155A, 3050–3053 (2011).

    Article  PubMed  CAS  Google Scholar 

  120. Rousseau, F. et al. Missense FGFR3 mutations create cysteine residues in thanatophoric dwarfism type I (TD1). Hum. Mol. Genet. 5, 509–512 (1996).

    Article  CAS  PubMed  Google Scholar 

  121. Shiang, R. et al. Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Cell 78, 335–342 (1994).

    Article  CAS  PubMed  Google Scholar 

  122. Bellus, G. A. et al. A recurrent mutation in the tyrosine kinase domain of fibroblast growth factor receptor 3 causes hypochondroplasia. Nat. Genet. 10, 357–359 (1995).

    Article  CAS  PubMed  Google Scholar 

  123. Wilkes, D. et al. A recurrent mutation, ala391glu, in the transmembrane region of FGFR3 causes Crouzon syndrome and acanthosis nigricans. J. Med. Genet. 33, 744–748 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Sarabipour, S. & Hristova, K. Mechanism of FGF receptor dimerization and activation. Nat. Commun. 7, 10262 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Sarabipour, S. & Hristova, K. FGFR3 unliganded dimer stabilization by the juxtamembrane domain. J. Mol. Biol. 427, 1705–1714 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Li, E., You, M. & Hristova, K. FGFR3 dimer stabilization due to a single amino acid pathogenic mutation. J. Mol. Biol. 356, 600–612 (2006).

    Article  CAS  PubMed  Google Scholar 

  127. Di Rocco, F. et al. FGFR3 mutation causes abnormal membranous ossification in achondroplasia. Hum. Mol. Genet. 23, 2914–2925 (2014).

    Article  PubMed  CAS  Google Scholar 

  128. Kannan, K. & Givol, D. FGF receptor mutations: dimerization syndromes, cell growth suppression, and animal models. IUBMB Life 49, 197–205 (2000).

    Article  CAS  PubMed  Google Scholar 

  129. 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. Nat. Genet. 13, 233–237 (1996).

    Article  CAS  PubMed  Google Scholar 

  130. Agochukwu, N. B., Solomon, B. D., Doherty, E. S. & Muenke, M. Palatal and oral manifestations of Muenke syndrome (FGFR3-related craniosynostosis). J. Craniofac. Surg. 23, 664–668 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  131. Grillo, L. et al. Increased FGF3 and FGF4 gene dosage is a risk factor for craniosynostosis. Gene 534, 435–439 (2014).

    Article  CAS  PubMed  Google Scholar 

  132. Hardelin, J. P. & Dode, C. The complex genetics of Kallmann syndrome: KAL1, FGFR1, FGF8, PROKR2, PROK2, et al. Sex. Dev. 2, 181–193 (2008).

    Article  CAS  PubMed  Google Scholar 

  133. 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).

    Article  CAS  PubMed  Google Scholar 

  134. Rodriguez-Zabala, M. et al. FGF9 mutation causes craniosynostosis along with multiple synostoses. Hum. Mutat. 38, 1471–1476 (2017).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  136. Tang, L. et al. A point mutation in Fgf9 impedes joint interzone formation leading to multiple synostoses syndrome. Hum. Mol. Genet. 26, 1280–1293 (2017).

    Article  CAS  PubMed  Google Scholar 

  137. 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).

    Article  CAS  PubMed  Google Scholar 

  138. Wu, X. L. et al. Multiple synostoses syndrome is due to a missense mutation in exon 2 of FGF9 gene. Am. J. Hum. Genet. 85, 53–63 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Chefetz, I. et al. A novel homozygous missense mutation in FGF23 causes familial tumoral calcinosis associated with disseminated visceral calcification. Hum. Genet. 118, 261–266 (2005).

    Article  CAS  PubMed  Google Scholar 

  140. 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).

    Article  CAS  PubMed  Google Scholar 

  141. Abbasi, F. et al. A new missense mutation in FGF23 gene in a male with hyperostosis-hyperphosphatemia syndrome (HHS). Gene 542, 269–271 (2014).

    Article  CAS  PubMed  Google Scholar 

  142. ADHR Consortium. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat. Genet. 26, 345–348 (2000).

    Article  CAS  Google Scholar 

  143. White, K. E. et al. Autosomal-dominant hypophosphatemic rickets (ADHR) mutations stabilize FGF-23. Kidney Int. 60, 2079–2086 (2001).

    Article  CAS  PubMed  Google Scholar 

  144. Gribaa, M. et al. An autosomal dominant hypophosphatemic rickets phenotype in a Tunisian family caused by a new FGF23 missense mutation. J. Bone Miner. Metab. 28, 111–115 (2010).

    Article  PubMed  Google Scholar 

  145. 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).

    Article  CAS  PubMed  Google Scholar 

  146. Ornitz, D. M. FGF signaling in the developing endochondral skeleton. Cytokine Growth Factor Rev. 16, 205–213 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Long, F. & Ornitz, D. M. Development of the endochondral skeleton. Cold Spring Harb. Perspect. Biol. 5, a008334 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  148. Sheeba, C. J., Andrade, R. P., Duprez, D. & Palmeirim, I. Comprehensive analysis of fibroblast growth factor receptor expression patterns during chick forelimb development. Int. J. Dev. Biol. 54, 1517–1526 (2010).

    Article  CAS  PubMed  Google Scholar 

  149. Orr-Urtreger, A., Givol, D., Yayon, A., Yarden, Y. & Lonai, P. Developmental expression of two murine fibroblast growth factor receptors, flg and bek. Development 113, 1419–1434 (1991).

    CAS  PubMed  Google Scholar 

  150. Moon, A. M., Boulet, A. M. & Capecchi, M. R. Normal limb development in conditional mutants of Fgf4. Development 127, 989–996 (2000).

    CAS  PubMed  Google Scholar 

  151. Mariani, F. V., Ahn, C. P. & Martin, G. R. Genetic evidence that FGFs have an instructive role in limb proximal-distal patterning. Nature 453, 401–405 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Jin, L., Wu, J., Bellusci, S. & Zhang, J.-S. Fibroblast growth factor 10 and vertebrate limb development. Front. Genet. 9, 705 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  153. Delezoide, A. L. et al. Spatio-temporal expression of FGFR 1, 2 and 3 genes during human embryo-fetal ossification. Mech. Dev. 77, 19–30 (1998).

    Article  CAS  PubMed  Google Scholar 

  154. Eswarakumar, V. P. et al. The IIIc alternative of Fgfr2 is a positive regulator of bone formation. Development 129, 3783–3793 (2002).

    CAS  PubMed  Google Scholar 

  155. Jacob, A. L., Smith, C., Partanen, J. & Ornitz, D. M. Fibroblast growth factor receptor 1 signaling in the osteo-chondrogenic cell lineage regulates sequential steps of osteoblast maturation. Dev. Biol. 296, 315–328 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Lazarus, J. E., Hegde, A., Andrade, A. C., Nilsson, O. & Baron, J. Fibroblast growth factor expression in the postnatal growth plate. Bone 40, 577–586 (2007).

    Article  CAS  PubMed  Google Scholar 

  157. Partanen, J. et al. FGFR-4, a novel acidic fibroblast growth factor receptor with a distinct expression pattern. EMBO J. 10, 1347–1354 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Cool, S., Jackson, R., Pincus, P., Dickinson, I. & Nurcombe, V. Fibroblast growth factor receptor 4 (FGFR4) expression in newborn murine calvaria and primary osteoblast cultures. Int. J. Dev. Biol. 46, 519–523 (2002).

    CAS  PubMed  Google Scholar 

  159. Karolak, M. R., Yang, X. & Elefteriou, F. FGFR1 signaling in hypertrophic chondrocytes is attenuated by the Ras-GAP neurofibromin during endochondral bone formation. Hum. Mol. Genet. 24, 2552–2564 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Hung, I. H., Yu, K., Lavine, K. J. & Ornitz, D. M. FGF9 regulates early hypertrophic chondrocyte differentiation and skeletal vascularization in the developing stylopod. Dev. Biol. 307, 300–313 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Karuppaiah, K. et al. FGF signaling in the osteoprogenitor lineage non-autonomously regulates postnatal chondrocyte proliferation and skeletal growth. Development 143, 1811–1822 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Longobardi, L. et al. Synovial joints: from development to homeostasis. Curr. Osteoporos. Rep. 13, 41–51 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  164. Lovinescu, I., Koyama, E. & Pacifici, M. Roles of FGF-10 on the development of diathrodial limb joints. Penn Dent. J. 103, 5–9 (2003).

    PubMed  Google Scholar 

  165. Yan, D. et al. Fibroblast growth factor receptor 1 is principally responsible for fibroblast growth factor 2-induced catabolic activities in human articular chondrocytes. Arthritis Res. Ther. 13, R130 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Chen, T. M., Chen, Y. H., Sun, H. S. & Tsai, S. J. Fibroblast growth factors: potential novel targets for regenerative therapy of osteoarthritis. Chin. J. Physiol. 62, 2–10 (2019).

    Article  CAS  PubMed  Google Scholar 

  167. Hagan, A. S. et al. Generation and validation of novel conditional flox and inducible Cre alleles targeting fibroblast growth factor 18 (Fgf18). Dev. Dyn. 248, 882–893 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Malemud, C. J. Growth hormone, VEGF and FGF: involvement in rheumatoid arthritis. Clin. Chim. Acta 375, 10–19 (2007).

    Article  CAS  PubMed  Google Scholar 

  169. Glyn-Jones, S. et al. Osteoarthritis. Lancet 386, 376–387 (2015).

    Article  CAS  PubMed  Google Scholar 

  170. Loeser, R. F., Collins, J. A. & Diekman, B. O. Ageing and the pathogenesis of osteoarthritis. Nat. Rev. Rheumatol. 12, 412–420 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Daouti, S. et al. Development of comprehensive functional genomic screens to identify novel mediators of osteoarthritis. Osteoarthr. Cartilage 13, 508–518 (2005).

    Article  CAS  Google Scholar 

  172. Im, H. J. et al. Basic fibroblast growth factor stimulates matrix metalloproteinase-13 via the molecular cross-talk between the mitogen-activated protein kinases and protein kinase Cδ pathways in human adult articular chondrocytes. J. Biol. Chem. 282, 11110–11121 (2007).

    Article  CAS  PubMed  Google Scholar 

  173. Weng, T. et al. Genetic inhibition of fibroblast growth factor receptor 1 in knee cartilage attenuates the degeneration of articular cartilage in adult mice. Arthritis Rheum. 64, 3982–3992 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Xu, W. et al. A novel fibroblast growth factor receptor 1 inhibitor protects against cartilage degradation in a murine model of osteoarthritis. Sci. Rep. 6, 24042 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Tang, J. et al. Fibroblast growth factor receptor 3 inhibits osteoarthritis progression in the knee joints of adult mice. Arthritis Rheumatol. 68, 2432–2443 (2016).

    Article  CAS  PubMed  Google Scholar 

  176. Zhou, S. et al. Conditional deletion of Fgfr3 in chondrocytes leads to osteoarthritis-like defects in temporomandibular joint of adult mice. Sci. Rep. 6, 24039 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Kuang, L. et al. FGFR3 deficiency enhances CXCL12-dependent chemotaxis of macrophages via upregulating CXCR7 and aggravates joint destruction in mice. Ann. Rheum. Dis. 79, 112–122 (2020).

    Article  CAS  PubMed  Google Scholar 

  178. Klag, K. A. & Horton, W. A. Advances in treatment of achondroplasia and osteoarthritis. Hum. Mol. Genet. 25, R2–R8 (2016).

    Article  CAS  PubMed  Google Scholar 

  179. Kisand, K., Tamm, A. E., Lintrop, M. & Tamm, A. O. New insights into the natural course of knee osteoarthritis: early regulation of cytokines and growth factors, with emphasis on sex-dependent angiogenesis and tissue remodeling. A pilot study. Osteoarthr. Cartilage 26, 1045–1054 (2018).

    Article  CAS  Google Scholar 

  180. Im, H. J. et al. Basic fibroblast growth factor accelerates matrix degradation via a neuro-endocrine pathway in human adult articular chondrocytes. J. Cell. Physiol. 215, 452–463 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Vincent, T. L., McLean, C. J., Full, L. E., Peston, D. & Saklatvala, J. FGF-2 is bound to perlecan in the pericellular matrix of articular cartilage, where it acts as a chondrocyte mechanotransducer. Osteoarthr. Cartilage 15, 752–763 (2007).

    Article  CAS  Google Scholar 

  182. Muddasani, P., Norman, J. C., Ellman, M., van Wijnen, A. J. & Im, H. J. Basic fibroblast growth factor activates the MAPK and NFκB pathways that converge on Elk-1 to control production of matrix metalloproteinase-13 by human adult articular chondrocytes. J. Biol. Chem. 282, 31409–31421 (2007).

    Article  CAS  PubMed  Google Scholar 

  183. Nummenmaa, E., Hamalainen, M., Moilanen, T., Vuolteenaho, K. & Moilanen, E. Effects of FGF-2 and FGF receptor antagonists on MMP enzymes, aggrecan, and type II collagen in primary human OA chondrocytes. Scand. J. Rheumatol. 44, 321–330 (2015).

    Article  CAS  PubMed  Google Scholar 

  184. Chong, K. W. et al. Fibroblast growth factor 2 drives changes in gene expression following injury to murine cartilage in vitro and in vivo. Arthritis Rheum. 65, 2346–2355 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Sawaji, Y., Hynes, J., Vincent, T. & Saklatvala, J. Fibroblast growth factor 2 inhibits induction of aggrecanase activity in human articular cartilage. Arthritis Rheum. 58, 3498–3509 (2008).

    Article  CAS  PubMed  Google Scholar 

  186. Tang, Z. F. & Li, H. Y. Effects of fibroblast growth factors 2 and low intensity pulsed ultrasound on the repair of knee articular cartilage in rabbits. Eur. Rev. Med. Pharmacol. Sci. 22, 2447–2453 (2018).

    PubMed  Google Scholar 

  187. Cuevas, P., Burgos, J. & Baird, A. Basic fibroblast growth factor (FGF) promotes cartilage repair in vivo. Biochem. Biophys. Res. Commun. 156, 611–618 (1988).

    Article  CAS  PubMed  Google Scholar 

  188. Chia, S. L. et al. Fibroblast growth factor 2 is an intrinsic chondroprotective agent that suppresses ADAMTS-5 and delays cartilage degradation in murine osteoarthritis. Arthritis Rheum. 60, 2019–2027 (2009).

    Article  CAS  PubMed  Google Scholar 

  189. Burt, P. M., Xiao, L., Doetschman, T. & Hurley, M. M. Ablation of low-molecular-weight FGF2 isoform accelerates murine osteoarthritis while loss of high-molecular-weight FGF2 isoforms offers protection. J. Cell. Physiol. 234, 4418–4431 (2019).

    Article  CAS  PubMed  Google Scholar 

  190. Li, R. et al. Upregulation of fibroblast growth factor 1 in the synovial membranes of patients with late stage osteoarthritis. Genet. Mol. Res. 14, 11191–11199 (2015).

    Article  CAS  PubMed  Google Scholar 

  191. El-Seoudi, A. et al. Catabolic effects of FGF-1 on chondrocytes and its possible role in osteoarthritis. J. Cell Commun. Signal. 11, 255–263 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  192. Uchii, M. et al. Role of fibroblast growth factor 8 (FGF8) in animal models of osteoarthritis. Arthritis Res. Ther. 10, R90 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  193. Rockel, J. S. et al. Hedgehog inhibits β-catenin activity in synovial joint development and osteoarthritis. J. Clin. Invest. 126, 1649–1663 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  194. Mori, Y. et al. Identification of fibroblast growth factor-18 as a molecule to protect adult articular cartilage by gene expression profiling. J. Biol. Chem. 289, 10192–10200 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  197. Zhou, S. et al. Exogenous fibroblast growth factor 9 attenuates cartilage degradation and aggravates osteophyte formation in post-traumatic osteoarthritis. Osteoarthr. Cartilage 24, 2181–2192 (2016).

    Article  CAS  Google Scholar 

  198. Sun, Y. et al. Analysis of meniscal degeneration and meniscal gene expression. BMC Musculoskelet. Disord. 11, 19 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  199. Li, Z. C. et al. Fibroblast growth factor-21 concentration in serum and synovial fluid is associated with radiographic bone loss of knee osteoarthritis. Scand. J. Clin. Lab. Invest. 75, 121–125 (2015).

    Article  CAS  PubMed  Google Scholar 

  200. Bianchi, A. et al. Fibroblast growth factor 23 drives MMP13 expression in human osteoarthritic chondrocytes in a Klotho-independent manner. Osteoarthr. Cartilage 24, 1961–1969 (2016).

    Article  CAS  Google Scholar 

  201. Meo Burt, P., Xiao, L. & Hurley, M. M. FGF23 regulates Wnt/β-catenin signaling-mediated osteoarthritis in mice overexpressing high-molecular-weight FGF2. Endocrinology 159, 2386–2396 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  202. Kim, J. H., Lee, M. C., Seong, S. C., Park, K. H. & Lee, S. Enhanced proliferation and chondrogenic differentiation of human synovium-derived stem cells expanded with basic fibroblast growth factor. Tissue Eng. Part A 17, 991–1002 (2011).

    Article  CAS  PubMed  Google Scholar 

  203. Li, J. & Pei, M. Optimization of an in vitro three-dimensional microenvironment to reprogram synovium-derived stem cells for cartilage tissue engineering. Tissue Eng. Part A 17, 703–712 (2011).

    Article  CAS  PubMed  Google Scholar 

  204. Chen, X. et al. Integration capacity of human induced pluripotent stem cell-derived cartilage. Tissue Eng. Part A 25, 437–445 (2018).

    Article  PubMed  CAS  Google Scholar 

  205. Gigout, A. et al. Sprifermin (rhFGF18) enables proliferation of chondrocytes producing a hyaline cartilage matrix. Osteoarthr. Cartilage 25, 1858–1867 (2017).

    Article  CAS  Google Scholar 

  206. Meloni, G. R. et al. Recombinant human FGF18 preserves depth-dependent mechanical inhomogeneity in articular cartilage. Eur. Cell Mater. 38, 23–34 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Sennett, M. L. et al. Sprifermin treatment enhances cartilage integration in an in vitro repair model. J. Orthop. Res. 36, 2648–2656 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Barr, L., Getgood, A., Guehring, H., Rushton, N. & Henson, F. M. The effect of recombinant human fibroblast growth factor-18 on articular cartilage following single impact load. J. Orthop. Res. 32, 923–927 (2014).

    Article  CAS  PubMed  Google Scholar 

  209. Yao, X. et al. Fibroblast growth factor 18 exerts anti-osteoarthritic effects through PI3K-AKT signaling and mitochondrial fusion and fission. Pharmacol. Res. 139, 314–324 (2019).

    Article  CAS  PubMed  Google Scholar 

  210. Howard, D., Wardale, J., Guehring, H. & Henson, F. Delivering rhFGF-18 via a bilayer collagen membrane to enhance microfracture treatment of chondral defects in a large animal model. J. Orthop. Res. 33, 1120–1127 (2015).

    Article  CAS  PubMed  Google Scholar 

  211. Power, J., Hernandez, P., Guehring, H., Getgood, A. & Henson, F. Intra-articular injection of rhFGF-18 improves the healing in microfracture treated chondral defects in an ovine model. J. Orthop. Res. 32, 669–676 (2014).

    Article  CAS  PubMed  Google Scholar 

  212. Eckstein, F., Wirth, W., Guermazi, A., Maschek, S. & Aydemir, A. Brief report: intraarticular sprifermin not only increases cartilage thickness, but also reduces cartilage loss: location-independent post hoc analysis using magnetic resonance imaging. Arthritis Rheumatol. 67, 2916–2922 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Lohmander, L. S. et al. Intraarticular sprifermin (recombinant human fibroblast growth factor 18) in knee osteoarthritis: a randomized, double-blind, placebo-controlled trial. Arthritis Rheumatol. 66, 1820–1831 (2014).

    Article  CAS  PubMed  Google Scholar 

  214. Hochberg, M. C. et al. Effect of intra-articular sprifermin vs placebo on femorotibial joint cartilage thickness in patients with osteoarthritis: the FORWARD randomized clinical trial. JAMA 322, 1360–1370 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Sanghani, A., Chimutengwende-Gordon, M., Adesida, A. & Khan, W. Applications of stem cell therapy for physeal injuries. Curr. Stem Cell Res. Ther. 8, 451–455 (2013).

    Article  CAS  PubMed  Google Scholar 

  216. Chung, R. & Xian, C. J. Recent research on the growth plate: mechanisms for growth plate injury repair and potential cell-based therapies for regeneration. J. Mol. Endocrinol. 53, T45–T61 (2014).

    Article  CAS  PubMed  Google Scholar 

  217. Henson, F. M., Bowe, E. A. & Davies, M. E. Promotion of the intrinsic damage-repair response in articular cartilage by fibroblastic growth factor-2. Osteoarthr. Cartilage 13, 537–544 (2005).

    Article  CAS  Google Scholar 

  218. Cucchiarini, M., Schetting, S., Terwilliger, E. F., Kohn, D. & Madry, H. rAAV-mediated overexpression of FGF-2 promotes cell proliferation, survival, and α-SMA expression in human meniscal lesions. Gene Ther. 16, 1363–1372 (2009).

    Article  CAS  PubMed  Google Scholar 

  219. Schmidt, L., Taiyab, A., Melvin, V. S., Jones, K. L. & Williams, T. Increased FGF8 signaling promotes chondrogenic rather than osteogenic development in the embryonic skull. Dis. Model. Mech. 11, dmm.031526 (2018).

    Article  CAS  Google Scholar 

  220. Dai, J. et al. The effect of co-culturing costal chondrocytes and dental pulp stem cells combined with exogenous FGF9 protein on chondrogenesis and ossification in engineered cartilage. Biomaterials 33, 7699–7711 (2012).

    Article  CAS  PubMed  Google Scholar 

  221. Tan, Q. et al. A novel FGFR1-binding peptide attenuates the degeneration of articular cartilage in adult mice. Osteoarthr. Cartilage 26, 1733–1743 (2018).

    Article  CAS  Google Scholar 

  222. Mobasheri, A. et al. The role of metabolism in the pathogenesis of osteoarthritis. Nat. Rev. Rheumatol. 13, 302–311 (2017).

    Article  CAS  PubMed  Google Scholar 

  223. Makower, A. M., Wroblewski, J. & Pawlowski, A. Effects of IGF-I, rGH, FGF, EGF and NCS on DNA-synthesis, cell proliferation and morphology of chondrocytes isolated from rat rib growth cartilage. Cell Biol. Int. Rep. 13, 259–270 (1989).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

M.M. and A.Z. acknowledge support provided by the National Institutes of Health (grant R01 DE13686 to M.M.). L.C. and X.Y. acknowledge support provided by the National Key Research and Development Program of China (grant 2018YFA0800802 to L.C.) and the National Natural Science Foundation of China (grants 81530071 and 81830075 to L.C.).

Author information

Author notes

  1. Allen Zinkle

    Present address: Columbia University, New York, NY, USA

  2. These authors contributed equally: Yangli Xie, Allen Zinkle

Authors and Affiliations

  1. Department of Wound Repair and Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Daping Hospital, Army Medical University, Chongqing, China

    Yangli Xie & Lin Chen

  2. Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY, USA

    Allen Zinkle & Moosa Mohammadi

Authors
  1. Yangli Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Allen Zinkle
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lin Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Moosa Mohammadi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The authors contributed equally to all aspects of the article.

Corresponding authors

Correspondence to Lin Chen or Moosa Mohammadi.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Protomers

The smallest repeatable structural subunits of hetero-oligomeric protein complexes.

Glycosyl hydrolase clan A

A group of glycosyl hydrolase families defined by its members containing one or two (β/α)8 triosephosphate isomerase barrel domains.

Apo unphosphorylated kinase

A kinase that is unbound (apo) and inactive (unphosphorylated).

Mesenchymal condensation

The first step in chondroinduction, in which the mesenchyme, the meshwork of embryonic connective tissue from which cartilage and bone are derived, condenses in one place.

Growth plate

Cartilage layer lying between the epiphyses and metaphyses, the developmental centre for longitudinal bone growth through endochondral ossification, also known as the epiphyseal plate.

Apical ectodermal ridge

The layer of surface ectodermal cells at the apex of the embryonic limb bud that acts as the signalling centre for the condensation of underlying mesenchyme and is necessary for limb outgrowth.

Prechondrogenic condensation region

A region of prechondrogenic cells that precede the development of cartilage (cartilage anlagen).

Perichondrium

A layer of dense fibrous connective tissue covering the surface of cartilage in developing bone.

Periosteum

A layer of membranous connective tissue present in the surface of bone, containing bone stem (or progenitor) cells and possessing bone-forming potentialities.

Hypertrophic chondrocytes

The terminally differentiated form of chondrocytes, which are enlarged and secrete large amounts of type X collagen.

Superficial zone

The surface zone of articular cartilage that contains cells with stem or chondro-progenitor capacity and is characterized by elongated and flat-shaped cells oriented parallel to the articular surface.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xie, Y., Zinkle, A., Chen, L. et al. Fibroblast growth factor signalling in osteoarthritis and cartilage repair. Nat Rev Rheumatol 16, 547–564 (2020). https://doi.org/10.1038/s41584-020-0469-2

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41584-020-0469-2

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing