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Fibroblast Growth Factor Receptor (FGFR) and Bone: Implications for Human Growth

  • Richard G. Boles
  • Valairat Dhamcharee
Chapter

Abstract

The fibroblast growth factors (FGFs) constitute a family of 22 structurally related polypeptides with diverse biological functions. Their expression is controlled at the levels of transcription, mRNA stability, and translation. Signal transduction occurs when FGFs interact with a family of seven fibroblast growth factors receptors (FGFRs) and cell-surface-associated heparan sulfate proteoglycans. FGFs and FGFRs are key players in the processes of proliferation and differentiation of a wide variety of cells and tissues, including roles in chondrogenesis, osteogenesis, angiogenesis, and wound healing. In osteogenesis, the FGF/FGFR system promotes proliferation, maturation, and differentiation of osteoblasts, as well as bone matrix mineralization. Known human mutations in the FGFR genes result in a gain of function and are broadly classified into two groups: craniosynostosis and chondrodysplasia. Craniosynostosis, or premature closure of one or more sutures of the skull, can occur alone or as part of a syndrome, associated with bony malformations of the face, hands, and/or feet. Paradoxically, the shortened bones of chondrodysplasia can result from receptor activation that inhibits chondrocyte cell growth through cell-type specific signaling pathways. Clinical manifestations range from mild short stature to extremely short limbs with lethal thoracic dysplasia, with the common dwarfism syndrome of achondroplasia located in the middle of this range. FGF23 plays critical roles in phosphate and vitamin D metabolism, and mutation results in the severely depleted bone mineralization of hypophosphatemia. Future advances in bone regeneration may result from a better understanding of the FGF/FGFR system.

Keywords

Fibroblast Growth Factor Receptor Acanthosis Nigricans Hypophosphatemic Rickets Apical Ectodermal Ridge Kallmann Syndrome 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations

ACH

Achondroplasia

ADHR

Autosomal dominant hypophosphatemic rickets

AER

Apical ectodermal ridge

BMP

Bone morphogenetic protein

CAM

Cell adhesion molecule

CMDBS

Carboxymethyl benzylamide sulfonate

ERK1/2

Extracellular signal-related kinases 1/2

FGF

Fibroblast growth factor

FGFR

Fibroblast growth factor receptor

FHF

Fibroblast growth factor homologous factor

FRS2

FGF receptor substrate 2 protein

Grb2

Growth factor receptor-bound protein 2

HCH

Hypochondroplasia

HSPG

Heparan sulfate proteoglycan

IGF

Insulin-like growth factor

KS

Kallmann syndrome

MAPK

Mitogen-activated protein kinase

Npt

Sodium phosphate transporters

OC

Osteocalcin

OPN

Osteopontin

PDGF

Platelets derived growth factor

PI3K

Phosphatidylinositol 3 kinase

PKC

Protein kinase C

PTH

Parathyroid hormone

PZ

Progress zone

Runx2

Runt-related transcription factor 2

SAPK/JNK

Stress-activated protein kinase/c-Jun N-terminal kinase

Sos

Son of sevenless protein

TD

Thanatophoric dysplasia

TGF

Transforming growth factor

TGF-β

Transforming growth factor-β

VEGF

Vascular endothelial growth factor

Wnt

Combination of Wg (wingless) and Int gene

ZPA

Zone of polarizing activity

References

  1. Ambrosetti D, Holmes G, Mansukhani A, Basilico C. Mol Cell Biol. 2008;28:4759–71.PubMedCrossRefGoogle Scholar
  2. Anderson J, Burns HD, Enriquez-Harris P, Wilkie AO, Heath JK. Hum Mol Genet. 1998;7:1475–83.PubMedCrossRefGoogle Scholar
  3. Cailliau K, Browaeys-Poly E, Vilain JP. Biochim Biophys Acta. 2001;1538:228–33.PubMedCrossRefGoogle Scholar
  4. Chaudhary LR, Hruska KA. J Cell Biochem. 2001;81:304–11.PubMedCrossRefGoogle Scholar
  5. Debiais F. Exp Cell Res. 2004;297:235–46.PubMedCrossRefGoogle Scholar
  6. Deng C, Wynshaw-Boris A, Zhou F, Kuo A, Leder P. Cell. 1996;84:911–21.PubMedCrossRefGoogle Scholar
  7. Devescovi V, Leonardi E, Ciapetti G, Cenni E. Chir Organi Mov. 2008;92:161–8.PubMedCrossRefGoogle Scholar
  8. Fakhry A. Bone. 2005;36:254–66.PubMedCrossRefGoogle Scholar
  9. Franceschi RT. J Dent Res. 2005;84:1093–103.PubMedCrossRefGoogle Scholar
  10. Fukumoto S. Intern Med. 2008;47:337–43.PubMedCrossRefGoogle Scholar
  11. Harada D, Yamanaka Y, Ueda K, Tanaka H, Seino Y. J Bone Miner Metab. 2009;27:9–15.PubMedCrossRefGoogle Scholar
  12. Itoh N, Ornitz DM. Trends Genet. 2004;20:563–9.PubMedCrossRefGoogle Scholar
  13. Jackson RA, Nurcombe V, Cool SM. Gene. 2006;379:79–91.PubMedCrossRefGoogle Scholar
  14. Lievens PM, Liboi E. J Biol Chem. 2003;278:17344–9.PubMedCrossRefGoogle Scholar
  15. Muenke M, Gripp KW, McDonald-McGinn DM, Gaudenz K, Whitaker LA, Bartlett SP, Markowitz RI, Robin NH, Nwokoro N, Mulvihill JJ, Losken HW, Mulliken JB, Guttmacher AE, Wilroy RS, Clarke LA, Hollway G, Adès LC, Haan EA, Mulley JC, Cohen MM Jr, Bellus GA, Francomano CA, Moloney DM, Wall SA, Wilkie AO. Am J Hum Genet. 1997;60:555–64.PubMedGoogle Scholar
  16. Nabeshima Y. Cell Mol Life Sci. 2008;65:3218–30.PubMedCrossRefGoogle Scholar
  17. Naski MC, Wang Q, Xu J, Ornitz DM. Nat Genet. 1996;13:233–7.PubMedCrossRefGoogle Scholar
  18. Ohbayashi N. Genes Dev. 2002;16:870–9.PubMedCrossRefGoogle Scholar
  19. Schindler S, Friedrich M, Wagener H, Lorenz B, Preising MN. J Med Genet. 2002;39:764–6.PubMedCrossRefGoogle Scholar
  20. Shimada T, Kakitani M, Yamazaki Y, Hasegawa H, Takeuchi Y, Fujita T, Fukumoto S, Tomizuka K, Yamashita T. Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J Clin Invest. 2004;113(4):561–8.PubMedGoogle Scholar
  21. Stevens DA, Harvey CB, Scott AJ, O’Shea PJ, Barnard JC, Williams AJ, Brady G, Samarut J, Chassande O, Williams GR. Mol Endocrinol. 2003;17:1751–66.PubMedCrossRefGoogle Scholar
  22. Su N, Yang J, Xie Y, Du X, Lu X, Yin Z, Yin L, Qi H, Zhao L, Feng J, Chen L. Gain-of-function mutation of FGFR3 results in impaired fracture healing due to inhibition of chondrocyte differentiation. Biochem Biophys Res Commun. 2008;376(3):454–9.PubMedCrossRefGoogle Scholar
  23. Szebenyi G, Fallon JF. Int Rev Cytol. 1999;185:45–106.PubMedCrossRefGoogle Scholar
  24. Walsh S, Jefferiss CM, Stewart K, Beresford JN. Bone. 2003;33:80–9.PubMedCrossRefGoogle Scholar
  25. Yu K, Herr AB, Waksman G, Ornitz DM. Proc Natl Acad Sci USA. 2000;97:14536–41.PubMedCrossRefGoogle Scholar
  26. Zhang X, Sobue T, Hurley MM. Biochem Biophys Res Commun. 2002;290:526–31.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Division of Medical GeneticsSaban Research Institute, Childrens Hospital Los AngelesLos AngelesUSA
  2. 2.Department of PediatricsKeck School of Medicine, Childrens Hospital Los Angeles, University of Southern CaliforniaLos AngelesUSA
  3. 3.USC Division of Neonatal Medicine, Department of PediatricsKeck School of Medicine, Childrens Hospital Los Angeles, University of Southern CaliforniaLos AngelesUSA

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