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FGF/FGFR Signaling in Skeletal Dysplasias

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Bone and Development

Part of the book series: Topics in Bone Biology ((TBB,volume 6))

Abstract

Fibroblast growth factor (FGF) signaling plays an important role during endochondral and intramembranous bone development. The identification of skeletal abnormalities induced by genetic mutations in FGF receptors (FGFR) that induce chondrodysplasias and craniosynostosis in humans has provided major insights into the role of FGF/FGFR signaling in the control of cartilage and bone formation. This chapter summarizes the role of FGF/FGFR signaling in cellular and molecular mechanisms in chondrogenesis in the growth plate and in ­osteogenesis in cranial bone. The chapter also describes what is known about the pathological processes that have resulted in skeletal dysplasias owing to FGR mutations.

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References

  1. Anderson J, Burns HD, Enriquez-Harris P, Wilkie AOM, Heath JK (1998) Apert syndrome mutations in fibroblast growth factor receptor 2 exhibit increased affinity for FGF ligand. Hum Mol Gen 7:1475-1483

    Article  CAS  PubMed  Google Scholar 

  2. Aviezer D, Golembo M, Yayon A (2003) Fibroblast growth factor receptor-3 as a therapeutic target for achondroplasia-genetic short limbed dwarfism. Curr Drug Targets 4:353-365

    Article  CAS  PubMed  Google Scholar 

  3. Baroni T, Carinci P, Lilli C, Bellucci C, Aisa MC, Scapoli L, Volinia S, Carinci F, Pezzetti F, Calvitti M, Farina A, Conte C, Bodo M (2005) P253R fibroblast growth factor receptor-2 mutation induces RUNX2 transcript variants and calvarial osteoblast differentiation. J Cell Physiol 202:524-535

    Article  CAS  PubMed  Google Scholar 

  4. Bellus GA, McIntosh I, Smith EA, Aylesworth AS, Kaitila I, Horton WA, Greenhaw GA, Hecht JT, Francomano CA (1995) A recurrent mutation in the tyrosine kinase domain of fibroblast growth factor receptor 3 causes hypochondroplasia. Nat Genet 10:357-359

    Article  CAS  PubMed  Google Scholar 

  5. Bonaventure J, Horne WC, Baron R (2007) The localization of FGFR3 mutations causing thanatophoric dysplasia type I differentially affects phosphorylation processing and ubiquitination of the receptor FEBS J 274:3078-3093. Erratum in: FEBS J 274(15):4008

    Article  CAS  PubMed  Google Scholar 

  6. Bresnick S, Schendel S (1995) Crouzon disease correlates with low fibroblast growth factor receptor activity in stenosed cranial sutures. J Craniofac Surg 6:245-250

    Article  CAS  PubMed  Google Scholar 

  7. Britto JA, Evans RD, Hayward RD, Jones BM (2001) From genotype to phenotype: the differential expression of FGF, FGFR, and TGFbeta genes characterizes human cranioskeletal development and reflects clinical presentation in FGFR syndromes, Plast Reconstr Surg 108:2026-2039

    Article  CAS  PubMed  Google Scholar 

  8. Canalis E, Centrella M, McCarthy T (1988) Effects of basic fibroblast growth factor on bone formation in vitro. J Clin Invest 81:1572-1577

    Article  CAS  PubMed  Google Scholar 

  9. Chen L, Adar R, Yang X, Monsonego EO, Li C, Hauschka PV, Yayon A, Deng CX (1999) Gly369Cys mutation in mouse FGFR3 causes achondroplasia by affecting both chondrogenesis and osteogenesis. J Clin Invest 104:1517-1525

    Article  CAS  PubMed  Google Scholar 

  10. Chen L, Li C, Qiao W, Xu X, Deng CA (2001) Ser(365)--> Cys mutation of fibroblast growth factor receptor 3 in mouse downregulates Ihh/PTHrP signals and causes severe achondroplasia. Hum Mol Genet 10:457-465

    Article  CAS  PubMed  Google Scholar 

  11. Chen L, Li D, Li C, Engel A, Deng CX (2003) A Ser252Trp [corrected] substitution in mouse fibroblast growth factor receptor 2 (Fgfr2) results in craniosynostosis Bone 33:169-178. Erratum in: Bone (2005)37:876

    Article  CAS  PubMed  Google Scholar 

  12. Chimal-Monroy J, Montero JA, Gañan Y, Macias D, Garcia-Porrero JA, Hurle JM (2002) Comparative analysis of the expression and regulation of Wnt5a Fz4 and Frzb1 during digit formation and in micromass cultures. Dev Dyn 224:314-320

    Article  CAS  PubMed  Google Scholar 

  13. Cho JY, Guo C, Torello M, Lunstrum GP, Iwata T, Deng C, Horton WA (2004) Defective lysosomal targeting of activated fibroblast growth factor receptor 3 in achondroplasia. Proc Natl Acad Sci U S A 101:609-614

    Article  CAS  PubMed  Google Scholar 

  14. Choi KY, Kim HJ, Lee MH, Kwon TG, Nah HD, Furuichi T, Komor T, Nam SH, Kim YJ, Kim HJ, Ryoo HM (2005) Runx2 regulates FGF2-induced Bmp2 expression during cranial bone development. Dev Dyn 233:115-121

    Article  CAS  PubMed  Google Scholar 

  15. Cohen MM Jr (2005) Perspectives on craniosynostosis. Am J Med Genet A 136:313-326

    Google Scholar 

  16. Colvin JS, Bohne BA, Harding DG, McEwen DG, Ornitz, DM (1996) Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3. Nat Genet 12:390-397

    Article  CAS  PubMed  Google Scholar 

  17. Colvin JS, Green RP, Schmahl J, Capel B, Ornitz D.M (2001) Male-to-female sex reversal in mice lacking fibroblast growth factor 9. Cell 104:875-889

    Article  CAS  PubMed  Google Scholar 

  18. Colvin JS, White A, Pratt SJ, Ornitz DM (2001) Lung hypoplasia and neonatal death in Fgf9-null mice identify this gene as an essential regulator of lung mesenchyme. Development 128:2095-2106

    CAS  PubMed  Google Scholar 

  19. Cormier S, Delezoide AL, Benoist-Lasselin C, Legeai-Mallet L, Bonaventure J, Silve C (2002) Parathyroid hormone receptor type 1/Indian hedgehog expression is preserved in the growth plate of human fetuses affected with fibroblast growth factor receptor type 3 activating mutations. Am J Pathol 161:1325-1335

    CAS  PubMed  Google Scholar 

  20. Coussens AK, Wilkinson CR, Hughes IP, Morris CP, van Daal A, Anderson PJ, Powell BC (2007) Unravelling the molecular control of calvarial suture fusion in children with craniosynostosis. BMC Genomics 8:458

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  22. Davidson D, Blanc A, Filion D, Wang H, Plut P, Pfeffer G, Buschmann MD, Henderson JE (2005) Fibroblast growth factor (FGF) 18 signals through FGF receptor 3 to promote chondrogenesis. J Biol Chem 280:20509-20515

    Article  CAS  PubMed  Google Scholar 

  23. de Frutos CA, Vega S, Manzanares M, Flores JM, Huertas H, Martíz-Frí ML, Nieto MA (2007) Snail1 is a transcriptional effector of FGFR3 signaling during chondrogenesis and achondroplasias. Dev Cell 13:872-883

    Article  PubMed  CAS  Google Scholar 

  24. Debiais F, Graulet AM, Marie PJ (1998) Fibroblast growth factor-2 differently affects human neonatal calvaria osteoblastic cells depending on the stage of cell differentiation. J Bone Miner Res 13:645-654

    Article  CAS  PubMed  Google Scholar 

  25. Delezoide AL, Lasselin-Benoist C, Legeai-Mallet L, Brice P, Senée V, Yayon A, Munnich A, Vekemans M, Bonaventure J (1997) Abnormal FGFR 3 expression in cartilage of thanatophoric dysplasia fetuses. Hum Mol Genet 6:1899-1906

    Article  CAS  PubMed  Google Scholar 

  26. Delezoide, AL, Benoist-Lasselin, C, Legeai-Mallet, L, Le Merrer, M, Munnich, A, Vekemans M, Bonaventure J (1998) Spatio-temporal expression of FGFR1, 2 and 3 genes during human embryo-fetal ossification. Mech Dev 77:19-30

    Article  CAS  PubMed  Google Scholar 

  27. Deng C, Wynshaw-Boris A, Zhou F, Kuo A, Leder P (1996) Fibroblast growth factor receptor 3 is a negative regulator of bone growth. Cell 84:911-921

    Article  CAS  PubMed  Google Scholar 

  28. Dufour C, Guenou H, Kaabeche K, Bouvard D, Sanjay A, Marie PJ (2008) FGFR2-Cbl interaction in lipid rafts triggers attenuation of PI3K/Akt signaling and osteoblast survival. Bone 42:1032-1039

    Article  CAS  PubMed  Google Scholar 

  29. Ellsworth JL, Berry J, Bukowski T, Claus J, Feldhaus A, Holderman S, Holdren MS, Lum KD, Moore EE, Raymond F, Ren H, Shea P, Sprecher C, Storey H, Thompson DL, Waggie K, Yao L, Fernandes RJ, Eyre DR, Hughes SD (2002) Fibroblast growth factor-18 is a trophic factor for mature chondrocytes and their progenitors Osteoarth Cart 10:308-320. Erratum in: Osteoarth Cart (2002)10:826

    Article  CAS  Google Scholar 

  30. Enomoto-Iwamoto M, Kitagaki J, Koyama E, Tamamura Y, Wu C, Kanatani N, Koike T, Okada H, Komori T, Yoneda T, Church V, Francis-West PH, Kurisu K, Nohno T, Pacifici M, Iwamoto M (2002) The Wnt antagonist Frzb-1 regulates chondrocyte maturation and long bone development during limb skeletogenesis. Dev Biol 251:142-156

    Article  CAS  PubMed  Google Scholar 

  31. Eswarakumar VP, Horowitz MC, Locklin R, Morriss-Kay GM, Lonai P (2004) A gain-of-function mutation of Fgfr2c demonstrates the roles of this receptor variant in osteogenesis. Proc Natl Acad Sci U S A 101:12555-12560

    Article  CAS  PubMed  Google Scholar 

  32. Eswarakumar VP, Lax I, Schlessinger J (2005) Cellular signaling by fibroblast growth factor receptors. Cytokine Growth Factor Rev 16:139-149

    Article  CAS  PubMed  Google Scholar 

  33. Eswarakumar VP, Monsonego-Ornan E, Pines M, Antonopoulou I, Morriss-Kay GM, Lonai P (2002) The IIIc alternative of Fgfr2 is a positive regulator of bone formation. Development 129:3783-3793

    CAS  PubMed  Google Scholar 

  34. Eswarakumar VP, Ozcan F, Lew ED, Bae JH, Tome F, Booth CJ, Adams DJ, Lax I, Schlessinger J (2006) Attenuation of signaling pathways stimulated by pathologically activated FGF-receptor 2 mutants prevents craniosynostosis. Proc Natl Acad Sci U S A 103:18603-18608

    Article  CAS  PubMed  Google Scholar 

  35. Eswarakumar VP, Schlessinger J (2007) Skeletal overgrowth is mediated by deficiency in a specific isoform of fibroblast growth factor receptor 3. Proc Natl Acad Sci U S A 104:3937-3942

    Article  CAS  PubMed  Google Scholar 

  36. Fragale A, Tartaglia M, Bernardini S, Michela Di Stasi AM, Di Rocco C, Velardi F, Teti A, Battaglia PA, Migliacco S (1999) Decreased proliferation and altered differentiation in osteoblasts from genetically and clinically distinct craniosynostotic disorders. Am J Pathol 154:1465-1477

    CAS  PubMed  Google Scholar 

  37. Fromigué O, Modrowski D, Marie PJ (2005) Apoptosis in membranous bone formation: role of fibroblast growth factor and bone morphogenetic protein signaling. Crit Rev Eukaryot Gene Expr 15:75-92

    Article  PubMed  Google Scholar 

  38. Galvin BD, Hart KC, Meyer AN, Webster MK, Donoghue DJ (1996) Constitutive receptor activation by Crouzon syndrome mutations in fibroblast growth factor receptor (FGFR)2 and FGFR2/Neu chimeras. Proc Natl Acad Sci U S A 93:7894-7899

    Article  CAS  PubMed  Google Scholar 

  39. Greenwald JA, Mehrara BJ, Spector JA, Warren SM, Fagenholz PJ, Smith LE, Bouletreau PJ, Crisera FE, Ueno H, Longaker MT (2001) In vivo modulation of FGF biological activity alters cranial suture fate. Am J Pathol 158:441-452

    CAS  PubMed  Google Scholar 

  40. Guenou H, Kaabeche K, Mee SL, Marie PJ (2005) A role for fibroblast growth factor receptor-2 in the altered osteoblast phenotype induced by Twist ­haploinsufficiency in the Saethre-Chotzen syndrome. Hum Mol Genet 14:1429-1439

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  42. Hajihosseini MK, Wilson S, De Moerlooze L, Dickson C (2001) A splicing switch and gain-of-function mutation in FgfR2-IIIc hemizygotes causes Apert/Pfeiffer-syndrome-like phenotypes. Proc Natl Acad Sci U S A 98:3855-3860

    Article  CAS  PubMed  Google Scholar 

  43. Harada D, Yamanaka Y, Ueda K, Nishimura R, Morishima T, Seino Y, Tanaka H (2007) Sustained phosphorylation of mutated FGFR3 is a crucial feature of genetic dwarfism and induces apoptosis in the ATDC5 chondrogenic cell line via PLCgamma-activated STAT1. Bone 41:273-281

    Article  CAS  PubMed  Google Scholar 

  44. Hart KC, Robertson SC, Donoghue DJ (2001) Identification of tyrosine residues in constitutively activated fibroblast growth factor receptor 3 involved in mitogenesis Stat activation and phosphatidylinositol 3-kinase activation. Mol Biol Cell 12:931-942

    CAS  PubMed  Google Scholar 

  45. Hart KC, Robertson SC, Kanemitsu MY, Meyer AN, Tynan JA, Donoghue DJ (2000) Transformation and Stat activation by derivatives of FGFR1, FGFR3, and FGFR4. Oncogene 19:3309-3320

    Article  CAS  PubMed  Google Scholar 

  46. Hartmann C, Tabin CJ (2000) Dual roles of Wnt signaling during chondrogenesis in the chicken limb. Development 127:3141-3159

    CAS  PubMed  Google Scholar 

  47. Hatch NE, Hudson M, Seto ML, Cunningham ML, Bothwell M (2006) Intracellular retention degradation and signaling of glycosylation-deficient FGFR2 and craniosynostosis syndrome-associated FGFR2 C278F. J Biol Chem 281:27292-27305

    Article  CAS  PubMed  Google Scholar 

  48. Henderson JE, Naski MC, Aarts MM, Wang D, Cheng L, Goltzman D, Ornitz DM (2000) Expression of FGFR3 with the G380R achondroplasia mutation inhibits proliferation and maturation of CFK2 chondrocytic cells. J Bone Miner Res 15:155-165

    Article  CAS  PubMed  Google Scholar 

  49. Hurley MM, Naski MC, Marie PJ (2007) Fibroblast growth factor (FGF) and FGF receptor families in bone. In: Bilezikian, Raisz LG, Rodan GA (eds) Principles of bone biology, 3rd edn. Academic Press, San Diego

    Google Scholar 

  50. Ibrahimi OA, Eliseenkova AV, Plotnikov AN, Yu K, Ornitz DM, Mohammadi M (2001) Structural basis for fibroblast growth factor receptor 2 activation in Apert syndrome. Proc Natl Acad Sci U S A 98:7182-7187

    Article  CAS  PubMed  Google Scholar 

  51. Iseki S, Wilkie AOM, Heath JK, Ishimaru T, Eto K, aMorrisskay GM (1997) Fgfr2 and osteopontin domains in the developing skull vault are mutually exclusive and can be altered by locally applied FGF2. Development 124:3375-3384

    CAS  PubMed  Google Scholar 

  52. Jabs EW (1998) Toward understanding the pathogenesis of craniosynostosis through clinical and molecular correlates. Clin Genet 53:79-86

    Article  CAS  PubMed  Google Scholar 

  53. Jacob AL, Smith C, Partanen J, Ornitz DM (2006) Fibroblast growth factor receptor 1 signaling in the osteo-chondrogenic cell lineage regulates sequential steps of osteoblast maturation. Dev Biol 296:315-318

    Article  CAS  PubMed  Google Scholar 

  54. Johnson D, Iseki S, Wilkie AO, Morriss-Kay GM (2000) Expression patterns of Twist and Fgfr1 -2 and -3 in the developing mouse coronal suture suggest a key role for Twist in suture initiation and biogenesis. Mech Dev 91:341-345

    Article  CAS  PubMed  Google Scholar 

  55. Kaabeche K, Guenou G, Bouvard D, Didelot N, Listrat A, Marie PJ (2005) Cbl-mediated ubiquitination of alpha 5 integrin subunit mediates fibronectin-dependent osteoblast detachment and apoptosis induced by FGFR2 activation. J Cell Sci 118:1223-1232

    Article  CAS  PubMed  Google Scholar 

  56. Kaabeche K, Lemonnier J, Le Mee S, Caverzasio J, Marie PJ (2004) Cbl-mediated degradation of Lyn and Fyn induced by constitutive fibroblast growth factor receptor-2 activation supports osteoblast differentiation. J Biol Chem 279:36259-36267

    Article  CAS  PubMed  Google Scholar 

  57. Kapadia, RM, Guntur, AR, Reinhold, MI, Naski, MC (2005) Glycogen synthase kinase 3 controls endochondral bone development: contribution of fibroblast growth factor 18. Dev Biol 285:496-507

    Article  CAS  PubMed  Google Scholar 

  58. Kim HJ, Lee MH, Park HS, Park MH, Lee SW, Kim SY, Choi JY, Shin HI, Kim HJ, Ryoo HM (2003) Erk pathway and activator protein 1 play crucial roles in FGF2-stimulated premature cranial suture closure. Dev Dyn 227:335-346

    Article  CAS  PubMed  Google Scholar 

  59. Kim HJ, Rice DP, Kettunen PJ, Thesleff I (1998) FGF- BMP- and Shh-mediated signaling pathways in the regulation of cranial suture morphogenesis and calvarial bone development. Development 125:1241-1251

    CAS  PubMed  Google Scholar 

  60. Koike M, Yamanaka Y, Inoue M, Tanaka H, Nishimura R, Seino Y (2003) Insulin-like growth factor-1 rescues the mutated FGF receptor 3 (G380R) expressing ATDC5 cells from apoptosis through phosphatidylinositol 3-kinase and MAPK. J Bone Miner Res 18:2043-2051

    Article  CAS  PubMed  Google Scholar 

  61. Lajeunie E, Catala M, Renier D (1999) Craniosynostosis: from a clinical description to an understanding of bone formation of the skull. Childs Nerv Syst 15:676-680

    Article  CAS  PubMed  Google Scholar 

  62. Laplantine E, Rossi F, Sahni M, Basilico C, Cobrinik D (2002) FGF signaling targets the pRb-related p107 and p130 proteins to induce chondrocyte growth arrest. J Cell Biol 158:741-750

    Article  CAS  PubMed  Google Scholar 

  63. Legeai-Mallet L, Benoist-Lasselin C, Delezoide A L, Munnich A, Bonaventure J, (1998) Fibroblast growth factor receptor 3 mutations promote apoptosis but do not alter chondrocyte proliferation in thanatophoric dysplasia J Biol Chem 273:13007-13014

    Article  CAS  PubMed  Google Scholar 

  64. Legeai-Mallet L, Benoist-Lasselin C, Munnich A, Bonaventure J (2004) Overexpression of FGFR3 Stat1 Stat5 and p21Cip1 correlates with phenotypic severity and defective chondrocyte differentiation in FGFR3-related chondrodysplasias. Bone 34:26-36

    Article  CAS  PubMed  Google Scholar 

  65. Lemonnier J, Delannoy P, Hott M, Lomri A, Modrowski D, Marie PJ (2000) The Ser252Trp fibroblast growth factor receptor-2 (FGFR-2) mutation induces PKC-independent downregulation of FGFR-2 associated with premature calvaria osteoblast differentiation. Exp Cell Res 256:158-167

    Article  CAS  PubMed  Google Scholar 

  66. Lemonnier J, Hay E, Delannoy P, Lomri A, Modrowski D, Caverzasio J, Marie PJ (2001) Role of N-cadherin and protein kinase C in osteoblast gene activation induced by the S252W fibroblast growth factor receptor 2 mutation in Apert craniosynostosis. J Bone Miner Res 16:832-845

    Article  CAS  PubMed  Google Scholar 

  67. Lemonnier J, Haÿ E, Delannoy Ph, Fromigué O, Lomri A, Modrowski M, Marie PJ (2001) Increased osteoblast in Apert craniosynostosis: Role of protein kinase C and interleukin-1. Am J Pathol 158:1833-1842

    CAS  PubMed  Google Scholar 

  68. Li C, Chen L, Iwata T, Kitagawa M, Fu XY, Deng CX (1999) A Lys644Glu substitution in fibroblast growth factor receptor 3 (FGFR3) causes dwarfism in mice by activation of STATs and ink4 cell cycle inhibitors. Hum Mol Genet 8:35-44

    Article  CAS  PubMed  Google Scholar 

  69. Li Y, Mangasarian K, Mansukhani A, Basilico C (1997) Activation of FGF receptors by mutations in the transmembrane domain. Oncogene 14:1397-1406

    Article  CAS  PubMed  Google Scholar 

  70. Lievens PM, Mutinelli C, Baynes D, Liboi E (2004) The kinase activity of fibroblast growth factor receptor 3 with activation loop mutations affects receptor ­trafficking and signaling. J Biol Chem 279(41):43254-43260

    Article  CAS  PubMed  Google Scholar 

  71. Lievens PM, Roncador A, Liboi EK (2006) 644E/M FGFR3 mutants activate Erk1/2 from the endoplasmic reticulum through FRS2 alpha and PLC gamma-independent pathways. J Mol Biol 357:783-792

    Article  CAS  PubMed  Google Scholar 

  72. Liu Z, Xu J, Colvin JS, Ornitz DM (2002) Coordination of chondrogenesis and osteogenesis by fibroblast growth factor 18. Genes Dev 16:859-869

    Article  CAS  PubMed  Google Scholar 

  73. Liu, Z, Lavine, KJ, Hung, IH, Ornitz, D M (2007) FGF18 is required for early chondrocyte proliferation, hypertrophy and vascular invasion of the growth plate. Dev Biol 302:80-91

    Article  CAS  PubMed  Google Scholar 

  74. Lomri A, Lemonnier J, Delannoy P, Marie PJ (2001) Identification of genes induced by the Ser252Trp FGFR-2 Apert mutation in osteoblasts using atlas human expression arrays: evidence for increased expression of PKCα IL-1αand RhoA GTPase. J Bone Miner Res 164:705-712

    Article  Google Scholar 

  75. Lomri A, Lemonnier J, Hott M, de Perseval N, Lajeunie E, Munnich A, Renier D, Marie PJ (1998) Increased calvaria cell differentiation and bone matrix formation induced by fibroblast growth factor receptor-2 mutations in Apert syndrome. J Clin Invest 101:1310-1317

    CAS  PubMed  Google Scholar 

  76. Mangasarian K, Li Y, Mansukhani A, Basilico C (1997) Mutation associated with Crouzon syndrome causes ligand-independent dimerization and activation of FGF receptor-2. J Cell Physiol 172:117-125

    Article  CAS  PubMed  Google Scholar 

  77. Mansukhani A, Bellosta P, Sahni M, Basilico C (2000) Signaling by fibroblast growth factors (FGF) and fibroblast growth factor receptor 2 (FGFR2)-activating mutations blocks mineralization and induces apoptosis in osteoblasts. J Cell Biol 149:1297-1308

    Article  CAS  PubMed  Google Scholar 

  78. Mansukhani A, Ambrosetti D, Holmes G, Cornivelli L, Basilico C (2005) Sox2 induction by FGF and FGFR2 activating mutations inhibits Wnt signaling and osteoblast differentiation. J Cell Biol 168:1065-1076

    Article  CAS  PubMed  Google Scholar 

  79. Marie PJ (2003) Fibroblast growth factor signaling controlling osteoblast differentiation. Gene 316:23-32

    Article  CAS  PubMed  Google Scholar 

  80. Marie PJ, Kaabeche K, Guenou H (2008) Roles of FGFR2 and Twist in human craniosynostosis: insights from genetic mutations in cranial osteoblasts. Front Oral Biol 12:144-159

    Article  PubMed  Google Scholar 

  81. Mathijssen IM, van Leeuwen JP, Vermeij-Keers C (2000) Simultaneous induction of apoptosis collagen type I expression and mineralization in the ­developing coronal suture following FGF4 and FGF2 application. J Craniofac Genet Dev Biol 20:127-136

    CAS  PubMed  Google Scholar 

  82. Matsushita T, Wilcox WR, Chan YY, Kawanami A, Bükülmez H, Balmes G, Krejci P, Mekikian PB, Otani K, Yamaura I, Warman ML, Givol D, Murakami S (2009) FGFR3 promotes synchondrosis closure and fusion of ossification centers through the MAPK pathway. Hum Mol Genet 18:227-240

    Article  CAS  Google Scholar 

  83. Meyers EN, Lewandoski M, Martin, GR (1998) An Fgf8 mutant allelic series generated by Cre- and Flp-mediated recombination. Nat Genet 18:136-141

    Article  CAS  PubMed  Google Scholar 

  84. Minina E, Wenzel HM, Kreschel C, Karp S, Gaffield W, McMahon AP, Vortkamp A (2001) BMP and Ihh/PTHrP signaling interact to coordinate chondrocyte proliferation and differentiation. Development 128:4523-4534

    CAS  PubMed  Google Scholar 

  85. Mohammadi M, Olsen SK, Ibrahimi OA (2005) Structural basis for fibroblast growth factor receptor activation. Cytokine Growth Factor Rev 16:107-137

    Article  CAS  PubMed  Google Scholar 

  86. Mohammadi M, Schlessinger J, Hubbard SR (1996) Structure of the FGF receptor tyrosine kinase domain reveals a novel autoinhibitory mechanism. Cell 86:577-587

    Article  CAS  PubMed  Google Scholar 

  87. Molteni A, Modrowski D, Hott M, Marie PJ (1999) Differential expression of fibroblast growth factor receptor-1 -2 and -3 and syndecan-1 -2 and -4 in neonatal rat mandibular condyle and calvaria during osteogenic differentiation in vitro. Bone 24:337-347

    Article  CAS  PubMed  Google Scholar 

  88. Monsonego-Ornan E, Adar R, Feferman T, Segev O, Yayon A (2000) The transmembrane mutation G380R in fibroblast growth factor receptor 3 uncouples ligand-mediated receptor activation from down-regulation. Mol Cell Biol 20:516-522

    Article  CAS  PubMed  Google Scholar 

  89. Montero A, Okada Y, Tomita M, Ito M, Tsurukami H, Nakamura T, Doetschman T, Coffin JD, Hurley MM (2000) Disruption of the fibroblast growth factor-2 gene results in decreased bone mass and bone formation. J Clin Invest 105:1085-1093

    Article  CAS  PubMed  Google Scholar 

  90. Moore R, Ferretti P, Copp A, Thorogood P (2002) Blocking endogenous FGF-2 activity prevents cranial osteogenesis. Dev Biol 243:99-114

    Article  CAS  PubMed  Google Scholar 

  91. Morriss-Kay GM, Wilkie AO (2005) Growth of the normal skull vault and its alteration in craniosynostosis: insights from human genetics and experimental studies. J Anat 207:637-653

    Article  PubMed  Google Scholar 

  92. Murakami S, Balmes G, McKinney S, Zhang Z, Givol D, de Crombrugghe BC (2004) Constitutive activation of MEK1 in chondrocytes causes Stat1-independent achondroplasia-like dwarfism and rescues the Fgfr3-deficient mouse phenotype Genes Dev 18:290-305

    Article  CAS  PubMed  Google Scholar 

  93. Naski MC, Colvin JS, Coffin JD, Ornitz DM (1998) Repression of hedgehog signaling and BMP4 expression in growth plate cartilage by fibroblast growth factor receptor 3. Development 125:4977-4988

    CAS  PubMed  Google Scholar 

  94. Naski MC, Wang Q, Xu J, Ornitz DM (1996) Graded activation of fibroblast growth factor receptor 3 by mutations causing achondroplasia and thanatophoric dysplasia. Nat Genet 13:233-237

    Article  CAS  PubMed  Google Scholar 

  95. Naski, MC, Ornitz, DM (1998) FGF signaling in skeletal development. Front Biosci 3:D781-DD94

    CAS  PubMed  Google Scholar 

  96. Neilson KM, Friesel RE (1995) Constitutive activation of fibroblast growth factor receptor-2 by a point mutation associated with Crouzon syndrome. J Biol Chem 270:26037-26040

    Article  CAS  PubMed  Google Scholar 

  97. Obayashi N, Shibayama M, Kurotaki Y, Imanishi M, Fujimori T, Itoh N (2002) FGF 18 is required for normal cell proliferation and differentiation during osteogenesis and chondrogenesis. Genes Dev 16:870-879

    Article  Google Scholar 

  98. Opperman LA (2000) Cranial sutures as intramembranous bone growth sites Dev Dyn 219:472-485

    Article  CAS  PubMed  Google Scholar 

  99. Ornitz D, Marie PJ (2002) FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease. Genes Dev 16:1446-1465

    Article  CAS  PubMed  Google Scholar 

  100. Ornitz DM (2001) Regulation of chondrocyte growth and differentiation by fibroblast growth factor receptor 3. Novartis Found Symp 232:63-76

    Article  CAS  PubMed  Google Scholar 

  101. Ornitz DM (2005) FGF signaling in the developing endochondral skeleton. Cytokine Growth Factor Rev 16:205-213

    Article  CAS  PubMed  Google Scholar 

  102. Park WJ, Meyers GA, Li X, Theda C, Day D, Orlow SJ, Jones MC, Jabs EW (1995) Novel FGFR2 mutations in Crouzon and Jackson-Weiss syndromes show allelic heterogeneity and phenotypic variability. Hum Mol Genet 4:1229-1233

    Article  CAS  PubMed  Google Scholar 

  103. Peters KG, Werner S, Chen G, William LT (1992) Two FGF receptor genes are differentially expressed in epithelial and mesenchymal tissues during limb formation and organogenesis in the mouse. Development 114:233-243

    CAS  PubMed  Google Scholar 

  104. Plotnikov AN, Hubbard SR, Schlessinger J, Mohammadi M (2000) Crystal structures of two FGF-FGFR complexes reveal the determinants of ligand-receptor specificity. Cell 101:413-434

    Article  CAS  PubMed  Google Scholar 

  105. Ratisoontorn C, Fan GF, McEntee K, Nah HD (2003) Activating (P253R C278F) and dominant negative mutations of FGFR2: differential effects on calvarial bone cell proliferation differentiation and mineralization. Connect Tissue Res 44(suppl 1):292-297

    CAS  PubMed  Google Scholar 

  106. Raucci A, Laplantine E, Mansukhani A, Basilico C (2004) Activation of the ERK1/2 and p38 mitogen-activated protein kinase pathways mediates fibroblast growth factor-induced growth arrest of chondrocytes. J Biol Chem 279:1747-1756

    Article  CAS  PubMed  Google Scholar 

  107. Reinhold MI, Abe M, Kapadia RM, Liao Z, Naski MC (2004) FGF18 represses noggin expression and is induced by calcineurin. J Biol Chem 279:38209-38219

    Article  CAS  PubMed  Google Scholar 

  108. Reinhold MI, Naski, MC (2007) Direct interactions of Runx2 and canonical Wnt signaling induce FGF18. J Biol Chem 282:3653-3663

    Article  CAS  PubMed  Google Scholar 

  109. Rice DP, Aberg T, Chan YS, Tang ZQ, Kettunen PJ, Pakarinen L, Maxson RE, Thesleff I (2000) Integration of FGF and TWIST in calvarial bone and suture development. Development 127:1845-1855

    CAS  PubMed  Google Scholar 

  110. Rice DP, Rice R (2008) Locate condense differentiate grow and confront: developmental mechanisms controlling intramembranous bone and suture formation and function. Front Oral Biol 12:22-40

    Article  PubMed  Google Scholar 

  111. Rice DP, Rice R, Thesleff I (2003) Fgfr mRNA isoforms in craniofacial bone development. Bone 33:14-27

    Article  CAS  PubMed  Google Scholar 

  112. Robertson SC, Meyer AN, Hart KC, Galvin BD, Webster MK, Donoghue DJ (1998) 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 U S A 95:4567-4572

    Article  CAS  PubMed  Google Scholar 

  113. Rousseau F, Bonaventure J, Legeal-Mallet L, Pelet A, Rozet J-M, Maroteaux P, Le Merrer M, Munnich A (1994) Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia. Nature 371:252-254

    Article  CAS  PubMed  Google Scholar 

  114. Rousseau F, el Ghouzzi V, Delezoide AL, Legeai-Mallet L, Le Merrer M, Munnich A, Bonaventure J (1996) Missense FGFR3 mutations create cysteine residues in thanatophoric dwarfism type I (TD1). Hum Mol Genet 5:509-512

    Article  CAS  PubMed  Google Scholar 

  115. Rousseau F, Saugier P, Le Merrer M, Munnich A, Delezoide AL, Maroteaux P, Bonaventure J, Narcy F, Sanak M (1995) Stop codon FGFR3 mutations in thanatophoric dwarfism type 1. Nat Genet 10:11-12

    Article  CAS  PubMed  Google Scholar 

  116. Rozenblatt-Rosen O, Mosonego-Ornan E, Sadot E, Madar-Shapiro L, Sheinin Y, Ginsberg D, Yayon A (2002) Induction of chondrocyte growth arrest by FGF: transcriptional and cytoskeletal alterations. J Cell Sci 115:553-562

    CAS  PubMed  Google Scholar 

  117. Sahni M, Ambrosetti DC, Mansukhani A, Gertner R, Levy D, Basilico C (1999) FGF signaling inhibits chondrocyte proliferation and regulates bone development through the STAT-1 pathway. Genes Dev 13:1361-1366

    Article  CAS  PubMed  Google Scholar 

  118. Segev O, Chumakov I, Nevo Z, Givol D, Madar-Shapiro L, Sheinin Y, Weinreb M, Yayon A (2000) Restrained chondrocyte proliferation and maturation with abnormal growth plate vascularization and ossification in human FGFR-3(G380R) transgenic mice. Hum Mol Genet 9:249-258

    Article  CAS  PubMed  Google Scholar 

  119. Shiang R, Thompson L M, Zhu, Y-Z, Church DM, Fielder TJ, Bocian M, Winokur S T, Wasmuth JJ (1994) Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Cell 78:335-342

    Article  CAS  PubMed  Google Scholar 

  120. Shimoaka T, Ogasawara T, Yonamine A, Chikazu D, Kawano H, Nakamura K, Itoh N, Kawaguchi H (2002) Regulation of osteoblast, chondrocyte, and osteoclast functions by fibroblast growth factor (FGF)-18 in comparison with FGF-2 and FGF-10. J Biol Chem 277:7493-7500

    Article  CAS  PubMed  Google Scholar 

  121. Shukla V, Coumoul X, Wang RH, Kim HS, Deng CX (2007) RNA interference and inhibition of MEK-ERK signaling prevent abnormal skeletal phenotypes in a mouse model of craniosynostosis. Nat Genet 39:1145-1150

    Article  CAS  PubMed  Google Scholar 

  122. Stott NS, Jiang TX, Chuong CM (1999) Successive formative stages of precartilaginous mesenchymal condensations in vitro: modulation of cell adhesion by Wnt-7A and BMP-2. J Cell Physiol 180:314-324

    Article  CAS  PubMed  Google Scholar 

  123. Su WC, Kitagawa M, Xue N, Xie B, Garofalo S, Cho J, Deng C, Horton WA, Fu XY (1997) Activation of Stat1 by mutant fibroblast growth-factor receptor in thanatophoric dysplasia type II dwarfism. Nature 386:288-292

    Article  CAS  PubMed  Google Scholar 

  124. Tanimoto Y, Yokozeki M, Hiura K, Matsumoto K, Nakanishi H, Matsumoto T, Marie PJ, Moriyama K (2004) 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

    Article  CAS  PubMed  Google Scholar 

  125. Tavormina PL, Rimoin DL, Cohn DH, Zhu YZ, Shiang R, Wasmuth JJ (1995) Another mutation that results in the substitution of an unpaired cysteine residue in the extracellular domain of FGFR3 in thanatophoric dysplasia type I. Hum Mol Genet 4:2175-2177

    Article  CAS  PubMed  Google Scholar 

  126. Tavormina PL, Shiang R, Thompson LM, Zhu Y, Wilkin DJ, Lachman RS, Wilcox WR, Rimoin DL, Cohn DH, Wasmuth JJ (1995) Thanatophoric dysplasia (types I and II) caused by distinct mutations in fibroblast growth factor receptor 3. Nat Genet 9:321-328

    Article  CAS  PubMed  Google Scholar 

  127. Wang Q, Green RP, Zhao G, Ornitz DM (2001) Differential regulation of endochondral bone growth and joint development by FGFR1 and FGFR3 tyrosine kinase domains Development 2128:3867-3876

    Google Scholar 

  128. Wang Y, Xiao R, Yang F, Karim BO, Iacovelli AJ, Cai J, Lerner CP, Richtsmeier JT, Leszl JM, Hill CA, Yu K, Ornitz DM, Elisseeff J, Huso DL, Jabs EW (2005) Abnormalities in cartilage and bone development in the Apert syndrome FGFR2(+/S252W) mouse. Development 132:3537-3548

    Article  CAS  PubMed  Google Scholar 

  129. Wang YC, Spatz MK, Kannan K, Hayk H, Avivi A, Gorivodsky M, Pines M, Yayon A, Lonai P, Givol D (1999) A mouse model for achondroplasia produced by targeting fibroblast growth factor receptor 3. Proc Natl Acad Sci U S A 96:4455-4460

    Article  CAS  PubMed  Google Scholar 

  130. Warren SM, Brunet LJ, Harland RM, Economides AN, Longaker MT (2003) The BMP antagonist noggin regulates cranial suture fusion. Nature 422:625-629

    Article  CAS  PubMed  Google Scholar 

  131. Webster MK, Donoghue DJ (1996) Constitutive activation of fibroblast growth factor receptor 3 by the transmembrane domain point mutation found in achondroplasia EMBO J 15:520-527

    CAS  PubMed  Google Scholar 

  132. Wilkie AO (2005) Bad bones, absent smell, selfish ­testes: the pleiotropic consequences of human FGF receptor mutations Cytokine Growth Factor Rev 16:187-203

    Article  CAS  PubMed  Google Scholar 

  133. Xu J, Lawshe A, MacArthur CA, Ornitz DM (1999) Genomic structure, mapping, activity and expression of fibroblast growth factor 17. Mech Dev 83:165-178

    Article  CAS  PubMed  Google Scholar 

  134. Xu JS, Liu, ZH, Ornitz, DM (2000) Temporal and spatial gradients of Fgf8 and Fgf17 regulate proliferation and differentiation of midline cerebellar structures. Development 127:1833-1843

    CAS  PubMed  Google Scholar 

  135. Yasoda A, Komatsu Y, Chusho H, Miyazawa T, Ozasa A, Miura M, Kurihara T, Rogi T, Tanaka S, Suda M, Tamura N, Ogawa Y, Nakao K (2004) Overexpression of CNP in chondrocytes rescues achondroplasia through a MAPK-dependent pathway. Nat Med 10:80-86

    Article  CAS  PubMed  Google Scholar 

  136. Yin L, Du X, Li C, Xu X, Chen Z, Su N, Zhao L, Qi H, Li F, Xue J, Yang J, Jin M, Deng C, Chen L (2008) A Pro253Arg mutation in fibroblast growth factor receptor 2 (Fgfr2) causes skeleton malformation mimicking human Apert syndrome by affecting both chondrogenesis and osteogenesis. Bone 42:631-643

    Article  CAS  PubMed  Google Scholar 

  137. Yoon BS, Pogue R, Ovchinnikov DA, Yoshii I, Mishina Y, Behringer RR, Lyons K M (2006) BMPs regulate multiple aspects of growth-plate chondrogenesis through opposing actions on FGF pathways. Development 133:4667-4678

    Article  CAS  PubMed  Google Scholar 

  138. Yu K, Herr AB, Waksman G, Ornitz DM (2000) Loss of fibroblast growth factor receptor 2 ligand-binding specificity in Apert syndrome. Proc Natl Acad Sci U S A 97:14536-14541

    Article  CAS  PubMed  Google Scholar 

  139. Yu K, Ornitz DM (2001) Uncoupling fibroblast growth factor receptor 2 ligand binding specificity leads to Apert syndrome-like phenotypes. Proc Natl Acad Sci U S A 98:3641-3643

    Article  CAS  PubMed  Google Scholar 

  140. Yu K, Xu J, Liu Z, Sosic D, Shao J, Olson EN, Towler DA, Ornitz DM (2003) Conditional inactivation of FGF receptor 2 reveals an essential role for FGF signaling in the regulation of osteoblast function and bone growth Development 130:3063-3074

    Article  CAS  PubMed  Google Scholar 

  141. Zhou YX, Xu X, Chen L, Li C, Brodie SG, Deng C X (2000) A Pro250Arg substitution in mouse Fgfr1 causes increased expression of Cbfal and premature fusion of calvarial sutures. Hum Mol Genet 12:2001-2008

    Article  Google Scholar 

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Acknowledgments

The work of the author on this subject was supported by INSERM and has been awarded by the French Academy of Medicine (2008).

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  1. Laboratory of Osteoblast Biology and Pathology, University Paris 7, Hôpital Lariboisière, Paris, FRA

    Pierre J. Marie

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  1. Pierre J. Marie
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  1. Health Center, University of Connecticut, Farmington Ave. 263, Farmington, 06030-6125, USA

    Felix Bronner

  2. Dept. Biological Sciences, University of Delaware, Newark, 19716, USA

    Mary C. Farach-Carson

  3. IDS Building, MP887, Bone & Joint Research Group, Tremona Road, Southampton, SO16 6YD, United Kingdom

    H.I (Trudy) Roach

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Marie, P.J. (2010). FGF/FGFR Signaling in Skeletal Dysplasias. In: Bronner, F., Farach-Carson, M., Roach, H. (eds) Bone and Development. Topics in Bone Biology, vol 6. Springer, London. https://doi.org/10.1007/978-1-84882-822-3_6

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