Fibroblast growth factor signaling in skeletal development and disease

Genes and Development

Volumn 29, Issue 14, 2015, Pages 1463-1486

  Ornitz, David M ^a   Marie, Pierre J ^b,c  

^a WASHINGTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b HÔPITAL LARIBOISIÈRE   (France)

^c UNIVERSITÉ PARIS DESCARTES   (France)

Author keywords

Bone; Cartilage; Chondrocyte; FGF; FGFR; Osteoblast

Indexed keywords

BONE MORPHOGENETIC PROTEIN RECEPTOR 1A; BONE MORPHOGENETIC PROTEIN RECEPTOR 1B; CELL ADHESION MOLECULE; FIBROBLAST GROWTH FACTOR; FIBROBLAST GROWTH FACTOR RECEPTOR 1; FIBROBLAST GROWTH FACTOR RECEPTOR 2; FIBROBLAST GROWTH FACTOR RECEPTOR 3; SCLEROPROTEIN; THYROID HORMONE; TRANSCRIPTION FACTOR RUNX2; TRANSCRIPTION FACTOR SOX9; VASCULOTROPIN A; MINERAL;

ACHONDROPLASIA; ALTERNATIVE RNA SPLICING; BONE DEVELOPMENT; BONE HOMEOSTASIS; BONE METABOLISM; BONE MINERALIZATION; BONE REGENERATION; CAMPTODACTYLY; CELL ACTIVITY; CELL DIFFERENTIATION; CELL PROLIFERATION; CHONDRODYSPLASIA; CHONDROGENESIS; CORTICAL BONE; CRANIOFACIAL SYNOSTOSIS; DOWN REGULATION; ENCHONDRAL OSSIFICATION; GENE INACTIVATION; GENETIC DISORDER; GROWTH PLATE; HEARING IMPAIRMENT; HOMEOSTASIS; HUMAN; HYPOCHONDROPLASIA; INTRACELLULAR SIGNALING; LIGAND BINDING; MISSENSE MUTATION; NONHUMAN; OSSIFICATION; OSTEOBLAST; OSTEOCLAST ACTIVITY; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN PHOSPHORYLATION; REVIEW; SKELETON MALFORMATION; TALL STATURE; THANATOPHORIC DWARFISM; TRABECULAR BONE; ANIMAL; BONE; BONE DISEASES; EMBRYOLOGY; GENETICS; METABOLISM; MUTATION; PATHOPHYSIOLOGY; PHYSIOLOGY; SIGNAL TRANSDUCTION;

VERTEBRATA;

ANIMALS; BONE AND BONES; BONE DISEASES; BONE REGENERATION; CHONDROGENESIS; FIBROBLAST GROWTH FACTORS; HUMANS; MINERALS; MUTATION; OSTEOGENESIS; SIGNAL TRANSDUCTION;

EID: 84938151232     PISSN: 08909369     EISSN: 15495477     Source Type: Journal    
DOI: 10.1101/gad.266551.115     Document Type: Review

References (333)

1. Abad V, Meyers JL, Weise M, Gafni RI, Barnes KM, Nilsson O, Bacher JD, Baron J. 2002. The role of the resting zone in growth plate chondrogenesis. Endocrinology 143: 1851-1857.
2. Agas D, Marchetti L, Menghi G, Materazzi S, Materazzi G, Capacchietti M, Hurley MM, Sabbieti MG. 2008. Anti-apoptotic Bcl-2 enhancing requires FGF-2/FGF receptor 1 binding in mouse osteoblasts. J Cell Physiol 214: 145-152.
3. Agas D, Sabbieti MG, Marchetti L, Xiao L, Hurley MM. 2013. FGF-2 enhances Runx-2/Smads nuclear localization in BMP2 canonical signaling in osteoblasts. J Cell Physiol 228: 2149-2158.
4. Agoston H, Khan S, James CG, Gillespie JR, Serra R, Stanton LA, Beier F. 2007. C-type natriuretic peptide regulates endochondral bone growth through p38 MAP kinase-dependent and -independent pathways. BMC Dev Biol 7: 18.
5. Aikawa T, Segre GV, Lee K. 2001. Fibroblast growth factor inhibits chondrocytic growth through induction of p21 and subsequent inactivation of cyclin E-Cdk2. J Biol Chem 276: 29347-29352.
6. Akiyama H, Chaboissier MC, Martin JF, Schedl A, de Crombrugghe B. 2002. The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6. Genes Dev 16: 2813-2828.
7. Ambrosetti D, Holmes G, Mansukhani A, Basilico C. 2008. Fibroblast growth factor signaling uses multiple mechanisms to inhibit Wnt-induced transcription in osteoblasts. Mol Cell Biol 28: 4759-4771.
8. Barnard JC, Williams AJ, Rabier B, Chassande O, Samarut J, Cheng SY, Bassett JH, Williams GR. 2005. Thyroid hormones regulate fibroblast growth factor receptor signaling during chondrogenesis. Endocrinology 146: 5568-5580.
9. Baroni T, Carinci P, Lilli C, Bellucci C, Aisa MC, Scapoli L, Volinia S, Carinci F, Pezzetti F, Calvitti M, et al. 2005. P253R fibroblast growth factor receptor-2 mutation induces RUNX2 transcript variants and calvarial osteoblast differentiation. J Cell Physiol 202: 524-535.
10. Beever JE, Smit MA, Meyers SN, Hadfield TS, Bottema C, Albretsen J, Cockett NE. 2006. A single-base change in the tyrosine kinase II domain of ovine FGFR3 causes hereditary chondrodysplasia in sheep. Anim Genet 37: 66-71.
11. Behr B, Leucht P, Longaker MT, Quarto N. 2010. Fgf-9 is required for angiogenesis and osteogenesis in long bone repair. Proc Natl Acad Sci 107: 11853-11858.
12. Behr B, Sorkin M, Manu A, Lehnhardt M, Longaker MT, Quarto N. 2011. Fgf-18 is required for osteogenesis but not angiogenesis during long bone repair. Tissue Eng Part A 17: 2061-2069.
13. Behr B, Sorkin M, Lehnhardt M, Renda A, Longaker MT, Quarto N. 2012. A comparative analysis of the osteogenic effects of BMP-2, FGF-2, and VEGFA in a calvarial defect model. Tissue Eng Part A 18: 1079-1086.
14. Bellus GA, McIntosh I, Smith EA, Aylsworth 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.
15. Bellus GA, Bamshad MJ, Przylepa KA, Dorst J, Lee RR, Hurko O, Jabs EW, Curry CJ, Wilcox WR, Lachman RS, et al. 1999. Severe achondroplasiawith developmental delay and acanthosis nigricans (SADDAN): phenotypic analysis of a new skeletal dysplasia caused by a Lys650Met mutation in fibroblast growth factor receptor 3. Am J Med Genet 85: 53-65.
16. Bellus GA, Spector EB, Speiser PW, Weaver CA, Garber AT, Bryke CR, Israel J, Rosengren SS, Webster MK, Donoghue DJ, et al. 2000. Distinct missense mutations of the FGFR3 Lys650 codon modulate receptor kinase activation and the severity of the skeletal dysplasia phenotype. Am J Hum Genet 67: 1411-1421.
17. Belov AA, Mohammadi M. 2013. Molecular mechanisms of fibroblast growth factor signaling in physiology and pathology. Cold Spring Harb Perspect Biol 5: 1-24.
18. Bi W, Deng JM, Zhang Z, Behringer RR, de Crombrugghe B. 1999. Sox9 is required for cartilage formation. Nat Genet 22: 85-89.
19. Blick C, Ramachandran A, Wigfield S, McCormick R, Jubb A, Buffa FM, Turley H, Knowles MA, Cranston D, Catto J, et al. 2013. Hypoxia regulates FGFR3 expression via HIF-1α and miR-100 and contributes to cell survival in non-muscle invasive bladder cancer. Br J Cancer 109: 50-59.
20. Bocciardi R, Giorda R, Buttgereit J, Gimelli S, Divizia MT, Beri S, Garofalo S, Tavella S, Lerone M, Zuffardi O, et al. 2007. Overexpression of the C-type natriuretic peptide (CNP) is associated with overgrowth and bone anomalies in an individual with balanced t(2;7) translocation. Hum Mutat 28: 724-731.
21. Bonaventure J, Rousseau F, Legeai-Mallet L, Le Merrer M, Munnich A, Maroteaux P. 1996. Common mutations in the fibroblast growth factor receptor 3 (FGFR 3) gene account for achondroplasia, hypochondroplasia, and thanatophoric dwarfism. Am J Med Genet 63: 148-154.
22. Bosetti M, Leigheb M, Brooks RA, Boccafoschi F, Cannas MF. 2010. Regulation of osteoblast and osteoclast functions by FGF-6. J Cell Physiol 225: 466-471.
23. Britto JA, Evans RD, Hayward RD, Jones BM. 2001. From genotype to phenotype: the differential expression of FGF, FGFR, and TGFβ genes characterizes human cranioskeletal development and reflects clinical presentation in FGFR syndromes. Plast Reconstr Surg 108: 2026-2039.
24. Brodie SG, Kitoh H, Lachman RS, Nolasco LM, Mekikian PB, Wilcox WR. 1999. Platyspondylic lethal skeletal dysplasia, San Diego type, is caused by FGFR3 mutations. Am J Med Genet 84: 476-480.
25. Browaeys-Poly E, Blanquart C, Perdereau D, Antoine AF, Goenaga D, Luzy JP, Chen H, Garbay C, Issad T, Cailliau K, et al. 2010. Grb14 inhibits FGF receptor signaling through the regulation of PLCγ recruitment and activation. FEBS Lett 584: 4383-4388.
26. Buchtova M, Oralova V, Aklian A, Masek J, Vesela I, Ouyang Z, Obadalova T, Konecna Z, Spoustova T, Pospisilova T, et al. 2015. Fibroblast growth factor and canonical WNT/β-catenin signaling cooperate in suppression of chondrocyte differentiation in experimental models of FGFR signaling in cartilage. Biochim Biophys Acta 1852: 839-850.
27. Camps M, Nichols A, Gillieron C, Antonsson B, Muda M, Chabert C, Boschert U, Arkinstall S. 1998. Catalytic activation of the phosphatase MKP-3 by ERK2 mitogen-activated protein kinase. Science 280: 1262-1265.
28. Carli A, Gao C, Khayyat-Kholghi M, Li A, Wang H, Ladel C, Harvey EJ, Henderson JE. 2012. FGF18 augments osseo integration of intra-medullary implants in osteopenic FGFR3−/− mice. Eur Cell Mater 24: 107-116.
29. Chen L, Deng CX. 2005. Roles of FGF signaling in skeletal development and human genetic diseases. Front Biosci 10: 1961-1976.
30. Chen Y, Gridley T. 2013. Compensatory regulation of the Snai1 and Snai2 genes during chondrogenesis. J Bone Miner Res 28: 1412-1421.
31. Chen L, Li C, Qiao W, Xu X, Deng C. 2001. A 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.
32. 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
33. Chen WJ, Jingushi S, Aoyama I, Anzai J, Hirata G, Tamura M, Iwamoto Y. 2004. Effects of FGF-2 on metaphyseal fracture repair in rabbit tibiae. J Bone Miner Metab 22: 303-309.
34. Chen P, Zhang L, Weng T, Zhang S, Sun S, Chang M, Li Y, Zhang B, Zhang L. 2014. A Ser252Trp mutation in fibroblast growth factor receptor 2 (FGFR2) mimicking human Apert syndrome reveals an essential role for FGF signaling in the regulation of endochondral bone formation. PLoS One 9: e87311.
35. Chikazu D, Hakeda Y, Ogata N, Nemoto K, Itabashi A, Takato T, Kumegawa M, Nakamura K, Kawaguchi H. 2000. Fibroblast growth factor (FGF)-2 directly stimulates mature osteoclast function through activation of FGF receptor 1 and p42/p44 MAP kinase. J Biol Chem 275: 31444-31450.
36. Chikazu D, Katagiri M, Ogasawara T, Ogata N, Shimoaka T, Takato T, Nakamura K, Kawaguchi H. 2001. Regulation of osteoclast differentiation by fibroblast growth factor 2: stimulation of receptor activator of nuclear factor κB ligand/osteoclast differentiation factor expression in osteoblasts and inhibition of macrophage colony-stimulating factor function in osteoclast precursors. J Bone Miner Res 16: 2074-2081.
37. Choi KY, Kim HJ, Lee MH, Kwon TG, Nah HD, Furuichi T, Komori T, Nam SH, Kim YJ, Ryoo HM. 2005. Runx2 regulates FGF2-induced Bmp2 expression during cranial bone development. Dev Dyn 233: 115-121.
38. Choi SC, Kim SJ, Choi JH, Park CY, Shim WJ, Lim DS. 2008. Fibroblast growth factor-2 and -4 promote the proliferation of bone marrow mesenchymal stem cells by the activation of the PI3K-Akt and ERK1/2 signaling pathways. Stem Cells Dev 17: 725-736.
39. Cobrinik D, Lee MH, Hannon G, Mulligan G, Bronson RT, Dyson N, Harlow E, Beach D, Weinberg RA, Jacks T. 1996. Shared role of the pRB-related p130 and p107 proteins in limb development. Genes Dev 10: 1633-1644.
40. Colvin JS, Bohne BA, Harding GW, McEwen DG, Ornitz DM. 1996. Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3. Nat Genet 12: 390-397.
41. Coumoul X, Shukla V, Li C, Wang RH, Deng CX. 2005. Conditional knockdown of Fgfr2 in mice using Cre-LoxP induced RNA interference. Nucleic Acids Res 33: e102.
42. Coutu DL, Francois M, Galipeau J. 2011. Inhibition of cellular senescence by developmentally regulated FGF receptors in mesenchymal stem cells. Blood 117: 6801-6812.
43. Cowan CM, Quarto N, Warren SM, Salim A, Longaker MT. 2003. Age-related changes in the biomolecular mechanisms of calvarial osteoblast biology affect fibroblast growth factor-2 signaling and osteogenesis. J Biol Chem 278: 32005-32013.
44. Dailey L, Laplantine E, Priore R, Basilico C. 2003. A network of transcriptional and signaling events is activated by FGF to induce chondrocyte growth arrest and differentiation. J Cell Biol 161: 1053-1066.
45. Dailey L, Ambrosetti D, Mansukhani A, Basilico C. 2005. Mechanisms underlying differential responses to FGF signaling. Cytokine Growth Factor Rev 16: 233-247.
46. Dakouane Giudicelli M, Serazin V, Le Sciellour CR, Albert M, Selva J, Giudicelli Y. 2008. Increased achondroplasia mutation frequency with advanced age and evidence for G1138A mosaicism in human testis biopsies. Fertil Steril 89: 1651-1656.
47. Debiais F, Hott M, Graulet AM, Marie PJ. 1998. The effects of fibroblast growth factor-2 on human neonatal calvaria osteoblastic cells are differentiation stage specific. J Bone Miner Res 13: 645-654.
48. de Frutos CA, Vega S, Manzanares M, Flores JM, Huertas H, Martinez-Frias ML, Nieto MA. 2007. Snail1 is a transcriptional effector of FGFR3 signaling during chondrogenesis and achondroplasias. Dev Cell 13: 872-883.
49. Delezoide AL, Benoist-Lasselin C, Legeai-Mallet L, Le Merrer M, Munnich A, Vekemans M, Bonaventure J. 1998. Spatio-temporal expression of FGFR 1, 2 and 3 genes during human embryo-fetal ossification. Mech Dev 77: 19-30.
50. 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.
51. Di Maggio N, Mehrkens A, Papadimitropoulos A, Schaeren S, Heberer M, Banfi A, Martin I. 2012. Fibroblast growth factor2 maintains a niche-dependent population of self-renewing highly potent non-adherent mesenchymal progenitors through FGFR2c. Stem Cells 30: 1455-1464.
52. Dirckx N, Van Hul M, Maes C. 2013. Osteoblast recruitment to sites of bone formation in skeletal development, homeostasis, and regeneration. Birth Defects Res C Embryo Today 99: 170-191.
53. Di Rocco F, Biosse Duplan M, Heuze Y, Kaci N, Komla-Ebri D, Munnich A, Mugniery E, Benoist-Lasselin C, Legeai-Mallet L. 2014. FGFR3 mutation causes abnormal membranous ossification in achondroplasia. Hum Mol Genet 23: 2914-2925.
54. Du X, Xie Y, Xian CJ, Chen L. 2012. Role of FGFs/FGFRs in skeletal development and bone regeneration. J Cell Physiol 227: 3731-3743.
55. 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.
56. Dy P, Wang W, Bhattaram P, Wang Q, Wang L, Ballock RT, Lefebvre V. 2012. Sox9 directs hypertrophic maturation and blocks osteoblast differentiation of growth plate chondrocytes. Dev Cell 22: 597-609.
57. 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 104: 3937-3942.
58. 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.
59. 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 101: 12555-12560.
60. Eswarakumar VP, Lax I, Schlessinger J. 2005. Cellular signaling by fibroblast growth factor receptors. Cytokine Growth Factor Rev 16: 139-149.
61. 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 103: 18603-18608.
62. Fakhry A, Ratisoontorn C, Vedhachalam C, Salhab I, Koyama E, Leboy P, Pacifici M, Kirschner RE, Nah HD. 2005. Effects of FGF-2/-9 in calvarial bone cell cultures: differentiationstage-dependent mitogenic effect, inverse regulation of BMP-2 and noggin, and enhancement of osteogenic potential. Bone 36: 254-266.
63. Fei Y, Xiao L, Doetschman T, Coffin DJ, Hurley MM. 2011. Fibroblast growth factor 2 stimulation of osteoblast differentiation and bone formation is mediated by modulation of the Wnt signaling pathway. J Biol Chem 286: 40575-40583.
64. Fei Y, Gronowicz G, Hurley MM. 2013. Fibroblast growth factor2, bone homeostasis and fracture repair. Curr Pharm Des 19: 3354-3363.
65. Feng JQ, Clinkenbeard EL, Yuan B, White KE, Drezner MK. 2013. Osteocyte regulation of phosphate homeostasis and bone mineralization underlies the pathophysiology of the heritable disorders of rickets and osteomalacia. Bone 54: 213-221.
66. Foldynova-Trantirkova S, Wilcox WR, Krejci P. 2012. Sixteen years and counting: the current understanding of fibroblast growth factor receptor 3 (FGFR3) signaling in skeletal dysplasias. Hum Mutat 33: 29-41.
67. Ford-Hutchinson AF, Ali Z, Lines SE, Hallgrimsson B, Boyd SK, Jirik FR. 2007. Inactivation of Pten in osteo-chondroprogenitor cells leads to epiphyseal growth plate abnormalities and skeletal overgrowth. J Bone Miner Res 22: 1245-1259.
68. Fromigue O, Modrowski D, Marie PJ. 2004. Growth factors and bone formation in osteoporosis: roles for fibroblast growth factor and transforming growth factor β. Curr Pharm Des 10: 2593-2603.
69. Fromigue 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.
70. Furdui CM, Lew ED, Schlessinger J, Anderson KS. 2006. Autophosphorylation of FGFR1 kinase is mediated by a sequential and precisely ordered reaction. Mol Cell 21: 711-717.
71. Garcia S, Dirat B, Tognacci T, Rochet N, Mouska X, Bonnafous S, Patouraux S, Tran A, Gual P, Le Marchand-Brustel Y, et al. 2013. Postnatal soluble FGFR3 therapy rescues achondroplasia symptoms and restores bone growth in mice. Sci Transl Med 5: 203ra124.
72. Goetz R, Mohammadi M. 2013. Exploring mechanisms of FGF signalling through the lens of structural biology. Nat Rev Mol Cell Biol 14: 166-180.
73. Gonzalez AM, Hill DJ, Logan A, Maher PA, Baird A. 1996. Distribution of fibroblast growth factor (FGF)-2 and FGF receptor-1 messenger RNA expression and protein presence in the midtrimester human fetus. Pediatr Res 39: 375-385.
74. Goriely A, Wilkie AO. 2012. Paternal age effect mutations and selfish spermatogonial selection: causes and consequences for human disease. Am J Hum Genet 90: 175-200.
75. Goriely A, McVean GA, Rojmyr M, Ingemarsson B, Wilkie AO. 2003. Evidence for selective advantage of pathogenic FGFR2 mutations in the male germ line. Science 301: 643-646.
76. Goriely A, McVean GA, van Pelt AM, O’Rourke AW, Wall SA, de Rooij DG, Wilkie AO. 2005. Gain-of-function amino acid substitutions drive positive selection of FGFR2 mutations in human spermatogonia. Proc Natl Acad Sci 102: 6051-6056.
77. 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 SaethreChotzen syndrome. Hum Mol Genet 14: 1429-1439.
78. Hadari Y, Schlessinger J. 2009. FGFR3-targeted mAb therapy for bladder cancer and multiple myeloma. J Clin Invest 119: 1077-1079.
79. Hajihosseini MK. 2008. Fibroblast growth factor signaling in cranial suture development and pathogenesis. Front Oral Biol 12: 160-177.
80. Hall BK, Miyake T. 2000. All for one and one for all: condensations and the initiation of skeletal development. Bioessays 22: 138-147.
81. Hamada T, Suda N, Kuroda T. 1999. Immunohistochemical localization of fibroblast growth factor receptors in the rat mandibular condylar cartilage and tibial cartilage. J Bone Miner Metab 17: 274-282.
82. Hamidouche Z, Fromigue O, Nuber U, Vaudin P, Pages JC, Ebert R, Jakob F, Miraoui H, Marie PJ. 2010. Autocrine fibroblast growth factor 18 mediates dexamethasone-induced osteogenic differentiation of murine mesenchymal stem cells. J Cell Physiol 224: 509-515.
83. Han X, Xiao Z, Quarles LD. 2015. Membrane and integrative nuclear fibroblastic growth factor receptor (FGFR) regulation of FGF-23. J Biol Chem 290: 10447-10459.
84. Hanafusa H, Torii S, Yasunaga T, Nishida E. 2002. Sprouty1 and Sprouty2 provide a control mechanism for the Ras/MAPK signalling pathway. Nat Cell Biol 4: 850-858.
85. Hannema SE, van Duyvenvoorde HA, Premsler T, Yang RB, Mueller TD, Gassner B, Oberwinkler H, Roelfsema F, Santen GW, Prickett T, et al. 2013. An activating mutation in the kinase homology domain of the natriuretic peptide receptor-2 causes extremely tall stature without skeletal deformities. J Clin Endocrinol Metab 98: E1988-E1998.
86. Harada M, Murakami H, Okawa A, Okimoto N, Hiraoka S, Nakahara T, Akasaka R, Shiraishi Y, Futatsugi N, Mizutani-Koseki Y, et al. 2009. FGF9 monomer/dimer equilibrium regulates extracellular matrix affinity and tissue diffusion. Nat Genet 41: 289-298.
87. Hatch NE, Hudson M, Seto ML, Cunningham ML, Bothwell M. 2006. Intracellular retention, degradation, and signaling of glycosylation-deficient FGFR2 and craniosynostosis syndromeassociated FGFR2C278F. J Biol Chem 281: 27292-27305.
88. Haupt LM, Murali S, Mun FK, Teplyuk N, Mei LF, Stein GS, van Wijnen AJ, Nurcombe V, Cool SM. 2009. The heparan sulfate proteoglycan (HSPG) glypican-3 mediates commitment of MC3T3-E1 cells toward osteogenesis. J Cell Physiol 220: 780-791.
89. Havens BA, Velonis D, Kronenberg MS, Lichtler AC, Oliver B, Mina M. 2008. Roles of FGFR3 during morphogenesis of Meckel’s cartilage and mandibular bones. Dev Biol 316: 336-349.
90. Heuze Y, Singh N, Basilico C, Jabs EW, Holmes G, Richtsmeier JT. 2014. Morphological comparison of the craniofacial phenotypes of mouse models expressing the Apert FGFR2 S252W mutation in neural crestor mesoderm-derived tissues. Bone 63: 101-109.
91. Hinoi E, Bialek P, Chen YT, Rached MT, Groner Y, Behringer RR, Ornitz DM, Karsenty G. 2006. Runx2 inhibits chondrocyte proliferation and hypertrophy through its expression in the perichondrium. Genes Dev 20: 2937-2942.
92. Holmes G, Rothschild G, Roy UB, Deng CX, Mansukhani A, Basilico C. 2009. Early onset of craniosynostosis in an Apert mouse model reveals critical features of this pathology. Dev Biol 328: 273-284.
93. Homer-Bouthiette C, Doetschman T, Xiao L, Hurley MM. 2014. Knockout of nuclear high molecular weight FGF2 isoforms in mice modulates bone and phosphate homeostasis. J Biol Chem 289: 36303-36314.
94. Horton WA, Hall JG, Hecht JT. 2007. Achondroplasia. Lancet 370: 162-172.
95. House SL, Branch K, Newman G, Doetschman T, Schultz Jel J. 2005. Cardioprotection induced by cardiac-specific overexpression of fibroblast growth factor-2 is mediated by the MAPK cascade. Am J Physiol Heart Circ Physiol 289: H2167-H2175.
96. Hung IH, Yu K, Lavine KJ, Ornitz DM. 2007. FGF9 regulates early hypertrophic chondrocyte differentiation and skeletal vascularization in the developing stylopod. Dev Biol 307: 300-313.
97. Hunziker EB, Schenk RK. 1989. Physiological mechanisms adopted by chondrocytes in regulating longitudinal bone growth in rats. J Physiol 414: 55-71.
98. Hunziker EB, Schenk RK, Cruz-Orive LM. 1987. Quantitation of chondrocyte performance in growth-plate cartilage during longitudinal bone growth. J Bone Joint Surg Am 69: 162-173.
99. Hurley MM, Tetradis S, Huang YF, Hock J, Kream BE, Raisz LG, Sabbieti MG. 1999. Parathyroid hormone regulates the expression of fibroblast growth factor-2 mRNA and fibroblast growth factor receptor mRNA in osteoblastic cells. J Bone Miner Res 14: 776-783.
100. Hutchison MR. 2012. BDNF alters ERK/p38 MAPK activity ratios to promote differentiation in growth plate chondrocytes. Mol Endocrinol 26: 1406-1416.
101. 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 5: 5.
102. Ignelzi MA Jr, Wang W, Young AT. 2003. Fibroblast growth factors lead to increased Msx2 expression and fusion in calvarial sutures. J Bone Miner Res 18: 751-759.
103. Ikegami D, Akiyama H, Suzuki A, Nakamura T, Nakano T, Yoshikawa H, Tsumaki N. 2011. Sox9 sustains chondrocyte survival and hypertrophy in part through Pik3ca-Akt pathways. Development 138: 1507-1519.
104. Iwata T, Chen L, Li C, Ovchinnikov DA, Behringer RR, Francomano CA, Deng CX. 2000. A neonatal lethal mutation in FGFR3 uncouples proliferation and differentiation of growth plate chondrocytes in embryos. Hum Mol Genet 9: 1603-1613.
105. Iwata T, Li CL, Deng CX, Francomano CA. 2001. Highlyactivated Fgfr3 with the K644M mutation causes prolonged survival in severe dwarf mice. Hum Mol Genet 10: 1255-1264.
106. Jackson RA, Murali S, van Wijnen AJ, Stein GS, Nurcombe V, Cool SM. 2007. Heparan sulfate regulates the anabolic activity of MC3T3-E1 preosteoblast cells by induction of Runx2. J Cell Physiol 210: 38-50.
107. 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: 315-328.
108. Jeon E, Yun YR, Kang W, Lee S, Koh YH, Kim HW, Suh CK, Jang JH. 2012. Investigating the role of FGF18 in the cultivation and osteogenic differentiation of mesenchymal stem cells. PLoS One 7: e43982.
109. Johnson D, Wilkie AO. 2011. Craniosynostosis. Eur J Hum Genet 19: 369-376.
110. 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.
111. Kaabeche K, Guenou H, Bouvard D, Didelot N, Listrat A, Marie PJ. 2005. Cbl-mediated ubiquitination of α5 integrin subunit mediates fibronectin-dependent osteoblast detachment and apoptosis induced by FGFR2 activation. J Cell Sci 118: 1223-1232.
112. Kalinina J, Byron SA, Makarenkova HP, Olsen SK, Eliseenkova AV, Larochelle WJ, Dhanabal M, Blais S, Ornitz DM, Day LA, et al. 2009. Homodimerization controls the fibroblast growth factor 9 subfamily’s receptor binding and heparan sulfate-dependent diffusion in the extracellular matrix. Mol Cell Biol 29: 4663-4678.
113. Kanazawa H, Tanaka H, Inoue M, Yamanaka Y, Namba N, Seino Y. 2003. Efficacy of growth hormone therapy for patients with skeletal dysplasia. J Bone Miner Metab 21: 307-310.
114. Kanazawa S, Fujiwara T, Matsuzaki S, Shingaki K, Taniguchi M, Miyata S, Tohyama M, Sakai Y, Yano K, Hosokawa K, et al. 2010. bFGF regulates PI3-kinase-Rac1-JNK pathway and promotes fibroblast migration in wound healing. PLoS One 5: e12228.
115. Kant SG, Cervenkova I, Balek L, Trantirek L, Santen GW, de Vries MC, van Duyvenvoorde HA, van der Wielen MJ, Verkerk AJ, Uitterlinden AG, et al. 2015. A novel variant of FGFR3 causes proportionate short stature. Eur J Endocrinol 172: 763-770.
116. Karlsson C, Thornemo M, Henriksson HB, Lindahl A. 2009. Identification of a stem cell niche in the zone of Ranvier within the knee joint. J Anat 215: 355-363.
117. Karolak MR, Yang X, Elefteriou F. 2015. FGFR1 signaling in hypertrophic chondrocytes is attenuated by the Ras-GAP neurofibromin during endochondral bone formation. Hum Mol Genet 24: 2552-2564.
118. Kawaguchi H, Pilbeam CC, Gronowicz G, Abreu C, Fletcher BS, Herschman HR, Raisz LG, Hurley MM. 1995. Transcriptional induction of prostaglandin G/H synthase-2 by basic fibroblast growth factor. J Clin Invest 96: 923-930.
119. Kawaguchi H, Chikazu D, Nakamura K, Kumegawa M, Hakeda Y. 2000. Direct and indirect actions of fibroblast growth factor 2 on osteoclastic bone resorption in cultures. J Bone Miner Res 15: 466-473.
120. Kawaguchi H, Oka H, Jingushi S, Izumi T, Fukunaga M, Sato K, Matsushita T, Nakamura K. 2010. A local application of recombinant human fibroblast growth factor-2 for tibial shaft fractures: a randomized, placebo-controlled trial. J Bone Miner Res 25: 2735-2743.
121. Kim HJ, Rice DP, Kettunen PJ, Thesleff I. 1998. FGF-, BMPand Shh-mediated signalling pathways in the regulation of cranial suture morphogenesis and calvarial bone development. Development 125: 1241-1251.
122. Kim HJ, Kim JH, Bae SC, Choi JY, Kim HJ, Ryoo HM. 2003. The protein kinase C pathway plays a central role in the fibroblast growth factor-stimulated expression and transactivation activity of Runx2. J Biol Chem 278: 319-326.
123. Kim JM, Shin HI, Cha SS, Lee CS, Hong BS, Lim S, Jang HJ, Kim J, Yang YR, Kim YH, et al. 2012. DJ-1 promotes angiogenesis and osteogenesis by activating FGF receptor-1 signaling. Nat Commun 3: 1296.
124. Kodama N, Nagata M, Tabata Y, Ozeki M, Ninomiya T, Takagi R. 2009. A local bone anabolic effect of rhFGF2-impregnated gelatin hydrogel by promoting cell proliferation and coordinating osteoblastic differentiation. Bone 44: 699-707.
125. Kolupaeva V, Laplantine E, Basilico C. 2008. PP2A-mediated dephosphorylation of p107 plays a critical role in chondrocyte cell cycle arrest by FGF. PLoS One 3: e3447.
126. Kolupaeva V, Daempfling L, Basilico C. 2013. The B55α regulatory subunit of protein phosphatase 2A mediates fibroblast growth factor-induced p107 dephosphorylation and growth arrest in chondrocytes. Mol Cell Biol 33: 2865-2878.
127. Komaki H, Tanaka T, Chazono M, Kikuchi T. 2006. Repair of segmental bone defects in rabbit tibiae using a complex of β-tricalcium phosphate, type I collagen, and fibroblast growth factor-2. Biomaterials 27: 5118-5126.
128. Kosher RA, Kulyk WM, Gay SW. 1986. Collagen gene expression during limb cartilage differentiation. J Cell Biol 102: 1151-1156.
129. Kouhara H, Hadari YR, Spivak-Kroizman T, Schilling J, Bar-Sagi D, Lax I, Schlessinger J. 1997. A lipid-anchored Grb2-binding protein that links FGF-receptor activation to the Ras/MAPK signaling pathway. Cell 89: 693-702.
130. Kozhemyakina E, Lassar AB, Zelzer E. 2015. A pathway to bone: signaling molecules and transcription factors involved in chondrocyte development and maturation. Development 142: 817-831.
131. Krejci P. 2014. The paradox of FGFR3 signaling in skeletal dysplasia: why chondrocytes growth arrest while other cells over proliferate. Mutat Res Rev Mutat Res 759: 40-48.
132. Krejci P, Salazar L, Goodridge HS, Kashiwada TA, Schibler MJ, Jelinkova P, Thompson LM, Wilcox WR. 2008a. STAT1 and STAT3 do not participate in FGF-mediated growth arrest in chondrocytes. J Cell Sci 121: 272-281.
133. Krejci P, Salazar L, Kashiwada TA, Chlebova K, Salasova A, Thompson LM, Bryja V, Kozubik A, Wilcox WR. 2008b. Analysis of STAT1 activation by six FGFR3 mutants associated with skeletal dysplasia undermines dominant role of STAT1 in FGFR3 signaling in cartilage. PLoS One 3: e3961.
134. Krejci P, Aklian A, Kaucka M, Sevcikova E, Prochazkova J, Masek JK, Mikolka P, Pospisilova T, Spoustova T, Weis M, et al. 2012. Receptor tyrosine kinases activate canonical WNT/β-catenin signaling via MAP kinase/LRP6 pathway and direct β-catenin phosphorylation. PLoS One 7: e35826.
135. Kuhn LT, Ou G, Charles L, Hurley MM, Rodner CM, Gronowicz G. 2013. Fibroblast growth factor-2 and bone morphogenetic protein-2 have a synergistic stimulatory effect on bone formation in cell cultures from elderly mouse and human bone. J Gerontol A Biol Sci Med Sci 68: 1170-1180.
136. Kumar D, Lassar AB. 2014. Fibroblast growth factor maintains chondrogenic potential of limb bud mesenchymal cells by modulating DNMT3A recruitment. Cell Rep 8: 1419-1431.
137. Kurimchak A, Haines DS, Garriga J, Wu S, De Luca F, Sweredoski MJ, Deshaies RJ, Hess S, Grana X. 2013. Activation of p107 by fibroblast growth factor, which is essential for chondrocyte cell cycle exit, is mediated by the protein phosphatase 2A/B55α holoenzyme. Mol Cell Biol 33: 3330-3342.
138. Kuro-o M. 2008. Endocrine FGFs and Klothos: emerging concepts. Trends Endocrinol Metab 19: 239-245.
139. Kurosu H, Ogawa Y, Miyoshi M, Yamamoto M, Nandi A, Rosenblatt KP, Baum MG, Schiavi S, Hu MC, Moe OW, et al. 2006. Regulation of fibroblast growth factor-23 signaling by klotho. J Biol Chem 281: 6120-6123.
140. Kwan MD, Sellmyer MA, Quarto N, Ho AM, Wandless TJ, Longaker MT. 2011. Chemical control of FGF-2 release for promoting calvarial healing with adipose stem cells. J Biol Chem 286: 11307-11313.
141. Kyono A, Avishai N, Ouyang Z, Landreth GE, Murakami S. 2012. FGF and ERK signaling coordinately regulate mineralizationrelated genes and play essential roles in osteocyte differentiation. J Bone Miner Metab 30: 19-30.
142. Laederich MB, Horton WA. 2012. FGFR3 targeting strategies for achondroplasia. Expert Rev Mol Med 14: e11.
143. Lamothe B, Yamada M, Schaeper U, Birchmeier W, Lax I, Schlessinger J. 2004. 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.
144. 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.
145. Lazarus JE, Hegde A, Andrade AC, Nilsson O, Baron J. 2007. Fibroblast growth factor expression in the postnatal growth plate. Bone 40: 577-586.
146. Legeai-Mallet L, Benoist-Lasselin C, Delezoide AL, 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.
147. 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.
148. Lemmon MA, Schlessinger J. 2010. Cell signaling by receptor tyrosine kinases. Cell 141: 1117-1134.
149. Lemonnier J, Hay E, Delannoy P, Fromigue O, Lomri A, Modrowski D, Marie PJ. 2001a. Increased osteoblast apoptosis in apert craniosynostosis: role of protein kinase C and interleukin-1. Am J Pathol 158: 1833-1842.
150. Lemonnier J, Hay E, Delannoy P, Lomri A, Modrowski D, Caverzasio J, Marie PJ. 2001b. 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.
151. Lenton KA, Nacamuli RP, Wan DC, Helms JA, Longaker MT. 2005. Cranial suture biology. Curr Top Dev Biol 66: 287-328.
152. Li C, Xu X, Nelson DK, Williams T, Kuehn MR, Deng CX. 2005. FGFR1 function at the earliest stages of mouse limb development plays an indispensable role in subsequent autopod morphogenesis. Development 132: 4755-4764.
153. Li M, Seki Y, Freitas PH, Nagata M, Kojima T, Sultana S, Ubaidus S, Maeda T, Shimomura J, Henderson JE, et al. 2010. FGFR3 down-regulates PTH/PTHrP receptor gene expression by mediating JAK/STAT signaling in chondrocytic cell line. J Electron Microsc (Tokyo) 59: 227-236.
154. Li Y, Ahrens MJ, Wu A, Liu J, Dudley AT. 2011. Calcium/calmodulin-dependent protein kinase II activity regulates the proliferative potential of growth plate chondrocytes. Development 138: 359-370.
155. Lian JB, Stein GS, Javed A, van Wijnen AJ, Stein JL, Montecino M, Hassan MQ, Gaur T, Lengner CJ, Young DW. 2006. Networks and hubs for the transcriptional control of osteoblastogenesis. Rev Endocr Metab Disord 7: 1-16.
156. Liao E. 2013. FGF23 associated bone diseases. Front Med 7: 65-80.
157. Liao S, Porter D, Scott A, Newman G, Doetschman T, Schultz Jel J. 2007. The cardioprotective effect of the low molecular weight isoform of fibroblast growth factor-2: the role of JNK signaling. J Mol Cell Cardiol 42: 106-120.
158. Lim J, Tu X, Choi K, Akiyama H, Mishina Y, Long F. 2015. BMP-Smad4 signaling is required for precartilaginous mesenchymal condensation independent of Sox9 in the mouse. Dev Biol 400: 132-138.
159. Liu Y, Olsen BR. 2014. Distinct VEGF functions during bone development and homeostasis. Arch Immunol Ther Exp (Warsz) 62: 363-368.
160. Liu Z, Xu J, Colvin JS, Ornitz DM. 2002. Coordination of chondrogenesis and osteogenesis by fibroblast growth factor 18. Genes Dev 16: 859-869.
161. Liu Z, Lavine KJ, Hung IH, Ornitz DM. 2007. FGF18 is required for early chondrocyte proliferation, hypertrophy and vascular invasion of the growth plate. Dev Biol 302: 80-91.
162. Liu J, Kwon TG, Nam HK, Hatch NE. 2013a. Craniosynostosisassociated Fgfr2(C342Y) mutant bone marrow stromal cells exhibit cell autonomous abnormalities in osteoblast differentiation and bone formation. Biomed Res Int 2013: 292506.
163. Liu J, Nam HK, Wang E, Hatch NE. 2013b. Further analysis of the Crouzon mouse: effects of the FGFR2(C342Y) mutation are cranial bone-dependent. Calcif Tissue Int 92: 451-466.
164. Lomri A, Lemonnier J, Hott M, de Parseval 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.
165. Lomri A, Lemonnier J, Delannoy P, Marie PJ. 2001. Increased expression of protein kinase Cα, interleukin-1α, and RhoA guanosine 5′-triphosphatase in osteoblasts expressing the Ser252Trp fibroblast growth factor 2 Apert mutation: identification by analysis of complementary DNA microarray. J Bone Miner Res 16: 705-712.
166. Long F. 2012. Building strong bones: molecular regulation of the osteoblast lineage. Nat Rev Mol Cell Biol 13: 27-38.
167. Long F, Ornitz DM. 2013. Development of the endochondral skeleton. Cold Spring Harb Perspect Biol 5: 1-20.
168. Lorget F, Kaci N, Peng J, Benoist-Lasselin C, Mugniery E, Oppeneer T, Wendt DJ, Bell SM, Bullens S, Bunting S, et al. 2012. Evaluation of the therapeutic potential of a CNP analog in a Fgfr3 mouse model recapitulating achondroplasia. Am J Hum Genet 91: 1108-1114.
169. Lu X, Su N, Yang J, Huang W, Li C, Zhao L, He Q, Du X, Shen Y, Chen B, et al. 2009. Fibroblast growth factor receptor 1 regulates the differentiation and activation of osteoclasts through Erk1/2 pathway. Biochem Biophys Res Commun 390: 494-499.
170. Maes C, Kobayashi T, Selig MK, Torrekens S, Roth SI, Mackem S, Carmeliet G, Kronenberg HM. 2010. Osteoblast precursors, but not mature osteoblasts, move into developing and fractured bones along with invading blood vessels. Dev Cell 19: 329-344.
171. Makrythanasis P, Temtamy S, Aglan MS, Otaify GA, Hamamy H, Antonarakis SE. 2014. A novel homozygous mutation in FGFR3 causes tall stature, severe lateral tibial deviation, scoliosis, hearing impairment, camptodactyly, and arachnodactyly. Hum Mutat 35: 959-963.
172. 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 Biology 149: 1297-1308. 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.
173. Mariani FV, Ahn CP, Martin GR. 2008. Genetic evidence that FGFs have an instructive role in limb proximal-distal patterning. Nature 453: 401-405.
174. Marie PJ. 2008. Transcription factors controlling osteoblastogenesis. Arch Biochem Biophys 473: 98-105.
175. Marie PJ. 2015. Osteoblast dysfunctions in bone diseases: from cellular and molecular mechanisms to therapeutic strategies. Cell Mol Life Sci 72: 1347-1361.
176. Marie PJ, Coffin JD, Hurley MM. 2005. FGF and FGFR signaling in chondrodysplasias and craniosynostosis. J Cell Biochem 96: 888-896.
177. 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.
178. Martin A, Liu S, David V, Li H, Karydis A, Feng JQ, Quarles LD. 2011. Bone proteins PHEX and DMP1 regulate fibroblastic growth factor Fgf23 expression in osteocytes through a common pathway involving FGF receptor (FGFR) signaling. FASEB J 25: 2551-2562.
179. Martinez-Torrecuadrada J, Cifuentes G, Lopez-Serra P, Saenz P, Martinez A, Casal JI. 2005. Targeting the extracellular domain of fibroblast growth factor receptor 3 with human single-chain Fv antibodies inhibits bladder carcinoma cell line proliferation. Clin Cancer Res 11: 6280-6290.
180. Maruyama T, Mirando AJ, Deng CX, Hsu W. 2010. The balance of WNT and FGF signaling influences mesenchymal stem cell fate during skeletal development. Sci Signal 3: ra40.
181. Matsushita T, Chan YY, Kawanami A, Balmes G, Landreth GE, Murakami S. 2009a. Extracellular signal-regulated kinase 1 (ERK1) and ERK2 play essential roles in osteoblast differentiation and in supporting osteoclastogenesis. Mol Cell Biol 29: 5843-5857.
182. Matsushita T, Wilcox WR, Chan YY, Kawanami A, Bukulmez H, Balmes G, Krejci P, Mekikian PB, Otani K, Yamaura I, et al. 2009b. FGFR3 promotes synchondrosis closure and fusion of ossification centers through the MAPK pathway. Hum Mol Genet 18: 227-240.
183. Matsushita M, Kitoh H, Ohkawara B, Mishima K, Kaneko H, Ito M, Masuda A, Ishiguro N, Ohno K. 2013. Meclozine facilitates proliferation and differentiation of chondrocytes by attenuating abnormally activated FGFR3 signaling in achondroplasia. PLoS One 8: e81569.
184. Matsushita M, Hasegawa S, Kitoh H, Mori K, Ohkawara B, Yasoda A, Masuda A, Ishiguro N, Ohno K. 2015. Meclozine promotes longitudinal skeletal growth in transgenic mice with achondroplasia carrying a gain-of-function mutation in the FGFR3 gene. Endocrinology 156: 548-554.
185. McDowell LM, Frazier BA, Studelska DR, Giljum K, Chen J, Liu J, Yu K, Ornitz DM, Zhang L. 2006. Inhibition or activation of Apert syndrome FGFR2 (S252W) signaling by specific glycosaminoglycans. J Biol Chem 281: 6924-6930.
186. McEwen DG, Green RP, Naski MC, Towler DA, Ornitz DM. 1999. Fibroblast growth factor receptor 3 gene transcription is suppressed by cyclic adenosine 3′,5′-monophosphate: identification of a chondrocytic regulatory element. J Biol Chem 274: 30934-30942.
187. Melville H, Wang Y, Taub PJ, Jabs EW. 2010. Genetic basis of potential therapeutic strategies for craniosynostosis. Am J Med Genet A 152A: 3007-3015.
188. Merrill AE, Sarukhanov A, Krejci P, Idoni B, Camacho N, Estrada KD, Lyons KM, Deixler H, Robinson H, Chitayat D, et al. 2012. Bent bone dysplasia-FGFR2 type, a distinct skeletal disorder, has deficient canonical FGF signaling. Am J Hum Genet 90: 550-557.
189. Miraoui H, Marie PJ. 2010. Fibroblast growth factor receptor signaling crosstalk in skeletogenesis. Sci Signal 3: re9.
190. Miraoui H, Oudina K, Petite H, Tanimoto Y, Moriyama K, Marie PJ. 2009. Fibroblast growth factor receptor 2 promotes osteogenic differentiation in mesenchymal cells via ERK1/2 and protein kinase C signaling. J Biol Chem 284: 4897-4904.
191. Miraoui H, Ringe J, Haupl T, Marie PJ. 2010a. Increased EGFand PDGFα-receptor signaling by mutant FGF-receptor 2 contributes to osteoblast dysfunction in Apert craniosynostosis. Hum Mol Genet 19: 1678-1689.
192. Miraoui H, Severe N, Vaudin P, Pages JC, Marie PJ. 2010b. Molecular silencing of Twist1enhances osteogenic differentiation of murine mesenchymal stem cells: implication of FGFR2 signaling. J Cell Biochem 110: 1147-1154.
193. Miura K, Kim OH, Lee HR, Namba N, Michigami T, Yoo WJ, Choi IH, Ozono K, Cho TJ. 2014. Overgrowth syndrome associated with a gain-of-function mutation of the natriuretic peptide receptor 2 (NPR2) gene. Am J Med Genet A 164A: 156-163.
194. Moenning A, Jager R, Egert A, Kress W, Wardelmann E, Schorle H. 2009. Sustained platelet-derived growth factor receptor α signaling in osteoblasts results in craniosynostosis by overactivating the phospholipase C-γ pathway. Mol Cell Biol 29: 881-891.
195. Molteni A, Modrowski D, Hott M, Marie PJ. 1999a. Alterations of matrix-and cell-associated proteoglycans inhibit osteogenesis and growth response to fibroblast growth factor-2 in cultured rat mandibular condyle and calvaria. Cell Tissue Res 295: 523-536.
196. Molteni A, Modrowski D, Hott M, Marie PJ. 1999b. 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.
197. 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.
198. Moon AM, Guris DL, Seo JH, Li L, Hammond J, Talbot A, Imamoto A. 2006. Crkl deficiency disrupts Fgf8 signaling in a mouse model of 22q11 deletion syndromes. Dev Cell 10: 71-80.
199. Moore R, Ferretti P, Copp A, Thorogood P. 2002. Blocking endogenous FGF-2 activity prevents cranial osteogenesis. Dev Biol 243: 99-114.
200. Morita J, Nakamura M, Kobayashi Y, Deng CX, Funato N, Moriyama K. 2014. Soluble form of FGFR2 with S252W partially prevents craniosynostosis of the apert mouse model. Dev Dyn 243: 560-567.
201. Motch Perrine SM, Cole TM III, Martinez-Abadias N, Aldridge K, Jabs EW, Richtsmeier JT. 2014. Craniofacial divergence by distinct prenatal growth patterns in Fgfr2 mutant mice. BMC Dev Biol 14: 8.
202. Mugniery E, Dacquin R, Marty C, Benoist-Lasselin C, de Vernejoul MC, Jurdic P, Munnich A, Geoffroy V, Legeai-Mallet L. 2012. An activating Fgfr3 mutation affects trabecular bone formation via a paracrine mechanism during growth. Hum Mol Genet 21: 2503-2513.
203. Murakami S, Kan M, McKeehan WL, de Crombrugghe B. 2000. Up-regulation of the chondrogenic Sox9 gene by fibroblast growth factors is mediated by the mitogen-activated protein kinase pathway. Proc Natl Acad Sci 97: 1113-1118.
204. Murakami S, Balmes G, McKinney S, Zhang Z, Givol D, De Crombrugghe B. 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.
205. Naganawa T, Xiao L, Coffin JD, Doetschman T, Sabbieti MG, Agas D, Hurley MM. 2008. Reduced expression and function of bone morphogenetic protein-2 in bones of Fgf2 null mice. J Cell Biochem 103: 1975-1988.
206. Nah HD, Rodgers BJ, Kulyk WM, Kream BE, Kosher RA, Upholt WB. 1988. In situ hybridization analysis of the expression of the type II collagen gene in the developing chicken limb bud. Coll Relat Res 8: 277-294.
207. Nakajima F, Nakajima A, Ogasawara A, Moriya H, Yamazaki M. 2007. Effects of a single percutaneous injection of basic fibroblast growth factor on the healing of a closed femoral shaft fracture in the rat. Calcif Tissue Int 81: 132-138.
208. Nakamura T, Hara Y, Tagawa M, Tamura M, Yuge T, Fukuda H, Nigi H. 1998. Recombinant human basic fibroblast growth factor accelerates fracture healing by enhancing callus remodeling in experimental dog tibial fracture. J Bone Miner Res 13: 942-949.
209. Nakamura Y, Tensho K, Nakaya H, Nawata M, Okabe T, Wakitani S. 2005. Low dose fibroblast growth factor-2 (FGF-2) enhances bone morphogenetic protein-2 (BMP-2)-induced ectopic bone formation in mice. Bone 36: 399-407.
210. Nakao K, Osawa K, Yasoda A, Yamanaka S, Fujii T, Kondo E, Koyama N, Kanamoto N, Miura M, Kuwahara K, et al. 2015. The Local CNP/GC-B system in growth plate is responsible for physiological endochondral bone growth. Sci Rep 5: 10554.
211. 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.
212. 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.
213. Neben CL, Idoni B, Salva JE, Tuzon CT, Rice JC, Krakow D, Merrill AE. 2014. Bent bone dysplasia syndrome reveals nucleolar activity for FGFR2 in ribosomal DNA transcription. Hum Mol Genet 23: 5659-5671.
214. Niger C, Luciotti MA, Buo AM, Hebert C, Ma V, Stains JP. 2013. The regulation of runt-related transcription factor 2 by fibroblast growth factor-2 and connexin43 requires the inositol polyphosphate/protein kinase Cδ cascade. J Bone Miner Res 28: 1468-1477.
215. Noonan KJ, Hunziker EB, Nessler J, Buckwalter JA. 1998. Changes in cell, matrix compartment, and fibrillar collagen volumes between growth-plate zones. J Orthop Res 16: 500-508.
216. Oh CD, Lu Y, Liang S, Mori-Akiyama Y, Chen D, de Crombrugghe B, Yasuda H. 2014. SOX9 regulates multiple genes in chondrocytes, including genes encoding ECM proteins, ECM modification enzymes, receptors, and transporters. PLoS One 9: e107577.
217. Ohbayashi N, Shibayama M, Kurotaki Y, Imanishi M, Fujimori T, Itoh N, Takada S. 2002. FGF18 is required for normal cell proliferation and differentiation during osteogenesis and chondrogenesis. Genes Dev 16: 870-879.
218. Okada Y, Montero A, Zhang X, Sobue T, Lorenzo J, Doetschman T, Coffin JD, Hurley MM. 2003. Impaired osteoclast formation in bone marrow cultures of Fgf2 null mice in response to parathyroid hormone. J Biol Chem 278: 21258-21266.
219. Olney RC, Prickett TC, Espiner EA, Mackenzie WG, Duker AL, Ditro C, Zabel B, Hasegawa T, Kitoh H, Aylsworth AS, et al. 2015. C-type natriuretic peptide plasma levels are elevated in subjects with achondroplasia, hypochondroplasia, and thanatophoric dysplasia. J Clin Endocrinol Metab 100: E355-E359.
220. Ono N, Ono W, Nagasawa T, Kronenberg HM. 2014. A subset of chondrogenic cells provides early mesenchymal progenitors in growing bones. Nat Cell Biol 16: 1157-1167.
221. Opperman LA. 2000. Cranial sutures as intramembranous bone growth sites [Review]. Dev Dyn 219: 472-485.
222. Ornitz DM. 2005. FGF signaling in the developing endochondral skeleton. Cytokine Growth Factor Rev 16: 205-213.
223. Ornitz DM, Itoh N. 2015. The Fibroblast Growth Factor signaling pathway. Wiley Interdiscip Rev Dev Biol 4: 215-266.
224. Ornitz DM, Marie PJ. 2002. FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease. Genes Dev 16: 1446-1465.
225. Orr-Urtreger A, Givol D, Yayon A, Yarden Y, Lonai P. 1991. Developmental expression of two murine fibroblast growth factor receptors, flg and bek. Development 113: 1419-1434.
226. Ozasa A, Komatsu Y, Yasoda A, Miura M, Sakuma Y, Nakatsuru Y, Arai H, Itoh N, Nakao K. 2005. Complementary antagonistic actions between C-type natriuretic peptide and the MAPK pathway through FGFR-3 in ATDC5 cells. Bone 36: 1056-1064.
227. Pannier S, Couloigner V, Messaddeq N, Elmaleh-Berges M, Munnich A, Romand R, Legeai-Mallet L. 2009. Activating Fgfr3 Y367C mutation causes hearing loss and inner ear defect in a mouse model of chondrodysplasia. Biochim Biophys Acta 1792: 140-147.
228. Park OJ, Kim HJ, Woo KM, Baek JH, Ryoo HM. 2010. FGF2-activated ERK mitogen-activated protein kinase enhances Runx2 acetylation and stabilization. J Biol Chem 285: 3568-3574.
229. Peake NJ, Hobbs AJ, Pingguan-Murphy B, Salter DM, Berenbaum F, Chowdhury TT. 2014. Role of C-type natriuretic peptide signalling in maintaining cartilage and bone function. Osteo-arthritis Cartilage 22: 1800-1807.
230. Perlyn CA, Morriss-Kay G, Darvann T, Tenenbaum M, Ornitz DM. 2006. A model for the pharmacological treatment of crouzon syndrome. Neurosurgery 59: 210-215.
231. Peters KG, Werner S, Chen G, Williams LT. 1992. Two FGF receptor genes are differentially expressed in epithelial and mesen-chymal tissues during limb formation and organogenesis in the mouse. Development 114: 233-243.
232. Peters K, Ornitz D, Werner S, Williams L. 1993. Unique expression pattern of the FGF receptor 3 gene during mouse organogenesis. Dev Biol 155: 423-430.
233. Priore R, Dailey L, Basilico C. 2006. Downregulation of Akt activity contributes to the growth arrest induced by FGF in chondrocytes. J Cell Physiol 207: 800-808.
234. Purcell P, Joo BW, Hu JK, Tran PV, Calicchio ML, O’Connell DJ, Maas RL, Tabin CJ. 2009. Temporomandibular joint formation requires two distinct hedgehog-dependent steps. Proc Natl Acad Sci 106: 18297-18302.
235. Qi H, Jin M, Duan Y, Du X, Zhang Y, Ren F, Wang Y, Tian Q, Wang X, Wang Q, et al. 2014. FGFR3 induces degradation of BMP type I receptor to regulate skeletal development. Biochim Biophys Acta 1843: 1237-1247.
236. Qing J, Du X, Chen Y, Chan P, Li H, Wu P, Marsters S, Stawicki S, Tien J, Totpal K, et al. 2009. Antibody-based targeting of FGFR3 in bladder carcinoma and t(4;14)-positive multiple myeloma in mice. J Clin Invest 119: 1216-1229.
237. Quarles LD. 2012. Skeletal secretion of FGF-23 regulates phosphate and vitamin D metabolism. Nat Rev Endocrinol 8: 276-286.
238. Quarto N, Behr B, Li S, Longaker MT. 2009. Differential FGF ligands and FGF receptors expression pattern in frontal and parietal calvarial bones. Cells Tissues Organs 190: 158-169.
239. 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.
240. Reinhold MI, Naski MC. 2007. Direct interactions of Runx2 and canonical Wnt signaling induce FGF18. J Biol Chem 282: 3653-3663.
241. 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.
242. 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.
243. Rice DP, Kim HJ, Thesleff I. 1999. Apoptosis in murine calvarial bone and suture development. Eur J Oral Sci 107: 265-275.
244. Rice DP, Aberg T, Chan Y, Tang Z, Kettunen PJ, Pakarinen L, Maxson RE, Thesleff I. 2000. Integration of FGF and TWIST in calvarial bone and suture development. Development 127: 1845-1855.
245. Rice DP, Rice R, Thesleff I. 2003. Fgfr mRNA isoforms in craniofacial bone development. Bone 33: 14-27.
246. Robinson D, Hasharoni A, Cohen N, Yayon A, Moskowitz RM, Nevo Z. 1999. Fibroblast growth factor receptor-3 as a marker for precartilaginous stem cells. Clin Orthop Relat Res: S163-S175.
247. Sabbieti MG, Agas D, Xiao L, Marchetti L, Coffin JD, Doetschman T, Hurley MM. 2009. Endogenous FGF-2 is critically important in PTH anabolic effects on bone. J Cell Physiol 219: 143-151.
248. Sabbieti MG, Agas D, Marchetti L, Coffin JD, Xiao L, Hurley MM. 2013. BMP-2 differentially modulates FGF-2 isoform effects in osteoblasts from newborn transgenic mice. Endocrinology 154: 2723-2733.
249. 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.
250. Saran U, Gemini Piperni S, Chatterjee S. 2014. Role of angiogenesis in bone repair. Arch Biochem Biophys 561: 109-117. Schlessinger J. 2000. Cell signaling by receptor tyrosine kinases. Cell 103: 211-225.
251. Schlessinger J. 2003. Signal transduction. Autoinhibition control. Science 300: 750-752.
252. Schmidt MH, Dikic I. 2005. The Cbl interactome and its functions. Nat Rev Mol Cell Biol 6: 907-918.
253. Schmid GJ, Kobayashi C, Sandell LJ, Ornitz DM. 2009. Fibroblast growth factor expression during skeletal fracture healing in mice. Dev Dyn 238: 766-774.
254. Sebastian A, Matsushita T, Kawanami A, Mackem S, Landreth GE, Murakami S. 2011. Genetic inactivation of ERK1 and ERK2 in chondrocytes promotes bone growth and enlarges the spinal canal. J Orthop Res 29: 375-379.
255. Senarath-Yapa K, Chung MT, McArdle A, Wong VW, Quarto N, Longaker MT, Wan DC. 2012. Craniosynostosis: molecular pathways and future pharmacologic therapy. Organogenesis 8: 103-113.
256. Severe N, Dieudonne FX, Marie PJ. 2013. E3 ubiquitin ligase-mediated regulation of bone formation and tumorigenesis. Cell Death Dis 4: e463.
257. Sheeba CJ, Andrade RP, Duprez D, Palmeirim I. 2010. Comprehensive analysis of fibroblast growth factor receptor expression patterns during chick forelimb development. Int J Dev Biol 54: 1517-1526.
258. Shiang R, Thompson LM, Zhu YZ, Church DM, Fielder TJ, Bocian M, Winokur ST, Wasmuth JJ. 1994. Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Cell 78: 335-342.
259. 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 FGF10. J Biol Chem 277: 7493-7500.
260. Shimokawa K, Kimura-Yoshida C, Nagai N, Mukai K, Matsubara K, Watanabe H, Matsuda Y, Mochida K, Matsuo I. 2011. Cell surface heparan sulfate chains regulate local reception of FGF signaling in the mouse embryo. Dev Cell 21: 257-272.
261. Shinde DN, Elmer DP, Calabrese P, Boulanger J, Arnheim N, Tiemann-Boege I. 2013. Newevidence for positive selection helps explain the paternal age effect observed in achondroplasia. Hum Mol Genet 22: 4117-4126.
262. 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.
263. Shung CY, Ota S, Zhou ZQ, Keene DR, Hurlin PJ. 2012. Disruption of a Sox9-β-catenin circuit by mutant Fgfr3 in thanatophoric dysplasia type II. Hum Mol Genet 21: 4628-4644.
264. Smith LB, Dally MR, Sainz RD, Rodrigue KL, Oberbauer AM. 2006. Enhanced skeletal growth of sheep heterozygous for an inactivated fibroblast growth factor receptor 3. J Anim Sci 84: 2942-2949.
265. Smith BN, Burton LJ, Henderson V, Randle DD, Morton DJ, Smith BA, Taliaferro-Smith L, Nagappan P, Yates C, Zayzafoon M, et al. 2014. Snail promotes epithelial mesenchymal transition in breast cancer cells in part via activation of nuclear ERK2. PLoS One 9: e104987.
266. 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.
267. Su N, Sun Q, Li C, Lu X, Qi H, Chen S, Yang J, Du X, Zhao L, He Q, et al. 2010. Gain-of-function mutation in FGFR3 in mice leads to decreased bone mass by affecting both osteoblastogenesis and osteoclastogenesis. Hum Mol Genet 19: 1199-1210.
268. Suzuki H, Suda N, Shiga M, Kobayashi Y, Nakamura M, Iseki S, Moriyama K. 2012. Apert syndrome mutant FGFR2 and its soluble form reciprocally alter osteogenesis of primary calvarial osteoblasts. J Cell Physiol 227: 3267-3277.
269. Szebenyi G, Savage MP, Olwin BB, Fallon JF. 1995. Changes in the expression of fibroblast growth factor receptors mark distinct stages of chondrogenesis in vitro and during chick limb skeletal patterning. Dev Dyn 204: 446-456.
270. Takai S, Tokuda H, Hanai Y, Harada A, Yasuda E, Matsushima-Nishiwaki R, Kato H, Ogura S, Ohta T, Kozawa O. 2007. Negative regulation by p70 S6 kinase of FGF-2-stimulated VEGF release through stress-activated protein kinase/c-Jun N-terminal kinase in osteoblasts. J Bone Miner Res 22: 337-346.
271. Tan Y, Rouse J, Zhang A, Cariati S, Cohen P, Comb MJ. 1996. FGF and stress regulate CREB and ATF-1 via a pathway involving p38 MAP kinase and MAPKAP kinase-2. EMBO J 15: 4629-4642.
272. 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.
273. Tavormina PL, Shiang R, Thompson LM, Zhu YZ, 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.
274. Tavormina PL, Bellus GA, Webster MK, Bamshad MJ, Fraley AE, McIntosh I, Szabo J, Jiang W, Jabs EW, Wilcox WR, et al. 1999. A novel skeletal dysplasiawith developmental delay and acanthosis nigricans is caused by a Lys650Met mutation in the fibroblast growth factor receptor 3 gene. Am J Hum Genet 64: 722-731.
275. Ten Berge D, Brugmann SA, Helms JA, Nusse R. 2008. Wnt and FGF signals interact to coordinate growth with cell fate specification during limb development. Development 135: 3247-3257.
276. Teplyuk NM, Haupt LM, Ling L, Dombrowski C, Mun FK, Nathan SS, Lian JB, Stein JL, Stein GS, Cool SM, et al. 2009. The osteogenic transcription factor Runx2 regulates components of the fibroblast growth factor/proteoglycan signaling axis in osteoblasts. J Cell Biochem 107: 144-154.
277. Timsah Z, Ahmed Z, Lin CC, Melo FA, Stagg LJ, Leonard PG, Jeyabal P, Berrout J, O’Neil RG, Bogdanov M, et al. 2014. Competition between Grb2 and Plcγ1 for FGFR2 regulates basal phospholipase activity and invasion. Nat Struct Mol Biol 21: 180-188.
278. Torii S, Kusakabe M, Yamamoto T, Maekawa M, Nishida E. 2004. Sef is a spatial regulator for Ras/MAP kinase signaling. Dev Cell 7: 33-44.
279. Toydemir RM, Brassington AE, Bayrak-Toydemir P, Krakowiak PA, Jorde LB, Whitby FG, Longo N, Viskochil DH, Carey JC, Bamshad MJ. 2006. A novel mutation in FGFR3 causes camptodactyly, tall stature, and hearing loss (CATSHL) syndrome. Am J Hum Genet 79: 935-941.
280. Tsang M, Dawid IB. 2004. Promotion and attenuation of FGF signaling through the Ras-MAPK pathway. Sci STKE 2004: pe17. Tsuji T, Kunieda T. 2005. A loss-of-function mutation in natriuretic peptide receptor 2 (Npr2) gene is responsible for disproportionate dwarfism in cn/cn mouse. J Biol Chem 280: 14288-14292.
281. Twigg SR, Healy C, Babbs C, Sharpe JA, Wood WG, Sharpe PT, Morriss-Kay GM, Wilkie AO. 2009. Skeletal analysis of the Fgfr3(P244R) mouse, a genetic model for the Muenke craniosynostosis syndrome. Dev Dyn 238: 331-342.
282. Twigg SR, Vorgia E, McGowan SJ, Peraki I, Fenwick AL, Sharma VP, Allegra M, Zaragkoulias A, Sadighi Akha E, Knight SJ, et al. 2013. Reduced dosage of ERF causes complex craniosynostosis in humans and mice and links ERK1/2 signaling to regulation of osteogenesis. Nat Genet 45: 308-313.
283. Urakawa I, Yamazaki Y, Shimada T, Iijima K, Hasegawa H, Okawa K, Fujita T, Fukumoto S, Yamashita T. 2006. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 444: 770-774.
284. Vajo Z, Francomano CA, Wilkin DJ. 2000. The molecular and genetic basis of fibroblast growth factor receptor 3 disorders: the achondroplasia family of skeletal dysplasias, Muenke craniosynostosis, and Crouzon syndrome with acanthosis nigricans. Endocr Rev 21: 23-39.
285. Valverde-Franco G, Liu H, Davidson D, Chai S, Valderrama-Carvajal H, Goltzman D, Ornitz DM, Henderson JE. 2004. Defective bone mineralization and osteopenia in young adult FGFR3−/− mice. Hum Mol Genet 13: 271-284.
286. Verheyden JM, Lewandoski M, Deng C, Harfe BD, Sun X. 2005. Conditional inactivation of Fgfr1 in mouse defines its role in limb bud establishment, outgrowth and digit patterning. Development 132: 4235-4245.
287. Wang Y, 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 96: 4455-4460.
288. 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 128: 3867-3876.
289. Wang Y, Xiao R, Yang F, Karim BO, Iacovelli AJ, Cai J, Lerner CP, Richtsmeier JT, Leszl JM, Hill CA, et al. 2005. Abnormalities in cartilage and bone development in the Apert syndrome FGFR2(+/S252W) mouse. Development 132: 3537-3548.
290. Wang Y, Sun M, Uhlhorn VL, Zhou X, Peter I, Martinez-Abadias N, Hill CA, Percival CJ, Richtsmeier JT, Huso DL, et al. 2010. Activation of p38 MAPK pathway in the skull abnormalities of Apert syndrome Fgfr2(+P253R) mice. BMC Dev Biol 10: 22.
291. Wang W, Nyman JS, Ono K, Stevenson DA, Yang X, Elefteriou F. 2011. Mice lacking Nf1 in osteochondroprogenitor cells display skeletal dysplasia similar to patients with neurofibromatosis type I. Hum Mol Genet 20: 3910-3924.
292. Warren SM, Brunet LJ, Harland RM, Economides AN, Longaker MT. 2003. The BMP antagonist noggin regulates cranial suture fusion. Nature 422: 625-629.
293. Wendt DJ, Dvorak-Ewell M, Bullens S, Lorget F, Bell SM, Peng J, Castillo S, Aoyagi-Scharber M, O’Neill CA, Krejci P, et al. 2015. Neutral endopeptidase-resistant C-type natriuretic peptide variant represents a new therapeutic approach for treatment of fibroblast growth factor receptor 3-related dwarfism. J Pharmacol Exp Ther 353: 132-149.
294. Weng T, Yi L, Huang J, Luo F, Wen X, Du X, Chen Q, Deng C, Chen D, Chen L. 2012. Genetic inhibition of FGFR1 in cartilage attenuates articular cartilage degeneration in adult mice. Arthritis Rheum 64: 3982-3992.
295. White KE, Cabral JM, Davis SI, Fishburn T, Evans WE, Ichikawa S, Fields J, Yu X, Shaw NJ, McLellan NJ, et al. 2005. Mutations that cause osteoglophonic dysplasia define novel roles for FGFR1 in bone elongation. Am J Hum Genet 76: 361-367.
296. White KE, Hum JM, Econs MJ. 2014. Hypophosphatemic rickets: revealing novel control points for phosphate homeostasis. Curr Osteoporos Rep 12: 252-262.
297. Wiedemann M, Trueb B. 2000. Characterization of a novel protein (FGFRL1) from human cartilage related to FGF receptors. Genomics 69: 275-279.
298. Wilkie AO. 2007. Cancer drugs to treat birth defects. Nat Genet 39: 1057-1059.
299. Wilkin DJ, Szabo JK, Cameron R, Henderson S, Bellus GA, Mack ML, Kaitila I, Loughlin J, Munnich A, Sykes B, et al. 1998. Mutations in fibroblast growth-factor receptor 3 in sporadic cases of achondroplasia occur exclusively on the paternally derived chromosome. Am J Hum Genet 63: 711-716.
300. Wohrle S, Henninger C, Bonny O, Thuery A, Beluch N, Hynes NE, Guagnano V, Sellers WR, Hofmann F, Kneissel M, et al. 2013. Pharmacological inhibition of fibroblast growth factor (FGF) receptor signaling ameliorates FGF23-mediated hypophosphatemic rickets. J Bone Miner Res 28: 899-911.
301. Wong A, Lamothe B, Lee A, Schlessinger J, Lax I. 2002. FRS2α attenuates FGF receptor signaling by Grb2-mediated recruitment of the ubiquitin ligase Cbl. Proc Natl Acad Sci 99: 6684-6689.
302. Wu ZL, Zhang L, Yabe T, Kuberan B, Beeler DL, Love A, Rosenberg RD. 2003. The involvement of heparan sulfate (HS) in FGF1/HS/FGFR1 signaling complex. J Biol Chem 278: 17121-17129.
303. Wu XL, Gu MM, Huang L, Liu XS, Zhang HX, Ding XY, Xu JQ, Cui B, Wang L, Lu SY, et al. 2009. Multiple synostoses syndrome is due to a missense mutation in exon 2 of FGF9 gene. Am J Hum Genet 85: 53-63.
304. Wu AL, Feng B, Chen MZ, Kolumam G, Zavala-Solorio J, Wyatt SK, Gandham VD, Carano RA, Sonoda J. 2013. Antibody-mediated activation of FGFR1 induces FGF23 production and hypophosphatemia. PLoS One 8: e57322.
305. Xiao G, Jiang D, Gopalakrishnan R, Franceschi RT. 2002. Fibroblast growth factor 2 induction of the osteocalcin gene requires MAPK activity and phosphorylation of the osteoblast transcription factor, Cbfa1/Runx2. J Biol Chem 277: 36181-36187.
306. Xiao L, Naganawa T, Obugunde E, Gronowicz G, Ornitz DM, Coffin JD, Hurley MM. 2004. Stat1 controls postnatal bone formation by regulating fibroblast growth factor signaling in osteoblasts. J Biol Chem 279: 27743-27752.
307. Xiao L, Liu P, Li X, Doetschman T, Coffin JD, Drissi H, Hurley MM. 2009. Exported 18-kDa isoform of fibroblast growth factor-2 is a critical determinant of bone mass in mice. J Biol Chem 284: 3170-3182.
308. Xiao L, Sobue T, Esliger A, Kronenberg MS, Coffin JD, Doetschman T, Hurley MM. 2010. Disruption of the Fgf2 gene activates the adipogenic and suppresses the osteogenic program in mesenchymal marrow stromal stem cells. Bone 47: 360-370.
309. Xiao L, Esliger A, Hurley MM. 2013. Nuclear fibroblast growth factor 2 (FGF2) isoforms inhibit bone marrow stromal cell mineralization through FGF23/FGFR/MAPK in vitro. J Bone Miner Res 28: 35-45.
310. Xiao Z, Huang J, Cao L, Liang Y, Han X, Quarles LD. 2014. Osteocyte-specific deletion of Fgfr1 suppresses FGF23. PLoS One 9: e104154.
311. Xie Y, Su N, Jin M, Qi H, Yang J, Li C, Du X, Luo F, Chen B, Shen Y, et al. 2012. Intermittent PTH (1-34) injection rescues the retarded skeletal development and postnatal lethality of mice mimicking human achondroplasia and thanatophoric dysplasia. Hum Mol Genet 21: 3941-3955.
312. Xu D, Esko JD. 2014. Demystifying heparan sulfate-protein interactions. Annu Rev Biochem 83: 129-157.
313. Yamashita A, Morioka M, Kishi H, Kimura T, Yahara Y, Okada M, Fujita K, Sawai H, Ikegawa S, Tsumaki N. 2014. Statin treatment rescues FGFR3 skeletal dysplasia phenotypes. Nature 513: 507-511.
314. Yan D, Chen D, Cool SM, van Wijnen AJ, Mikecz K, Murphy G, Im HJ. 2011. 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.
315. Yang F, Wang Y, Zhang Z, Hsu B, Jabs EW, Elisseeff JH. 2008. The study of abnormal bone development in the Apert syndrome Fgfr2+/S252W mouse using a 3D hydrogel culture model. Bone 43: 55-63.
316. Yang L, Tsang KY, Tang HC, Chan D, Cheah KS. 2014. Hypertrophic chondrocytes can become osteoblasts and osteocytes in endochondral bone formation. Proc Natl Acad Sci 111: 12097-12102.
317. Yasoda A, Komatsu Y, Chusho H, Miyazawa T, Ozasa A, Miura M, Kurihara T, Rogi T, Tanaka S, Suda M, et al. 2004. Overexpression of CNP in chondrocytes rescues achondroplasia through a MAPK-dependent pathway. Nat Med 10: 80-86.
318. Yeh E, Atique R, Ishiy FA, Fanganiello RD, Alonso N, Matushita H, da Rocha KM, Passos-Bueno MR. 2012. FGFR2 mutation confers a less drastic gain of function in mesenchymal stem cells than in fibroblasts. Stem Cell Rev 8: 685-695.
319. Yeung Tsang K, Wa Tsang S, Chan D, Cheah KS. 2014. The chondrocytic journey in endochondral bone growth and skeletal dysplasia. Birth Defects Res C Embryo Today 102: 52-73.
320. Yin L, Du X, Li C, Xu X, Chen Z, Su N, Zhao L, Qi H, Li F, Xue J, et al. 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.
321. Yokota M, Kobayashi Y, Morita J, Suzuki H, Hashimoto Y, Sasaki Y, Akiyoshi K, Moriyama K. 2014. Therapeutic effect of nanogel-based delivery of soluble FGFR2 with S252W mutation on craniosynostosis. PLoS One 9: e101693.
322. Yoon BS, Ovchinnikov DA, Yoshii I, Mishina Y, Behringer RR, Lyons KM. 2005. Bmpr1a and Bmpr1b have overlapping functions and are essential for chondrogenesis in vivo. Proc Natl Acad Sci 102: 5062-5067.
323. Yoon WJ, Cho YD, Kim WJ, Bae HS, Islam R, Woo KM, Baek JH, Bae SC, Ryoo HM. 2014. Prolyl isomerase Pin1-mediated conformational change and subnuclear focal accumulation of Runx2 are crucial for fibroblast growth factor 2 (FGF2)-induced osteoblast differentiation. J Biol Chem 289: 8828-8838.
324. Yoshida CA, Yamamoto H, Fujita T, Furuichi T, Ito K, Inoue K, Yamana K, Zanma A, Takada K, Ito Y, et al. 2004. Runx2 and Runx3 are essential for chondrocyte maturation, and Runx2 regulates limb growth through induction of Indian hedgehog. Genes Dev 18: 952-963.
325. Yu K, Ornitz DM. 2001. Uncoupling fibroblast growth factor receptor 2 ligand binding specificity leads to Apert syndromelike phenotypes. Proc Natl Acad Sci 98: 3641-3643.
326. Yu K, Ornitz DM. 2008. FGF signaling regulates mesenchymal differentiation and skeletal patterning along the limb bud proximodistal axis. Development 135: 483-491.
327. 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 97: 14536-14541.
328. 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.
329. Zeller R, Lopez-Rios J, Zuniga A. 2009. Vertebratelimb bud development: moving towards integrative analysis of organogenesis. Nat Rev Genet 10: 845-858.
330. Zhang K, Corsa CA, Ponik SM, Prior JL, Piwnica-Worms D, Eliceiri KW, Keely PJ, Longmore GD. 2013. The collagen receptor discoidin domain receptor 2 stabilizes SNAIL1 to facilitate breast cancer metastasis. Nat Cell Biol 15: 677-687.
331. Zhou YX, Xu X, Chen L, Li C, Brodie SG, Deng CX. 2000. A Pro250Arg substitution in mouse Fgfr1 causes increased expression of Cbfa1 and premature fusion of calvarial sutures. Hum Mol Genet 9: 2001-2008.
332. Zhou X, von der Mark K, Henry S, Norton W, Adams H, de Crombrugghe B. 2014. Chondrocytes transdifferentiate into osteoblasts in endochondral bone during development, postnatal growth and fracture healing in mice. PLoS Genet 10: e1004820.
333. Zhou ZQ, Ota S, Deng C, Akiyama H, Hurlin PJ. 2015. Mutant activated FGFR3 impairs endochondral bone growth by preventing SOX9 downregulation in differentiating chondrocytes. Hum Mol Genet 24: 1764-1773.