FGFR1 signaling in hypertrophic chondrocytes is attenuated by the Ras-GAP neurofibromin during endochondral bone formation

Human Molecular Genetics

Volumn 24, Issue 9, 2015, Pages 2552-2564

  Karolak, Matthew R ^a,b   Yang, Xiangli ^a,b   Elefteriou, Florent ^a,b  

^a VANDERBILT UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b VANDERBILT UNIVERSITY MEDICAL CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

COLLAGEN TYPE 2; COLLAGENASE 3; FIBROBLAST GROWTH FACTOR RECEPTOR 1; FIBROBLAST GROWTH FACTOR RECEPTOR 3; GELATINASE B; MITOGEN ACTIVATED PROTEIN KINASE 1; MITOGEN ACTIVATED PROTEIN KINASE 3; NEUROFIBROMIN; OSTEOCLAST DIFFERENTIATION FACTOR; OSTEOPONTIN; SONIC HEDGEHOG PROTEIN; 3-(2,6-DICHLORO-3,5-DIMETHOXYPHENYL)-1-(6-(4-(4-ETHYLPIPERAZIN-1-YL)-PHENYLAMINO)PYRIMIDIN-4-YL)-1-METHYLUREA; CARBANILAMIDE DERIVATIVE; COL2A1 PROTEIN, MOUSE; PYRIMIDINE DERIVATIVE;

ANIMAL CELL; ANIMAL TISSUE; ARTICLE; BODY HEIGHT; BODY WEIGHT; BONE GROWTH; BONE LENGTH; CARTILAGE CELL; CELL DIFFERENTIATION; CELL EXPANSION; CELL HYPERPLASIA; CELL MATURATION; CELL PROLIFERATION; CONTROLLED STUDY; ENCHONDRAL OSSIFICATION; ENZYME ACTIVATION; FEMALE; GENE EXPRESSION; GROWTH PLATE; IN VIVO STUDY; LEG LENGTHENING; MALE; MORPHOMETRICS; MOUSE; NONHUMAN; OSTEOCLAST; PHENOTYPE; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN LOCALIZATION; SIGNAL TRANSDUCTION; ANIMAL; ANTAGONISTS AND INHIBITORS; BONE DEVELOPMENT; CHONDROGENESIS; DRUG EFFECTS; GENE INACTIVATION; GENETICS; HYPERTROPHY; KNOCKOUT MOUSE; METABOLISM; PATHOLOGY; PROTEIN TRANSPORT;

ANIMALS; CHONDROCYTES; CHONDROGENESIS; COLLAGEN TYPE II; FEMALE; GENE EXPRESSION; GENE KNOCKOUT TECHNIQUES; GROWTH PLATE; HYPERTROPHY; MALE; MICE; MICE, KNOCKOUT; NEUROFIBROMIN 1; OSTEOCLASTS; OSTEOGENESIS; PHENOTYPE; PHENYLUREA COMPOUNDS; PROTEIN TRANSPORT; PYRIMIDINES; RECEPTOR, FIBROBLAST GROWTH FACTOR, TYPE 1; RECEPTOR, FIBROBLAST GROWTH FACTOR, TYPE 3; SIGNAL TRANSDUCTION;

EID: 84938082039     PISSN: 09646906     EISSN: 14602083     Source Type: Journal    
DOI: 10.1093/hmg/ddv019     Document Type: Article

References (63)

1. Kronenberg, H.M. (2003) Developmental regulation of the growth plate. Nature, 423, 332-336.
2. Lefebvre, V. and Bhattaram, P. (2010) Vertebrate Skeletogenesis. Curr. Top. Dev. Biol., 90, 291-317.
3. Spranger, J. (2005) Skeletal dysplasias. In: Hall, JG (eds), Human Malformations and Related Anomalies. Oxford University Press, USA, pp. 997-1020.
4. Abou-Khalil, R. and Colnot, C. (2014) Cellular and molecular bases of skeletal regeneration: what canwe learn from genetic mouse models? Bone, 64, 211-221.
5. Peters, K.G.,Werner, S., Chen, G. andWilliams, L.T. (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.
6. Peters, K., Ornitz, D., Werner, S. and Williams, L. (1993) Unique expression pattern of the FGF receptor 3 gene during mouse organogenesis. Dev. Biol., 155, 423-430.
7. Jacob, A.L., Smith, C., Partanen, J. and Ornitz, D.M. (2006) Fibroblast growth factor receptor 1 signaling in the osteochondrogenic cell lineage regulates sequential steps of osteoblast maturation. Dev. Biol., 296, 315-328.
8. Delezoide, A.L., Benoist-Lasselin, C., Legeai-Mallet, L., Le Merrer, M., Munnich, A., Vekemans, M. and Bonaventure, J. (1998) Spatio-temporal expression of FGFR 1, 2 and 3 genes during human embryo-fetal ossification. Mech. Dev., 77, 19-30.
9. Deng, C., Wynshaw-Boris, A., Zhou, F., Kuo, A. and Leder, P. (1996) Fibroblast growth factor receptor 3 is a negative regulator of bone growth. Cell, 84, 911-921.
10. Sahni, M., Raz, R., Coffin, J.D., Levy, D. and Basilico, C. (2001) STAT1 mediates the increased apoptosis and reduced chondrocyte proliferation in mice overexpressing FGF2. Development, 128, 2119-2129.
11. Murakami, S., Balmes, G., McKinney, S., Zhang, Z., Givol, D. and 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.
12. Iwata, T., Chen, L., Li, C., Ovchinnikov, D.A., Behringer, R.R., Francomano, C.A. and Deng, C.X. (2000) A neonatal lethal mutation in FGFR3 uncouples proliferation and differentiation of growth plate chondrocytes in embryos. Hum. Mol. Gen., 9, 1603-1613.
13. Naski, M.C.,Wang, Q., Xu, J. and Ornitz, D.M. (1996) Graded activation of fibroblast growth factor receptor 3 by mutations causing achondroplasia and thanatophoric dysplasia. Nat. Genet., 13, 233-237.
14. Tavormina, P.L., Shiang, R., Thompson, L.M., Zhu, Y.Z., Wilkin, D.J., Lachman, R.S., Wilcox, W.R., Rimoin, D.L., Cohn, D.H. and Wasmuth, J.J. (1995) Thanatophoric dysplasia (types I and II) caused by distinct mutations in fibroblast growth factor receptor 3. Nat. Genet., 9, 321-328.
15. Rousseau, F., Bonaventure, J., Legeai-Mallet, L., Pelet, A., Rozet, J.M., Maroteaux, P., Le Merrer, M. and Munnich, A. (1994) Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia. Nature, 371, 252-254.
16. Shiang, R., Thompson, L.M., Zhu, Y.Z., Church, D.M., Fielder, T.J., Bocian, M.,Winokur, S.T. and Wasmuth, J.J. (1994) Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Cell, 78, 335-342.
17. Wang, Y., Spatz, M.K., Kannan, K., Hayk, H., Avivi, A., Gorivodsky, M., Pines, M., Yayon, A., Lonai, P. and Givol, D. (1999) Amouse model for achondroplasia produced by targeting fibroblast growth factor receptor 3. Proc. Natl Acad. Sci. USA, 96, 4455-4460.
18. Su, W.C., Kitagawa, M., Xue, N., Xie, B., Garofalo, S., Cho, J., Deng, C., Horton, W.A. and Fu, X.Y. (1997) Activation of Stat1 by mutant fibroblast growth-factor receptor in thanatophoric dysplasia type II dwarfism. Nature, 386, 288-292.
19. Li, C., Chen, L., Iwata, T., Kitagawa, M., Fu, X.Y. and Deng, C.X. (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. Gen., 8, 35-44.
20. Muenke, M., Schell, U., Hehr, A., Robin, N.H., Losken, H.W., Schinzel, A., Pulleyn, L.J., Rutland, P., Reardon,W. andMalcolm, S. (1994) A common mutation in the fibroblast growth factor receptor 1 gene in Pfeiffer syndrome. Nat. Genet., 8, 269-274.
21. Schell, U., Hehr, A., Feldman, G.J., Robin, N.H., Zackai, E.H., de Die-Smulders, C., Viskochil, D.H., Stewart, J.M., Wolff, G. and Ohashi, H. (1995) Mutations in FGFR1 and FGFR2 cause familial and sporadic Pfeiffer syndrome. Hum. Mol. Gen., 4, 323-328.
22. Roscioli, T., Flanagan, S., Kumar, P., Masel, J., Gattas, M., Hyland, V.J. and Glass, I.A. (2000) Clinical findings in a patient with FGFR1 P252R mutation and comparison with the literature. Am. J. Med. Genet., 93, 22-28.
23. White, K.E., Cabral, J.M., Davis, S.I., Fishburn, T., Evans, W.E., Ichikawa, S., Fields, J., Yu, X., Shaw, N.J., McLellan, N.J. et al. (2005) Mutations that cause osteoglophonic dysplasia define novel roles for FGFR1 in bone elongation. Am. J. Hum. Genet., 76, 361-367.
24. Farrow, E.G., Davis, S.I., Mooney, S.D., Beighton, P., Mascarenhas, L., Gutierrez, Y.R., Pitukcheewanont, P. and White, K.E. (2006) Extended mutational analyses of FGFR1 in osteoglophonic dysplasia. Am. J. Med. Genet., 140A, 537-539.
25. Sklower Brooks, S., Kassner, G., Qazi, Q., Keogh, M.J. and Gorlin, R.J. (1996) Osteoglophonic dysplasia: review and further delineation of the syndrome. Am. J. Med. Genet., 66, 154-162.
26. Beighton, P., Cremin, B. and Kozlowski, K. (1980) Osteoglophonic dwarfism. Pediatr. Radiol., 10, 46-50.
27. Azouz, E.M. and Kozlowski, K. (1997) Osteoglophonic dysplasia: appearance and progression of multiple nonossifying fibromata. Pediatr. Radiol., 27, 75-78.
28. Kelley, R.I., Borns, P.F., Nichols, D. and Zackai, E.H. (1983) Osteoglophonic dwarfism in two generations. J. Med. Genet., 20, 436-440.
29. Lemmon, M.A. and Schlessinger, J. (2010) Cell signaling by receptor tyrosine kinases. Cell, 141, 1117-1134.
30. Traverse, S., Gomez, N., Paterson, H., Marshall, C. and Cohen, P. (1992) Sustained activation of the mitogen-activated protein (MAP) kinase cascade may be required for differentiation of PC12 cells. Comparison of the effects of nerve growth factor and epidermal growth factor. Biochem. J., 288, 351-355.
31. Raucci, A., Laplantine, E., Mansukhani, A. and Basilico, C. (2004) Activation of the ERK1/2 and p38 Mitogen-activated Protein Kinase Pathways Mediates Fibroblast Growth Factorinduced Growth Arrest of Chondrocytes. J. Biol. Chem., 279, 1747-1756.
32. Crawford,A.H. and Bagamery,N. (1986) Osseousmanifestations of neurofibromatosis in childhood. J. Pediatr. Orthop., 6, 72-88.
33. Crawford, A.H. and Schorry, E.K. (1999) Neurofibromatosis in children: the role of the orthopaedist. J. Am. Acad. Orthop. Surg., 7, 217-230.
34. Kuorilehto, T., Pöyhönen, M., Bloigu, R., Heikkinen, J., Väänänen, K. and Peltonen, J. (2004) Decreased bone mineral density and content in neurofibromatosis type 1: lowest local values are located in the load-carrying parts of the body. Osteoporos. Int., 16, 928-936.
35. Stevenson, D.A., Moyer-Mileur, L.J., Murray, M., Slater, H., Sheng, X., Carey, J.C., Dube, B. and Viskochil, D.H. (2007) Bone mineral density in children and adolescents with neurofibromatosis type 1. J. Pediatr., 150, 83-88.
36. Elefteriou, F., Kolanczyk, M., Schindeler, A., Viskochil, D.H., Hock, J.M., Schorry, E.K., Crawford, A.H., Friedman, J.M., Little, D., Peltonen, J. et al. (2009) Skeletal abnormalities in neurofibromatosis type 1: approaches to therapeutic options. Am. J. Med. Genet., 149A, 2327-2338.
37. Wang,W., Nyman, J.S., Ono, K., Stevenson, D.A., Yang, X. and Elefteriou, F. (2011) Mice lacking Nf1 in osteochondroprogenitor cells display skeletal dysplasia similar to patients with neurofibromatosis type I. Hum. Mol. Gen., 20, 3910-3924.
38. Ono, K., Karolak, M.R., Ndong, J.deL.C., Ndong, J.D.L.C.,Wang, W., Yang, X. and Elefteriou, F. (2013) The ras-GTPase activity of neurofibromin restrains ERK-dependent FGFR signaling during endochondral bone formation. Hum. Mol. Gen., 22, 3048-3062.
39. Zhou, Y.X., Xu, X., Chen, L., Li, C., Brodie, S.G. and Deng, C.X. (2000) A Pro250Arg substitution in mouse Fgfr1 causes increased expression of Cbfa1 and premature fusion of calvarial sutures. Hum. Mol. Gen., 9, 2001-2008.
40. Kuorilehto, T., Nissinen, M., Koivunen, J., Benson, M.D. and Peltonen, J. (2004) NF1 tumor suppressor protein and mRNA in skeletal tissues of developing and adult normal mouse and NF1-deficient embryos. J. Bone Miner. Res., 19, 983-989.
41. Ndong, J.D.L.C., Makowski, A.J., Uppuganti, S., Vignaux, G., Ono, K., Perrien, D.S., Joubert, S., Baglio, S.R., Granchi, D., Stevenson, D.A. et al. (2014) Asfotase-a improves bone growth, mineralization and strength in mouse models of neurofibromatosis type-1. Nat. Med., 20, 904-910.
42. Gebhard, S., Hattori, T., Bauer, E., Schlund, B., Bösl, M.R., de Crombrugghe, B. and Mark, von der, K. (2008) Specific expression of Cre recombinase in hypertrophic cartilage under the control of a BAC-Col10a1 promoter. Matrix Biol., 27, 693-699.
43. Soriano, P. (1999) Generalized lacZ expression with the ROSA26 Cre reporter strain. Nat. Genet., 21, 70-71.
44. Golovchenko, S., Hattori, T., Hartmann, C., Gebhardt, M., Gebhard, S., Hess, A., Pausch, F., Schlund, B. and Mark, von der, K. (2013) Deletion of beta catenin in hypertrophic growth plate chondrocytes impairs trabecular bone formation. Bone, 55, 102-112.
45. Xiong, J., Onal, M., Jilka, R.L., Weinstein, R.S., Manolagas, S.C. and O'Brien, C.A. (2011) Matrix-embedded cells control osteoclast formation. Nat. Med., 17, 1235-1241.
46. Wang, Q., Green, R.P., Zhao, G. and Ornitz, D.M. (2001) Differential regulation of endochondral bone growth and joint development by FGFR1 and FGFR3 tyrosine kinase domains. Development, 128, 3867-3876.
47. Guagnano, V., Furet, P., Spanka, C., Bordas, V., Le Douget, M., Stamm, C., Brueggen, J., Jensen, M.R., Schnell, C., Schmid, H. et al. (2011) Discovery of 3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea (NVP-BGJ398), A Potent and Selective Inhibitor of the Fibroblast Growth Factor Receptor Family of Receptor Tyrosine Kinase. J. Med. Chem., 54, 7066-7083.
48. Sahni, M., Ambrosetti, D.C., Mansukhani, A., Gertner, R., Levy, D. and Basilico, C. (1999) FGF signaling inhibits chondrocyte proliferation and regulates bone development through the STAT-1 pathway. Genes Dev., 13, 1361-1366.
49. Eswarakumar, V.P., Lax, I. and Schlessinger, J. (2005) Cellular signaling by fibroblast growth factor receptors. Cytokine Growth Factor Rev., 16, 139-149.
50. Lax, I., Wong, A., Lamothe, B., Lee, A., Frost, A., Hawes, J. and Schlessinger, J. (2002) The docking protein FRS2alpha controls a MAP kinase-mediated negative feedback mechanism for signaling by FGF receptors. Mol. Cell, 10, 709-719.
51. Naski, M.C., Colvin, J.S., Coffin, J.D. and Ornitz, D.M. (1998) Repression of hedgehog signaling and BMP4 expression in growth plate cartilage by fibroblast growth factor receptor 3. Development, 125, 4977-4988.
52. Colvin, J.S., Bohne, B.A., Harding, G.W., McEwen, D.G. and Ornitz, D.M. (1996) Skeletal overgrowthand deafness inmice lacking fibroblast growth factor receptor 3. Nat. Genet., 12, 390-397.
53. Elefteriou, F., Benson, M.D., Sowa, H., Starbuck, M., Liu, X., Ron, D., Parada, L.F. and Karsenty, G. (2006) ATF4 mediation of NF1 functions in osteoblast reveals a nutritional basis for congenital skeletal dysplasiae. Cell Metab., 4, 441-451.
54. Provot, S., Nachtrab, G., Paruch, J., Chen, A.P., Silva, A. and Kronenberg, H.M. (2008) A-raf and B-raf are dispensable for normal endochondral bone development, and parathyroid hormone-related peptide suppresses extracellular signalregulated kinase activation in hypertrophic chondrocytes. Mol. Cell. Biol., 28, 344-357.
55. Sebastian, A., Matsushita, T., Kawanami, A., Mackem, S., Landreth, G.E. and 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.
56. Yang, X., Harkins, L.K., Zubanova, O., Harrington, A., Kovalenko, D., Nadeau, R.J., Chen, P.-Y., Toher, J.L., Lindner, V., Liaw, L. et al. (2008) Overexpression of Spry1 in chondrocytes causes attenuated FGFR ubiquitination and sustained ERK activation resulting in chondrodysplasia. Dev. Biol., 321, 64-76.
57. Legeai-Mallet, L., Benoist-Lasselin, C., Delezoide, A.L., Munnich, A. and 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.
58. Stevenson, D.A., Little, D., Armstrong, L., Crawford, A.H., Eastwood, D., Friedman, J.M., Greggi, T., Gutierrez, G., Hunter-Schaedle, K., Kendler, D.L. et al. (2013) Approaches to treating NF1 tibial pseudarthrosis: consensus from the children's tumor foundation NF1 bone abnormalities consortium. J. Pediatr. Orthop., 33, 269-275.
59. Ovchinnikov, D.A., Deng, J.M., Ogunrinu, G. and Behringer, R.R. (2000) Col2a1-directed expression of Cre recombinase in differentiating chondrocytes in transgenic mice. Genesis, 26, 145-146.
60. Zhu, Y., Romero, M.I., Ghosh, P., Ye, Z., Charnay, P., Rushing, E. J., Marth, J.D. and Parada, L.F. (2001) Ablation of NF1 function in neurons induces abnormal development of cerebral cortex and reactive gliosis in the brain. Genes Dev., 15, 859-876.
61. Hoch, R.V. and Soriano, P. (2006) Context-specific requirements for Fgfr1 signaling through Frs2 and Frs3 during mouse development. Development, 133, 663-673.
62. Takeda, S., Bonnamy, J.P., Owen, M.J., Ducy, P. and Karsenty, G. (2001) Continuous expression of Cbfa1 in nonhypertrophic chondrocytes uncovers its ability to induce hypertrophic chondrocyte differentiation and partially rescues Cbfa1-deficient mice. Genes Dev., 15, 467-481.
63. Ducy, P., Zhang, R., Geoffroy, V., Ridall, A.L. and Karsenty, G. (1997) Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell, 89, 747-754.