FGFR3 promotes synchondrosis closure and fusion of ossification centers through the MAPK pathway

被引:105
作者
Matsushita, Takehiko [1 ]
Wilcox, William R. [3 ,4 ]
Chan, Yuk Yu [1 ]
Kawanami, Aya [1 ]
Bukulmez, Huelya [2 ,5 ]
Balmes, Gener [6 ]
Krejci, Pavel [3 ,7 ,8 ]
Mekikian, Pertchoui B. [3 ]
Otani, Kazuyuki [9 ]
Yamaura, Isakichi [9 ]
Warman, Matthew L. [10 ,11 ]
Givol, David [12 ]
Murakami, Shunichi [1 ,2 ]
机构
[1] Case Western Reserve Univ, Dept Orthopaed, Cleveland, OH 44106 USA
[2] Case Western Reserve Univ, Dept Genet, Cleveland, OH 44106 USA
[3] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA
[4] Univ Calif Los Angeles, Sch Med, Dept Pediat, Los Angeles, CA 90095 USA
[5] Metrohlth Med Ctr, Dept Pediat, Cleveland, OH 44109 USA
[6] Univ Texas MD Anderson Canc Ctr, Dept Mol Genet, Houston, TX 77030 USA
[7] Masaryk Univ, Inst Expt Biol, CS-61137 Brno, Czech Republic
[8] Inst Biophys ASCR, Dept Cytokinet, Brno 61265, Czech Republic
[9] Kudanzaka Hosp, Dept Orthopaed Surg, Chiyoda Ku, Tokyo 1020071, Japan
[10] Childrens Hosp, Dept Orthopaed Surg, Boston, MA 02115 USA
[11] Childrens Hosp, Howard Hughes Med Inst, Boston, MA 02115 USA
[12] Weizmann Inst Sci, IL-76100 Rehovot, Israel
基金
新加坡国家研究基金会; 美国国家卫生研究院;
关键词
FIBROBLAST-GROWTH-FACTOR; FACTOR RECEPTOR-3; TRANSGENIC MICE; CRE RECOMBINASE; BONE-FORMATION; CHONDROCYTE PROLIFERATION; THANATOPHORIC DYSPLASIA; TARGETED DISRUPTION; ACHONDROPLASIA; EXPRESSION;
D O I
10.1093/hmg/ddn339
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Activating mutations in FGFR3 cause achondroplasia and thanatophoric dysplasia, the most common human skeletal dysplasias. In these disorders, spinal canal and foramen magnum stenosis can cause serious neurologic complications. Here, we provide evidence that FGFR3 and MAPK signaling in chondrocytes promote synchondrosis closure and fusion of ossification centers. We observed premature synchondrosis closure in the spine and cranial base in human cases of homozygous achondroplasia and thanatophoric dysplasia as well as in mouse models of achondroplasia. In both species, premature synchondrosis closure was associated with increased bone formation. Chondrocyte-specific activation of Fgfr3 in mice induced premature synchondrosis closure and enhanced osteoblast differentiation around synchondroses. FGF signaling in chondrocytes increases Bmp ligand mRNA expression and decreases Bmp antagonist mRNA expression in a MAPK-dependent manner, suggesting a role for Bmp signaling in the increased bone formation. The enhanced bone formation would accelerate the fusion of ossification centers and limit the endochondral bone growth. Spinal canal and foramen magnum stenosis in heterozygous achondroplasia patients, therefore, may occur through premature synchondrosis closure. If this is the case, then any growth-promoting treatment for these complications of achondroplasia must precede the timing of the synchondrosis closure.
引用
收藏
页码:227 / 240
页数:14
相关论文
共 59 条
[1]   Extracellular regulation of BMP signaling in vertebrates: A cocktail of modulators [J].
Balemans, W ;
Van Hul, W .
DEVELOPMENTAL BIOLOGY, 2002, 250 (02) :231-250
[2]   A RECURRENT MUTATION IN THE TYROSINE KINASE DOMAIN OF FIBROBLAST GROWTH-FACTOR RECEPTOR-3 CAUSES HYPOCHONDROPLASIA [J].
BELLUS, GA ;
MCINTOSH, I ;
SMITH, EA ;
AYLSWORTH, AS ;
KAITILA, I ;
HORTON, WA ;
GREENHAW, GA ;
HECHT, JT ;
FRANCOMANO, CA .
NATURE GENETICS, 1995, 10 (03) :357-359
[3]   Gly369Cys mutation in mouse FGFR3 causes achondroplasia by affecting both chondrogenesis and osteogenesis [J].
Chen, L ;
Adar, R ;
Yang, X ;
Monsonego, EO ;
Li, CL ;
Hauschka, PV ;
Yayon, A ;
Deng, CX .
JOURNAL OF CLINICAL INVESTIGATION, 1999, 104 (11) :1517-1525
[4]   A Ser365→Cys mutation of fibroblast growth factor receptor 3 in mouse downregulates Ihh/PTHrP signals and causes severe achondroplasia [J].
Chen, L ;
Li, CL ;
Qiao, WH ;
Xu, XL ;
Deng, CX .
HUMAN MOLECULAR GENETICS, 2001, 10 (05) :457-465
[5]   Mouse α1(I)-collagen promoter is the best known promoter to drive efficient Cre recombinase expression in osteoblast [J].
Dacquin, R ;
Starbuck, M ;
Schinke, T ;
Karsenty, G .
DEVELOPMENTAL DYNAMICS, 2002, 224 (02) :245-251
[6]   Dynamic cervicomedullary cord compression and alterations in cerebrospinal fluid dynamics in children with achondroplasia [J].
Danielpour, Mom ;
Wilcox, William R. ;
Alanay, Yasemin ;
Pressman, Barry D. ;
RimoiN, David L. .
JOURNAL OF NEUROSURGERY, 2007, 107 (06) :504-507
[7]   Spatio-temporal expression of FGFR 1, 2 and 3 genes during human embryo-fetal ossification [J].
Delezoide, AL ;
Benoist-Lasselin, C ;
Legeai-Mallet, L ;
Le Merrer, M ;
Munnich, A ;
Vekemans, M ;
Bonaventure, J .
MECHANISMS OF DEVELOPMENT, 1998, 77 (01) :19-30
[8]   Identification of tyrosine residues in constitutively activated fibroblast growth factor receptor 3 involved in mitogenesis, Stat activation, and phosphatidylinositol 3-kinase activation [J].
Hart, KC ;
Robertson, SC ;
Donoghue, DJ .
MOLECULAR BIOLOGY OF THE CELL, 2001, 12 (04) :931-942
[9]  
HECHT JT, 1987, AM J HUM GENET, V41, P454
[10]   NEUROLOGIC MORBIDITY ASSOCIATED WITH ACHONDROPLASIA [J].
HECHT, JT ;
BUTLER, IJ .
JOURNAL OF CHILD NEUROLOGY, 1990, 5 (02) :84-97