Human Molecular Genetics Advance Access published online on October 15, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn339
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FGFR3 promotes synchondrosis closure and fusion of ossification centers through the MAPK pathway
1 Department of Orthopaedics, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA 2 Medical Genetics Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, California 90048, USA 3 Department of Pediatrics, UCLA School of Medicine, Los Angeles, California 90095, USA 4 Department of Genetics, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA 5 Department of Pediatrics, Pediatric Rheumatology, MetroHealth Medical Center, 2500 MetroHealth Drive, Cleveland, Ohio 44109, USA 6 Department of Molecular Genetics, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, Texas 77030, USA 7 Institute of Experimental Biology, Masaryk University, 61137 Brno, Czech Republic 8 Department of Cytokinetics, Institute of Biophysics ASCR, 61265 Brno, Czech Republic 9 Department of Orthopaedic Surgery, Kudanzaka Hospital, 2-1-39 Kudanzakaminami, Chiyoda-ku, Tokyo, 102-0071, Japan 10 Department of Orthopaedic Surgery and the Howard Hughes Medical Institute at Children's Hospital Boston, 300 Longwood Avenue, Boston, Massachusetts 02115, USA 11 Weizmann Institute of Science, Rehovot, Israel, 76100
* Corresponding author: Shunichi Murakami, Dept of Orthopaedics, Case Western Reserve University, 2109 Adelbert Road, BRB 329, Cleveland, Ohio 44106, USA, Phone: 216-368-1371, Fax: 216-368-1332, E-mail: shun{at}case.edu
Received July 9, 2008; Revised October 6, 2008; Accepted October 13, 2008
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.
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