FGFR3 Promotes Synchondrosis Closure and Fusion of Ossification Centers Through the MAPK Pathway

Overview

Journal Hum Mol Genet

Specialties Genetics
Molecular Biology

Date 2008 Oct 17

PMID 18923003

Citations 56

Authors

Takehiko Matsushita

William R Wilcox

Yuk Yu Chan

Aya Kawanami

Hulya Bukulmez

Gener Balmes

Pavel Krejci

Pertchoui B Mekikian

Kazuyuki Otani

Isakichi Yamaura

Matthew L Warman

David Givol

Shunichi Murakami

Affiliations

Soon will be listed here.

Abstract

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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