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

Department of Orthopaedics, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
Human Molecular Genetics (Impact Factor: 6.39). 11/2008; 18(2):227-40. DOI: 10.1093/hmg/ddn339
Source: PubMed


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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    • "While their tissue distribution is substantially established [68], their specific roles are still poorly known. Several studies have shown that the ERK MAPK pathway plays an essential role in mediating fibroblast growth factor signaling in skeletal cells [69], [70]. In a mouse model, genetic inactivation of MAPK1/3 in undifferentiated mesenchymal cells, induced severe impairment of osteoblast differentiation and bone formation [71], [72], while their inhibition induced ectopic cartilage formation in mouse perichondrium [50], supporting their pivotal role in skeletal development. "
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    • "Telomerase has been shown to increase proliferation and delay apoptosis in cells [18], whereas FGFR3 promotes apoptosis and cessation of proliferation in the growth plate [1,45]. In vivo, the presence of a single functional FGFR3 copy results in enhanced skeletal growth and delayed maturation [6,7]. "
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    • "signaling pathway components have been identified in patients with craniosynostosis (Gripp et al. 2000; Nuckolls et al. 1999; Wilkie 1997), and missense mutations affecting TGFb are associated with a variety of craniofacial abnormalities (Loeys et al. 2006). Mice with alleles equivalent to the human mutations also exhibit abnormal synchondrosis closure (Bourgeois et al. 1998; Matsushita et al. 2009; Wang et al. 2005; Yin et al. 2008). Conditional inactivation of other pathways in mice reveals roles for Indian hedgehog (Young et al. 2006) and primary cilium-based signaling (Kolpakova-Hart et al. 2008; Koyama et al. 2007; Ochiai et al. 2009). "
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