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.

Full-text preview

Available from:
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: A growing number of studies have been showing that dietary probiotics can exert beneficial health effects in both humans and animals. We previously demonstrated that dietary supplementation with Lactobacillus rhamnosus - a component of the human gut microflora - enhances reproduction, larval development, and the biomineralization process in Danio rerio (zebrafish). The aim of this study was to identify the pathways affected by L. rhamnosus during zebrafish larval development. Our morphological and histochemical findings show that L. rhamnosus accelerates bone deposition through stimulation of the expression of key genes involved in ossification, e.g. runt-related transcription factor 2 (runx2), Sp7 transcription factor (sp7), matrix Gla protein (mgp), and bone gamma-carboxyglutamate (gla) protein (bglap) as well as through inhibition of sclerostin (sost), a bone formation inhibitor. Western blot analysis of mitogen-activated protein kinase 1 and 3-(Mapk1 and Mapk3), which are involved in osteoblast and osteocyte differentiation, documented an increase in Mapk1 16 days post fertilization (dpf) and of Mapk3 23 dpf in individuals receiving L. rhamnosus supplementation. Interestingly, a reduction of sost detected in the same individuals suggests that the probiotic may help treat bone disorders.
    Full-text · Article · Dec 2013 · PLoS ONE
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Fibroblast growth factor receptor 3 (FGFR3) inhibits growth-plate chondrocyte proliferation and limits bone elongation. Gain-of-function FGFR3 mutations cause dwarfism, reduced telomerase activity and shorter telomeres in growth plate chondroyctes suggesting that FGFR3 reduces proliferative capacity, inhibits telomerase, and enhances senescence. Thyroid hormone (T3) plays a role in cellular maturation of growth plate chondrocytes and a known target of T3 is FGFR3. The present study addressed whether reduced FGFR3 expression enhanced telomerase activity, mRNA expression of telomerase reverse transcriptase (TERT) and RNA component of telomerase (TR), and chondrocyte proliferation, and whether the stimulation of FGFR3 by T3 evoked the opposite response. Results Sheep growth-plate proliferative zone chondrocytes were cultured and transfected with siRNA to reduce FGFR3 expression; FGFR3 siRNA reduced chondrocyte FGFR3 mRNA and protein resulting in greater proliferation and increased TERT mRNA expression and telomerase activity (p < 0.05). Chondrocytes treated with T3 significantly enhanced FGFR3 mRNA and protein expression and reduced telomerase activity (p < 0.05); TERT and TR were not significantly reduced. The action of T3 at the growth plate may be partially mediated through the FGFR3 pathway. Conclusions The results suggest that FGFR3 inhibits chondrocyte proliferation by down-regulating TERT expression and reducing telomerase activity indicating an important role for telomerase in sustaining chondrocyte proliferative capacity during bone elongation.
    Full-text · Article · Dec 2012 · Journal of Animal Science and Biotechnology
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cranial base growth plates are important centers of longitudinal growth in the skull and are responsible for the proper anterior placement of the face and the stimulation of normal cranial vault development. We report that the presphenoidal synchondrosis (PSS), a midline growth plate of the cranial base, closes in the DBA/2J mouse strain but not in other common inbred strains. We investigated the genetics of PSS closure in DBA/2J mice by evaluating F1, F1 backcross, and/or F1 intercross offspring from matings with C57BL/6J and DBA/1J mice, whose PSS remain open. We observed that PSS closure is genetically determined, but not inherited as a simple Mendelian trait. Employing a genome-wide SNP array, we identified a region on chromosome 11 in the C57BL/6J strain that affected the frequency of PSS closure in F1 backcross and F1 intercross offspring. The equivalent region in the DBA/1J strain did not affect PSS closure in F1 intercross offspring. We conclude that PSS closure in the DBA/2J strain is complex and modified by different loci when outcrossed with C57BL/6J and DBA/1J mice. Electronic supplementary material The online version of this article (doi:10.1007/s00335-012-9437-8) contains supplementary material, which is available to authorized users.
    Full-text · Article · Nov 2012 · Mammalian Genome
Show more