Analysis of STAT1 Activation by Six FGFR3 Mutants Associated with Skeletal Dysplasia Undermines Dominant Role of STAT1 in FGFR3 Signaling in Cartilage

Krejčı́, Pavel; Salazar, Lisa; Kashiwada, Tamara; Chlebová, Katarina; Salašová, Alena; Thompson, Leslie M.; Bryja, Vı́tězslav; Kozubı́k, Alois; Wilcox, William R.

doi:10.1371/journal.pone.0003961

Cited by 43 publications

(49 citation statements)

References 32 publications

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“…The mutations in FGFR3 associated with dwarfism activate the receptor to varying degrees (Naski et al 1996;Krejci et al 2008b). The N540K mutation causing hypochondroplasia is a weak gain-of-function mutation, and mutations causing achondroplasia and thantophoric dysplasia result in progressively stronger activation and, in the case of the R248C mutation, ligand-independent constitutive activation.…”

Section: Chondrodysplasia Syndromesmentioning

confidence: 99%

“…The N540K mutation causing hypochondroplasia is a weak gain-of-function mutation, and mutations causing achondroplasia and thantophoric dysplasia result in progressively stronger activation and, in the case of the R248C mutation, ligand-independent constitutive activation. FGFR3 is expressed prominently in proliferating and prehypertrophic chondrocytes in the growth plate, and activation of FGFR3 results in phenotypes that include decreased chondrocyte proliferation, impaired hypertrophic differentiation, and increased apoptosis (discussed below; Legeai-Mallet et al 1998Naski et al 1998;Wang et al 1999Wang et al , 2001Krejci et al 2008b;Pannier et al 2009). …”

Section: Chondrodysplasia Syndromesmentioning

confidence: 99%

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Fibroblast growth factor signaling in skeletal development and disease

2015

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Fibroblast growth factor (FGF) signaling pathways are essential regulators of vertebrate skeletal development. FGF signaling regulates development of the limb bud and formation of the mesenchymal condensation and has key roles in regulating chondrogenesis, osteogenesis, and bone and mineral homeostasis. This review updates our review on FGFs in skeletal development published in Genes & Development in 2002, examines progress made on understanding the functions of the FGF signaling pathway during critical stages of skeletogenesis, and explores the mechanisms by which mutations in FGF signaling molecules cause skeletal malformations in humans. Links between FGF signaling pathways and other interacting pathways that are critical for skeletal development and could be exploited to treat genetic diseases and repair bone are also explored.

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Section: Chondrodysplasia Syndromesmentioning

confidence: 99%

Section: Chondrodysplasia Syndromesmentioning

confidence: 99%

Fibroblast growth factor signaling in skeletal development and disease

2015

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“…Activation of STAT1-P21 pathway is considered as a potential mechanism for FGFR3-induced proliferation arrest (25)(26)(27)(28). The inhibited hypertrophic differentiation of chondrocytes resulting from activated FGFR3 is related to ERK MAPK signaling (4).…”

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confidence: 99%

Chondrocyte FGFR3 Regulates Bone Mass by Inhibiting Osteogenesis

Wen

Tang

et al. 2016

Journal of Biological Chemistry

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Edited by Xiao-Fan WangChondrogenesis can regulate bone formation. Fibroblast growth factor receptor 3, highly expressed in chondrocytes, is a negative regulator of bone growth. To investigate whether chondrocyte FGFR3 regulates osteogenesis, thereby contributing to postnatal bone formation and bone remodeling, mice with conditional knock-out of Fgfr3 in chondrocytes (mutant (MUT)) were generated. MUT mice displayed overgrowth of bone with lengthened growth plates. Bone mass of MUT mice was significantly increased at both 1 month and 4 months of age. Histological analysis showed that osteoblast number and bone formation were remarkably enhanced after deletion of Fgfr3 in chondrocytes. Chondrocyte-osteoblast co-culture assay further revealed that Fgfr3 deficiency in chondrocytes promoted differentiation and mineralization of osteoblasts by up-regulating the expressions of Ihh, Bmp2, Bmp4, Bmp7, Wnt4, and Tgf-␤1, as well as down-regulating Nog expression. In addition, osteoclastogenesis was also impaired in MUT mice with decreased number of osteoclasts lining trabecular bone, which may be related to the reduced ratio of Rankl to Opg in Fgfr3-deficient chondrocytes. This study reveals that chondrocyte FGFR3 is involved in the regulation of bone formation and bone remodeling by a paracrine mechanism.

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“…We therefore anticipated the mutation p.M528I to be pathogenic and responsible for the observed phenotype. In order to functionally validate this prediction, we expressed FGFR3-M528I in RCS chondrocytes, which have successfully been used before to compare the relative levels of activation of different FGFR3 mutants associated with skeletal dysplasia (17). Figure 4A shows that FGFR3-M528I triggered ERK/MAP kinase activation in RCS cells to the levels similar to those induced by FGFR3-G380R, which is the most common mutation associated with ACH.…”

Section: Discussionmentioning

confidence: 96%

A novel variant of FGFR3 causes proportionate short stature

Kant

Cervenkova

Bálek

et al. 2015

European Journal of Endocrinology

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Objective: Mutations of the fibroblast growth factor receptor 3 (FGFR3) cause various forms of short stature, of which the least severe phenotype is hypochondroplasia, mainly characterized by disproportionate short stature. Testing for an FGFR3 mutation is currently not part of routine diagnostic testing in children with short stature without disproportion. Design: A three-generation family A with dominantly transmitted proportionate short stature was studied by whole-exome sequencing to identify the causal gene mutation. Functional studies and protein modeling studies were performed to confirm the pathogenicity of the mutation found in FGFR3. We performed Sanger sequencing in a second family B with dominant proportionate short stature and identified a rare variant in FGFR3. Methods: Exome sequencing and/or Sanger sequencing was performed, followed by functional studies using transfection of the mutant FGFR3 into cultured cells; homology modeling was used to construct a three-dimensional model of the two FGFR3 variants. Results: A novel p.M528I mutation in FGFR3 was detected in family A, which segregates with short stature and proved to be activating in vitro. In family B, a rare variant (p.F384L) was found in FGFR3, which did not segregate with short stature and showed normal functionality in vitro compared with WT. Conclusions: Proportionate short stature can be caused by a mutation in FGFR3. Sequencing of this gene can be considered in patients with short stature, especially when there is an autosomal dominant pattern of inheritance. However, functional studies and segregation studies should be performed before concluding that a variant is pathogenic.

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Analysis of STAT1 Activation by Six FGFR3 Mutants Associated with Skeletal Dysplasia Undermines Dominant Role of STAT1 in FGFR3 Signaling in Cartilage

Cited by 43 publications

References 32 publications

Fibroblast growth factor signaling in skeletal development and disease

Fibroblast growth factor signaling in skeletal development and disease

Chondrocyte FGFR3 Regulates Bone Mass by Inhibiting Osteogenesis

A novel variant of FGFR3 causes proportionate short stature

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