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1.
J Bone Miner Res ; 2024 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-38590263

RESUMO

Achondroplasia, the most common form of disproportionate short stature, is caused by gain-of-function point mutations in fibroblast growth factor receptor 3 (FGFR3). Abnormally elevated activation of FGFR3 modulates chondrocyte proliferation and differentiation via multiple signaling pathways, such as the MAPK pathway. Using a mouse model mimicking achondroplasia (Fgfr3Y367C/+), we have previously shown that daily treatment with infigratinib (BGJ398), a selective and orally bioavailable FGFR1-3 inhibitor, at a dose of 2 mg/kg, significantly increased bone growth. In this study, we investigated the activity of infigratinib administered at substantially lower doses (0.2 and 0.5 mg/kg, given once daily) and using an intermittent dosing regimen (1 mg/kg every 3 days). Following a 15-day treatment period, these low dosages were sufficient to observe significant improvement of clinical hallmarks of achondroplasia such as growth of the axial and appendicular skeleton and skull development. Immunohistological labeling demonstrated the positive impact of infigratinib on chondrocyte differentiation in the cartilage growth plate and the cartilage end plate of the vertebrae. Macroscopic and microcomputed analyses showed enlargement of the foramen magnum area at the skull base, thus improving foramen magnum stenosis, a well-recognized complication in achondroplasia. No changes in FGF23 or phosphorus levels were observed, indicating that the treatment did not modify phosphate homeostasis. This proof-of-concept study demonstrates that infigratinib administered at low doses has the potential to be a safe and effective therapeutic option for children with achondroplasia.

2.
JCI Insight ; 8(12)2023 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-37345656

RESUMO

Hypochondroplasia (HCH) is a mild dwarfism caused by missense mutations in fibroblast growth factor receptor 3 (FGFR3), with the majority of cases resulting from a heterozygous p.Asn540Lys gain-of-function mutation. Here, we report the generation and characterization of the first mouse model (Fgfr3Asn534Lys/+) of HCH to our knowledge. Fgfr3Asn534Lys/+ mice exhibited progressive dwarfism and impairment of the synchondroses of the cranial base, resulting in defective formation of the foramen magnum. The appendicular and axial skeletons were both severely affected and we demonstrated an important role of FGFR3 in regulation of cortical and trabecular bone structure. Trabecular bone mineral density (BMD) of long bones and vertebral bodies was decreased, but cortical BMD increased with age in both tibiae and femurs. These results demonstrate that bones in Fgfr3Asn534Lys/+ mice, due to FGFR3 activation, exhibit some characteristics of osteoporosis. The present findings emphasize the detrimental effect of gain-of-function mutations in the Fgfr3 gene on long bone modeling during both developmental and aging processes, with potential implications for the management of elderly patients with hypochondroplasia and osteoporosis.


Assuntos
Nanismo , Osteoporose , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos , Animais , Camundongos , Calcificação Fisiológica , Nanismo/genética , Mutação com Ganho de Função , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética
3.
J Exp Med ; 219(4)2022 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-35254402

RESUMO

Crouzon syndrome with acanthosis nigricans (CAN, a rare type of craniosynostosis characterized by premature suture fusion and neurological impairments) has been linked to a gain-of-function mutation (p.Ala391Glu) in fibroblast growth factor receptor 3 (FGFR3). To characterize the CAN mutation's impact on the skull and on brain functions, we developed the first mouse model (Fgfr3A385E/+) of this syndrome. Surprisingly, Fgfr3A385E/+ mice did not exhibit craniosynostosis but did show severe memory impairments, a structurally abnormal hippocampus, low activity-dependent synaptic plasticity, and overactivation of MAPK/ERK and Akt signaling pathways in the hippocampus. Systemic or brain-specific pharmacological inhibition of FGFR3 overactivation by BGJ398 injections rescued the memory impairments observed in Fgfr3A385E/+ mice. The present study is the first to have demonstrated cognitive impairments associated with brain FGFR3 overactivation, independently of skull abnormalities. Our results provide a better understanding of FGFR3's functional role and the impact of its gain-of-function mutation on brain functions. The modulation of FGFR3 signaling might be of value for treating the neurological disorders associated with craniosynostosis.


Assuntos
Acantose Nigricans , Disostose Craniofacial , Craniossinostoses , Acantose Nigricans/complicações , Acantose Nigricans/genética , Animais , Encéfalo , Disostose Craniofacial/complicações , Disostose Craniofacial/genética , Craniossinostoses/genética , Modelos Animais de Doenças , Transtornos da Memória/genética , Camundongos , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética
4.
Bone Res ; 10(1): 8, 2022 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-35078974

RESUMO

A gain-of-function mutation in the fibroblast growth factor receptor 3 gene (FGFR3) results in achondroplasia (ACH), the most frequent form of dwarfism. Constitutive activation of FGFR3 impairs bone formation and elongation and many signal transduction pathways. Identification of new and relevant compounds targeting the FGFR3 signaling pathway is of broad importance for the treatment of ACH, and natural plant compounds are prime drug candidate sources. Here, we found that the phenolic compound (-)-epicatechin, isolated from Theobroma cacao, effectively inhibited FGFR3's downstream signaling pathways. Transcriptomic analysis in an Fgfr3 mouse model showed that ciliary mRNA expression was modified and influenced significantly by the Indian hedgehog and PKA pathways. (-)-Epicatechin is able to rescue mRNA expression impairments that control both the structural organization of the primary cilium and ciliogenesis-related genes. In femurs isolated from a mouse model (Fgfr3Y367C/+) of ACH, we showed that (-)-epicatechin eliminated bone growth impairment during 6 days of ex vivo culture. In vivo, we confirmed that daily subcutaneous injections of (-)-epicatechin to Fgfr3Y367C/+ mice increased bone elongation and rescued the primary cilium defects observed in chondrocytes. This modification to the primary cilia promoted the typical columnar arrangement of flat proliferative chondrocytes and thus enhanced bone elongation. The results of the present proof-of-principle study support (-)-epicatechin as a potential drug for the treatment of ACH.

5.
JCI Insight ; 6(9)2021 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-33986191

RESUMO

Activating mutations in fibroblast growth factor receptor 3 (FGFR3) and inactivating mutations in the natriuretic peptide receptor 2 (NPR2) guanylyl cyclase both result in decreased production of cyclic GMP in chondrocytes and severe short stature, causing achondroplasia (ACH) and acromesomelic dysplasia, type Maroteaux, respectively. Previously, we showed that an NPR2 agonist BMN-111 (vosoritide) increases bone growth in mice mimicking ACH (Fgfr3Y367C/+). Here, because FGFR3 signaling decreases NPR2 activity by dephosphorylating the NPR2 protein, we tested whether a phosphatase inhibitor (LB-100) could enhance BMN-111-stimulated bone growth in ACH. Measurements of cGMP production in chondrocytes of living tibias, and of NPR2 phosphorylation in primary chondrocytes, showed that LB-100 counteracted FGF-induced dephosphorylation and inactivation of NPR2. In ex vivo experiments with Fgfr3Y367C/+ mice, the combination of BMN-111 and LB-100 increased bone length and cartilage area, restored chondrocyte terminal differentiation, and increased the proliferative growth plate area, more than BMN-111 alone. The combination treatment also reduced the abnormal elevation of MAP kinase activity in the growth plate of Fgfr3Y367C/+ mice and improved the skull base anomalies. Our results provide a proof of concept that a phosphatase inhibitor could be used together with an NPR2 agonist to enhance cGMP production as a therapy for ACH.


Assuntos
Acondroplasia/genética , Desenvolvimento Ósseo/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Peptídeo Natriurético Tipo C/análogos & derivados , Monoéster Fosfórico Hidrolases/antagonistas & inibidores , Piperazinas/farmacologia , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Receptores do Fator Natriurético Atrial/agonistas , Animais , Doenças do Desenvolvimento Ósseo/genética , Cartilagem/efeitos dos fármacos , Cartilagem/crescimento & desenvolvimento , Diferenciação Celular/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Sinergismo Farmacológico , Lâmina de Crescimento/efeitos dos fármacos , Lâmina de Crescimento/crescimento & desenvolvimento , Camundongos , Peptídeo Natriurético Tipo C/farmacologia , Tamanho do Órgão , Fosforilação , Cultura Primária de Células , Receptores do Fator Natriurético Atrial/genética , Tíbia/efeitos dos fármacos , Tíbia/crescimento & desenvolvimento
6.
JCI Insight ; 6(9)2021 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-33784257

RESUMO

Activating mutations in the fibroblast growth factor receptor 3 (FGFR3) or inactivating mutations in guanylyl cyclase-B (GC-B), also known as NPR-B or Npr2, cause short-limbed dwarfism. FGFR3 activation causes dephosphorylation and inactivation of GC-B, but the contribution of GC-B dephosphorylation to achondroplasia (ACH) is unknown. GC-B7E/7E mice that express a glutamate-substituted version of GC-B that cannot be inactivated by dephosphorylation were bred with mice expressing FGFR3-G380R, the most common human ACH mutation, to determine if GC-B dephosphorylation is required for ACH. Crossing GC-B7E/7E mice with FGFR3G380R/G380R mice increased naso-anal and long (tibia and femur), but not cranial, bone length twice as much as crossing GC-B7E/7E mice with FGFR3WT/WT mice from 4 to 16 weeks of age. Consistent with increased GC-B activity rescuing ACH, long bones from the GC-B7E/7E/FGFR3G380R/G380R mice were not shorter than those from GC-BWT/WT/FGFR3WT/WT mice. At 2 weeks of age, male but not female FGFR3G380R/G380R mice had shorter long bones and smaller growth plate hypertrophic zones, whereas female but not male GC-B7E/7E mice had longer bones and larger hypertrophic zones. In 2-week-old males, crossing FGFR3G380R/G380R mice with GC-B7E/7E mice increased long bone length and hypertrophic zone area to levels observed in mice expressing WT versions of both receptors. We conclude that preventing GC-B dephosphorylation rescues reduced axial and appendicular skeleton growth in a mouse model of achondroplasia.


Assuntos
Acondroplasia/genética , Desenvolvimento Ósseo/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Receptores do Fator Natriurético Atrial/genética , Animais , Tamanho Corporal/genética , Fêmur/crescimento & desenvolvimento , Lâmina de Crescimento/crescimento & desenvolvimento , Lâmina de Crescimento/patologia , Camundongos , Camundongos Transgênicos , Tamanho do Órgão , Fosforilação , Receptores do Fator Natriurético Atrial/metabolismo , Crânio/crescimento & desenvolvimento , Tíbia/crescimento & desenvolvimento
7.
Hum Mol Genet ; 27(1): 1-13, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29040558

RESUMO

Fibroblast growth factor receptor 3 (FGFR3) gain-of-function mutations cause dwarfisms, including achondroplasia (ACH) and thanatophoric dysplasia (TD). The constitutive activation of FGFR3 disrupts the normal process of skeletal growth. Bone-growth anomalies have been identified in skeletal ciliopathies, in which primary cilia (PC) function is disrupted. In human ACH and TD, the impact of FGFR3 mutations on PC in growth plate cartilage remains unknown. Here we showed that in chondrocytes from human (ACH, TD) and mouse Fgfr3Y367C/+ cartilage, the constitutively active FGFR3 perturbed PC length and the sorting and trafficking of intraflagellar transport (IFT) 20 to the PC. We demonstrated that inhibiting FGFR3 with FGFR inhibitor, PD173074, rescued both PC length and IFT20 trafficking. We also studied the impact of rapamycin, an inhibitor of mammalian target of rapamycin (mTOR) pathway. Interestingly, mTOR inhibition also rescued PC length and IFT20 trafficking. Together, we provide evidence that the growth plate defects ascribed to FGFR3-related dwarfisms are potentially due to loss of PC function, and these dwarfisms may represent a novel type of skeletal disorders with defective ciliogenesis.


Assuntos
Acondroplasia/metabolismo , Proteínas de Transporte/metabolismo , Condrócitos/metabolismo , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/metabolismo , Acondroplasia/genética , Acondroplasia/patologia , Animais , Desenvolvimento Ósseo/genética , Proteínas de Transporte/genética , Cartilagem/metabolismo , Cartilagem/patologia , Diferenciação Celular/fisiologia , Linhagem Celular , Movimento Celular/fisiologia , Condrócitos/patologia , Cílios/genética , Cílios/metabolismo , Modelos Animais de Doenças , Feminino , Lâmina de Crescimento/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Pirimidinas/farmacologia , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Transdução de Sinais
8.
Hum Mol Genet ; 25(14): 2997-3010, 2016 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-27260401

RESUMO

Activating FGFR3 mutations in human result in achondroplasia (ACH), the most frequent form of dwarfism, where cartilages are severely disturbed causing long bones, cranial base and vertebrae defects. Because mandibular development and growth rely on cartilages that guide or directly participate to the ossification process, we investigated the impact of FGFR3 mutations on mandibular shape, size and position. By using CT scan imaging of ACH children and by analyzing Fgfr3Y367C/+ mice, a model of ACH, we show that FGFR3 gain-of-function mutations lead to structural anomalies of primary (Meckel's) and secondary (condylar) cartilages of the mandible, resulting in mandibular hypoplasia and dysmorphogenesis. These defects are likely related to a defective chondrocyte proliferation and differentiation and pan-FGFR tyrosine kinase inhibitor NVP-BGJ398 corrects Meckel's and condylar cartilages defects ex vivo. Moreover, we show that low dose of NVP-BGJ398 improves in vivo condyle growth and corrects dysmorphologies in Fgfr3Y367C/+ mice, suggesting that postnatal treatment with NVP-BGJ398 mice might offer a new therapeutic strategy to improve mandible anomalies in ACH and others FGFR3-related disorders.


Assuntos
Acondroplasia/genética , Cartilagem/anormalidades , Mandíbula/anormalidades , Côndilo Mandibular/anormalidades , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Acondroplasia/diagnóstico por imagem , Acondroplasia/tratamento farmacológico , Acondroplasia/fisiopatologia , Animais , Cartilagem/crescimento & desenvolvimento , Cartilagem/fisiopatologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Condrócitos/metabolismo , Condrócitos/patologia , Modelos Animais de Doenças , Humanos , Mandíbula/crescimento & desenvolvimento , Mandíbula/fisiopatologia , Côndilo Mandibular/crescimento & desenvolvimento , Côndilo Mandibular/fisiopatologia , Camundongos , Osteogênese/efeitos dos fármacos , Osteogênese/genética , Compostos de Fenilureia/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinas/administração & dosagem
9.
J Clin Invest ; 126(5): 1871-84, 2016 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-27064282

RESUMO

Achondroplasia (ACH) is the most frequent form of dwarfism and is caused by gain-of-function mutations in the fibroblast growth factor receptor 3-encoding (FGFR3-encoding) gene. Although potential therapeutic strategies for ACH, which aim to reduce excessive FGFR3 activation, have emerged over many years, the use of tyrosine kinase inhibitor (TKI) to counteract FGFR3 hyperactivity has yet to be evaluated. Here, we have reported that the pan-FGFR TKI, NVP-BGJ398, reduces FGFR3 phosphorylation and corrects the abnormal femoral growth plate and calvaria in organ cultures from embryos of the Fgfr3Y367C/+ mouse model of ACH. Moreover, we demonstrated that a low dose of NVP-BGJ398, injected subcutaneously, was able to penetrate into the growth plate of Fgfr3Y367C/+ mice and modify its organization. Improvements to the axial and appendicular skeletons were noticeable after 10 days of treatment and were more extensive after 15 days of treatment that started from postnatal day 1. Low-dose NVP-BGJ398 treatment reduced intervertebral disc defects of lumbar vertebrae, loss of synchondroses, and foramen-magnum shape anomalies. NVP-BGJ398 inhibited FGFR3 downstream signaling pathways, including MAPK, SOX9, STAT1, and PLCγ, in the growth plates of Fgfr3Y367C/+ mice and in cultured chondrocyte models of ACH. Together, our data demonstrate that NVP-BGJ398 corrects pathological hallmarks of ACH and support TKIs as a potential therapeutic approach for ACH.


Assuntos
Acondroplasia/tratamento farmacológico , Condrócitos/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Compostos de Fenilureia/farmacologia , Pirimidinas/farmacologia , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/metabolismo , Acondroplasia/genética , Acondroplasia/metabolismo , Acondroplasia/patologia , Animais , Linhagem Celular Transformada , Condrócitos/patologia , Modelos Animais de Doenças , Células HEK293 , Humanos , Disco Intervertebral/metabolismo , Disco Intervertebral/patologia , Vértebras Lombares/metabolismo , Vértebras Lombares/patologia , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Camundongos Mutantes , Fosfolipase C gama/genética , Fosfolipase C gama/metabolismo , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Fatores de Transcrição SOX9/genética , Fatores de Transcrição SOX9/metabolismo , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/metabolismo
10.
PLoS Genet ; 10(5): e1004311, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24786642

RESUMO

Impairment of the tightly regulated ossification process leads to a wide range of skeletal dysplasias and deciphering their molecular bases has contributed to the understanding of this complex process. Here, we report a homozygous mutation in the mitochondria-associated granulocyte macrophage colony stimulating factor-signaling gene (MAGMAS) in a novel and severe spondylodysplastic dysplasia. MAGMAS, also referred to as PAM16 (presequence translocase-associated motor 16), is a mitochondria-associated protein involved in preprotein translocation into the matrix. We show that MAGMAS is specifically expressed in trabecular bone and cartilage at early developmental stages and that the mutation leads to an instability of the protein. We further demonstrate that the mutation described here confers to yeast strains a temperature-sensitive phenotype, impairs the import of mitochondrial matrix pre-proteins and induces cell death. The finding of deleterious MAGMAS mutations in an early lethal skeletal dysplasia supports a key role for this mitochondrial protein in the ossification process.


Assuntos
Doenças do Desenvolvimento Ósseo/genética , Proteínas Mitocondriais/fisiologia , Sequência de Aminoácidos , Animais , Doenças do Desenvolvimento Ósseo/diagnóstico por imagem , Exoma , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Proteínas do Complexo de Importação de Proteína Precursora Mitocondrial , Proteínas Mitocondriais/química , Proteínas Mitocondriais/genética , Dados de Sequência Molecular , Mutação de Sentido Incorreto , Linhagem , RNA Mensageiro/genética , Radiografia , Saccharomyces cerevisiae/genética , Homologia de Sequência de Aminoácidos
11.
Hum Mol Genet ; 23(11): 2914-25, 2014 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-24419316

RESUMO

FGFR3 gain-of-function mutations lead to both chondrodysplasias and craniosynostoses. Achondroplasia (ACH), the most frequent dwarfism, is due to an FGFR3-activating mutation which results in impaired endochondral ossification. The effects of the mutation on membranous ossification are unknown. Fgfr3(Y367C/+) mice mimicking ACH and craniofacial analysis of patients with ACH and FGFR3-related craniosynostoses provide an opportunity to address this issue. Studying the calvaria and skull base, we observed abnormal cartilage and premature fusion of the synchondroses leading to modifications of foramen magnum shape and size in Fgfr3(Y367C/+) mice, ACH and FGFR3-related craniosynostoses patients. Partial premature fusion of the coronal sutures and non-ossified gaps in frontal bones were also present in Fgfr3(Y367C/+) mice and ACH patients. Our data provide strong support that not only endochondral ossification but also membranous ossification is severely affected in ACH. Demonstration of the impact of FGFR3 mutations on craniofacial development should initiate novel pharmacological and surgical therapeutic approaches.


Assuntos
Acondroplasia/enzimologia , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Acondroplasia/genética , Acondroplasia/patologia , Animais , Condrócitos/citologia , Condrócitos/enzimologia , Feminino , Humanos , Lactente , Masculino , Camundongos , Camundongos Transgênicos , Mutação de Sentido Incorreto , Ossificação Heterotópica , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/metabolismo , Crânio/anatomia & histologia , Crânio/embriologia , Crânio/enzimologia , Crânio/patologia
12.
Am J Hum Genet ; 91(6): 1108-14, 2012 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-23200862

RESUMO

Achondroplasia (ACH), the most common form of dwarfism, is an inherited autosomal-dominant chondrodysplasia caused by a gain-of-function mutation in fibroblast-growth-factor-receptor 3 (FGFR3). C-type natriuretic peptide (CNP) antagonizes FGFR3 downstream signaling by inhibiting the pathway of mitogen-activated protein kinase (MAPK). Here, we report the pharmacological activity of a 39 amino acid CNP analog (BMN 111) with an extended plasma half-life due to its resistance to neutral-endopeptidase (NEP) digestion. In ACH human growth-plate chondrocytes, we demonstrated a decrease in the phosphorylation of extracellular-signal-regulated kinases 1 and 2, confirming that this CNP analog inhibits fibroblast-growth-factor-mediated MAPK activation. Concomitantly, we analyzed the phenotype of Fgfr3(Y367C/+) mice and showed the presence of ACH-related clinical features in this mouse model. We found that in Fgfr3(Y367C/+) mice, treatment with this CNP analog led to a significant recovery of bone growth. We observed an increase in the axial and appendicular skeleton lengths, and improvements in dwarfism-related clinical features included flattening of the skull, reduced crossbite, straightening of the tibias and femurs, and correction of the growth-plate defect. Thus, our results provide the proof of concept that BMN 111, a NEP-resistant CNP analog, might benefit individuals with ACH and hypochondroplasia.


Assuntos
Acondroplasia/tratamento farmacológico , Peptídeo Natriurético Tipo C/análogos & derivados , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Acondroplasia/diagnóstico , Acondroplasia/genética , Animais , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Modelos Animais de Doenças , Lâmina de Crescimento/efeitos dos fármacos , Lâmina de Crescimento/patologia , Humanos , Camundongos , Mutação , Peptídeo Natriurético Tipo C/química , Peptídeo Natriurético Tipo C/fisiologia , Peptídeo Natriurético Tipo C/uso terapêutico , Tamanho do Órgão/efeitos dos fármacos , Radiografia , Crânio/diagnóstico por imagem , Crânio/efeitos dos fármacos , Crânio/patologia , Resultado do Tratamento
13.
Hum Mol Genet ; 21(4): 841-51, 2012 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-22072392

RESUMO

Activating germline fibroblast growth factor receptor 3 (FGFR3) mutations cause achondroplasia (ACH), the most common form of human dwarfism and a spectrum of skeletal dysplasias. FGFR3 is a tyrosine kinase receptor and constitutive FGFR3 activation impairs endochondral ossification and triggers severe disorganization of the cartilage with shortening of long bones. To decipher the role of FGFR3 in endochondral ossification, we analyzed the impact of a novel tyrosine kinase inhibitor (TKI), A31, on both human and mouse mutant FGFR3-expressing cells and on the skeleton of Fgfr3(Y367C/+) dwarf mice. We found that A31 inhibited constitutive FGFR3 phosphorylation and restored the size of embryonic dwarf femurs using an ex vivo culture system. The increase in length of the treated mutant femurs was 2.6 times more than for the wild-type. Premature cell cycle exit and defective chondrocyte differentiation were observed in the Fgfr3(Y367C/+) growth plate. A31 restored normal expression of cell cycle regulators (proliferating cell nuclear antigen, KI67, cyclin D1 and p57) and allowed pre-hypertrophic chondrocytes to properly differentiate into hypertrophic chondocytes. Our data reveal a specific role for FGFR3 in the cell cycle and chondrocyte differentiation and support the development of TKIs for the treatment of FGFR3-related chondrodysplasias.


Assuntos
Desenvolvimento Ósseo/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Condrócitos/citologia , Condrócitos/efeitos dos fármacos , Modelos Animais , Inibidores de Proteínas Quinases/farmacologia , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Animais , Proteínas de Ciclo Celular/análise , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Fêmur/efeitos dos fármacos , Fêmur/embriologia , Lâmina de Crescimento/efeitos dos fármacos , Técnicas In Vitro , Camundongos , Modelos Moleculares , Fosforilação/efeitos dos fármacos , Antígeno Nuclear de Célula em Proliferação/metabolismo , Biossíntese de Proteínas/efeitos dos fármacos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Piridinas/química , Piridinas/metabolismo , Piridinas/farmacologia , Pirimidinas/química , Pirimidinas/metabolismo , Pirimidinas/farmacologia , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/biossíntese , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/química , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética
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