Overexpression of FGFR3, Stat1, Stat5 and p21Cip1 correlates with phenotypic severity and defective chondrocyte differentiation in FGFR3-related chondrodysplasias

Autor: Laurence Legeai-Mallet, Jacky Bonaventure, Arnold Munnich, Catherine Benoist-Lasselin
Rok vydání: 2004
Předmět:
Cyclin-Dependent Kinase Inhibitor p21
musculoskeletal diseases
Heterozygote
medicine.medical_specialty
Histology
Physiology
Endocrinology
Diabetes and Metabolism
Receptor expression
Cellular differentiation
DNA Mutational Analysis
Gene Expression
Gestational Age
Biology
Fibroblast growth factor
Chondrocyte
Mice
Chondrocytes
Growth factor receptor
Cyclins
Internal medicine
STAT5 Transcription Factor
medicine
Animals
Humans
Receptor
Fibroblast Growth Factor
Type 3
Growth Plate
Cells
Cultured
STAT5
Cartilage
Cell Differentiation
3T3 Cells
Hyperostosis
Protein-Tyrosine Kinases
Fibroblast growth factor receptor 3
Milk Proteins
Receptors
Fibroblast Growth Factor
Cell biology
DNA-Binding Proteins
Phenotype
STAT1 Transcription Factor
medicine.anatomical_structure
Endocrinology
Microscopy
Fluorescence
Aborted Fetus
Mutation
Trans-Activators
biology.protein
Cell Division
Collagen Type X
Zdroj: Bone. 34:26-36
ISSN: 8756-3282
DOI: 10.1016/j.bone.2003.09.002
Popis: Achondroplasia (ACH) and thanatophoric dysplasia (TD) are human skeletal disorders of increasing severity accounted for by mutations in the fibroblast growth factor receptor 3 (FGFR3). Attempts to elucidate the molecular signaling pathways leading to these phenotypes through mouse model engineering have provided relevant information mostly in the postnatal period. The availability of a large series of human fetuses including 14 ACH and 26 TD enabled the consequences of FGFR3 mutations on endogenous receptor expression during the prenatal period to be assessed by analysis of primary cultured chondrocytes and cartilage growth plates. Overexpression and ligand-independent phosphorylation of the fully glycosylated isoform of FGFR3 were observed in ACH and TD cells. Immunohistochemical analysis of fetal growth plates showed a phenotype-related reduction of the collagen type X-positive hypertrophic zone. Abnormally high amounts of Stat1, Stat5 and p21Cip1 proteins were found in prehypertrophic-hypertrophic chondrocytes, the extent of overexpression being directly related to the severity of the disease. Double immunostaining procedures revealed an overlap of FGFR3 and Stat1 expression in the prehypertrophic-hypertrophic zone, suggesting that constitutive activation of the receptor accounts for Stat overexpression. By contrast, expression of Stat and p21Cip1 proteins in the proliferative zone differed only slightly from control cartilage and differences were restricted to the last arrays of proliferative cells. Our results indicate that FGFR3 mutations in the prenatal period upregulate FGFR3 and Stat-p21Cip1 expression, thus inducing premature exit of proliferative cells from the cell cycle and their differentiation into prehypertrophic chondrocytes. We conclude that defective differentiation of chondrocytes is the main cause of longitudinal bone growth retardation in FGFR3-related human chondrodysplasias.
Databáze: OpenAIRE
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