Fibroblast growth factor receptor 3 mutations promote apoptosis but do not alter chondrocyte proliferation in thanatophoric dysplasia.
Thanatophoric dysplasia (TD) is a lethal skeletal disorder caused by recurrent mutations in the fibroblast growth factor receptor 3 (FGFR 3) gene. The mitogenic response of fetal TD I chondrocytes in primary cultures upon stimulation by either FGF 2 or FGF 9 did not significantly differ from controls. Although the levels of FGFR 3 mRNAs in cultured TD chondrocytes were similar to controls, an abundant immunoreactive material was observed at the perinuclear level using an anti-FGFR 3 antibody in TD cells. Transduction signaling via the mitogen-activated protein kinase pathway was assessed by measuring extracellular signal-regulated kinase activity (ERK 1 and ERK 2). Early ERKs activation following FGF 9 supplementation was observed in TD chondrocytes (2 min) as compared with controls (5 min) but no signal was detected in the absence of ligand. By contrast ligand-independent activation of the STAT signaling pathway was demonstrated in cultured TD cells and confirmed by immunodetection of Stat 1 in the nuclei of hypertrophic TD chondrocytes. Moreover, the presence of an increased number of apoptotic chondrocytes in TD fetuses was associated with a higher expression of Bax and the simultaneous decrease of Bcl-2 levels. Taken together, these results indicate that FGFR 3 mutations in TD I fetuses do not hamper chondrocyte proliferation but rather alter their differentiation by triggering premature apoptosis through activation of the STAT signaling pathway.
Legeai-Mallet
L
L
Unité de Recherches sur les Handicaps Génétiques de l'Enfant, INSERM U393, Institut Necker, 75743 Paris Cedex 15, France.
Benoist-Lasselin
C
C
Delezoide
A L
AL
Munnich
A
A
Bonaventure
J
J
D017209:Apoptosis / Q000235:genetics*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002455:Cell Division / Q000235:genetics*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D005315:Fetal Diseases / Q000473:pathology; D005838:Genotype; D006132:Growth Plate / Q000166:cytology* / Q000201:enzymology; D006801:Humans; D007150:Immunohistochemistry; D009154:Mutation; D010641:Phenotype; D011505:Protein-Tyrosine Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics* / Q000378:metabolism; D050794:STAT1 Transcription Factor; D013796:Thanatophoric Dysplasia / Q000473:pathology*; D015534:Trans-Activators / Q000378:metabolism
D004268:DNA-Binding Proteins; D017468:Receptors, Fibroblast Growth Factor; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; C496365:FGFR3 protein, human; D011505:Protein-Tyrosine Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3; D017871:Calcium-Calmodulin-Dependent Protein Kinases