Constitutively-active FGFR3 disrupts primary cilium length and IFT20 trafficking in various chondrocyte models of achondroplasia
doi: 10.1093/hmg/ddx374
pmid: 29040558
Constitutively-active FGFR3 disrupts primary cilium length and IFT20 trafficking in various chondrocyte models of achondroplasia
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.
Male, Bone Development, Cell Differentiation, Achondroplasia, Cell Line, Mice, Inbred C57BL, Disease Models, Animal, Mice, Cartilage, Chondrocytes, Pyrimidines, Cell Movement, Animals, Humans, Receptor, Fibroblast Growth Factor, Type 3, Female, Cilia, Growth Plate, Phosphorylation, Carrier Proteins
Male, Bone Development, Cell Differentiation, Achondroplasia, Cell Line, Mice, Inbred C57BL, Disease Models, Animal, Mice, Cartilage, Chondrocytes, Pyrimidines, Cell Movement, Animals, Humans, Receptor, Fibroblast Growth Factor, Type 3, Female, Cilia, Growth Plate, Phosphorylation, Carrier Proteins
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