Gly369Cys mutation in mouse FGFR3 causes achondroplasia by affecting both chondrogenesis and osteogenesis
Gly369Cys mutation in mouse FGFR3 causes achondroplasia by affecting both chondrogenesis and osteogenesis
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DOI：
10.1172/jci6690
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发表时间：
1999-12-01
影响因子：
15.9
通讯作者：
Deng, CX
中科院分区：
文献类型：
--
作者：
Chen, L;Adar, R;Deng, CX
成纤维细胞生长因子受体 3 (FGFR3) 的错义突变会导致多种人类骨骼发育不良，包括最常见的侏儒症——软骨发育不全。在这里，我们发现人 FGFR3 中 375 位（Gly375Cys）的甘氨酸到半胱氨酸的取代会导致 FGFR3 的配体独立二聚化和磷酸化，而小鼠 FGFR3 中 369 位（Gly369Cys）的等效取代会导致侏儒症，其特征类似于人类软骨发育不全。因此，纯合子小鼠比杂合子小鼠受到的影响更严重。由此产生的突变小鼠由于软骨内骨生长迟缓和颅底软骨过早闭合而表现出大头畸形和四肢缩短。与野生型同窝小鼠相比，突变小鼠的生长板具有扩大的静止区和缩小的增殖区和肥大区，这与 Stat 蛋白的激活和细胞周期抑制剂的上调相关。骨密度降低伴随着破骨细胞活性的增加以及与成骨细胞分化相关的基因的上调，包括骨桥蛋白、骨连接蛋白和骨钙蛋白。这些数据揭示了 FGF/FGFR3 信号在软骨内骨化过程中软骨形成和成骨中的重要作用。
Missense mutations in fibroblast growth factor receptor 3 (FGFR3) result in several human skeletal dysplasias, including the most common form of dwarfism, achondroplasia. Here we show that a glycine-to-cysteine substitution at position 375 (Gly375Cys) in human FGFR3 causes ligand-independent dimerization and phosphorylation of FGFR3 and that the equivalent substitution at position 369 (Gly369Cys) in mouse FGFR3 causes dwarfism with features mimicking human achondroplasia. Accordingly, homozygous mice were more severely affected than heterozygotes. The resulting mutant mice exhibited macrocephaly and shortened limbs due to retarded endochondral bone growth and premature closure of cranial base synchondroses. Compared with their wild-type littermates, mutant mice growth plates shared an expanded resting zone and narrowed proliferating and hypertrophic zones, which is correlated with the activation of Stat proteins and upregulation of cell-cycle inhibitors. Reduced bone density is accompanied by increased activity of osteoclasts and upregulation of genes that are related to osteoblast differentiation, including osteopontin, osteonectin, and osteocalcin. These data reveal an essential role for FGF/FGFR3 signals in both chondrogenesis and osteogenesis during endochondral ossification.