FGFR2功能获得性突变对长骨发育过程的影响  

Influence of gain-of-function mutation (Ser252Trp) in fibroblast growth factor receptor 2 gene on long bone development

作　　者：陈鹏[1,2] 张波[1] 张莉[1] 张连阳[1] 

机构地区：[1]第三军医大学大坪医院野战外科研究所创伤、烧伤及复合伤国家重点实验室,重庆400042 [2]解放军324医院普通外科

出　　处：《解放军医学杂志》2013年第7期540-544,共5页Medical Journal of Chinese People's Liberation Army

基　　金：国家重点基础研究发展计划(973计划)(2011CB964701)~~

摘　　要：目的对比观察Fgfr2+/S252W突变型小鼠和同窝野生型小鼠长骨的生长发育情况,探讨FGFR2功能持续增强对软骨内成骨过程的影响。方法采用经基因敲入技术建立的模拟人Apert综合征的Fgfr2+/S252W小鼠模型,经繁殖、鉴定后分为Fgfr2+/S252W功能获得突变型和同窝野生型。于出生后7、10、14、28d分别处死突变型和野生型小鼠各3只,对长骨进行长度测量、X线检查及Micro CT检查,另取部分长骨标本进行HE染色和免疫组化染色观察。结果 Fgfr2+/S252W突变小鼠呈典型Apert综合征圆颅和短颅畸形,体形发育缓慢,体长、四肢长度明显小于同窝野生小鼠,且长骨发育障碍,第二骨化中心延迟出现,骨密度及骨小梁数量低于同窝野生型小鼠。组织学观察可见突变小鼠胫骨近端生长板软骨细胞增殖区和肥大区厚度缩短,细胞排列不及野生型整齐,肥大软骨细胞体积小,免疫组化检测显示软骨相关增殖、分化基因表达均减弱。结论 FGFR2功能持续增强可导致小鼠长骨发育障碍。FGFR2可能具有调控成骨细胞系及软骨细胞系发育的功能,在骨骼发育等方面发挥重要作用。Objective To observe the early postnatal long bone development in Fgfr2＋/S252W mutant mice and littermate wild-type（WT） mice,and explore the effect of continued function enhancement of fibroblast growth factor receptor 2（FGFR2） gene on endochondral ossification.Methods A mouse model of Fgfr2＋/S252Wsimulated human Apert syndrome was reproduced by knock-in technique,and then the gain-of-function mutation Fgfr2＋/S252W mice and littermate WT mice were obtained after breeding and identification.Three Fgfr2＋/S252W and same number of WT mice were sacrificed at 7,10,14 and 28 postnatal days respectively,and the morphology of long bone was examined with X-ray and Micro CT,the structure of bone and cartilage was observed by HE staining,and the expression of gene in growth plate was observed by immunohistochemical analysis.Results Fgfr2＋/S252W mouse model exhibited typical craniosynostosis and brachycephalium of Apert syndrome,accompanied by short stature,growth retardation of long bone,delayed appearance of secondary ossification center,decrease of bone density and trabecula number.HE staining showed noticeable shortened zones of proliferation and hypertrophic chondrocytes,irregularity of cell arrangement,and small hypertrophic chondrocytes in the growth plates of the mutant mice.Immunohistochemical analysis revealed that the expression of genes related to chondrocytes proliferation and differentiation was decreased in mutant mice.Conclusions Gain-of-function mutation in FGFR2 may lead to abnormal development of long bone in mice.FGFR2 may have the function of regulating the development both of osteoblast and chondrocyte lineages,and play an important role in the process of skeletal development.

关 键 词：受体 成纤维细胞生长因子 2型 尖头并指(趾)畸形 软骨发生 骨生成 

分 类 号：R682.19[医药卫生—骨科学]