Mechanism of Bone Growth : Research on proliferation and apoptosis of growth plate chondrocyte.

骨生长机制：生长板软骨细胞增殖与凋亡的研究。

基本信息

批准号：
12470220
负责人：
SEINO Yoshiki
金额：
$ 9.34万
依托单位：
Okayama University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12470220/
关键词：
軟骨無形成症 FGFR3 IGF-1 Bcl-2 stat-1 apoptosis PTHrP 成長軟骨線維芽細胞成長因子受容体3 細胞死 IGF-I 器官培養変異FGFR3 ATDC-5 VPRKO 軟骨細胞 bcl-2

项目摘要

We aimed to explore molecular basis of the cell proliferation, differentiation, and cell death(apoptosis) of the growth plate chondrocyte in this project. To this aid, we selected achondroplasia as a model disorder of growth plate chondrocyte. The responsible gene to this disorder is the gene coding fibroblast growth factor receptor 3 (FGFR3). The major mutation is G380R, which activate receptor constitutively. And related severe form, thanatophoric dysplasia is due to the mutation, K650E, which induce receptor activation more profoundly. We at first introduced these mutations into chondrogenic cell line, ATDC5, and studied phenotypic change of these cells. The chondrocytes expressing mutated FGFR3 showed deteriorated cell growth and increased apoptosis. The inhibition of the cell growth was mediated by the activation of p21 and increased apoptosis was due to the decreased bcl-2 expression. Moreover K650E mutation induced stat 1 activation and its nuclear translocation and this event l … More ooked to located upstream of deteriorated cell growth and increased apoptosis. IGF-I induced by the Growth hormone treatment may activate PI3K and then increase bcl-2 expression. This mechanism may be responsible to the rescue chondrocyte from apoptosis and to GH stimulated bone growth in achondroplasia.From thee analogy of achondroplasia to PTHrP KO mice, we next studied PTHrP expression in this cellular model. The cells expressing mutated FGFR3 showed decreased expression of PTHrP mRNA. Moreover, this decrease was more severe in K650E mutation. Next we administered PTHrP to the cells by several methods and confirmed that PTHrP signal may blockk pathogenic pathway induced by constitutively activated FGFR3 and rescue the cells from apoptosis. Bone organ culture system using cartilage specific mutated FGFR3 transgenic mice showed increased bone length, which was mainly due to the expansion of proliferative chondrocyte zone. In vivo experiment similarly indicates promising effect of PTH on the bone growth of achondroplasia. Less

我们旨在探索该项目中生长板软骨细胞的细胞增殖，分化和细胞死亡（凋亡）的分子基础。为此，我们选择了钙质质症作为生长板软骨细胞的模型障碍。该疾病的负责基因是编码成纤维细胞生长因子受体3（FGFR3）的基因。主要突变是G380R，它组成型激活受体。相关的严重形式，胜超增生症是由于突变K650E引起的，它更深刻地诱导了接收器的激活。我们首先将这些突变引入了这些细胞的软骨生成细胞系，ATDC5和Studiod表型变化中。表达突变FGFR3的软骨细胞显示出检测到的细胞生长和凋亡增加。细胞生长的抑制是通过p21的激活介导的，凋亡增加是由于Bcl-2表达降低所致。此外，K650E突变诱导了STAT 1激活及其核易位，并且此事件l…更多……更多地利用了被检测到的细胞生长和凋亡增加的位置。生长马治疗引起的IGF-I可能会激活PI3K，然后增加Bcl-2表达。这种机制可能是从细胞凋亡中挽救软骨细胞的原因，并刺激了刺激性的骨骼生长。从钙质质质质的类比到PTHRP KO小鼠，我们接下来在此细胞模型中研究了PTHRP的表达。表达突变FGFR3的细胞显示PTHRP mRNA的表达降低。此外，在K650E突变中，这种减少更为严重。接下来，我们通过多种方法将PTHRP施用到细胞上，并确认PTHRP信号可能会阻止由组成型激活的FGFR3诱导的致病途径并从凋亡中挽救细胞。使用软骨特异性突变FGFR3转基因小鼠的骨骼器官培养系统显示出骨长的增加，这主要是由于增殖软骨细胞区域的扩展。体内实验类似地表明，PTH对肌浮肿的骨骼生长的有希望的影响。较少的