权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Analysis of cranio-facial deformities caused by abnormal endochondral ossification

软骨内骨化异常所致颅面部畸形分析

基本信息

批准号：
13671896
负责人：
AMIZUKA Norio
金额：
$ 1.98万
依托单位：
Niigata University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2003
项目状态：
已结题

项目摘要

Achondroplasia and chondrodysplaisa, both of which are congenital deformities, are caused by constitutively-active forms of FGFR3 and PTH/PTHrP receptor, respectively. We have attempted to clarify which of FGFR3 and PTHrP show predominant function on chondrocyte differentiation. Furthermore, PTHrP has a nucleolar targeting signal in the internal region., without mediating the common receptor with PTH. Thus, we examined the biological action of PTHrPand FGFR3 in cartilage development.(1)The 18-day-old fetus with null mutation of FGFR3/PTHrP genes revealed shorted limbs, consistent with the abnormalities of the PTHrP^<-/-> fetuses. The FGFR3^<-/->/PTHrP^<-/-> compound mutant fetuses showed reduced numbers of epiphyseal chondrocytes and a form of chondrodysplasia, which are characteristic features of the PTHrP^<-/-> fetus. Therefore, PTHrP appeared to function predominantly to FGFR3, or to lie down-stream of PTHrP on chondrocyte proliferation. However, the numbers of apoptotic chondrocytes were significantly reduced in FGFR3^<-/->/PTHrP^<-/-> fetuses, compared with that of PTHrP^<-/-> fetus. In addition, the FGFR3^<-/-> and the compound fetuses revealed the markedly reduced expression of VEGF in the hypertrophic zone, whereas the PTHrP deficient fetus displayed the abundant mRNA of VEGF in the matched region. Thus, FGFR3 appears to act functionally in the upstream to PTHrP signaling on proliferating chondrocytes, as well as to act independently on hypertrophic chondrocytes.(2)The majority of the biological activity of PTHrP is mediated through the binding to the common receptor with PTH. However, PTHrP shows a nucleolar targeting signal in the internal region. Chondrocytic cell line transfected with truncated forms of PTHrP cDNA showed this peptide in the nucleoli mediated by translation initiating from AUG-codon and alternatively initiating from CUG codons.

软骨发育不全和软骨发育不良都是先天性畸形，分别由 FGFR3 和 PTH/PTHrP 受体的组成型活性形式引起。我们试图阐明 FGFR3 和 PTHrP 中哪一个在软骨细胞分化中显示出主要功能。此外，PTHrP在内部区域具有核仁靶向信号，而不介导与PTH的共同受体。因此，我们检测了PTHrP和FGFR3在软骨发育中的生物学作用。(1)FGFR3/PTHrP基因无效突变的18天胎儿显示出四肢短小，与PTHrP^</-/->胎儿的异常一致。 FGFR3^</->/PTHrP^</-/->复合突变胎儿表现出骨骺软骨细胞数量减少和某种形式的软骨发育不良，这是PTHrP^</-/->胎儿的特征。因此，PTHrP 似乎主要对 FGFR3 起作用，或者在软骨细胞增殖方面位于 PTHrP 的下游。然而，与PTHrP^-/-胎儿相比，FGFR3^-/->/PTHrP^-/-胎儿中凋亡软骨细胞的数量显着减少。此外，FGFR3^-/-和复合胎儿显示肥厚区VEGF表达显着降低，而PTHrP缺陷胎儿在匹配区域显示丰富的VEGF mRNA。因此，FGFR3 似乎在增殖软骨细胞上的 PTHrP 信号传导上游发挥功能，并且独立地作用于肥大软骨细胞。(2)PTHrP 的大部分生物活性是通过与 PTH 共同受体结合介导的。然而，PTHrP 在内部区域显示核仁靶向信号。用截短形式的PTHrP cDNA转染的软骨细胞系显示，该肽在核仁中由从AUG密码子起始或从CUG密码子起始的翻译介导。