Depletion of cartilage collagen fibrils in mice carrying a dominant negative Col2a1 transgene affects chondrocyte differentiation
Depletion of cartilage collagen fibrils in mice carrying a dominant negative Col2a1 transgene affects chondrocyte differentiation
复制标题
DOI：
10.1152/ajpcell.00579.2002
复制
发表时间：
2003-12-01
影响因子：
5.5
通讯作者：
Garofalo, S
中科院分区：
文献类型：
--
作者：
Barbieri, O;Astigiano, S;Garofalo, S
我们已经产生了小鼠Alpha1(II)前胶原基因(Col2a1)外显子48缺失的转基因小鼠。这是在人类α1(II)前胶原基因(COL2A1)中发现的第一个显性负突变。携带这种突变的单个等位基因的患者患有一种严重的骨骼疾病，称为先天性脊柱骨盆发育不良(SED)。转基因小鼠的表型在新生儿中是致命的，并伴有严重的呼吸衰竭、短骨和腭裂。转基因mR-NA高水平表达。转基因小鼠生长板软骨形态异常，II型胶原纤维数量减少。携带该突变的软骨细胞表现出几种分化标志物的表达变化，如成纤维细胞生长因子受体3(FGFR3)、印度刺猬(IHH)、Runx2、细胞周期蛋白依赖的激酶抑制物P21(CIP/WAF)(CDKN1A)和X型胶原(Col10a1)，这表明缺乏胶原纤维的细胞外基质(ECM)缺陷影响软骨细胞的分化，这种缺陷参与了COL2A1突变引起的软骨发育不良症中软骨内骨生长的减少。
We have generated transgenic mice harboring the deletion of exon 48 in the mouse alpha1(II) procollagen gene (Col2a1). This was the first dominant negative mutation identified in the human alpha1(II) procollagen gene (COL2A1). Patients carrying a single allele with this mutation suffer from a severe skeletal disorder called spondyloepiphyseal dysplasia congenita ( SED). Transgenic mice phenotype was neonatally lethal with severe respiratory failure, short bones, and cleft palate. Transgene mRNA was expressed at high levels. Growth plate cartilage of transgenic mice presented morphological abnormalities and reduced number of collagen type II fibrils. Chondrocytes carrying the mutation showed altered expression of several differentiation markers, like fibroblast growth factor receptor 3 (Fgfr3), Indian hedgehog (Ihh), runx2, cyclin- dependent kinase inhibitor P21(CIP/WAF) (Cdkn1a), and collagen type X (Col10a1), suggesting that a defective extracellular matrix (ECM) depleted of collagen fibrils affects chondrocytes differentiation and that this defect participates in the reduced endochondral bone growth observed in chondrodysplasias caused by mutations in COL2A1.