REDUCED AMOUNTS OF CARTILAGE COLLAGEN FIBRILS AND GROWTH PLATE ANOMALIES IN TRANSGENIC MICE HARBORING A GLYCINE-TO-CYSTEINE MUTATION IN THE MOUSE TYPE-II PROCOLLAGEN ALPHA-1-CHAIN GENE
REDUCED AMOUNTS OF CARTILAGE COLLAGEN FIBRILS AND GROWTH PLATE ANOMALIES IN TRANSGENIC MICE HARBORING A GLYCINE-TO-CYSTEINE MUTATION IN THE MOUSE TYPE-II PROCOLLAGEN ALPHA-1-CHAIN GENE
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DOI：
10.1073/pnas.88.21.9648
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发表时间：
1991-11-01
影响因子：
11.1
通讯作者：
DECROMBRUGGHE, B
中科院分区：
文献类型：
--
作者：
GAROFALO, S;VUORIO, E;DECROMBRUGGHE, B
我们已经产生了转基因小鼠，在小鼠II型胶原的三螺旋结构域的85个残基上存在甘氨酸到半胱氨酸的突变。不同创始人的后代表现出严重的软骨发育不良表型，特征是四肢和躯干较短，颅面畸形和腭裂。受影响的幼崽死于急性呼吸窘迫，原因是出生时肺部无法充气。对骨骼的染色显示，几乎所有的骨骼都严重生长迟缓。光镜检查显示软骨基质密度降低，生长板结构严重紊乱，软骨基质中存在纤维状物质条纹。电子显微镜分析显示，典型的软骨细小胶原纤维数量明显减少，软骨细胞粗面内质网扩张，并存在异常大的带状胶原纤维束。突变的II型前胶原α-1链转基因在软骨组织中的表达水平与内源性基因在其中两株中的表达水平大致相同。我们认为，突变的主要结果是典型的薄软骨胶原纤维密度显著降低，这种现象导致生长板严重解体。我们还推测，异常增厚的胶原纤维可能与胶原分子之间的交联性缺陷有关。这些转基因小鼠表现出的软骨异常与某些人类软骨发育不良的软骨异常非常相似。
We have generated transgenic mice harboring a glycine-to-cysteine mutation in residue 85 of the triple helical domain of mouse type II collagen. The offspring of different founders displayed a phenotype of severe chondrodysplasia characterized by short limbs and trunk, cranio-facial deformities, and cleft palate. The affected pups died of acute respiratory distress caused by an inability to inflate lungs at birth. Staining of the skeleton showed a severe retardation of growth for practically all bones. Light microscopic examination indicated a decrease in cartilage matrix density, a severe disorganization of growth plate architecture, and the presence of streaks of fibrillar material in the cartilage matrix. Electron microscopic analysis showed a pronounced decrease in the number of typical thin cartilage collagen fibrils, distension of the rough endoplasmic reticulum of chondrocytes, and the presence of abnormally large banded collagen fibril bundles. The level of expression of the mutant type II procollagen alpha-1 chain transgene in cartilage tissues was approximately equal to that of the endogenous gene in two of the strains. We propose that the principal consequence of the mutation is a considerable reduction in density of the typical thin cartilage collagen fibrils and that this phenomenon causes the severe disorganization of the growth plate. We also postulate that the abnormal thick collagen fibrils are probably related to a defect in crosslinking between the collagen molecules. The cartilage anomalies displayed by these transgenic mice are remarkably similar to those of certain human chondrodysplasias.