Transgenic mice expressing D469Δ mutated cartilage oligomeric matrix protein (COMP) show growth plate abnormalities and sternal malformations
Transgenic mice expressing D469Δ mutated cartilage oligomeric matrix protein (COMP) show growth plate abnormalities and sternal malformations
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DOI：
10.1016/j.matbio.2007.08.001
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发表时间：
2008-03-01
期刊：
影响因子：
6.9
通讯作者：
Zaucke, Frank
中科院分区：
文献类型：
--
作者：
Schmitz, Markus;Niehoff, Anja;Zaucke, Frank
在人类中，软骨寡聚基质蛋白（COMP）的突变导致常染色体显性遗传的骨骼发育不良。我们已经产生了转基因小鼠品系，以研究突变体D469 Delta COMP在假性软骨发育不全发病机制中的作用。软骨组织的生物化学表征表明，转基因和内源性COMP亚基能够在体内形成混合的五聚体分子。突变COMP比野生型蛋白更难提取，表明基质内的锚定改变。虽然转基因野生型和突变体COMP都在整个生长板中检测到，但突变体分子仅限于细胞周基质，而野生型COMP在整个细胞外基质中显示出均匀分布。表达突变转基因的小鼠表现出轻微的性别特异性生长迟缓。在突变动物中，生长板中的柱状组织被扰乱，蛋白聚糖丢失，并观察到不正确形成的胶原纤维。在一些软骨细胞中，内质网扩张，最可能是由于突变COMP的分泌受损，类似于在患者中观察到的。在发育后期，生长板形状不规则，过早地被骨组织侵入。此外，经常观察到第三和第四胸骨节融合。(c)2007年Elsevier B. V./国际矩阵生物学学会。All rights reserved.
In humans, mutations in cartilage oligomeric matrix protein (COMP) cause autosomal dominantly inherited skeletal dysplasias. We have generated transgenic mouse lines to study the role of mutant D469 Delta COMP in the pathogenesis of pseudoachondroplasia. Biochemical characterization of cartilage tissue demonstrated that transgenic and endogenous COMP subunits were able to form mixed, pentameric molecules in vivo. Mutant COMP was more difficult to extract than the wildtype protein, suggesting an altered anchorage within the matrix. Although both transgenic wildtype and mutant COMP were detected throughout the growth plate, mutant molecules were restricted to the pericellular matrix while wildtype COMP showed a uniform distribution throughout the extracellular matrix. Mice expressing the mutant transgene showed a slight gender specific growth retardation. In mutant animals, the columnar organization in the growth plate was disturbed, proteoglycans were lost and improperly formed collagen fibrils were observed. In some chondrocytes the endoplasmic reticulum was dilated, most probably due to an impaired secretion of mutant COMP similar to that observed in patients. Later in development, the growth plate was irregularly shaped and prematurely invaded by bony tissue. In addition, a fusion of the third and fourth sternebrae was frequently observed. (c) 2007 Elsevier B.V./International Society of Matrix Biology. All rights reserved.