Osteoarthritis-like lesions in transgenic mice harboring a small deletion mutation in type II collagen gene
Osteoarthritis-like lesions in transgenic mice harboring a small deletion mutation in type II collagen gene
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DOI：
10.1053/joca.2000.0298
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发表时间：
2000-07-01
影响因子：
7
通讯作者：
Metsäranta, MPH
中科院分区：
文献类型：
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作者：
Säämänen, AMK;Salminen, HJ;Metsäranta, MPH
目的：本研究是在转基因 Del1 (+/-) 小鼠上进行的，该小鼠含有 6 个转基因拷贝，该转基因带有小缺失突变，被设计到小鼠 II 型胶原蛋白基因中。将转基因掺入小鼠基因组预计会导致关节软骨的机械强度降低，并沉积结构较差的胶原网络，从而使动物易患早发性关节退化。设计：在 3 至 22 个月龄之间，每隔 3-5 个月对 Del1 (+/-) 和对照小鼠膝关节退化机会的进展进行宏观和组织学分析。采用Northern杂交、RNA酶保护实验和免疫组织化学方法研究II型胶原蛋白的表达和分布。结果：Del1(+/-)小鼠3月龄时关节软骨开始出现浅表纤维性颤动。这些变化与内源性和转基因衍生的 II 型胶原 mRNA 表达显着减少同时发生。缺损逐渐进展为侵蚀关节软骨、骨质硬化、半月板变性、各种关节结构矿化、囊肿形成和软骨下骨暴露。非转基因对照也出现了骨关节炎病变，但这些病变出现的时间明显晚一些，而且不太严重。在 Del1 (+/-) 小鼠中，六个月时还观察到典型的软骨祖细胞和软骨修复的 IIA 型前胶原 mRNA 转录增加。 结论：这些发现表明，截短的 II 型胶原转基因的影响，以及与成熟相关的 II 型胶原生成减少，显着促进了 Del1 (+/-) 小鼠膝关节的早发性退化。这些具有骨关节炎样表型的小鼠应该为研究关节软骨退变的早期致病机制提供有用的模型。 (C) 2000 年国际骨关节炎研究协会。
Objective: The present study was conducted on transgenic Del1 (+/-) mice harboring six copies of a transgene with small deletion mutation engineered into mouse type II collagen gene. Incorporation of transgene into mouse genome was predicted to cause reduced mechanical strength of articular cartilage with deposition of structurally inferior collagen network and consequently to predispose the animal to early-onset joint degeneration.Design: Progression of degenerative chances in the knee joints of Del1 (+/-) and control mice was followed by macroscopic and histologic analyses at 3-5 month intervals between 3 and 22 months of age. Expression and distribution of type II collagen was studied with Northern hybridization, RNase protection assay and immunohistochemistry.Results: Articular cartilage degeneration began with superficial fibrillation at the age of 3 months in Del1 (+/-) mice. These changes coincided with a significant reduction in the expression of both endogenous and transgene-derived type II collagen mRNA. The defects gradually progressed into erosions penetrating the articular cartilage, bony sclerosis, degeneration of menisci, mineralization of various joint structures, cyst formation and exposure of subchondral bone. Nontransgenic controls also developed osteoarthritic lesions, but these appeared significantly later and were less severe. Increased transcription of type IIA procollagen mRNA, typical for chondroprogenitor cells and cartilage repair was also observed at six months in Del1 (+/-) mice.Conclusion: These findings suggest that the impact of truncated type II collagen transgene, together with maturation-related reduction in type II collagen production significantly contribute to the early-onset degeneration of knee joints in Del1 (+/-) mice. These mice with osteoarthritis-like phenotype should provide a useful model for studies on the early pathogenic mechanisms involved in articular cartilage degeneration. (C) 2000 OsteoArthritis Research Society International.