Nakata K, Ono K, Miyazaki J, Olsen B R, Muragaki Y, Adachi E, Yamamura K, Kimura T
Department of Orthopaedic Surgery, Osaka University Medical School, Japan.
Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):2870-4. doi: 10.1073/pnas.90.7.2870.
Type IX collagen, containing molecules of the three distinct polypeptides alpha 1(IX), alpha 2(IX), and alpha 3(IX), is an interesting hybrid extracellular matrix component in cartilage and eye tissues, with the properties of both a proteoglycan and a collagen. The alpha 1 (IX) chain has two forms, as a result of the tissue-specific utilization of two alternative promoters; the alpha 2(IX) chain carries a covalently attached glycosaminoglycan side chain. We have introduced a gene construct controlled by a tissue-specific promoter/enhancer and expressing a truncated alpha 1(IX) chain into mice. Examination of the offspring of two different founders revealed pathological changes similar to osteoarthritis in the articular cartilage of knee joints. In addition, mice homozygous for the transgene developed mild chondrodysplasia (i.e., mild dwarfism, anterior tonguing in the vertebral bodies, and ophthalmopathy). The relative ratio of transgene product to the endogenous alpha 1(IX) chain was approximately one in homozygotes and less than one in heterozygotes. Therefore, the phenotypic severity correlated well with the level of transgene expression. These findings suggest that mutations in type IX collagen genes may cause certain forms of osteoarthritis and chondrodysplasia in humans.
IX型胶原蛋白由三种不同的多肽α1(IX)、α2(IX)和α3(IX)组成，是软骨和眼组织中一种有趣的混合细胞外基质成分，兼具蛋白聚糖和胶原蛋白的特性。由于两种替代启动子的组织特异性利用，α1(IX)链有两种形式；α2(IX)链带有共价连接的糖胺聚糖侧链。我们将一个由组织特异性启动子/增强子控制并表达截短α1(IX)链的基因构建体导入小鼠体内。对两个不同奠基者的后代进行检查发现，膝关节的关节软骨出现了类似于骨关节炎的病理变化。此外，转基因纯合子小鼠出现了轻度软骨发育不良（即轻度侏儒症、椎体前部舌样改变和眼病）。转基因产物与内源性α1(IX)链的相对比例在纯合子中约为1，在杂合子中小于1。因此，表型严重程度与转基因表达水平密切相关。这些发现表明，IX型胶原蛋白基因突变可能导致人类某些形式的骨关节炎和软骨发育不良。
