Osteo-chondroprogenitor-specific deletion of the selenocysteine tRNA gene, Trsp, leads to chondronecrosis and abnormal skeletal development: a putative model for Kashin-Beck disease.
Osteo-chondroprogenitor-specific deletion of the selenocysteine tRNA gene, Trsp, leads to chondronecrosis and abnormal skeletal development: a putative model for Kashin-Beck disease.
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DOI：
10.1371/journal.pgen.1000616
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发表时间：
2009-08
期刊：
影响因子：
4.5
通讯作者：
Jirik FR
中科院分区：
文献类型：
--
作者：
Downey CM;Horton CR;Carlson BA;Parsons TE;Hatfield DL;Hallgrímsson B;Jirik FR
大骨节病是一种以身材矮小、骨骼畸形和多关节关节病为特征的综合征，在亚洲特定地区非常流行。据推测，这种疾病是由不同环境因素的组合引起的，包括霉菌毒素对大麦的污染、碘缺乏、饮用水中存在腐殖物质，以及重要的硒缺乏。这种多功能微量元素，以硒代半胱氨酸的形式，是必不可少的正常硒蛋白功能，包括过度氧化应激的衰减，并参与细胞生长和分化的氧化还原敏感分子的控制。为了研究骨骼硒蛋白缺乏的影响，使用Cre重组酶转基因小鼠系来触发骨软骨祖细胞中的Trsp基因缺失。Trsp编码硒代半胱氨酸tRNA[Ser]Sec，这是将硒代半胱氨酸残基掺入硒蛋白所需的。突变小鼠表现出生长迟缓，骨骺生长板异常，骨骼骨化延迟，以及关节，耳廓和气管软骨的显着软骨坏死。从表型上看，小鼠复制了大骨节病的许多病理特征，支持了硒缺乏对这种综合征的发展很重要的观点。大骨节病（KBD）是一种严重、慢性和变形的肌肉骨骼疾病，影响亚洲特定地区的数百万人。从童年开始，这种疾病导致关节和肢体畸形，身材矮小，骨骼发育迟缓。由于软骨坏死和肢体畸形导致的关节软骨损伤然后导致继发性骨关节炎和严重残疾。引起大骨节病的因素包括缺硒、缺碘、有毒霉菌污染粮食和井水中的腐殖物质。土壤和水缺乏硒（和碘）是大骨节病流行区的一贯特征，受影响的人表现出这两种元素的严重缺乏。到目前为止，还没有令人信服的啮齿动物模型的大骨节病的基础上硒（和/或碘）缺乏症，通过饮食控制。我们的手稿描述了一种条件性基因突变的方法，在小鼠中，实际上，模拟严重的硒缺乏症，实现这一特定的骨骼祖细胞。通过删除骨软骨祖细胞中的硒代半胱氨酸tRNA（正常硒蛋白活性所需），我们发现小鼠出生后骨骼生长受损，侏儒症，骨化延迟，软骨内骨形成受损，以及严重的软骨坏死。我们的突变小鼠支持硒缺乏是大骨节病骨骼病理学的关键的观点。
Kashin-Beck disease, a syndrome characterized by short stature, skeletal deformities, and arthropathy of multiple joints, is highly prevalent in specific regions of Asia. The disease has been postulated to result from a combination of different environmental factors, including contamination of barley by mold mycotoxins, iodine deficiency, presence of humic substances in drinking water, and, importantly, deficiency of selenium. This multifunctional trace element, in the form of selenocysteine, is essential for normal selenoprotein function, including attenuation of excessive oxidative stress, and for the control of redox-sensitive molecules involved in cell growth and differentiation. To investigate the effects of skeletal selenoprotein deficiency, a Cre recombinase transgenic mouse line was used to trigger Trsp gene deletions in osteo-chondroprogenitors. Trsp encodes selenocysteine tRNA[Ser]Sec, required for the incorporation of selenocysteine residues into selenoproteins. The mutant mice exhibited growth retardation, epiphyseal growth plate abnormalities, and delayed skeletal ossification, as well as marked chondronecrosis of articular, auricular, and tracheal cartilages. Phenotypically, the mice thus replicated a number of the pathological features of Kashin-Beck disease, supporting the notion that selenium deficiency is important to the development of this syndrome. Kashin-Beck disease (KBD) is a severe, chronic, and deforming musculoskeletal disease affecting millions of individuals in specific regions of Asia. Starting in childhood, the disorder leads to joint and limb deformities, short stature, and delayed skeletal development. Articular cartilage damage due to chondronecrosis and limb deformities then lead to secondary osteoarthritis and severe disability. Factors proposed to cause KBD include selenium deficiency, iodine deficiency, contamination of grain with toxic molds, and humic substances in well water. Soil and water deficiency in selenium (and iodine) are a consistent feature of KBD endemic areas, and affected individuals show profound deficiencies of these two elements. Thus far, there have been no convincing rodent models of KBD based on selenium (and/or iodine) deficiency achieved through dietary manipulation. Our manuscript describes a conditional gene mutation approach in mice that, in effect, mimics severe selenium deficiency, achieving this specifically within skeletal progenitor cells. By deleting selenocysteine tRNA (required for normal selenoprotein activity) in osteo-chondroprogenitors, we found that mice develop post-natal impairment of skeletal growth, dwarfism, delayed ossification, impaired endochondral bone formation, as well as severe chondronecrosis. Our mutant mouse supports the idea that selenium deficiency is key to the skeletal pathology of KBD.
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