Involvement of the aging-suppressor gene klotho in the skeletal

Klotho基因突变的纯合子小鼠(Klotho小鼠)表现出与人类衰老相似的多种病理情况。我们观察到骨转换率低的骨量减少，其中骨形成的减少超过骨吸收的减少，导致净骨丢失。Klotho骨髓中B淋巴细胞数量减少，提示该细胞在破骨细胞生成中的作用。脊髓形态观察显示尼氏小体减少，视网膜区异常。然后，我们探索了人类klotho基因多态性是否与年龄相关的骨骼疾病有关：骨质疏松症和脊椎病。Klotho基因的微卫星多态被认为是骨质疏松症和脊椎病遗传调控的候选基因。我们进一步研究了Klotho基因多态与两个遗传不同的种族群体：高加索人和日本人的骨密度之间的关系。对Klotho基因的单核苷酸多态性(SNPs)进行检测，共发现11个多态性，其中3个在两个群体中都是常见的。在老年绝经后妇女(大于或等于65岁)中，启动子区域的一个与骨密度密切相关，但在绝经前或年轻的绝经后妇女中则没有。电泳迁移率改变分析表明，启动子区域的G-&GT；A替换影响DNA-蛋白质相互作用。这些结果表明Klothogem可能参与了人类的一种与年龄相关的疾病的病理生理学。

The mouse homozygous for a disruption of the klotho locus (klotho mouse) exhibited multiple pathological conditions resembling human ageing. We observed osteopenia in klothomce with a low bone turnover, in which the decrease in bone formation exceeded the decrease in bone resorption and resulted in the net bone loss. The number of B lymphocytes was decreased in the klotho bone marrow, suggesting the role of the cells in osteoclastogenesis. Morphological observation of the spinal cord revealed the decrease in Nissle bodies and abnormality of the rER. We then explored whether human klotho gene polymorphism is associated with age-related skeletal disorders : osteoporosis and spondylosis. The microsatellite polymorphism of the klotho gene was shown to be a candidate for the genetic regulation of osteoporosis and spondylosis. We further examined the association between klotho gene polymorphisms and bone density in two genetically distinct racial populations: the Caucasian and the Japanese. Screening of single-nucleotide polymorphisms (SNPs) in the human klotho gene identified a total of 11 polymorphisms, and three of them were common in both populations. One in the promoter region was strongly associated with bone density in aged postmenopausal women (【greater than or equal】65 yrs.), but not in premenopausal or younger postmenopausal women. An electrophoretic mobility shift analysis revealed that the G->A substitution in the promoter region affected DNA-protein interaction. These results indicate that the klothogem may be involved in the pathophysiology an age-related disorder in humans.