Involvement of the aging-suppressor gene klotho in the skeletal

klotho基因座破坏的纯合子小鼠（klotho小鼠）表现出类似人类衰老的多种病理状况。我们在klothomce中观察到骨量减少伴低骨转换，其中骨形成的减少超过骨吸收的减少，并导致净骨丢失。klotho骨髓中B淋巴细胞的数量减少，表明细胞在破骨细胞生成中的作用。脊髓形态学观察显示尼氏体减少，rER异常。然后，我们探讨人类klotho基因多态性是否与年龄相关的骨骼疾病：骨质疏松症和颈椎病。klotho基因的微卫星多态性被证明是骨质疏松症和颈椎病的遗传调控的候选者。我们进一步研究了klotho基因多态性和骨密度之间的关联，在两个遗传不同的种族人群：高加索人和日本人。对人类klotho基因的单核苷酸多态性（SNP）进行筛选，共发现11种多态性，其中3种在两个人群中都很常见。启动子区的一个与绝经后老年妇女（[大于或等于]65岁）的骨密度密切相关，但在绝经前或绝经后较年轻的妇女中没有。电泳迁移率变动分析表明，启动子区的G->A取代影响DNA-蛋白质相互作用。这些结果表明，klothogem可能参与病理生理学的年龄相关的疾病在人类。

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.