Involvement of the aging-suppressor gene klotho in the skeletal

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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.