ELONGATION OF THE EPIPHYSEAL TRABECULAR BONE IN TRANSGENIC MICE CARRYING A KLOTHO GENE LOCUS MUTATION THAT LEADS TO A SYNDROME RESEMBLING AGING

Bone diseases such as osteoporosis and osteoarthritis are regarded as age-associated diseases, and occur in a significantly increasing numbe r of patients, but the underlying mechanisms of these age-associated b one diseases are not yet clear, We have established a transgenic mouse line by an insertion mutation. These mice exhibit many features relat ed to precocious aging. Homozygote mutant mice, which lack expression of the newly identified targeted gene, klotho (kl), exhibit atheroscle rosis, emphysema, hypogonadism and calcification of soft tissues, and die within 3-4 months. We describe here the radiological and histologi cal characteristics of the skeletal abnormalities in the bones of the mice with a mutation in the kl gene locus. In heterozygous mice (+/kl) , the skeletal patterns and structures remain normal and most features are similar to those in the wild-type, whereas histological examinati ons of homozygous mice (kl/kl) show abnormal elongation of the trabecu lar bone(s) in the epiphyses of long bones. As with their long bones, on radiographic examination the mid parts of the vertebral bones of th ese mice show less radiopacity compared with the wild-type, again rese mbling human vertebrae of osteoporotic patients. The elongation of the trabecular bones results in high radiopacity on both ends of each of the vertebrae, and in the epiphyses oi the long bones. Cancellous bone volume in the epiphyses of the homozygote mice is three times that of the wild-type mice. The kl/kl mice are smaller than the wild-type lit ter mates and hence the size of their long bones is less than that of the wild-type litter mates. These observations, and the osteopenia in the vertebrae and long bones in these mice, suggest the presence of ab normality in bone metabolism, the elongation of the trabecular bone ap parently resulting from the relatively low levels of bone resorption. Therefore, the kl/kl mutant mice could serve as an interesting tool to study the effects of the lack of the product of the new gene, klotho, on bone metabolism.