Yamashita T, Nifuji A, Furuya K, Nabeshima Y, Noda M
Department of Molecular Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
J Endocrinol. 1998 Oct;159(1):1-8. doi: 10.1677/joe.0.1590001.
Bone diseases such as osteoporosis and osteoarthritis are regarded as age-associated diseases, and occur in a significantly increasing number of patients, but the underlying mechanisms of these age-associated bone diseases are not yet clear. We have established a transgenic mouse line by an insertion mutation. These mice exhibit many features related to precocious aging. Homozygote mutant mice, which lack expression of the newly identified targeted gene,klotho (kl), exhibit atherosclerosis, emphysema, hypogonadism and calcification of soft tissues, and die within 3-4 months. We describe here the radiological and histological 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 examinations of homozygous mice (kl/kl) show abnormal elongation of the trabecular bone(s) in the epiphyses of long bones. As with their long bones, on radiographic examination the mid parts of the vertebral bones of these mice show less radiopacity compared with the wild-type, again resembling 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 of 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 litter 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 abnormality in bone metabolism, the elongation of the trabecular bone apparently resulting from the relatively low levels of bone resorption. Therefore, thekl/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.
骨质疏松症和骨关节炎等骨骼疾病被视为与年龄相关的疾病，且患病人数在显著增加，但这些与年龄相关的骨骼疾病的潜在机制尚不清楚。我们通过插入突变建立了一个转基因小鼠品系。这些小鼠表现出许多与早衰相关的特征。缺乏新鉴定的靶基因klotho（kl）表达的纯合突变小鼠表现出动脉粥样硬化、肺气肿、性腺功能减退和软组织钙化，并在3至4个月内死亡。我们在此描述了kl基因座发生突变的小鼠骨骼中骨骼异常的放射学和组织学特征。在杂合子小鼠（+/kl）中，骨骼模式和结构保持正常，大多数特征与野生型相似，而纯合子小鼠（kl/kl）的组织学检查显示长骨骺端的小梁骨异常延长。与它们的长骨一样，在放射学检查中，这些小鼠椎骨的中部与野生型相比显示出较低的放射密度，再次类似于骨质疏松症患者的人类椎骨。小梁骨的延长导致每个椎骨两端以及长骨骺端的放射密度较高。纯合子小鼠骨骺中的松质骨体积是野生型小鼠的三倍。kl/kl小鼠比野生型同窝小鼠小，因此它们长骨的尺寸小于野生型同窝小鼠。这些观察结果以及这些小鼠椎骨和长骨中的骨质减少表明骨代谢存在异常，小梁骨的延长显然是由于相对较低水平的骨吸收所致。因此，kl/kl突变小鼠可以作为研究新基因klotho产物缺乏对骨代谢影响的有趣工具。
