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Klotho mutant (kl/kl) mice exhibit growth retardation after weaning, and previous electron microscopic examination of GH-producing cells in pituitary glands revealed a reduction in GH granules. However, it has not been known whether growth retardation in klotho mutant mice is related to the loss of GH function. We therefore examined whether treatment with GH could rescue the retardation of growth. At the end of 3 weeks of treatment with human GH, the body weight of wild-type (WT) mice was increased. In contrast, body weight was not increased in klotho mutant mice even after the treatment with human GH. Another feature of klotho mutant mice is the presence of osteopetrosis in the epiphyses of long bones and vertebrae. Treatment with human GH increased trabecular bone volume in the epiphyseal region of WT tibiae. Interestingly, increase in trabecular bone volume by GH treatment was also observed in klotho mutant mice and, therefore, the phenotype of high bone volume in the klotho mice was further enhanced. These findings indicate that a GH receptor system in cancellous bones could operate in mutant mice. Thus, growth retardation in the klotho mutant mice is resistant against GH treatment even when these mice respond to GH treatment in terms of cancellous bone volume.

Unloading induces bone loss as seen in experimental animals as well as in space flight or in bed-ridden conditions; however, the mechanisms involved in this phenomenon are not fully understood. Klotho mutant mice exhibit osteopetrosis in the metaphyseal regions indicating that the klotho gene product is involved in the regulation of bone metabolism. To examine whether the klotho gene product is involved in the unloading-induced bone loss, the response of the osteopetrotic cancellous bones in these mice was investigated. Sciatic nerve resection was conducted using klotho mutant (kl/kl) and control heterozygous mice (+/kl) and its effect on bone was examined by micro-computed tomography (microCT). As reported previously for wild-type mice (+/+), about 30% bone loss was induced in heterozygous mice (+/kl) by unloading due to neurectomy within 30 days of the surgery. By contrast, kl/kl mice were resistant against bone loss induced by unloading after neurectomy. Unloading due to neurectomy also induced a small but significant bone loss in the cortical bone of the mid-shaft of the femur in the heterozygous mice; no reduction in the cortical bone was observed in kl/kl mice. These results indicate that klotho mutant mice are resistant against bone loss induced by unloading due to neurectomy in both cortical and trabecular bone and indicate that klotho is one of the molecules involved in the loss of bone by unloading.