Yoshida Toru, Fujimori Toshihiko, Nabeshima Yo-Ichi
Department of Pathology and Tumor Biology, The Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
Endocrinology. 2002 Feb;143(2):683-9. doi: 10.1210/endo.143.2.8657.
Homozygous klotho mutant (kl-/-) mice exhibit multiple phenotypes resembling human aging. To elucidate the molecular basis of these singular phenotypes, we focused on the mechanisms underlying increased serum concentrations of calcium and phosphorus in kl-/- mice. Serum concentrations of calcitonin and PTH of kl-/- mice were normally up- and down-regulated, respectively, in response to the high levels of calcium. On the other hand, despite the high concentrations of calcium, serum levels of 1,25-dihydroxyvitamin D [1,25-(OH)2D] in kl-/- mice were significantly higher than that of wild type (WT). The expression of 25-hydroxyvitamin D 1alpha-hydroxylase gene, the key enzyme of vitamin D metabolism, was also greatly enhanced in kidneys of kl-/- mice. Furthermore, the normal genetic responses to administered 1,25-(OH)2D3, such as down-regulation of the 25-hydroxyvitamin D 1alpha-hydroxylase gene and up-regulation of 24-hydroxylase and VDR genes, were apparently impaired in kl-/- mice. These findings suggest that this deterioration in the vitamin D endocrine system may result in many of the phenotypes in kl-/- mice through effects of increased levels of calcium and phosphorus and 1,25-(OH)2D. Klotho protein may participate in calcium and phosphorus homeostasis via the regulation of the 1,25-(OH)2D signaling pathway.
纯合的klotho突变体(kl-/-)小鼠表现出多种类似于人类衰老的表型。为了阐明这些独特表型的分子基础,我们聚焦于kl-/-小鼠血清钙和磷浓度升高的潜在机制。kl-/-小鼠的降钙素和甲状旁腺激素(PTH)血清浓度通常分别对高水平的钙做出上调和下调反应。另一方面,尽管钙浓度很高,但kl-/-小鼠的血清1,25-二羟维生素D [1,25-(OH)2D]水平显著高于野生型(WT)小鼠。维生素D代谢的关键酶25-羟维生素D 1α-羟化酶基因的表达在kl-/-小鼠的肾脏中也大大增强。此外,kl-/-小鼠对给予的1,25-(OH)2D3的正常基因反应,如25-羟维生素D 1α-羟化酶基因的下调以及24-羟化酶和维生素D受体(VDR)基因的上调,显然受到损害。这些发现表明,维生素D内分泌系统的这种恶化可能通过钙、磷和1,25-(OH)2D水平升高的影响导致kl-/-小鼠出现许多表型。Klotho蛋白可能通过调节1,25-(OH)2D信号通路参与钙和磷的稳态。