Abstract
Vitamin D(D) exerts a wide variety of biological actions such as calcium homeostasis, celluar differentiation and proliferation. Most of these actions are thought to be mediated through D receptor-mediated gene expression. Vitamin D receptor(VDR) is a member of steroid/thyroid hormone, vitamin A, nuclear receptor superfamily, and acts as a ligand-inducible transcription factor. The transactivation function of VDR is activated by binding of a hormonal form of D, 1,25-(OH)_2D_3. Our preliminary study of vitamin A deficient animals suggested that an ultimate model for D deficiency remains to be established. Therefore, to know the role of 1,25(OH)_2D_3-VDR axis in the D actions in intact animals, we have generated VDR deficient mice by gene targeting. The heterozygous and homozygous(null) VDR mutant mice gave a birth, grew normaly until weaning, and displayed no abnormality. However, only the VDR null mice showed growth retardation after weaning, and became rickets with alopecia, similar to human type II rickets, reaching a death at around 15 weeks. Detailed analysis revealed that impaired bone formation is due to impaired mineralization, but the numbers of osteoblasts and osteoclasts are apparently normal. Along with this finding, the in vitro co-culture system confirmed the significant, but not essential, role of D in the cytodifferentiation of osteoclasts. Consistent with infertility, uterine hypoplasia was found, but such abnormality could not be detected in the male reproductive organs. Thus, the present study established in vivo role of VDR in intact animals.
