The physiological and beneficial actions of vitamin D in bone health have been experimentally and clinically proven in mammals. The active form of vitamin D [1α,25(OH)(2)D(3)] binds and activates its specific nuclear receptor, the vitamin D receptor (VDR). Activated VDR prevents the release of calcium from its storage in bone to serum by stimulating intestinal calcium absorption and renal reabsorption. However, the direct action of VDR in bone tissue is poorly understood because serum Ca(2+) homeostasis is maintained through tightly regulated ion transport by the kidney, intestine, and bone. In addition, conventional genetic approaches using VDR knockout (VDR-KO, VDR(-/-)) mice could not identify VDR action in bone because of the animals' systemic defects in calcium metabolism. In this study, we report that systemic VDR heterozygous KO (VDR(+/L-)) mice generated with the Cre/loxP system as well as conventional VDR heterozygotes (VDR(+/-)) showed increased bone mass in radiological assessments. Because mineral metabolism parameters were unaltered in both types of mice, these bone phenotypes imply that skeletal VDR plays a role in bone mass regulation. To confirm this assumption, osteoblast-specific VDR-KO (VDR(ΔOb/ΔOb)) mice were generated with 2.3 kb α1(I)-collagen promoter-Cre transgenic mice. They showed a bone mass increase without any dysregulation of mineral metabolism. Although bone formation parameters were not affected in bone histomorphometry, bone resorption was obviously reduced in VDR(ΔOb/ΔOb) mice because of decreased expression of receptor activator of nuclear factor kappa-B ligand (an essential molecule in osteoclastogenesis) in VDR(ΔOb/ΔOb) osteoblasts. These findings establish that VDR in osteoblasts is a negative regulator of bone mass control.

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