title: Vitamin D receptor in osteoblasts is a negative regulator of bone mass control.
abstract: 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.
authors: Institute of Molecular and Cellular Biosciences, The University of Tokyo, Bunkyo-ku, 113-0032, Japan.
authors: Yoko
authors: Y
authors: Yamamoto
authors: Tatsuya
authors: T
authors: Yoshizawa
authors: Toru
authors: T
authors: Fukuda
authors: Yuko
authors: Y
authors: Shirode-Fukuda
authors: Taiyong
authors: T
authors: Yu
authors: Keisuke
authors: K
authors: Sekine
authors: Takashi
authors: T
authors: Sato
authors: Hirotaka
authors: H
authors: Kawano
authors: Ken-Ichi
authors: K
authors: Aihara
authors: Yuko
authors: Y
authors: Nakamichi
authors: Tomoyuki
authors: T
authors: Watanabe
authors: Masayo
authors: M
authors: Shindo
authors: Kazuki
authors: K
authors: Inoue
authors: Erina
authors: E
authors: Inoue
authors: Naoya
authors: N
authors: Tsuji
authors: Maiko
authors: M
authors: Hoshino
authors: Gerard
authors: G
authors: Karsenty
authors: Daniel
authors: D
authors: Metzger
authors: Pierre
authors: P
authors: Chambon
authors: Shigeaki
authors: S
authors: Kato
authors: Yuuki
authors: Y
authors: Imai
mesh_terms: D000818:Animals; D015519:Bone Density; D001862:Bone Resorption / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001842:Bone and Bones / Q000033:anatomy & histology* / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000378:metabolism*; D010010:Osteoclasts / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012279:Rickets / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D018167:Receptors, Calcitriol; D002118:Calcium