VDR in Osteoblast-Lineage Cells Primarily Mediates Vitamin D Treatment-Induced Increase in Bone Mass by Suppressing Bone Resorption.
Long-term treatment with active vitamin D [1α,25(OH)2D3] and its derivatives is effective for increasing bone mass in patients with primary and secondary osteoporosis. Derivatives of 1α,25(OH)2D3, including eldecalcitol (ELD), exert their actions through the vitamin D receptor (VDR). ELD is more resistant to metabolic degradation than 1α,25(OH)2D3. It is reported that ELD treatment causes a net increase in bone mass by suppressing bone resorption rather than by increasing bone formation in animals and humans. VDR in bone and extraskeletal tissues regulates bone mass and secretion of osteotropic hormones. Therefore, it is unclear what types of cells expressing VDR preferentially regulate the vitamin D-induced increase in bone mass. Here, we examined the effects of 4-week treatment with ELD (50 ng/kg/day) on bone using osteoblast lineage-specific VDR conditional knockout (Ob-VDR-cKO) and osteoclast-specific VDR cKO (Ocl-VDR-cKO) male mice aged 10 weeks. Immunohistochemically, VDR in bone was detected preferentially in osteoblasts and osteocytes. Ob-VDR-cKO mice showed normal bone phenotypes, despite no appreciable immunostaining of VDR in bone. Ob-VDR-cKO mice failed to increase bone mass in response to ELD treatment. Ocl-VDR-cKO mice also exhibited normal bone phenotypes, but normally responded to ELD. ELD-induced FGF23 production in bone was regulated by VDR in osteoblast-lineage cells. These findings suggest that the vitamin D treatment-induced increase in bone mass is mediated by suppressing bone resorption through VDR in osteoblast-lineage cells. © 2017 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.
Institute for Oral Science, Matsumoto Dental University, Nagano, Japan.
Yuko
Y
Nakamichi
Department of Biochemistry, Matsumoto Dental University, Nagano, Japan.
Nobuyuki
N
Udagawa
Department of Oral Histology, Matsumoto Dental University, Nagano, Japan.
Kanji
K
Horibe
Institute for Oral Science, Matsumoto Dental University, Nagano, Japan.
Toshihide
T
Mizoguchi
Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan.
Yoko
Y
Yamamoto
Department of Biochemistry & Integrative Medical Biology, School of Medicine, Keio University, Tokyo, Japan.
Takashi
T
Nakamura
Department of Oral Histology, Matsumoto Dental University, Nagano, Japan.
Akihiro
A
Hosoya
Jyoban Hospital, Tokiwa Foundation, Fukushima, Japan.
Shigeaki
S
Kato
Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan.
Tatsuo
T
Suda
Institute for Oral Science, Matsumoto Dental University, Nagano, Japan.
Naoyuki
N
Takahashi
D000818:Animals; D001862:Bone Resorption / Q000188:drug therapy* / Q000473:pathology*; D001842:Bone and Bones / Q000187:drug effects / Q000473:pathology*; D019070:Cell Lineage / Q000187:drug effects; D000089703:Fibroblast Growth Factor-23; D017353:Gene Deletion; D008297:Male; D018345:Mice, Knockout; D008954:Models, Biological; D009929:Organ Size / Q000187:drug effects; D010006:Osteoblasts / Q000378:metabolism*; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects; D010641:Phenotype; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism*; D014807:Vitamin D / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use*
C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D018167:Receptors, Calcitriol; D014807:Vitamin D; D000089703:Fibroblast Growth Factor-23; C547512:eldecalcitol
ANTIRESORPTIVES; OSTEOBLASTS; OSTEOCLASTS; OSTEOCYTES; PTH/VIT D/FGF23