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The Vitamin D Receptor in Osteoblast-Lineage Cells Is Essential for the Proresorptive Activity of 1α,25(OH)2D3 In Vivo.

Endocrinology. 2020 Nov 01;161(11)
Tomoki Mori 1 , Kanji Horibe 2 , Masanori Koide 3 , Shunsuke Uehara 4 , Yoko Yamamoto 5 , Shigeaki Kato 6 , Hisataka Yasuda 7 , Naoyuki Takahashi 3 , Nobuyuki Udagawa 4 , Yuko Nakamichi 3
Tomoki Mori 1 , Kanji Horibe 2 , Masanori Koide 3 , Shunsuke Uehara 4 , Yoko Yamamoto 5 , Shigeaki Kato 6 , Hisataka Yasuda 7 , Naoyuki Takahashi 3 , Nobuyuki Udagawa 4 , Yuko Nakamichi 3
+ et al

[No authors listed]

Author information
  • 1 Graduate School of Oral Medicine, Matsumoto Dental University, Shiojiri, Nagano, Japan.
  • 2 Department of Oral Histology, Matsumoto Dental University, Shiojiri, Nagano, Japan.
  • 3 Institute for Oral Science, Matsumoto Dental University, Shiojiri, Nagano, Japan.
  • 4 Department of Biochemistry, Matsumoto Dental University, Shiojiri, Nagano, Japan.
  • 5 Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan.
  • 6 Department of Basic Pathology, Fukushima Medical University, Fukushima, Japan.
  • 7 Nagahama Institute for Biochemical Science, Oriental Yeast Co., Ltd., Nagahama, Shiga, Japan.

摘要


We previously reported that daily administration of a pharmacological dose of eldecalcitol, an analog of 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3], increased bone mass by suppressing bone resorption. These antiresorptive effects were found to be mediated by the vitamin D receptor (VDR) in osteoblast-lineage cells. Using osteoblast-lineage-specific VDR conditional knockout (Ob-VDR-cKO) mice, we examined whether proresorptive activity induced by the high-dose 1α,25(OH)2D3 was also mediated by VDR in osteoblast-lineage cells. Administration of 1α,25(OH)2D3 (5 μg/kg body weight/day) to wild-type mice for 4 days increased the number of osteoclasts in bone and serum concentrations of C-terminal crosslinked telopeptide of type I collagen (CTX-I, a bone resorption marker). The stimulation of bone resorption was concomitant with the increase in serum calcium (Ca) and fibroblast growth factor 23 (FGF23) levels, and decrease in body weight. This suggests that a toxic dose of 1α,25(OH)2D3 can induce bone resorption and hypercalcemia. In contrast, pretreatment of wild-type mice with neutralizing anti-receptor activator of NF-κB ligand (RANKL) antibody inhibited the 1α,25(OH)2D3-induced increase of osteoclast numbers in bone, and increase of CTX-I, Ca, and FGF23 levels in serum. The pretreatment with anti-RANKL antibody also inhibited the 1α,25(OH)2D3-induced decrease in body weight. Consistent with observations in mice conditioned with anti-RANKL antibody, the high-dose administration of 1α,25(OH)2D3 to Ob-VDR-cKO mice failed to significantly increase bone osteoclast numbers, serum CTX-I, Ca, or FGF23 levels, and failed to reduce the body weight. Taken together, this study demonstrated that the proresorptive, hypercalcemic, and toxic actions of high-dose 1α,25(OH)2D3 are mediated by VDR in osteoblast-lineage cells.

KEYWORDS: Ob-VDR-cKO mice, Proresorptive action, VDR, hypercalcemia, osteoblast-lineage cells, toxic action