VDR in Osteoblast‐Lineage Cells Primarily Mediates Vitamin D Treatment‐Induced Increase in Bone Mass by Suppressing Bone Resorption

Nakamichi, Yuko; Udagawa, Nobuyuki; Horibe, Kanji; Mizoguchi, Takahiro; Yamamoto, Yasutake; Nakamura, Takashi; Hosoya, Akihiro; Kato, Shigeaki; Suda, Toshio; Takahashi, Naoyuki

doi:10.1002/jbmr.3096

Cited by 70 publications

(59 citation statements)

References 52 publications

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“…Transgenically overexpressed VDR in mature osteoblast-lineage cells in mice also increased bone mass by suppressing bone resorption ( 24 , 25 ). These antiresorptive effects were not observed in Ob-VDR-cKO mice ( 30 ). Thus, the proresorptive action and the antiresorptive action of bioactive vitamin D are mediated by VDR in osteoblast-lineage cells.…”

Section: Discussionmentioning

confidence: 86%

“…We confirmed that eldecalcitol administration increased bone mass by suppressing bone resorption via downregulation of the RANKL/OPG ratio in bone tissues without affecting the number of osteoclast precursors ( 29 ). To clarify which type of VDR-expressing cells preferentially regulated the eldecalcitol-induced increase in bone mass, we generated osteoblast-lineage (osteoblast and osteocyte)-specific VDR conditional knockout [Ob-VDR-cKO, osterix (Osx)-Cre Tg/0 ; VDR fl/fl ] and osteoclast-specific VDR-cKO [Ocl-VDR-cKO, cathepsin (Ctsk) Cre/+ ; VDR fl/fl ] mice ( 30 ). Administration of eldecalcitol for 4 weeks neither suppressed bone resorption nor increased bone mass in Ob-VDR-cKO mice ( 30 ).…”

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confidence: 99%

“…To clarify which type of VDR-expressing cells preferentially regulated the eldecalcitol-induced increase in bone mass, we generated osteoblast-lineage (osteoblast and osteocyte)-specific VDR conditional knockout [Ob-VDR-cKO, osterix (Osx)-Cre Tg/0 ; VDR fl/fl ] and osteoclast-specific VDR-cKO [Ocl-VDR-cKO, cathepsin (Ctsk) Cre/+ ; VDR fl/fl ] mice ( 30 ). Administration of eldecalcitol for 4 weeks neither suppressed bone resorption nor increased bone mass in Ob-VDR-cKO mice ( 30 ). In contrast, it suppressed bone resorption and subsequently increased bone mass in Ocl-VDR-cKO mice and control mice ( 30 ).…”

mentioning

confidence: 99%

“…Administration of eldecalcitol for 4 weeks neither suppressed bone resorption nor increased bone mass in Ob-VDR-cKO mice ( 30 ). In contrast, it suppressed bone resorption and subsequently increased bone mass in Ocl-VDR-cKO mice and control mice ( 30 ). These results suggested that VDR in osteoblast-lineage cells, but not enterocytes, renal cells, or osteoclasts, primarily mediates the eldecalcitol and other bioactive vitamin D-induced increase in bone mass ( 14 , 15 , 24 , 25 , 29 , 30 ).…”

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confidence: 99%

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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

et al. 2020

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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 cross-linked 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.

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Section: Discussionmentioning

confidence: 86%

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confidence: 99%

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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

et al. 2020

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“…1α,25-Dihydroxyvitamin D3 (1,25D3) is the most active metabolite of vitamin D3 and plays a major role in the enhancement of bone formation [10]. 1,25D3 exerts its actions via binding with and modulating the vitamin D receptor (VDR), a transcriptional regulator [11][12][13]. 1,25D3 also activates Wnt/β-catenin to facilitate osteoblast differentiation [14][15][16].…”

Section: Introductionmentioning

confidence: 99%

DKK1 Induced by 1,25D3 Is Required for the Mineralization of Osteoblasts

Yoon

Lee

et al. 2020

Cells

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1α,25-dihydroxyvitamin D3 (1,25D3), the most popular drug for osteoporosis treatment, drives osteoblast differentiation and bone mineralization. Wnt/β-catenin signaling is involved in commitment and differentiation of osteoblasts, but the role of the Dickkopf-related protein 1 (DKK1), a Wnt antagonist, in osteoblasts remains unknown. Here, we demonstrate the molecular mechanism of DKK1 induction by 1,25D3 and its physiological role during osteoblast differentiation. 1,25D3 markedly promoted the expression of both CCAAT/enhancer binding protein beta (C/EBPβ) and DKK1 at day 7 during osteoblast differentiation. Interestingly, mRNA and protein levels of C/EBPβ and DKK1 in osteoblasts were elevated by 1,25D3. We also found that C/EBPβ, in response to 1,25D3, directly binds to the human DKK1 promoter. Knockdown of C/EBPβ downregulated the expression of DKK1 in osteoblasts, which was partially reversed by 1,25D3. In contrast, overexpression of C/EBPβ upregulated DKK1 expression in osteoblasts, which was enhanced by 1,25D3. Furthermore, 1,25D3 treatment in osteoblasts stimulated secretion of DKK1 protein within the endoplasmic reticulum to extracellular. Intriguingly, blocking DKK1 attenuated calcified nodule formation in mineralized osteoblasts, but not ALP activity or collagen synthesis. Taken together, these observations suggest that 1,25D3 promotes the mineralization of osteoblasts through activation of DKK1 followed by an increase of C/EBPβ.

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Integrated View on the Role of Vitamin D Actions on Bone and Growth Plate Homeostasis

Verlinden

Carmeliet

2021

JBMR Plus

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1,25(OH) 2 D 3 , the biologically active form of vitamin D 3 , is a major regulator of mineral and bone homeostasis and exerts its actions through binding to the vitamin D receptor (VDR), a ligand-activated transcription factor that can directly modulate gene expression in vitamin D-target tissues such as the intestine, kidney, and bone. Inactivating VDR mutations or vitamin D deficiency during development results in rickets, hypocalcemia, secondary hyperparathyroidism, and hypophosphatemia, pointing to the critical role of 1,25 (OH) 2 D 3 -induced signaling in the maintenance of mineral homeostasis and skeletal health. 1,25(OH) 2 D 3 is a potent stimulator of VDRmediated intestinal calcium absorption, thus increasing the availability of calcium required for proper bone mineralization. However, when intestinal calcium absorption is impaired, renal calcium reabsorption is increased and calcium is mobilized from the bone to preserve normocalcemia. Multiple cell types within bone express the VDR, thereby allowing 1,25(OH) 2 D 3 to directly affect bone homeostasis. In this review, we will discuss different transgenic mouse models with either Vdr deletion or overexpression in chondrocytes, osteoblasts, osteocytes, or osteoclasts to delineate the direct effects of 1,25(OH) 2 D 3 on bone homeostasis. We will address the bone cell type-specific effects of 1,25(OH) 2 D 3 in conditions of a positive calcium balance, where the amount of (re)absorbed calcium equals or exceeds fecal and renal calcium losses, as well as during a negative calcium balance, due to selective Vdr knockdown in the intestine or triggered by a low calcium diet.

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VDR in Osteoblast‐Lineage Cells Primarily Mediates Vitamin D Treatment‐Induced Increase in Bone Mass by Suppressing Bone Resorption

Cited by 70 publications

References 52 publications

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

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

DKK1 Induced by 1,25D3 Is Required for the Mineralization of Osteoblasts

Integrated View on the Role of Vitamin D Actions on Bone and Growth Plate Homeostasis

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