A potent analog of 1α,25-dihydroxyvitamin D
            <sub>3</sub>
            selectively induces bone formation

Shevde, Nirupama K.; Plum, Lori A.; Clagett‐Dame, Margaret; Yamamoto, Hironori; Pike, J. Wesley; DeLuca, Hector F.

doi:10.1073/pnas.202471299

Cited by 171 publications

(163 citation statements)

References 25 publications

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“…A previous study (65) has suggested that calcitriol dose-dependently exhibited inhibitory effects on osteoblastic activity. Thus, although we are unable to rule out an effect of calcitriol in producing the ABD in our animal model, the dose and the actions of 1,25(OH)2D3 in previous studies (57,58,61) suggest that it may not have been the cause of the ABD we observed.…”

Section: Discussioncontrasting

confidence: 62%

“…Studies have shown that vitamin D-deficient animals infused with calcium and phosphate had similar histomorphometry, bone growth, and mineralization compared with animals supplemented with vitamin D, and the mineralization defect is directly due to insufficient calcium and phosphorus in plasma at sites of mineralization (59,60). Recent studies have shown that even higher doses of calcitriol greater than were used here did not decrease bone formation in ovariectomized rats (61). In transgenic mice deficient in the 1␣-hydroxylase gene (CYP27B1), a marked decrease in skeletal modeling and growth is observed corrected with a rescue diet that normalizes the serum calcium.…”

Section: Discussionmentioning

confidence: 59%

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Successful Treatment of an Adynamic Bone Disorder with Bone Morphogenetic Protein-7 in a Renal Ablation Model

Lund¹,

Davies²,

Brown³

et al. 2004

Journal of the American Society of Nephrology

103

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Abstract. An adynamic bone disorder (ABD) is an important complication of chronic kidney disease (CKD) of unknown etiology for which there is no adequate treatment. Reported is an animal model of ablative CKD complicated by an ABD characterized by the absence of secondary hyperparathyroidism and its successful treatment with a skeletal anabolic factor, bone morphogenetic protein-7 (BMP-7). Adult mice were subjected to electrocautery of the right kidney followed by left nephrectomy. Animals were randomized into groups fed normal chow or fed low-phosphate chow supplemented with calcitriol to maintain normophosphatemia in CKD. All groups were maintained on the regimens for 12 wk. Hyperphosphatemia, secondary hyperparathyroidism, and a mild osteodystrophy developed in the CKD/chow-fed group, as expected. When dietary phosphorus was restricted and calcitriol was administered in the CKD low-phosphate/calcitriol group (ABD), Ca, PO 4 , and parathyroid hormone levels were maintained normal. A significant ABD developed in the ABD group characterized by significant depressions in osteoblast number, perimeters, bone formation rates, and mineral apposition rates when compared with the sham-operated, chow-fed group. The abnormal skeletal histomorphometry was reversed by BMP-7 therapy to normal values and significantly improved from the ABD group (P Ͻ 0.05). The sham-operated low-phosphate/ calcitriol-fed control group and the CKD low-phosphate/calcitriol/BMP-7 groups had reduced phosphate levels compared with the other groups (P Ͻ 0.05). ABD produced in mice with CKD in the absence of hyperparathyroidism was successfully reversed with a bone anabolic, BMP-7, associated with a reduction in plasma phosphorus.Renal osteodystrophy is a term used to describe a heterogeneous spectrum of skeletal abnormalities found in patients with chronic kidney disease (CKD) and end-stage kidney disease (ESKD). Renal osteodystrophy ranges from states of high bone turnover to states of low bone turnover (1-3). Predominantly hyperparathyroid bone disease results in a high turnover osteodystrophy (osteitis fibrosa), and it is considered the most prevalent bone disorder in chronic kidney disease and ESKD. Low-turnover osteodystrophy reflects the lack of capacity to produce and mineralize bone matrix and has two main histologic forms: osteomalacia and the adynamic bone disorder (ABD). The ABD is an important complication of CKD associated with high rates of bone fractures (4), impaired growth (5,6), and probably vascular calcification (7,8). There has been an increase in the prevalence of ABD in patients with ESKD on dialysis (9).The pathogenesis of the ABD is unknown. It may occur when parathyroid hormone (PTH) levels are aggressively suppressed (10). As a result, practice standards target maintaining elevated intact PTH levels (about three to five times normal) sufficient to prevent the ABD (11,12). Therapy of the ABD besides adjustment of PTH levels is not available. Because secondary hyperparathyroidism in CKD causes a distinct osteodystrophy, in...

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Section: Discussioncontrasting

confidence: 62%

Section: Discussionmentioning

confidence: 59%

Successful Treatment of an Adynamic Bone Disorder with Bone Morphogenetic Protein-7 in a Renal Ablation Model

Lund¹,

Davies²,

Brown³

et al. 2004

Journal of the American Society of Nephrology

103

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“…5A). 2MD is known to induce RANKL expression in osteoblastic cells (20,21). Then, RANKL was injected into CSF-1 op/op mice, but neither the osteoclast formation nor the increase in erosion surface (ES/BS) was observed (Fig.…”

Section: Resultsmentioning

confidence: 98%

Spleen serves as a reservoir of osteoclast precursors through vitamin D-induced IL-34 expression in osteopetrotic op/op mice

Nakamichi¹,

Mizoguchi²,

Arai³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Osteoclasts are generated from monocyte/macrophage-lineage precursors in response to colony-stimulating factor 1 (CSF-1) and receptor activator of nuclear factor-κB ligand (RANKL). CSF-1-mutated CSF-1 op/op mice as well as RANKL −/− mice exhibit osteopetrosis (OP) caused by osteoclast deficiency. We previously identified RANKL receptor (RANK)/CSF-1 receptor (CSF-1R) double-positive cells as osteoclast precursors (OCPs), which existed in bone in RANKL −/− mice. Here we show that OCPs do not exist in bone but in spleen in CSF-1 op/op mice, and spleen acts as their reservoir. IL-34, a newly discovered CSF-1R ligand, was highly expressed in vascular endothelial cells in spleen in CSF-1 op/op mice. Vascular endothelial cells in bone also expressed IL-34, but its expression level was much lower than in spleen, suggesting a role of IL-34 in the splenic generation of OCPs. Splenectomy (SPX) blocked CSF-1-induced osteoclastogenesis in CSF-1 op/op mice. Osteoclasts appeared in aged CSF-1 op/op mice with up-regulation of IL-34 expression in spleen and bone. Splenectomy blocked the age-associated appearance of osteoclasts. The injection of 2-methylene-19-nor-(20S)-1α,25(OH) 2 D 3 (2MD), a potent analog of 1α,25-dihidroxyvitamin D 3 , into CSF-1 op/op mice induced both hypercalcemia and osteoclastogenesis. Administration of 2MD enhanced IL-34 expression not only in spleen but also in bone through a vitamin D receptor-mediated mechanism. Either splenectomy or siRNA-mediated knockdown of IL-34 suppressed 2MD-induced osteoclastogenesis. These results suggest that IL-34 plays a pivotal role in maintaining the splenic reservoir of OCPs, which are transferred to bone in response to diverse stimuli, in CSF-1 op/op mice. The present study also suggests that the IL-34 gene in vascular endothelial cells is a unique target of vitamin D. CSF-1 is the most potent growth factor for monocytes/macrophages (3), but its synthesis by osteoblasts occurs independently of PTH and 1α,25(OH) 2 D 3 (2). CSF-1 op/op mice cannot produce a functionally active CSF-1 (4), and therefore, exhibit monocytopenia and osteopetrosis (OP) (5, 6). However, several curious phenomena have been observed in CSF-1 op/op mice. First, osteoclasts are totally absent in young CSF-1 op/op mice, but appear in aged CSF-1 op/op mice (7). Second, osteopetrotic characteristics of CSF-1R −/− mice are more severe than those of CSF-1 op/op mice (8). Third, F4/80 + [F4/80(+)] macrophages exist in the splenic red pulp in CSF-1 op/op mice as well as in WT mice, and their number is regulated by a mechanism independently of CSF-1 (9, 10). Fourth, the administration of vascular endothelial growth factor (VEGF) rescues osteopetrosis in CSF-1 op/op mice (11, 12), but VEGF cannot substitute for CSF-1 to induce osteoclast formation in vitro (13).Recently, Lin et al. (14) discovered IL-34, as a new ligand for CSF-1R. The amino acid sequence of IL-34 was quite different from that of CSF-1, but IL-34 promoted macrophage colony formation like CSF-1 did. IL-34 was specifically expressed in splen...

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“…Primary calvarial osteoblasts (mOBs) were obtained as previously described [9] and cultured in α-MEM. Human osteosarcoma MG63 cells were grown in Dulbeccos's modified Eagle's medium (DMEM) supplemented with 1% non-essential amino acids.…”

Section: Cell Culturementioning

confidence: 99%

Multiple enhancer regions located at significant distances upstream of the transcriptional start site mediate RANKL gene expression in response to 1,25-dihydroxyvitamin D3

Kim

Yamazaki

Zella

et al. 2007

The Journal of Steroid Biochemistry and Molecular Biology

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One of the primary regulators of Receptor activator of NF-κB ligand (RANKL) is 1,25-dihydoxyvitamin D 3 (1,25(OH) 2 D 3 ). To elucidate the mechanism whereby 1,25(OH) 2 D 3 activates RANKL expression we screened some 300 kb of the RANKL gene locus using a ChIP on chip analysis and identified five potential regulatory regions lying significant distances upstream of the transcription start site (TSS), the farthest over 70 kb from the TSS. A direct ChIP analysis confirmed the presence of the VDR/RXR heterodimer at these sites. The binding of the VDR was associated with histone modification and enhanced entry of RNA polymerase II, indicating an important functional consequence to the localization of these transcription factors in response to 1,25 (OH) 2 D 3 . The region -76kb upstream from the TSS, termed D5, was capable of mediating VDRdependent transcriptional output in response to 1,25(OH) 2 D 3 in luciferase assays. The identified VDRE in this region was able to confer dramatic 1,25(OH) 2 D 3 sensitivity to heterologous promoters. This region was highly evolutionarily conserved and functionally active in the human RANKL gene as well. We propose that the RANKL gene is regulated via multiple enhancers that while located at significant distances from the TSS, likely form a chromatin hub centered on the RankL promoter.

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A potent analog of 1α,25-dihydroxyvitamin D ₃ selectively induces bone formation

Cited by 171 publications

References 25 publications

Successful Treatment of an Adynamic Bone Disorder with Bone Morphogenetic Protein-7 in a Renal Ablation Model

Successful Treatment of an Adynamic Bone Disorder with Bone Morphogenetic Protein-7 in a Renal Ablation Model

Spleen serves as a reservoir of osteoclast precursors through vitamin D-induced IL-34 expression in osteopetrotic op/op mice

Multiple enhancer regions located at significant distances upstream of the transcriptional start site mediate RANKL gene expression in response to 1,25-dihydroxyvitamin D3

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A potent analog of 1α,25-dihydroxyvitamin D 3 selectively induces bone formation

Cited by 171 publications

References 25 publications

Successful Treatment of an Adynamic Bone Disorder with Bone Morphogenetic Protein-7 in a Renal Ablation Model

Successful Treatment of an Adynamic Bone Disorder with Bone Morphogenetic Protein-7 in a Renal Ablation Model

Spleen serves as a reservoir of osteoclast precursors through vitamin D-induced IL-34 expression in osteopetrotic op/op mice

Multiple enhancer regions located at significant distances upstream of the transcriptional start site mediate RANKL gene expression in response to 1,25-dihydroxyvitamin D3

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A potent analog of 1α,25-dihydroxyvitamin D ₃ selectively induces bone formation