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1alpha,25-dihydroxy vitamin D(3) induces nuclear matrix association of the 1alpha,25-dihydroxy vitamin D(3) receptor in osteoblasts independently of its ability to bind DNA.

ABSTRACT: 1alpha,25-dihydroxy vitamin D(3) (vitamin D(3)) has an important role during osteoblast differentiation as it directly modulates the expression of key bone-related genes. Vitamin D(3) binds to the vitamin D(3) receptor (VDR), a member of the superfamily of nuclear receptors, which in turn interacts with transcriptional activators to target this regulatory complex to specific sequence elements within gene promoters. Increasing evidence demonstrates that the architectural organization of the genome and regulatory proteins within the eukaryotic nucleus support gene expression in a physiological manner. Previous reports indicated that the VDR exhibits a punctate nuclear distribution that is significantly enhanced in cells grown in the presence of vitamin D(3). Here, we demonstrate that in osteoblastic cells, the VDR binds to the nuclear matrix in a vitamin D(3)-dependent manner. This interaction of VDR with the nuclear matrix occurs rapidly after vitamin D(3) addition and does not require a functional VDR DNA-binding domain. Importantly, nuclear matrix-bound VDR colocalizes with its transcriptional coactivator DRIP205/TRAP220/MED1 which is also matrix bound. Together these results indicate that after ligand stimulation the VDR rapidly enters the nucleus and associates with the nuclear matrix preceding vitamin D(3)-transcriptional upregulation.

SUBMITTER: Arriagada G

PROVIDER: S-EPMC3106996 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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1alpha,25-dihydroxy vitamin D(3) induces nuclear matrix association of the 1alpha,25-dihydroxy vitamin D(3) receptor in osteoblasts independently of its ability to bind DNA.

Arriagada Gloria G Paredes Roberto R van Wijnen Andre J AJ Lian Jane B JB van Zundert Brigitte B Stein Gary S GS Stein Janet L JL Montecino Martin M

Journal of cellular physiology 20100201 2

1alpha,25-dihydroxy vitamin D(3) (vitamin D(3)) has an important role during osteoblast differentiation as it directly modulates the expression of key bone-related genes. Vitamin D(3) binds to the vitamin D(3) receptor (VDR), a member of the superfamily of nuclear receptors, which in turn interacts with transcriptional activators to target this regulatory complex to specific sequence elements within gene promoters. Increasing evidence demonstrates that the architectural organization of the genom ...[more]

PMID: 19885846

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Project description:The cytochrome P450 mitochondrial enzyme 25-hydroxyvitamin D3 1alpha-hydroxylase (1alpha-hydroxylase) of renal tubule cells hydroxylates the major circulating form of vitamin D (25(OH)D3) to the active systemic hormone 1,25(OH)2D3. Local production of 1,25(OH)2D3 appears to occur also at other sites where 1alpha-hydroxylase is expressed for autocrine/paracrine regulation. To reduce risks of hypercalcemia during treatment with vitamin D, we have previously suggested use of non-1alpha-hydroxylated vitamin D analogues to target tissues where 1alpha-hydroxylase is expressed, including the parathyroid glands in secondary hyperparathyroidism. The present study was undertaken to examine expression of 1alpha-hydroxylase in breast cancer and to investigate whether a non-1alpha-hydroxylated vitamin D analogue displayed biological function. In addition, expression of the 25-hydroxyvitamin D3 24-hydroxylase (24-hydroxylase) and the vitamin D receptor (VDR) was investigated.The expression of 1alpha-hydroxylase, 24-hydroxylase and VDR was investigated in breast cancer specimens (n = 19) and normal breast tissues (n = 10) by immunohistochemistry and/or RT-PCR. Consecutive cryosections of 6 mum essentially free of immune cells were used in the analyses. The effect of vitamin D analogues on transcriptional activation was analyzed in transiently transfected MCF-7 breast cancer cells.1alpha-hydroxylase protein was demonstrated in 79% and 100% of breast cancer specimens and normal breast, respectively. The overall relative mRNA levels of 1alpha-hydroxylase and 24-hydroxylase in normal breast compared to breast tumors were: 1alpha-hydroxylase, 1 +/- 0.07 versus 0.7 +/- 0.05, respectively (p < 0.001); 24-hydroxylase, 1 +/- 0.08 verus 2.1 +/- 0.2, respectively (p < 0.001). The VDR was expressed in 95% of the tumors as expected, with mRNA levels of 1 +/- 0.09 and 1.4 +/- 0.12 (p < 0.05) in breast cancer and normal breast, respectively. The ketoconazole-sensitive transcription activation potential of the non-1alpha-hydroxylated vitamin D analogue prodrug of EB1089 (EB1285) was demonstrated in MCF-7 cells, which express 1alpha-hydroxylase. The activity of EB1285 was about 20% of 1,25(OH)2D3.These results demonstrate nearly normal expression levels of 1alpha-hydroxylase, 24-hydroxylase and VDR in the majority of investigated breast cancer specimens. A non-1alpha-hydroxylated vitamin D analogue displayed activity in breast cancer cells. Such analogues may present future therapeutic options for proliferative disorders where 1alpha-hydroxylase is expressed.

Project description:Impaired apoptosis of fibroblast-like synoviocytes (FLSs) causes synovial hyperplasia, facilitating destruction of cartilage and bone in rheumatoid arthritis (RA). Tumor necrosis factor (TNF)-α, a dominant inflammatory mediator in RA pathogenesis, promotes progression of RA symptoms. Prevalence of 1, 25-dihydroxy-vitamin D3 (hereafter termed VD) deficiency is 30-63% in patients with RA. Whether VD leads to apoptosis or enhances TNF-α-mediated apoptosis in FLSs to ameliorate RA is unclear. To determine this, 10-week-old CYP27B1-deficient (CYP27B1-/-) mice with collagen-induced arthritis (CIA) were intraperitoneally treated with 1 μg/kg VD every other day for 9 weeks. RA phenotypes were compared between vehicle-treated CYP27B1-/- and wild-type CIA mice. Human rheumatoid FLS-MH7A cells were treated with Dulbecco's modified Eagle's medium (DMEM) without fetal bovine serum (FBS) for 24 h, then with different concentrations of VD and TNF-α, human vitamin D receptor (VDR) siRNA or the p53 pro-apoptotic inhibitor pifithrin-α. Apoptosis and p53 pro-apoptotic signaling were analyzed. The 19-week-old vehicle-treated CYP27B1-/- CIA mice had increased cumulative arthritis scores and levels of serous rheumatoid factors and C-reactive protein. They had exacerbated articular cartilage and bone destruction, joint space narrowing, joint stiffness, deformity and dysfunction, synovitis and TNF-α secretion, FLS hyperplasia with increased proliferation and decreased apoptosis compared to CIA mice. These RA phenotypes that were aggravated in CIA mice by CYP27B1 deficiency were largely rescued by VD treatment. In vitro, VD with TNF-α treatment upregulated p53 acetylation-mediated apoptosis in MH7A cells by promoting Sirt1 translocation from the nucleus to the cytoplasm. These findings indicated that VD with TNF-α protected against RA by promoting apoptosis of FLSs. The results indicated that clinical administration of VD could be a specific therapy to promote FLS apoptosis and prevent RA progression.

Dataset Information

1alpha,25-dihydroxy vitamin D(3) induces nuclear matrix association of the 1alpha,25-dihydroxy vitamin D(3) receptor in osteoblasts independently of its ability to bind DNA.

Publications

1alpha,25-dihydroxy vitamin D(3) induces nuclear matrix association of the 1alpha,25-dihydroxy vitamin D(3) receptor in osteoblasts independently of its ability to bind DNA.

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