Nuclear Factor-E2-related Factor-1 Mediates Ascorbic Acid Induction of Osterix Expression via Interaction with Antioxidant-Responsive Element in Bone Cells

Xing, Weirong; Singgih, Anny; Kapoor, Anil; Alarcon, Catrina; Baylink, David J.; Mohan, Subburaman

doi:10.1074/jbc.m702614200

Cited by 78 publications

(96 citation statements)

References 46 publications

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“…These data are supported by a recent report by Xing et al (55), who suggested that the supportive effect of a micronutrient (vitamin C) on bone formation is mediated by EpRE/ARE activation. Some studies that investigated the effects of nondietary stimuli on Nrf2/ARE activity have also suggested a positive role for Nrf2 in bone cells (6,47); other studies, however, reported a deleterious effect of Nrf2 (3,17,53).…”

Section: Discussionsupporting

confidence: 80%

Polyphenols, isothiocyanates, and carotenoid derivatives enhance estrogenic activity in bone cells but inhibit it in breast cancer cells

Veprik

Khanin

Linnewiel-Hermoni

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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-While exposure to estrogens is a major risk factor of breast and endometrial cancer, it well established that estrogens are beneficial for bone health. We have previously shown that carotenoids inhibit estrogen signaling in breast and endometrial cancer cells. The aim of this study was to compare the effects of various phytonutrients, (carotenoid derivatives, polyphenols, isothiocyanates) on estrogenic activity in breast cancer cells and osteoblast-like cells. All the tested phytonutrients inhibited estrogen response element (ERE) transactivation in breast cancer cells. In contrast, these compounds either did not affect or enhanced ERE activity and the expression of several bone-forming genes. These results were obtained using two osteoblast-like cell lines, MG-63 human osteosarcoma cells stably transfected with estrogen receptor-␣ (ER␣) and MC3T3-E1 mouse calvaria-derived cells expressing endogenous ER. Phytonutrients-induced ERE inhibition in breast cancer cells, and its potentiation in osteoblast-like cells were associated both with a decrease and a rise in total and nuclear ER␣ levels, respectively. Phytonutrients activated the electrophile/antioxidant response element (EpRE/ARE) transcription system to various extents in both cancer and bone cell lines. Overexpression of Nrf2, the major EpRE/ ARE activating transcription factor, mimicked the effects of phytonutrients, causing inhibition and enhancement of ERE transactivation in breast cancer cells and in osteoblast-like cells, respectively. Moreover, reduction in Nrf2 levels by RNAi led to a decrease in the phytonutrient potentiation of ERE activity transactivation in osteoblast-like cells. These findings suggest that the enhancement and inhibition of estrogen signaling by phytonutrients in bone-derived cells and breast cancer cells, respectively, is partially mediated by the activation of the Nrf2/ARE system. Nrf2; estrogen receptor; osteoblasts; antioxidant response element; lycopene; curcumin INCIDENCE RATES of breast and endometrial cancer have been rising in the last decades, due to increased exposure to estrogens resulting from changes in lifestyle (19,39). Thus, reduction of estrogen receptor activity is a major strategy for prevention of hormone-dependent malignancies. This preventive approach, however, must be implemented by taking into consideration that estrogens are beneficial to bone health. Women who enter menopause are at high risk for osteoporosis due to low blood levels of estrogens (42). Thus, since women today live longer after menopause than in a reproductive state, osteoporosis has become a serious threat to their health. To prevent hormone-dependent cancer without compromising bone health, specific estrogen receptor modulators (SERMs) have been developed (41). SERMs such as tamoxifen and raloxifen were successfully used for prevention of breast cancer in women who are at high risk for the disease and were also found to reduce the incidence of bone fractures (11, 54). However, for long-term prevention in the general population, dietary...

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Section: Discussionsupporting

confidence: 80%

Polyphenols, isothiocyanates, and carotenoid derivatives enhance estrogenic activity in bone cells but inhibit it in breast cancer cells

Veprik

Khanin

Linnewiel-Hermoni

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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“…Previous reports have shown that prolonged exposure of calvaria-derived osteoblasts to PTH results in decreased osteoblast differentiation with decreased expression of collagen 1a1, bone sialoprotein, and osteocalcin (Xing et al 2007). Some of these genes could have been suppressed as a result of PTH-mediated Osx inhibition, as both osteocalcin and collagen 1a1 are regulated by Osx.…”

Section: Discussionmentioning

confidence: 99%

“…Both BMP-2 and insulin-like growth factor-1 (IGF-1) can induce Osx expression in undifferentiated mesenchymal stem cells through Runx2-dependent (Celil & Campbell 2005) and Runx2-independent (Lee et al 2003) pathways. Ascorbic acid and 1,25 (OH) 2 vitamin D 3 , which have positive roles in osteoblast function, have also been shown to up-regulate Osx expression (Maehata et al 2006, Xing et al 2007. Negative regulators of osteoblastogenesis, such as tumor necrosis factor-a (TNF-a) and p53, can inhibit Osx expression (Lu et al 2006, Wang et al 2006a,b, Zambetti et al 2006.…”

Section: Introductionmentioning

confidence: 99%

Regulation of osterix (Osx, Sp7) and the Osx promoter by parathyroid hormone in osteoblasts

Hong

Lu²,

Nanes³

et al. 2009

Journal of Molecular Endocrinology

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Parathyroid hormone (PTH) binds to its receptor on osteoblasts to regulate gene transcription primarily through the elevation of the second messenger cAMP. A number of genes regulated by PTH in osteoblasts contain GC-rich and Sp-binding sites. Osterix (Osx, Sp7) is a transcription factor required for the differentiation of osteoblasts that can bind to Sp-binding sites on gene promoters and regulate their expression. Here, we report the effect of PTH (1-34) on Osx expression in osteoblastic UMR-106-01 cells and murine calvaria. PTH (1-34) and PTH (1-31) inhibited Osx mRNA and protein expression, and this effect could be mimicked by forskolin, 8-bromo-cAMP, or expression of constitutively active Gsa (caGsa). Treatment of the cells with PTH (3-34) or the EPAC-selective agonist 8CPT-2Me-cAMP had no effect on Osx mRNA, whereas PTH (7-34) or expression of caGqa-stimulated Osx mRNA levels. PTH (1-34) treatment did not require new protein synthesis and did not involve changes in Osx mRNA stability. Osx promoter fragments coupled to a luciferase reporter were inhibited by PTH (1-34) treatment in a similar manner to the inhibition of Osx mRNA and protein.Deletion analysis localized PTH inhibition to two regions flanking the Osx1 start site; K304/K119 and K71/C91. These results demonstrate that prolonged exposure to PTH inhibits Osx expression in osteoblasts through sites on its proximal promoter and this suppression occurs through PTH stimulation of cellular cAMP.

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“…Bone marrow stromal cells (BMSC) were isolated from the femur and tibia of WT mice, as reported previously (25). Primary osteoblasts were isolated from the calvarias of newborn mice, using a previously described modified sequential digestion protocol (42). BMSC, primary osteoblasts, MC3T3-E1 cells, an osteoblast precursor cell line, and RAW 264.7 cells, an osteoclast precursor line, were cultured in ␣-MEM containing 10% FBS, penicillin (100 U/ml), and streptomycin (100 g/ml).…”

Section: Animals and Genotyping Cldn-18-deficient (Cldn-18mentioning

confidence: 99%

Disruption of claudin-18 diminishes ovariectomy-induced bone loss in mice

Kim

Alarcon

Pourteymour

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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, a member of the tight junction family of proteins, is a negative regulator of RANKL-induced osteoclast differentiation and bone resorption (BR) in vivo. Since estrogen deficiency decreases bone mass in part by a RANKL-mediated increase in BR, we evaluated whether estrogen regulates Cldn-18 expression in bone. We found that Cldn-18 expression was reduced in the bones of estrogen deficient mice, whereas it was increased by estrogen treatment in osteoblasts and osteoclasts in vitro. We next evaluated the role of Cldn-18 in mediating estrogen-induced bone loss. Cldn-18 knockout (KO) and littermate wild-type (WT) mice were ovariectomized (OVX) or sham operated at 6 wk of age, and the skeletal phenotype was evaluated at 14 wk of age. PIXImus revealed that total body, femur, and lumbar BMD were reduced 8 -13% (P Ͻ 0.05) after 8 wk of OVX compared with sham in WT mice. As expected, total body, femur, and lumbar BMD were reduced 14 -21% (P Ͻ 0.05) in Cldn-18 KO sham mice compared with sham WT mice. However, ovariectomy failed to induce significant changes in BMD of total body, femur, or vertebra in the Cldn-18 KO mice. CT analysis of the distal femur revealed that trabecular (Tb) bone volume was decreased 50% in the OVX WT mice compared with sham that was caused by a 26% decrease in Tb number and a 30% increase in Tb separation (all P Ͻ 0.05). By contrast, none of the Tb parameters were significantly different in OVX Cldn-18 KO mice compared with sham KO mice. Histomorphometric analyses at the Tb site revealed that neither osteoclast surface nor osteoclast perimeter was increased significantly as a consequence of OVX in either genotype at the time point examined. Based on our findings, we conclude that the estrogen effects on osteoclasts may in part be mediated via regulation of Cldn-18 signaling.claudins; estrogen; bone resorption; bone density; osteoblasts; gene expression ESTROGEN DEFICIENCY IN MENOPAUSAL WOMEN is a serious health issue due to increased bone turnover, resulting in osteoporosis and increased fracture risk consequent to deterioration of microarchitectural bone structure (32). It is now recognized that estrogen prevents bone loss via multiple and complex effects on bone marrow and bone cells that result in decreased osteoclastogenesis, increased osteoclast apoptosis, and decreased capacity of mature osteoclasts to resorb bone (20). The canonical mechanism for osteoclast differentiation depends on activation of receptor activator of nuclear factor-B (RANK) by its ligand RANKL and tyrosine kinase receptor fms by macrophage colony-stimulating factor. Estrogen probably affects osteoclast differentiation in part indirectly through its modulation of osteoblast RANKL and osteoprotegerin expression (46) and directly by decreasing the responsiveness of osteoclast precursors to the RANKL (36). There is also evidence that estrogen blocks the production of the pro-osteoclastogenic cytokines IL-1, IL-6, and TNF (1, 18, 29). It has also been suggested that estrogen modulates osteoclast apoptosis and osteoclast acti...

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Nuclear Factor-E2-related Factor-1 Mediates Ascorbic Acid Induction of Osterix Expression via Interaction with Antioxidant-Responsive Element in Bone Cells

Cited by 78 publications

References 46 publications

Polyphenols, isothiocyanates, and carotenoid derivatives enhance estrogenic activity in bone cells but inhibit it in breast cancer cells

Polyphenols, isothiocyanates, and carotenoid derivatives enhance estrogenic activity in bone cells but inhibit it in breast cancer cells

Regulation of osterix (Osx, Sp7) and the Osx promoter by parathyroid hormone in osteoblasts

Disruption of claudin-18 diminishes ovariectomy-induced bone loss in mice

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