Sequence elements in the human osteocalcin gene confer basal activation and inducible response to hormonal vitamin D3.

Kerner, Sandra A.; Scott, R.; Pike, J. Wesley

doi:10.1073/pnas.86.12.4455

Cited by 370 publications

(157 citation statements)

References 36 publications

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“…New evidence indicates that osteocalcin participates in the regulation of mineralization and bone turnover [28]. A vitamin D regulatory element was identified in its promoter [66][67][68][69]. In most species, 1a,25-(OH) 2 D 3 upregulates osteocalcin biosynthesis.…”

Section: Discussionmentioning

confidence: 99%

Fetal bone cells for tissue engineering

Montjovent

Burri

Mark

et al. 2004

Bone

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We envision the use of human fetal bone cells for engineered regeneration of adult skeletal tissue. A description of their cellular function is then necessary. To our knowledge, there is no description of human primary fetal bone cells treated with differentiation factors. The characterization of fetal bone cells is particularly important as the pattern of secreted proteins from osteoblasts has been shown to change during aging. In the first part of this work, human primary fetal bone cells were compared to adult bone cells and mesenchymal stem cells for their ability to proliferate and to differentiate into osteoblasts in vitro. Cell proliferation, gene expression of bone markers, alkaline phosphatase (ALP) activity, and mineralization were analyzed during a time-course study. In the second part of this paper, bone fetal cells behavior exposed to osteogenic factors is further detailed. The doubling time of fetal bone cells was comparable to mesenchymal stem cells but significantly shorter than for adult bone cells. Gene expression of cbfa-1, ALP, a1 chain of type I collagen, and osteocalcin were upregulated in fetal bone cells after 12 days of treatment, with higher inductions than for adult and mesenchymal stem cells. The increase of ALP enzymatic activity was stronger for fetal than for adult bone cells reaching a maximum at day 10, but lower than for mesenchymal stem cells. Importantly, the mineralization process of bone fetal cells started earlier than adult bone and mesenchymal stem cells. Proliferation of fetal and adult bone cells was increased by dexamethasone, whereas 1a,25-dihydroxyvitamin D 3 did not show any proliferative effect. Mineralization studies clearly demonstrated the presence of calcium deposits in the extracellular matrix of fetal bone cells. Nodule formation and calcification were strongly increased by the differentiation treatment, especially by dexamethasone. This study shows for the first time that human primary fetal bone cells could be of great interest for bone research, due to their fast growth rate and their ability to differentiate into mature osteoblasts. They represent an interesting and promising potential for therapeutic use in bone tissue engineering.

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Section: Discussionmentioning

confidence: 99%

Fetal bone cells for tissue engineering

Montjovent

Burri

Mark

et al. 2004

Bone

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“…The first VDRE was identified in the osteocalcin gene in 1989 and consisted of two identical hexanucleotide repeats, separated by either a three (Kerner et al 1989) or six base pair region (Haussler et al 2013). Each of the two adjacent six nucleotide motifs interact with the dual zinc finger DNA-binding domain of VDR and RXR, with each receptor binding at the 3′ and 5′ sequence respectively (Haussler et al 2013).…”

Section: Vitamin D Response Elements (Vdres) and Co-regulatory Proteinsmentioning

confidence: 99%

Molecular actions of vitamin D in reproductive cell biology

et al. 2017

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Vitamin D (VitD) is an important secosteroid and has attracted attention in several areas of research due to common VitD deficiency in the population, and its potential to regulate molecular pathways related to chronic and inflammatory diseases. VitD metabolites and the VitD receptor (VDR) influence many tissues including those of the reproductive system. VDR expression has been demonstrated in various cell types of the male reproductive tract, including spermatozoa and germ cells, and in female reproductive tissues including the ovaries, placenta and endometrium. However, the molecular role of VitD signalling and metabolism in reproductive function have not been fully established. Consequently, the aim of this work is to review current metabolic and molecular aspects of the VitD-VDR axis in reproductive medicine and to propose the direction of future research. Specifically, the influence of VitD on sperm motility, calcium handling, capacitation, acrosin reaction and lipid metabolism is examined. In addition, we will also discuss the effect of VitD on sex hormone secretion and receptor expression in primary granulosa cells, along with the impact on cytokine production in trophoblast cells. The review concludes with a discussion of the recent developments in VitD-VDR signalling specifically related to altered cellular bioenergetics, which is an emerging concept in the field of reproductive medicine.Reproduction (2017) 153 R29-R42

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“…Although OC itself does not play a critical role in osteoblast differentiation and bone formation (14), studies of the OC gene promoter contributed milestones toward our current understanding of transcriptional control in osteoblasts. Examples include the early elucidation of vitamin D action (15,16) and the more recent discovery of Runx2 as an osteoblast master transcription factor (17)(18)(19)(20)(21)(22). Because OC gene expression is acutely inhibited by glucocorticoids in vivo (23,24), its promoter could potentially serve as a molecular tool for the discovery of transcriptional mechanisms underlying the deleterious effects of glucocorticoids in osteoblasts.…”

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confidence: 99%

Glucocorticoids inhibit osteocalcin transcription in osteoblasts by suppressing Egr2/Krox20‐binding enhancer

Leclerc¹,

Noh²,

Khokhar³

et al. 2005

Arthritis & Rheumatism

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Objective. Glucocorticoids are widely used for the management of rheumatoid arthritis. Osteoporosis is a major side effect of glucocorticoid therapy and is attributable to inhibition of bone formation. We developed an osteoblast culture system in which glucocorticoids strongly inhibit development of the osteoblast phenotype, including expression of the bone-specific osteocalcin (OC) gene. Using this gene as a model, the goal of this study was to discover glucocorticoid-sensitive transcriptional mechanisms in osteoblasts.Methods. Dexamethasone (DEX; 1 M) was administered to murine MC3T3-E1 osteoblastic cultures under conditions that inhibit mineralized extracellular matrix formation and OC messenger RNA levels by >10-fold. Because standard (short-term) transient transfection assays with OC promoter-reporter constructs did not recapitulate the strong DEX-mediated repression, mapping of OC negative glucocorticoid response elements (GREs) was performed initially by stable transfection and then with long-term transient transfection assays. Transcription factor binding to the OC negative GRE was studied by electrophoretic mobility shift assays.Results. Several-fold repression of OC-luciferase constructs was recapitulated in stable and long-term transient transfection assays, in which the transfected cells were allowed to progress to a sufficiently advanced developmental stage. Analysis of a 5 promoter deletion series mapped an OC negative GRE to a 15-bp G/C-rich motif (؊161/؊147) located just upstream of the binding site for the osteoblast master transcription factor Runx2. Oligonucleotides encompassing this element and MC3T3-E1 cell extracts formed a protein-DNA complex that contained an Egr/Krox family member(s). Complex formation was competed by either an oligonucleotide containing 2 consensus Egr motifs or by anti-Egr2/Krox20 antibodies. Three copies of this Kroxbinding element conferred 20-fold transcriptional activation on the 147-bp basal OC promoter in osteoblasts, and the enhancer activity was inhibited by DEX. Enhancer activity was not observed in 10T1/2 fibroblasts unless these cells were cotransfected with Runx2.Conclusion. An Egr2/Krox20-binding site located immediately upstream of the Runx2 site of the mouse OC promoter was identified as an enhancer in osteoblasts, whose activity is repressed by glucocorticoids. Sequence similarity suggests that such a mechanism is likely operative in both murine and human cells. Because glucocorticoids inhibit Egr2/Krox20 expression in osteoblasts, and because trabecular bone formation is arrested in Egr2/Krox20-knockout mice, the inhibition of Egr2/Krox20 activity likely contributes to glucocorticoid-induced osteoporosis.Since the 1950 Nobel laureates E. Kendall, T. Reichstein, and P. Hench introduced glucocorticoids for the treatment of rheumatoid arthritis, these drugs have been widely used for the treatment of autoimmune and inflammatory diseases. The enthusiasm with which glucocorticoids were initially accepted was quickly dampened upon realization of their deleter...

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Sequence elements in the human osteocalcin gene confer basal activation and inducible response to hormonal vitamin D3.

Cited by 370 publications

References 36 publications

Fetal bone cells for tissue engineering

Fetal bone cells for tissue engineering

Molecular actions of vitamin D in reproductive cell biology

Glucocorticoids inhibit osteocalcin transcription in osteoblasts by suppressing Egr2/Krox20‐binding enhancer

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