Analysis of mechanism of the bone complication in diabetes mellitus by reactivation of the gene expression through oxidative stress
Project/Area Number |
21790351
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Research Category |
Grant-in-Aid for Young Scientists (B)
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Allocation Type | Single-year Grants |
Research Field |
Human pathology
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Research Institution | National Hospital Organization Osaka National Hospital Institute for Clinical Reserch (2011-2012) Kobe University (2009-2010) |
Principal Investigator |
MORI Kiyoshi 独立行政法人国立病院機構大阪医療センター(臨床研究センター), 研究員 (70432573)
|
Project Period (FY) |
2009 – 2012
|
Project Status |
Completed (Fiscal Year 2012)
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Budget Amount *help |
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2012: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2011: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2010: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2009: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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Keywords | 骨 / 関節 / 筋肉 / 皮膚 / 感覚器 / 遺伝子変異マウス / sFRP-4 / 初代培養細胞 / 加齢 / 骨形態計測 / μCT / 骨形成パラメータ / 酸化的ストレス / 遺伝子発現制御 / 骨代謝 / メチル化シトシン / TBP / MeCP2 |
Research Abstract |
To elucidate the mechanism of diabetic bone complication, we focused on the oxidative stress and performed in vitro studies by using mouse bone marrow stromal cell line. Oxidative stress induced by methylglyoxal (MG) treatment upregulated secreted Frizzled-related protein 4 (sFRP-4) gene expression as well that of osteoclast differentiating factor (RANKL) gene while MG treatment suppressed the expression of Osteoprotegerin (OPG, a RANKL antagonist) gene in reciprocal manner. Furthermore we observed oxidative stress suppressed Wnt/ β -catenin signal transduction pathway. In the analysis of sFRP-4 gene promoter region, we found highly methylated two-tandem cytosine-guanine sequences (CpGs) at 5 bases upstream of TATA-box following to downregulation of sFRP-4 gene transcription through methylcytosine binding protein 2 (MeCP2) recruitment. We observed enhanced adhesion of TATA-box binding protein (TBP) to TATA-box under the condition of oxidative stress. These findings elucidated a part of the mechanisms of restoration in sFRP-4 gene expression induced by oxidative stress. We next designed in vivo studies, in which we histomorphologically compared long bones obtained from drug-induced diabetic mice and healthy mice, and we observed reduction of trabecular bones in diabetic mouse femur. Moreover, we originally established sFRP-4 knock-out mice and observed that this animal was resistant to osteopenia due to senescence in natural course. These studies suggest that acute oxidative stress promotes bone resorption through RANKL signaling whereas, in mild and persistent oxidative stress as senescence, sFPR-4 represses turnover of bone metabolism through Wnt/ β-catenin signaling prior to the onset of osteopenia and ultimately osteoporosis
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Report
(5 results)
Research Products
(15 results)
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[Book] Microscopy : Science, Technology, Applications and Education2010
Author(s)
Kitazawa S., Mori K, Idei Y, Fujimoto M, Kito K, Haraguchi R, Abe Y, Kondo T, Kitazawa R.
Publisher
In situ detection of specific gene expression during and immediately after transcription at electron microscopic level.
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