| Project/Area Number |
16590907
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Endocrinology
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| Research Institution | The University of Tokushima |
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Principal Investigator |
INOUE Daisuke The University of Tokushima, Graduate school, Institute of Health BioSciences, Lecturer (60314853)
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| Project Period (FY) |
2004 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2006: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2005: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2004: ¥1,100,000 (Direct Cost: ¥1,100,000)
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| Keywords | glucocorticoid-induced osteoporosis / osteoblast / apoptosis / interleukin-11 / activated protein(AP)-l / transcription / glucocorticoid receptor / parathyroid hormone(PTH) |
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| Research Abstract |
1) Mechanism of transcriptional repression of IL-11 gene by dexamethasone (DEX)
In mouse primary osteoblasts and a preosteoblast cell line MC3T3-E1, dexamethasone inhibited IL-11 gene transcription in luciferase reporter gene assay. This inhibitory effect was lost when the AP-1 site was disrupted by site-directed mutagenesis, indicating AP-1 dependency. Consistently, Transcription from constructs with tandem AP-1 sites alone was also inhibited by DEX. Furthermore, The effect of DEX was blocked by a GR antagonist RU-486, suggesting that the repression occurs via DEX binding to GR.
2) Anti-apoptotic effect of IL-11
IL-11 inhibited osteoblast apoptosis induced by DEX and etoposide (EPO) in a dose-dependent manner. The maximal effect was approximately 50% inhibition. Similar anti-apoptotic effect, was observed with PTH, which we found is an inducer of IL-11 expression. We found that osteoblast apoptosis induced by DEX and EPO was accompanied by decreased expression of BCL-2, and that both PTH and IL-11 blocked the suppression of Bcl-2 expression during apoptosis. Because the anti-apoptotic effect of PTH was reversed by a simultaneous treatment with an anti-IL-11 neutralizing antibody, the PTH effect was at least in part mediated by IL-11.
Based on these results, we conclude that IL-11 is an anti-apoptotic factor, which is induced by PTH and suppressed by DEX at the transcriptional level, and may thus participate in the pathogenesis of glucocorticoid-induced suppression of bone formation as well as therapeutic effect of PTH on glucocorticoid-induced osteoporosis (GIO). IL-11 can be a new molecular target for the treatment of GIO.
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