| Project/Area Number |
20591178
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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 |
膠原病・アレルギー・感染症内科学
|
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| Research Institution | Aichi Medical University |
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Principal Investigator |
YAMAMURA Masahiro Aichi Medical University, 医学部, 教授 (80252956)
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| Co-Investigator(Kenkyū-buntansha) |
向井 知之 愛知医科大学, 医学部, 助教 (00454421)
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| Project Period (FY) |
2008 – 2010
|
| Project Status |
Completed (Fiscal Year 2010)
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| Budget Amount *help |
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2010: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2009: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2008: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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| Keywords | 関節リウマチ / 骨芽細胞 / 炎症性サイトカイン / 骨形成蛋白質 / 腫瘍壊死因子 / Smad / 骨形成タンパク質 |
|---|
| Research Abstract |
The cellular mechanism for cytokine-mediated inhibition of BMP-induced osteoblastic differentiation was investigated using mouse myoblast C2C12 cells. Osteoblast transformation of BMP-cultured C2C12 cells, and their Runx2/osteocalcin expression, ALP activity, and parathyroid hormone (PTH) responsiveness (cAMP production) were inhibited by TNF-α, but not by IL-1, IL-6, or IL-17. BMP-induced Smad1, 5, 8 phosphorylation in the cells was suppressed by TNF-α signaling, but inhibitory Smad6 gene activation was increased as determined by cDNA array. MAP kinase analysis showed that ERK1/ERK2 and SAPK/JNK phosphorylation were selectively activated in the cells with TNF-α. BMPs had no effect on TNF type 1 and 2 receptor-expression. Notably, SAPK/JNK inhibitors restored TNF-α inhibition of osteoblast differentiation, as demonstrated by Id-1-promoter activity as well as Runx2/osteocalcin mRNA levels. These results suggest that TNF-α may have a crucial role in BMP-induced osteogenic inhibition in the diseases such as rheumatoid arthritis, through its SAPK/JNK activation and Smad6 induction.
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