| Project/Area Number |
15390450
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Orthopaedic surgery
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| Research Institution | The University of Tokyo |
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Principal Investigator |
YAMAMOTO Aiichiro The University of Tokyo, Faculty of Medicine, Assistant, 医学部附属病院, 助手 (90359612)
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| Co-Investigator(Kenkyū-buntansha) |
TANAKA Sakae The University of Tokyo, Faculty of Medicine, Lecturer, 医学部附属病院, 講師 (50282661)
ODA Hiromi Saitama medical University, School of Medicine, Professor, 医学部, 教授 (60101698)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥11,800,000 (Direct Cost: ¥11,800,000)
Fiscal Year 2004: ¥5,700,000 (Direct Cost: ¥5,700,000)
Fiscal Year 2003: ¥6,100,000 (Direct Cost: ¥6,100,000)
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| Keywords | Osteoclast / Apoptosis / Bim / FADD / 骨吸収 / ユビキチン化 |
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| Research Abstract |
Osteoclasts are multinucleated giant cells primarily responsible for bone resorption. They are terminally differentiated cells, and undergo rapid apoptosis in the absence of trophic factors such as macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL). Osteoclasts undergo rapid apoptosis without trophic factors, such as macrophage colony-stimulating factor (M-CSF). Their apoptosis was associated with a rapid and sustained increase in the pro-apoptotic BH-3-only Bcl-2 family member Bim. This was caused by the reduced ubiquitination and proteasomal degradation of Bim that is mediated by c-Cbl. Although the number of OCs was increased in the skeletal tissues of bim-/-mice, the mice exhibited mild osteosclerosis due to reduced bone resorption. OCs differentiated from bone marrow cells of bim-/-animals showed a marked prolongation of survival in the absence of M-CSF, compared to bim+/+ OCs, but the bone-resorbing activity of bim-/-OCs was significantly reduced. Overexpression of a degradation-resistant lysine-free Bim mutant in bim-/-cells abrogated the anti-apoptotic effect of M-CSF, while wild type Bim did not. These results demonstrate that ubiquitination-dependent regulation of Bim levels is critical for controlling apoptosis and activation of OCs.
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