| Project/Area Number |
17390410
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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 |
HARA Yukinori The University of Tokyo, Faculty of Medicine, Assistant Professor (30396741)
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| Co-Investigator(Kenkyū-buntansha) |
OGATA Naoshi The University of Tokyo, Faculty of Medicine, Visiting Assistant Professor (10361495)
MABUCHI Akihiko The University of Tokyo, Faculty of Medicine, Associate Professor (80312312)
HARA Yoshinori The University of Tokyo, Faculty of Medicine, Assistant Professor (00422296)
川口 浩 東京大学, 医学部附属病院, 助教授 (40282660)
中村 耕三 東京大学, 医学部附属病院, 教授 (60126133)
門脇 孝 東京大学, 医学部附属病院, 教授 (30185889)
石山 典幸 東京大学, 医学部附属病院, 助手 (60376481)
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| Project Period (FY) |
2005 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥16,310,000 (Direct Cost: ¥15,500,000、Indirect Cost: ¥810,000)
Fiscal Year 2007: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000)
Fiscal Year 2006: ¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 2005: ¥9,800,000 (Direct Cost: ¥9,800,000)
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| Keywords | Bone / Bone mineral density / Akt / Osteoporosis / Osteoblast / Osteoclast / Knockout mouse / Apoptosis / 軟骨 / 成長板 / 石灰化 / インスリン / 軟骨内骨化 |
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| Research Abstract |
Bone mass and turnover are maintained by the coordinated balance between bone formation by osteoblasts and bone resorption by osteoclasts, under regulation of many systemic and local factors. Phosphoinositide-dependent serine-threonine protein kinase Akt is one of the key players in the signaling of potent bone anabolic factors. This study initially showed that the disruption of Akt1, a major Akt in osteoblasts and osteoclasts, in mice led to low-turnover osteopenia through dysfunctions of both cells. Ex vivo cell culture analyses revealed that the osteoblast dysfunction was traced to the increased susceptibility to the mitochondria-dependent apoptosis and the decreased transcriptional activity of runt-related transcription factor 2 (Runx2), a master regulator of osteoblast differentiation. Notably, our findings revealed a novel role of Akt1/forkhead box class O (FoxO) 3a/Bim axis in the apoptosis of osteoblasts : Akt1 phosphorylates the transcription factor FoxO3a to prevent its nuclear localization, leading to impaired transactivation of its target gene Bim which was also shown to be a potent proapoptotic molecule in osteoblasts. The osteoclast dysfunction was attributed to the cell autonomous defects of differentiation and survival in osteoclasts and the decreased expression of receptor activator of nuclear factor-κB ligand (RANKL), a major determinant of osteoclastogenesis, in osteoblasts. Akt1 was established as a crucial regulator of osteoblasts and osteoclasts by promoting their differentiation and survival to maintain bone mass and turnover. The molecular network found in this study will provide a basis for rational therapeutic targets for bone disorders.
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