| Project/Area Number |
13557127
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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 | 展開研究 |
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| Research Field |
Orthopaedic surgery
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| Research Institution | Keio University |
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Principal Investigator |
TOYAMA Yoshiaki Keio Medical School, Department of Orthopedics, Professor, 医学部, 教授 (40129549)
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| Co-Investigator(Kenkyū-buntansha) |
OHTA Hideo Kirin Brewery Company, 医薬探索研究所・創薬グループ, 主任研究員(研究職)
HOZUMI Nobumichi Research Institute for Biological Sciences, Tokyo University of Science, Professor, 生命科学研究所, 教授 (60051744)
YAMADA Taketo Department of Pathology, Assistant Professor, 医学部, 講師 (60230463)
堀内 圭輔 慶應義塾大学, 医学部, 助手 (30327564)
岩本 潤 慶應義塾大学, 医学部, 助手 (40245527)
手塚 建一 東京理科大学, 生命科学研究所, 講師 (50236973)
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| Project Period (FY) |
2001 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥12,100,000 (Direct Cost: ¥12,100,000)
Fiscal Year 2002: ¥5,400,000 (Direct Cost: ¥5,400,000)
Fiscal Year 2001: ¥6,700,000 (Direct Cost: ¥6,700,000)
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| Keywords | HuBone-NOD-SCID mice / Notch / Human mesenchymal stem cells / MC3T3-EI / ATDC5 / Adenovirus vector / Signal Sequence Trap / 骨芽細胞 / 内軟骨性骨化 / 軟骨細胞 / POEM / 力学負荷 / 運動療法 |
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| Research Abstract |
The objective of the current project is to develop a pre-clinical animal model system for osteoporosis research using HuBone-NOD-SCID mice, with emphasis on the following points; regulation of bone formation by Notch and changes of bone mass by mechanical load. The genetically engineered mice carrying mutations in the Notch ligand genes undergo skeletal abnormalities. This prompted us to investigate involvement of Notch in bone and cartilage formation. We have found that the osteoblastic cell line, MC3T3-E1 (MC3T3), expresses Notch at early differentiation stage, then the expression declines. The Notch1 gene (activated cytoplasmic region: NIC) was introduced into MC3T3 cells mediated via Notch1/adeno virus vector. The introduction of the gene into the cells resulted in increased calcified nodule formation. The same vector was transfected into human mesenchymal stem cells (HMCS). NIC expression in HMSC induced both spontaneous and stimulated osteoblastic differentiation. Scaffold carryi
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ng HMSC were infected with the viral vector and were implanted into NOD-SCID mice subcutaneously. We confirmed increased angiogenesis in the scaffolds recovered from the mice. NIC transfection inhibited adipocyte differentiation in HMSC. Long bones are developed by endochondral ossification. Thus, it is important to investigate the effects of Notch on chondrogenesis. The vector was transferred to the chondrogenic cell line (ATDC5) which differentiates into chondrocytes following the addition of insulin. NIC was demonstrated to inhibit the chondrocyte differentiation. Our results suggest that Notch promotes osteoblastic differentiation, but inhibi the differentiation into adipocyte and chondrocyte from MSC. Currently, we are working on the experiments to decipher the molecular mechanisms involved in the cellular differentiation pathways. We have investigated the relationship between physical exercise and bone mass in postmenopausal women. Physical exercise was demonstrated to increase bone mass, but the increased bone mass was quickly lost after withdrawal from physical exercise. Less
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