| Project/Area Number |
09307034
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| Research Category |
Grant-in-Aid for Scientific Research (A).
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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 | Tokyo Medical Dental University |
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Principal Investigator |
NODA Masaki Med.Res.Inst., Dept.of Mol.Pharmacol., Tokyo Medical Dental University Professor, 難治疾患研究所, 教授 (50231725)
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| Co-Investigator(Kenkyū-buntansha) |
YAMASHITA Teruhito Med.Res.Inst., Dept.of Mol.Pharmacol., Tokyo Medical Dental University Asistant Professor, 難治疾患研究所, 助手 (90302893)
NIFUJI Akira Med.Res.Inst., Dept.of Mol.Pharmacol., Tokyo Medical Dental University Associate Professor, 難治疾患研究所, 助教授 (00240747)
田村 正人 鹿児島大学, 歯学部, 助手 (30236757)
川口 奈奈子 東京医科歯科大学, 難治疾患研究所, 助手 (10200700)
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| Project Period (FY) |
1997 – 2000
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| Project Status |
Completed (Fiscal Year 2000)
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| Budget Amount *help |
¥40,300,000 (Direct Cost: ¥40,300,000)
Fiscal Year 2000: ¥5,300,000 (Direct Cost: ¥5,300,000)
Fiscal Year 1999: ¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 1998: ¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 1997: ¥27,700,000 (Direct Cost: ¥27,700,000)
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| Keywords | Osteoporosis / Osteoclast / Osteoblast / Gene Regulation / Osteopontin / Klotho / Tob / Mechanical Stress / 骨形成 / 骨吸収 / 軟骨細胞 / 転写因子 / 細胞外基質分子・オステオポンチン / 骨形成因子 / 老化関連遺伝子 / CBFA / MITF / BMP |
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| Research Abstract |
We established the molecular bases of regulation ofosteoblasts as well as osteoclasts. With regard to bone resorption, osteopontin knock out mice were produced (JBMR, 1998) and the following study indicated that this molecule is required for rapid bone resorption after estrogen depletion (Proceedings of the National Academy of Sciences U.S.A., 1999., 1999).
Bone formation mechanism was studied using knockout mice and we identified (1) Tab as a novel inhibitor of bone formation in response to BMP (Cell, 2000) , (2) a unique Smad regulation of Cbfa gene expression (Journal of Biological Chemistry (JBC) 1998)(3) a novel mechanism of vitamin D regulation of ld, a negative regulator of helix loop helix type transcription factor (JBC,1997) , (4) a positive type helix-loop-helix transcription factor, Scleraxis and an HMG factor to be responsible for connective tissue gene regulation (JBC,1997)(JBC,2000).
We also identified that klotho gene is involved in the regulation of bone resorption activity by regulating osteoprotegerin (Endocrinology, 2000 ; J of Endocrinology, 2000), and the klotho phenotype in bone could be rescued by virus mediated klotho expression (Journal of Gene Medicine, 2000)
Mechanical stress is one of the most important aspects in contemplating osteoporosis treatment, however, no mechanism has been clarified. We found that osteopontin and klotho play critical roles and prerequisite for the bone loss in the unloaded mice (Journal of Experimental Medicine, 2001)(J of Endocrinology, 2001).
Over all our research identified key molecular players in the bone volume maintenance and loss and these findings are important in understanding the pathogenesis of osteoporosis and to contemplate measures to treat patients suffering from this disease which is one of the major health problems in the modern society.
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