| Project/Area Number |
17K11000
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Orthopaedic surgery
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
Koga Daisuke 東京医科歯科大学, 医学部附属病院, 非常勤講師 (60422482)
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| Co-Investigator(Kenkyū-buntansha) |
辻 邦和 東京医科歯科大学, 大学院医歯学総合研究科, 寄附講座准教授 (20323694)
麻生 義則 東京医科歯科大学, 大学院医歯学総合研究科, ジョイントリサーチ講座教授 (50345279)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | 閉経 / 骨粗鬆症 / PAI-1 / 骨形成 / 骨吸収 / 骨代謝 / 薬理学 |
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| Outline of Final Research Achievements |
Menopause is a potent risk factor of osteoporosis. In this study, we evaluated the therapeutic benefits of novel orally available small molecule PAI-1 inhibitor (iPAI-1) in an estrogen deficiency-induced osteoporosis model. Eight-week old C57BL/6J female mice were divided into three groups, including a sham+vehicle (Sham), ovariectomy (OVX)+vehicle (OVX+v), and OVX+iPAI-1 (OVX+i) group. Six weeks of iPAI-1 treatment prevented OVX-induced trabecular bone loss. Bone formation activity was significantly higher in the OVX+i group than the OVX+v group and sham group. Unexpectedly, OVX-induced osteoclastgenesis was partially, but significantly reduced. Bone marrow ablation analysis indicated that the remodeled trabecular bone volume was significantly higher in the iPAI-1-treated group than that in the control group. In conclusion, our results suggest PAI-1 blockade via a small molecule inhibitor is a new therapeutic approach for the anabolic treatment of postmenopausal osteoporosis.
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| Academic Significance and Societal Importance of the Research Achievements |
現在市場にある治療薬は、ほとんどが破骨細胞を標的とする骨吸収阻害剤である。これらは骨量を増加させるが、一方で骨代謝回転を抑制し、長期投与によって骨質を低下させる。実際に骨吸収阻害剤の長期投与に起因すると考えられる非定型骨折の発生が整形外科では問題となっている。PAI-1阻害剤は骨形成促進の効果を有し、骨質を改善する全く新しい骨粗鬆症治療剤として有望と予想される。この研究が順調に推進されれば、高齢者医療の現場が得られる恩恵はきわめて大きい。
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