| Project/Area Number |
15K11053
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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 |
Functional basic dentistry
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| Research Institution | Showa University |
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Principal Investigator |
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| Research Collaborator |
Yoshimura Kentaro
Funato Sakie
Izumida Eri
Kaneko Kotaro
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| Project Period (FY) |
2015-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | 破骨細胞 / 歯周病 / 骨吸収 / プロテアーゼ / オステオプロテゲリン / 好中球 / エラスターゼ / 炎症 |
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| Outline of Final Research Achievements |
Bone loss in periodontitis is caused by enhanced production of bone resorbing factors such as pro-inflammatory cytokines that induce the expression of RANKL, a major osteoclast differentiation-inducing factor, in osteoblasts. On the other hand, osteoblasts secrete OPG, an inhibitor of osteoclast differentiation. In this study, we found that human neutrophils and neutrophil elastase degraded OPG, which was suppressed by addition of alpha1-protease inhibitor, a major elastase inhibitor in the blood circulation. Amino acid sequence analyses of OPG fragments obtained after treatment of OPG with human neutrophil elastase indicated that elastase cleaves OPG in its death domain. Finally, human neutrophils enhanced osteoclast differentiation in cocultures of bone marrow cells and osteoblasts. These results suggest that neutrophil elastase is involved in enhanced osteoclastogenesis under an inflammatory conditions via degradation of OPG.
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| Academic Significance and Societal Importance of the Research Achievements |
歯周病性骨破壊を含め骨吸収を担う破骨細胞分化は、RANKL/OPGの発現比の変化によって制御されると考えられている。一方、我々は世界で初めて、細菌性プロテアーゼによるOPGの分解によるRANKL/OPG比の上昇が破骨細胞分化の調節に重要な役割を持つことを提唱した。本研究は、この概念を発展させるもので、我々自身の持つプロテアーゼが破骨細胞分化調節において同様の役割を持つことを明らかにしたものである。この成果は、歯周病性骨破壊にとどまらず、骨粗鬆症や関節リウマチなど全身性の骨疾患の病態形成の理解に大きく寄与する可能性を持つものであり、それらの疾患の治療法の開発にも重要な示唆を与えるものである。
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