Elucidation of Involvement of LOX-1 in inflammatory bone destruction and the molecular mechanism for the LOX-1 actions, and an approach to develop the new drug for bone diseases.
| Project/Area Number |
16H05505
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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 |
Morphological basic dentistry
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| Research Institution | Meikai University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
沢村 達也 信州大学, 学術研究院医学系, 教授 (30243033)
伊東 順太 城西大学, 薬学部, 助教 (40609096)
岡安 麻里 東京大学, 医学部附属病院, 助教 (10610941)
小笠原 徹 東京大学, 医学部附属病院, 講師 (20359623)
森 芳史 明海大学, 歯学部, 助教 (60757954)
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| Project Period (FY) |
2016-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000)
Fiscal Year 2019: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
Fiscal Year 2018: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
Fiscal Year 2017: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
Fiscal Year 2016: ¥7,280,000 (Direct Cost: ¥5,600,000、Indirect Cost: ¥1,680,000)
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| Keywords | 破骨細胞 / 細胞融合 / LDL受容体 / LOX-1 / 細胞膜外葉 / phosphatidylethanolamine / ABCG1 / 炎症整骨破壊 / 脂質 / 炎症性骨破壊 |
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| Outline of Final Research Achievements |
In this study, we found that like low-density lipoprotein receptor (LDLR) single KO (sKO), LDLR/lectin-like oxidized LDL receptor-1 (LOX-1) double KO (dKO) impaired osteoclast cell-cell fusion. LDLR/LOX-1 dKO and LDLR sKO preosteoclasts decreased uptake of LDL. The cell surface cholesterol levels of both genotypic osteoclasts were lower than the levels of wild-type osteoclasts. Additionally, the amount of phosphatidylethanolamine (PE) on the cell surface was attenuated in LDLR/LOX-1 dKO and LDLR sKO preosteoclasts, while the PE distribution in wild-type osteoclasts was concentrated on the filopodia in contact with neighboring cells. Abrogation of ATP binding cassette G1 (ABCG1) transporter, which transfers PE to the cell surface, caused decreased PE translocation to the cell surface and subsequent cell-cell fusion. The findings of this study indicate the involvement of a novel cascade (LDLR ~ ABCG1 ~ PE translocation to cell surface ~ cell-cell fusion) in osteoclast multinucleation.
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| Academic Significance and Societal Importance of the Research Achievements |
破骨細胞の過剰な活性化がもたらす骨粗鬆症や炎症性骨破壊の発症機構に関連して、従来考えられてきた破骨細胞の細胞融合機構とは異なって、本研究は、破骨細胞融合には細胞膜上のリン脂質、特にホスファチジルエタノールアミン（PE）の細胞膜内葉から外葉への分布転換が重要であり、その分布転換にはLDL受容体を介したLDLの細胞内への取り込みに依存したABCG１トランスポーターの発現が大きく関与することを示した。このことは、骨疾患に対する新しい観点からの治療につながる研究で学術的意義および社会的意義が大きい。
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Report
(5 results)
Research Products
(5 results)
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[Journal Article] LDL uptake-dependent phosphatidylethanolamine translocation to the cell surface promotes fusion of osteoclast-like cells.2020
Author(s)
Kitano J F V, Ohyama Y, Hayashida C, Ito J, Okayasu M, Sato T, Ogasawara T, Tsujita M, Kakino A, Shimada J, Sawamura T, and Hakeda Y.
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Journal Title
Journal of Cell Science
Volume: ー
Related Report
Peer Reviewed
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