2019 Fiscal Year Final Research Report

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.

Research Project

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Project/Area Number	16H05505
Research Category	Grant-in-Aid for Scientific Research (B)
Allocation Type	Single-year Grants
Section	一般
Research Field	Morphological basic dentistry
Research Institution	Meikai University
Principal Investigator	HAKEDA Yoshiyuki 明海大学, 歯学部, 教授 (90164772)
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)
Project Period (FY)	2016-04-01 – 2020-03-31
Keywords	破骨細胞 / 細胞融合 / LDL受容体 / LOX-1 / 細胞膜外葉 / phosphatidylethanolamine / ABCG1
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.
Free Research Field	口腔解剖学
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。