Elucidation of the pathophysiology of aggressive periodontitis using MMD2 mutant mice

• Project/Area Number: 18H02978
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 57030:Conservative dentistry-related
• Research Institution: Hiroshima University
• Principal Investigator: Mizuno Noriyoshi 広島大学, 医系科学研究科(歯), 教授 (60325181)
• Co-Investigator(Kenkyū-buntansha): 加治屋 幹人 広島大学, 医系科学研究科(歯), 助教 (00633041) ; 岩田 倫幸 広島大学, 病院(歯), 助教 (30418793) ; 川上 秀史 広島大学, 原爆放射線医科学研究所, 教授 (70253060) ; 栗原 英見 広島大学, 医系科学研究科(歯), 教授 (40161765)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2020: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2018: ¥8,190,000 (Direct Cost: ¥6,300,000、Indirect Cost: ¥1,890,000)
• Keywords: 侵襲性歯周炎 / 浸襲性歯周炎 / 遺伝子改変マウス

Outline of Final Research Achievements

Two families with A116V and R126P mutations were found in monocyte to macrophage associated protein (MMD) 2. Patients in these families had a higher inhibition of neutrophil chemotaxis for fMLP than healthy individuals. Knock-in mice having these mutations were generated. When periodontitis was induced by the silk ligation model, severe periodontitis was induced in knock-in mice as compared with wild-type mice. In addition, neutrophils in knock-in mice had a inhibition of chemotaxis for fMLP as compared with neutrophils in wild-type mice. Experiments with HEK cells have shown that these mutations inhibit ERK phosphorylation.

Academic Significance and Societal Importance of the Research Achievements

急速で高度な歯周組織破壊を特徴とする侵襲性歯周炎の発症機序の一部が解明されたことによって、現在の対症療法中心である治療とはまったく違った、発症機序にもとづいた治療法の開発の基礎的なデータが得られた。MMD2が遺伝学的のみならず、機能面からも侵襲性歯周炎の原因遺伝子であることが示されたため、侵襲性歯周炎は可能な限り早期の確定診断が求められることから、将来的に罹患する可能性のある本家系内の若年者の血液を採取することによって本疾患を遺伝子診断することおよび孤発例のスクリーニングが可能となり、予防医療にも発展させることができる。

Research Products

• [Journal Article] Aggressive periodontitis and NOD2 variants (2020)
  • Author(s): Mizuno Noriyoshi, Kume Kodai, Nagatani Yukiko, Matsuda Shinji, Iwata Tomoyuki, Ouhara Kazuhisa, Kajiya Mikihito, Takeda Katsuhiro, Matsuda Yukiko, Tada Yui, Ohsawa Ryosuke, Morino Hiroyuki, Mihara Keichiro, Fujita Tsuyoshi, Kawaguchi Hiroyuki, Shiba Hideki, Kawakami Hideshi, Kurihara Hidemi
  • Journal Title: Journal of Human Genetics Volume: 65(10) Issue: 10 Pages: 841-846
  • DOI: 10.1038/s10038-020-0777-z
  • Peer Reviewed / Open Access
• [Journal Article] Optineurin regulates osteoblastogenesis through STAT1 (2020)
  • Author(s): Mizuno Noriyoshi、Iwata Tomoyuki、Ohsawa Ryosuke、Ouhara Kazuhisa、Matsuda Shinji、Kajiya Mikihito、Matsuda Yukiko、Kume Kodai、Tada Yui、Morino Hiroyuki、Yoshimoto Tetsuya、Ueki Yasuyoshi、Mihara Keichiro、Sotomaru Yusuke
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 525(4) Issue: 4 Pages: 889-894
  • DOI: 10.1016/j.bbrc.2020.03.028
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 侵襲性歯周炎の家族内発症を考える (2020)
  • Author(s): 水野智仁
  • Organizer: 第5回日本歯周病学会近畿地区臨床研修会