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Elucidation of extraction tooth socket healing mechanism and MRONJ pathological condition from the perspective of stem cell niche

Research Project

Project/Area Number 19K24146
Research Category

Grant-in-Aid for Research Activity Start-up

Allocation TypeMulti-year Fund
Review Section 0907:Oral science and related fields
Research InstitutionOkayama University

Principal Investigator

Mikai Akihiro  岡山大学, 大学病院, 医員 (20845375)

Project Period (FY) 2019-08-30 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
KeywordsMRONJ / 幹細胞 / 骨形成
Outline of Research at the Start

骨代謝異常が病因として考えられている「薬剤関連顎骨壊死(MRONJ)」の病態は不明な点が多い.明確な治療法は確立されておらず,病態発生メカニズムの解明や治療法の開発が急務である.これまで,MRONJを間葉系幹細胞機能不全もしくは動員不全モデルとしてとらえる科学的根拠が十分蓄積され,幹細胞誘導・ニッチの観点から理解する必要性がでてきた.
本研究では,抜歯後の歯槽骨再生機序を最新の組織幹細胞生物学により明らかにする.間葉系幹細胞,ニッチを形成する細胞を領域・時期特異的に可視化できる遺伝子改変マウスを作製し,抜歯窩創傷治癒や成熟機序, MRONJ の病態を幹細胞誘導・ニッチの観点から解明する.

Outline of Final Research Achievements

For the purpose of clarifying the onset mechanism of MRONJ, we have carried out the construction and evaluation of MRONJ like model mice, and the analysis using genetically modified mice. It was confirmed that the extraction socket of the MRONJ like model mouse did not heal even 4 weeks after the operation, and the bone around the extraction socket was necrotic. Furthermore, while a large number of mesenchymal stem cells were observed during the healing process of femoral fractures in genetically modified mice, most of the mesenchymal stem cells were not observed during the healing process of the extraction socket.
In this study, stem cells play an important role in bone marrow formation, suggesting that differences in the amount of mesenchymal stem cells during the wound healing process between the femur and the extraction socket may be involved in MRONJ development.

Academic Significance and Societal Importance of the Research Achievements

高齢化が進行する日本では骨粗鬆症患者も増加し続けている.骨粗鬆症の第1選択薬であるビスフォスフォネート (BP) 製剤だが強力な骨吸収抑制作用を持つ一方で,投与されている患者において侵襲的歯科治療などを引き金に顎骨壊死が発生するMRONJが社会的問題となっている.MRONJはその発症原因及び治療法も未だ解明されていない.本研究により抜歯を引き金に発生したMRONJの発生メカニズムには何らかの形で間葉系幹細胞が関わっていることが明らかとなった.今後はさらに詳細に検討していく予定である。これらの研究はこれまで解明されていない,MRONJのメカニズムおよび治療法の開発において大きな一歩である.

Report

(3 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • Research Products

    (8 results)

All 2020

All Journal Article (2 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 2 results,  Open Access: 2 results) Presentation (6 results) (of which Int'l Joint Research: 2 results)

  • [Journal Article] BMP-2/β-TCP Local Delivery for Bone Regeneration in MRONJ-Like Mouse Model2020

    • Author(s)
      Mikai Akihiro、Ono Mitsuaki、Tosa Ikue、Nguyen Ha Thi Thu、Hara Emilio Satoshi、Nosho Shuji、Kimura-Ono Aya、Nawachi Kumiko、Takarada Takeshi、Kuboki Takuo、Oohashi Toshitaka
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 21 Issue: 19 Pages: 7028-7028

    • DOI

      10.3390/ijms21197028

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Distinct Osteogenic Potentials of BMP-2 and FGF-2 in Extramedullary and Medullary Microenvironments2020

    • Author(s)
      Nosho Shuji、Tosa Ikue、Ono Mitsuaki、Hara Emilio Satoshi、Ishibashi Kei、Mikai Akihiro、 Tanaka Yukie、Kimura-Ono Aya、Komori Taishi、Maekawa Kenji、Kuboki Takuo、Oohashi Toshitaka
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 21 Issue: 21 Pages: 7967-7967

    • DOI

      10.3390/ijms21217967

    • NAID

      120006937500

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] 骨髄存在・非存在下にてrhBMP-2,rhFGF-2が骨形成に与える影響の検討2020

    • Author(s)
      納所秋二, 大野充昭, 土佐郁恵, 三海晃弘, 石橋 啓, 大野 彩, 窪木拓男, 大橋俊孝
    • Organizer
      公益社団法人日本補綴歯科学会第129回学術大会
    • Related Report
      2020 Annual Research Report
  • [Presentation] BMP-2 local administration for MRONJ-mice induced partial bone regeneration2020

    • Author(s)
      Akihiro Mikai, Mitsuaki Ono, Shuji Nosho, Ikue Tosa, Emilio S Hara, Aya Kimura-Ono, Kumiko Nawachi, Takuo Kuboki, Toshitaka Oohashi
    • Organizer
      International Association for Dental Research (IADR) 98th General Session and Exhibition and 49th Annual Meeting of the American Association for Dental Research (AADR)
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] マウス薬剤関連性顎骨壊死モデルにおけるBMP-2の骨形成能の検討2020

    • Author(s)
      三海晃弘, 大野充昭, 納所秋二, 土佐郁恵, 縄稚久美子, 大野 彩, 窪木拓男, 大橋俊孝
    • Organizer
      岡山大学次世代研究拠点シンポジウム2020
    • Related Report
      2019 Research-status Report
  • [Presentation] BMP-2,FGF-2が骨髄内・外における骨形成に及ぼす影響の検討2020

    • Author(s)
      納所秋二, 大野充昭, Ha Nguyen, 三海晃弘, 窪木拓男, 大橋俊孝
    • Organizer
      岡山大学次世代研究拠点シンポジウム2020
    • Related Report
      2019 Research-status Report
  • [Presentation] 大型動物歯槽骨欠損モデルを用いた大腸菌由来rhBMP-2の骨再生能の検討2020

    • Author(s)
      田仲由希恵, 大野充昭, 納所秋二, 石橋啓, 三海晃弘, 土佐郁恵, 笈田育尚, 大野彩, 秋山謙太郎, 大橋俊孝, 入江洋之, 窪木拓男
    • Organizer
      岡山大学次世代研究拠点シンポジウム2020
    • Related Report
      2019 Research-status Report
  • [Presentation] Bone-inducing effects of rhBMP-2 and rhFGF-2 in bone marrow microenvironment2020

    • Author(s)
      Shuji Nosho, Mitsuaki Ono, Akihiro Mikai, Kumiko Nawachi, Aya Kimura-Ono, Emilio S Hara, Takuo Kuboki, Toshitaka Oohashi
    • Organizer
      International Association for Dental Research (IADR) 98th General Session and Exhibition and 49th Annual Meeting of the American Association for Dental Research (AADR)
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research

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Published: 2019-09-03   Modified: 2022-01-27  

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