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Cherubism-like Jawbone Expansion in Mice Reveals Unrecognized Contributions of Neutrophils to Cherubism Pathogenesis

Research Project

Project/Area Number 21K17098
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 57060:Surgical dentistry-related
Research InstitutionTokyo Medical University

Principal Investigator

Fujii Yasuyuki  東京医科大学, 医学部, 助教 (90829748)

Project Period (FY) 2021-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2022: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2021: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
Keywords遺伝性骨疾患 / 骨代謝 / 遺伝性骨系統疾患
Outline of Research at the Start

チェルビズム(CBM)は両側性に生じる顎骨の膨隆と炎症性骨破壊を特徴とする遺伝性骨系統疾患であり、Src Homology3 Domain-Binding Protein2(SH3BP2)遺伝子のGain-of-function変異の関与が報告されている。しかし、CBMモデルマウスはCBMの最大の特徴である自発的な顎骨膨隆をきたすことはない。本研究では、病原体関連分子パターンを顎骨に限局して導入することによって、発症までの時間と発症部位に関して再現性が得られる新規CBMモデルの確立を行う。さらに、このモデルの解析を行うことにより、これまでのCBM研究で困難であった発症機序の解明を目指す。

Outline of Final Research Achievements

Cherubism (CBM), characterized by expansile jawbones with multilocular fibrocystic lesions, is caused by gain-of-function mutations in SH3 domain-binding protein 2.We hypothesize that bony inflammation of an unknown cause triggers jawbone expansion in CBM. Bacterial invasion from the exposed pulp resulted in jawbone expansion in Sh3bp2KI/+ and Sh3bp2KI/KI mice. CBM-like lesions developed exacerbated inflammation with increased neutrophil, and these lesions displayed excessive neutrophil extracellular traps. Our study reveals a previously unrecognized role of neutrophils that may play a vital role in promoting CBM lesions

Academic Significance and Societal Importance of the Research Achievements

不明な点が多い希少遺伝性疾患の発症メカニズムの解明に繋がる基礎的な知見を得ることができた。本研究の成果はこれまで不明であったCBMのバイオマーカーや新規治療ターゲットの発見に繋がり、CBMの診断や治療にパラダイムシフトをもたらす可能性が高いと考えている。また、本研究の成果は他の炎症性骨疾患の理解や治療への応用も期待できる。

Report

(3 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • Research Products

    (1 results)

All 2021

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

  • [Journal Article] Tlr2/4-Mediated Hyperinflammation Promotes Cherubism-Like Jawbone Expansion in Sh3bp2 (P416R) Knockin Mice2021

    • Author(s)
      Fujii Yasuyuki、Monteiro Nelson、Sah Shyam Kishor、Javaheri Homan、Ueki Yasuyoshi、Fan Zhichao、Reichenberger Ernst J、Chen I‐Ping
    • Journal Title

      JBMR Plus

      Volume: 6 Issue: 1

    • DOI

      10.1002/jbm4.10562

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research

URL: 

Published: 2021-04-28   Modified: 2024-01-30  

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