Exploration of pathogenesis of medication-related osteonecrosis of the jaw based on macrophages

• Project/Area Number: 20K18607
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 57050:Prosthodontics-related
• Research Institution: Nagasaki University
• Principal Investigator: HAYANO Hiroki 長崎大学, 医歯薬学総合研究科(歯学系), 客員研究員 (20866644)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: マクロファージ / MRONJ / BRONJ / DRONJ / リンパ管 / 血管 / 薬剤関連顎骨壊死 / 極性変化 / リンパ管内皮細胞 / ビスホスホネート製剤 / 分化転換

Outline of Research at the Start

この研究は、ビスフォスフォネート製剤やデノスマブという薬を使用して治療を受けている患者さんの一部に起こる、薬剤関連顎骨壊死という骨が壊死してしまう病気の原因を解明するために行う研究です。ネズミを使って薬剤関連顎骨壊死を発症させ、免疫細胞のひとつに焦点を当てて、研究を行う予定です。

Outline of Final Research Achievements

This study aimed to comprehensively investigate and determine the effects of anti-resorptive agents on tooth extraction socket healing. We found that M1 M2 macrophages in the connective tissue of tooth extraction sockets and osteal macrophages in the bone marrow of tooth extraction sockets could be associated with the pathophysiology of MRONJ with suppressed lymphangiogenesis in a murine MRONJ models.

Academic Significance and Societal Importance of the Research Achievements

本研究は，現在でも世界中で問題となっている骨吸収抑制薬（ビスホスホネート製剤とデノスマブ）の副作用のひとつである薬剤関連顎骨壊死に関して，その原因を基礎的な観点から細胞レベルで突き止めるための基礎研究である．本研究では，現在までよく分かっていなかった薬剤関連顎骨壊死に対して，免疫細胞であるマクロファージとリンパ管形成が関わる可能性を証明でき，大きな学術的意義と国民に向けた社会的意義があったと思われる．

Research Products

• [Journal Article] Zoledronate/Anti-VEGF Neutralizing Antibody Combination Administration Increases Osteal Macrophages in a Murine Model of MRONJ Stage 0-like Lesions (2023)
  • Author(s): Haruka Kaneko, Shinichiro Kuroshima, Ryohei Kozutsumi, Farah A. Al-Omari, Hiroki Hayano, Kazunori Nakajima, Takashi Sawase
  • Journal Title: J Clin Med. Volume: 12 Issue: 5 Pages: 1914-1914
  • DOI: 10.3390/jcm12051914
  • Peer Reviewed / Open Access
• [Journal Article] Gene expression analysis of fresh extraction wounds prior to onset of bisphosphonate-related osteonecrosis of the jaw-like lesions in mice: A preliminary animal study (2021)
  • Author(s): Kuroshima S, Nakajima K, Sasaki M, Hayano H, Inoue M, Kozutsumi R, Sawase T
  • Journal Title: Journal of Prosthodontic Research Volume: 65 Issue: 4 Pages: 546-553
  • DOI: 10.2186/jpr.JPR_D_20_00027
  • NAID: 130008104554
  • ISSN: 1883-1958, 1883-9207
  • Peer Reviewed / Open Access
• [Journal Article] Distinct immunopathology in the early stages between different antiresorptive-related osteonecrosis of the jaw-like lesions in mice. (2020)
  • Author(s): Hayano H, Kuroshima S, Sasaki M, Tamki S, Inoue M, Ishisaki A, Sawase T
  • Journal Title: Bone Volume: - Pages: 115308-115308
  • DOI: 10.1016/j.bone.2020.115308
  • Peer Reviewed
• [Journal Article] Dynamic polarization shifting from M1 to M2 macrophages in reduced osteonecrosis of the jaw-like lesions by cessation of anti-RANKL antibody in mice (2020)
  • Author(s): Tamaki Saki、Kuroshima Shinichiro、Hayano Hiroki、Nakajima Kazunori、Kakehashi Hiroe、Ishisaki Akira、Sawase Takashi
  • Journal Title: Bone Volume: 141 Pages: 115560-115560
  • DOI: 10.1016/j.bone.2020.115560
  • Peer Reviewed / Open Access
• [Presentation] 高頻度発現型BRONJ様病変の組織・免疫病理学所見と早期遺伝子プロファイル分析 (2020)
  • Author(s): 黒嶋伸一郎，佐々木宗輝，中島和慶，早野博紀，井上真愛弥，澤瀬 隆
  • Organizer: 公益社団法人日本補綴歯科学会 第129回学術大会
• [Presentation] 高頻度発現型BRONJマウスモデルを用いた早期における遺伝子パターン解析 (2020)
  • Author(s): 黒嶋伸一郎，早野博紀，佐々木宗輝，中島和慶，澤瀬 隆
  • Organizer: 第38回日本骨代謝学会学術集会
• [Presentation] Relationship between gene profiles and histopathology/immunopathology in high-prevalence BRONJ-like lesions in mice (2020)
  • Author(s): Kuroshima S, Sasaki M, Hayano H, Kozutsumi R, Inoue M, Sawase T
  • Organizer: 30th Annual Congress of the European College of Gerodontology
  • Int'l Joint Research
• [Presentation] Histopathology/immunopathology in high-prevalence bisphosphonate-related osteonecrosis of the jaw around implants in rat maxillae (2020)
  • Author(s): Inoue M, Matsumoto C, Nakajima K, Hayano H, Kozutsumi R, Kuroshima S, Sawase T
  • Organizer: 30th Australian and New Zealand Bone and Mineral Society Annual Scientific Meeting Virtual
  • Int'l Joint Research
• [Presentation] Gene expression profiling and histopathology/immunopathology in high-prevalence bisphosphonate-related osteonecrosis of the jaw in mice (2020)
  • Author(s): Kuroshima S, Sasaki M, Nakajima K, Hayano H, Inoue M, Kozutsumi R, Sawase T
  • Organizer: 30th Australian and New Zealand Bone and Mineral Society Annual Scientific Meeting Virtual
  • Int'l Joint Research