Immunological study of the effects of fungal secondary metabolite terrein on drug-related osteonecrosis of the jaw

• Project/Area Number: 21K21087
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0907:Oral science and related fields
• Research Institution: Okayama University
• Principal Investigator: Sakaida Kyosuke 岡山大学, 大学病院, 医員 (20907927)
• Project Period (FY): 2021-08-30 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2022: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 真菌二次代謝産物Terrein / MRONJ / 骨粗鬆症

Outline of Research at the Start

現在，骨粗鬆症の治療として，破骨細胞を標的としたビスフォスフォネート（BP）製剤や抗RANKL抗体薬が用いられており，抜歯に伴う薬剤関連性顎骨壊死（MRONJ）の発症が懸念される。近年，高齢者の残存歯が増加し，歯科診療におけるMRONJ発症リスクが高まっている。
申請者は，真菌二次代謝産物Terreinに着目し，既存薬とは異なる機序でマウス骨粗鬆症モデルにおける破骨細胞分化抑制による骨破壊抑制効果を見出した。本知見から，Terreinを新規骨粗鬆症治療薬として応用できる可能性がある。本研究では，マウス骨粗鬆症モデルを用いて，抜歯介入に伴うMRONJ発症病態にTerreinが及ぼす影響を検証する。

Outline of Final Research Achievements

The number of osteoporosis patients is increasing. Osteonecrosis of the jaw (MRONJ) is a major side effect of therapeutic drugs, and how to deal with it is a major problem in clinical dentistry. In this study, we investigated the effect of fungal secondary metabolite terrein on the pathogenesis of MRONJ, which is capable of regulating osteoclast differentiation through a mechanism different from that of existing drugs.
Various test drugs were administered at the same time as the initiation of osteoporosis induction, and after tooth extraction in the 4th week, administration of the test drug was continued for an additional 4 weeks, and in the 8th week, the inflammatory status of the extracted tooth was evaluated by live imaging. After that, the maxilla and other bones were removed, and the condition of the hard tissue was evaluated by micro-CT. Tissue sections were prepared using samples after analysis, and the differentiation state of osteoclasts was evaluated by TRAP staining.

Academic Significance and Societal Importance of the Research Achievements

我が国において，骨粗鬆症患者は年々増加している。骨粗鬆症の進行に伴い大腿骨近位部骨折や椎体骨折などが生じると，日常生活能力（ADL）が低下する大きな要因となる。骨粗鬆症の進行を抑制するために，BP製剤や抗RANKL抗体薬等の投与が推奨されているが，副作用として顎骨壊死（MRONJ）の発症があり，その対応が歯科臨床現場では大きな問題となっている。既存薬とは異なる機序で破骨細胞の分化誘導を制御しうる真菌二次代謝産物Terreinは，骨粗鬆症のみならずMRONJ発症を抑制する可能性がある。本研究成果により，今後の骨粗鬆症治療に新たな選択肢を提供できる可能性があり，学術的・社会的意義は高いと考える。

Research Products

• [Journal Article] The fungal metabolite (+)-terrein abrogates ovariectomy-induced bone loss and receptor activator of nuclear factor-κB ligand-induced osteoclastogenesis by suppressing protein kinase-C α/βII phosphorylation. (2021)
  • Author(s): Kyosuke Sakaida, Kazuhiro Omori, Masaaki Nakayama, Hiroki Mandai, Saki Nakagawa, Hidefumi Sako, Chiaki Kamei, Satoshi Yamamoto, Hiroya Kobayashi, Satoki Ishii, Mitsuaki Ono, Soichiro Ibaragi, Keisuke Yamashiro, Tadashi Yamamoto, Seiji Suga and Shogo Takashiba
  • Journal Title: Frontiers in Pharmacology Volume: 12 Pages: 674366-674366
  • DOI: 10.3389/fphar.2021.674366
  • Peer Reviewed / Open Access