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Tooth extraction in mice administered zoledronate increases inflammatory cytokine levels and promotes osteonecrosis of the jaw

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Abstract

Introduction

Osteonecrosis of the jaw (ONJ) occurring after invasive dental treatment often adversely affects patients’ activities of daily living. Long-term administration of strong anti-bone resorptive agents such as bisphosphonates prior to invasive dental treatment is considered an ONJ risk factor; however, pathological mechanisms underlying ONJ development remain unclear.

Materials and Methods

We developed an ONJ mouse model in which a tooth is extracted during treatment with the bisphosphonate zoledronate.

Results

We observed induction of apoptosis in osteocytes, resulting in formation of empty lacunae in jaw bones at sites of tooth extraction but not in other bones of the same mice. We also observed elevated levels of inflammatory cytokines such as TNFα, IL-6 and IL-1 in jaw bone at the extraction site relative to other sites in zoledronate-treated mice. We also report that treatment in vitro with either zoledronate or an extract from Porphyromonas gingivalis, an oral bacteria, promotes expression of inflammatory cytokines in osteoclast progenitor cells. We demonstrate that gene-targeting of either TNFα, IL-6 or IL-1 or treatment with etanercept, a TNFα inhibitor, or a neutralizing antibody against IL-6 can antagonize ONJ development caused by combined tooth extraction and zoledronate treatment.

Conclusions

Taken together, the cytokine storm induced by invasive dental treatment under bisphosphonate treatment promotes ONJ development due to elevated levels of inflammatory cytokine-producing cells. Our work identifies novel targets potentially useful to prevent ONJ.

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Acknowledgements

T. Miyamoto was supported by a grant-in-aid for Scientific Research in Japan and a grant from the Japan Agency for Medical Research and Development. Y. Sato and K. Miyamoto were supported by a grant-in-aid for Scientific Research in Japan. This study was supported in part by Tei**.

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Authors and Affiliations

  1. Division of Oral and Maxillofacial Surgery, Department of Dentistry and Oral Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Tomoya Soma, Ryotaro Iwasaki, Seiji Asoda, Hiromasa Kawana & Taneaki Nakagawa

  2. Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Yuiko Sato, Tami Kobayashi, Satoshi Nakamura, Yosuke Kaneko, Kana Miyamoto, Morio Matsumoto, Masaya Nakamura & Takeshi Miyamoto

  3. Department of Advanced Therapy for Musculoskeletal Disorders II, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Yuiko Sato & Takeshi Miyamoto

  4. Department of Musculoskeletal Reconstruction and Regeneration Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Tami Kobayashi & Takeshi Miyamoto

  5. Institute for Integrated Sports Medicine, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Eri Ito

  6. Department of Orthopedic Surgery, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan

    Hiroyuki Okada & Hisato Watanabe

  7. Department of Oral and Maxillofacial Implantology, School of Dentistry, Kanagawa Dental University, 82 Inaoka-cho, Yokosuka, Kanagawa, 238-8580, Japan

    Hiromasa Kawana

  8. Department of Orthopedic Surgery, Kumamoto University, 1-1- Honjo, Chuo-ku, Kumamoto, 860-8556, Japan

    Kana Miyamoto & Takeshi Miyamoto

Authors
  1. Tomoya Soma
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  2. Ryotaro Iwasaki
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  3. Yuiko Sato
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  16. Takeshi Miyamoto
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Contributions

Investigation: TS, YS, and TK; conceptualization: TM; data curation: SN, YK, EI, HO, HW, and KM; funding acquisition: RI, YS, KM, and TM; supervision: RI, MM, MN, SA, HK, and TN; writing: TM.

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Correspondence to Takeshi Miyamoto.

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The authors declare that they have no conflict of interest with the contents of this article.

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Animals were maintained under specific pathogen-free conditions in animal facilities certified by the Keio University Institutional Animal Care and Use Committee, and animal protocols were approved by that committee. All animal studies were performed in accordance with Institutional Guidelines on Animal Experimentation at Keio University of The Keio University Institutional Animal Care and Use Committee.

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Soma, T., Iwasaki, R., Sato, Y. et al. Tooth extraction in mice administered zoledronate increases inflammatory cytokine levels and promotes osteonecrosis of the jaw. J Bone Miner Metab 39, 372–384 (2021). https://doi.org/10.1007/s00774-020-01174-2

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