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Occlusal Trauma and Bisphosphonate-Related Osteonecrosis of the Jaw in Mice

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Abstract

Osteonecrosis of the jaw (ONJ) is a serious adverse event that is associated with antiresorptive agents, and it manifests as bone exposure in the maxillofacial region. Previous clinical reports suggest that mechanical trauma would trigger ONJ in a manner that is similar to tooth extractions. To the best of our knowledge, there have been few detailed pathophysiological investigations of the mechanisms by which occlusal/mechanical trauma influences ONJ. Here, we developed a novel mouse model that exhibits ONJ following experimental hyperocclusion and nitrogen-containing bisphosphonate (N-BP) treatment. This in vivo model exhibited ONJ in alveolar bone, particularly in the mandible. Moreover, the experimental hyperocclusion induced remarkable alveolar bone resorption in both mouse mandible and maxilla, whereas N-BP treatment completely prevented alveolar bone resorption. In this study, we also modeled trauma by exposing clumps of mesenchymal stem cells (MSCs)/extracellular matrix complex to hydrostatic pressure in combination with N-BP. Hydrostatic pressure loading induced lactate dehydrogenase (LDH) release by calcified cell clumps that were differentiated from MSCs; this LDH release was enhanced by N-BP priming. These in vivo and in vitro models may contribute further insights into the effect of excessive mechanical loading on ONJ onset in patients with occlusal trauma.

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Acknowledgements

This study was partially supported by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan to Y.M. [17K17181 and 20K18604].

Funding

This study was partially supported by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan to Y.M. [17K17181 and 20K18604].

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Authors and Affiliations

  1. Department of Medical System Engineering, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi Minami-ku, Hiroshima, 734-8553, Japan

    Yuichi Mine, Karin Okuda, Reina Yoshioka, Yuuki Sasaki & Takeshi Murayama

  2. Research Center of Digital Oral Science and Technology, College of Oral Medicine, Taipei Medical University, 250 Wu-Hsing Street, Taipei, 110, Taiwan

    Tzu-Yu Peng

  3. Department of Anatomy and Functional Restorations, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi Minami-ku, Hiroshima, 734-8553, Japan

    Tzu-Yu Peng & Masato Kaku

  4. School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, 11031, Taiwan

    Tzu-Yu Peng

  5. Department of Calcified Tissue Biology, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi Minami-ku, Hiroshima, 734-8553, Japan

    Yuji Yoshiko

  6. Department of Oral Biology & Engineering, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi Minami-ku, Hiroshima, 734-8553, Japan

    Hiroki Nikawa

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  1. Yuichi Mine
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  9. Takeshi Murayama
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Contributions

YM: Conceptualization, formal analysis, funding acquisition, investigation, methodology, project administration, resources, visualization, and writing—original draft. KO: Data curation, formal analysis, and investigation. RY: Data curation, investigation, and validation. YS: Data curation, formal analysis, investigation, and validation. T-YP: Resources and supervision. MK: Methodology and supervision. YY: Methodology and supervision. HN: Funding acquisition and supervision. TM: Supervision. All authors critically reviewed and edited the article; all authors agreed with its submission for publication.

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Correspondence to Yuichi Mine.

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Conflict of interest

Yuichi Mine, Karin Okuda, Reina Yoshioka, Yuuki Sasaki, Tzu-Yu Peng, Masato Kaku, Yuji Yoshiko, Hiroki Nikawa, and Takeshi Murayama declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

Animal care and experiments were performed in accordance with the guidelines of relevant institutional authorities and approved by the Ethics Committee for Animal Experiments at Hiroshima University (Approval No. A18-106). No human studies were performed in the manuscript.

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Mine, Y., Okuda, K., Yoshioka, R. et al. Occlusal Trauma and Bisphosphonate-Related Osteonecrosis of the Jaw in Mice. Calcif Tissue Int 110, 380–392 (2022). https://doi.org/10.1007/s00223-021-00916-2

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