1. Biochemistry and Chemical Biology
  2. Immunology and Inflammation

Mechanism of bisphosphonate-related osteonecrosis of the jaw (BRONJ) revealed by targeted removal of legacy bisphosphonate from jawbone using equilibrium competing inert hydroxymethylene diphosphonate

  1. Hiroko Okawa
  2. Takeru Kondo
  3. Akishige Hokugo  Is a corresponding author
  4. Philip Cherian
  5. Jesus J Campagna
  6. Nicholas A Lentini
  7. Eric C Sung
  8. Samantha Chiang
  9. Yi-Ling Lin
  10. Frank H Ebetino
  11. Varghese John
  12. Shuting Sun  Is a corresponding author
  13. Charles E McKenna  Is a corresponding author
  14. Ichiro Nishimura  Is a corresponding author
  1. University of California, Los Angeles, United States
  2. BioVinc, United States
  3. University of Southern California, United States
https://doi.org/10.7554/eLife.76207
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  1. Hiroko Okawa
  2. Takeru Kondo
  3. Akishige Hokugo
  4. Philip Cherian
  5. Jesus J Campagna
  6. Nicholas A Lentini
  7. Eric C Sung
  8. Samantha Chiang
  9. Yi-Ling Lin
  10. Frank H Ebetino
  11. Varghese John
  12. Shuting Sun
  13. Charles E McKenna
  14. Ichiro Nishimura
(2022)
Mechanism of bisphosphonate-related osteonecrosis of the jaw (BRONJ) revealed by targeted removal of legacy bisphosphonate from jawbone using equilibrium competing inert hydroxymethylene diphosphonate
eLife 11:e76207.
https://doi.org/10.7554/eLife.76207
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Abstract

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) presents as a morbid jawbone lesion in patients exposed to a nitrogen-containing bisphosphonate (N-BP). Although it is rare, BRONJ has caused apprehension among patients and healthcare providers and decreased acceptance of this anti-resorptive drug class to treat osteoporosis and metastatic osteolysis. We report here a novel method to elucidate the pathological mechanism of BRONJ by the selective removal of legacy N-BP from the jawbone using an intra-oral application of hydroxymethylene diphosphonate (HMDP) formulated in liposome-based deformable nanoscale vesicles (DNV). After maxillary tooth extraction, zoledronate-treated mice developed delayed gingival wound closure, delayed tooth extraction socket healing and increased jawbone osteonecrosis consistent with human BRONJ lesion. Single cell RNA sequencing of mouse gingival cells revealed oral barrier immune dysregulation and unresolved pro-inflammatory reaction. HMDP-DNV topical applications to nascent mouse BRONJ lesions resulted in accelerated gingival wound closure and bone socket healing as well as attenuation of osteonecrosis development. The gingival single cell RNA sequencing demonstrated resolution of chronic inflammation by increased anti-inflammatory signature gene expression of lymphocytes and myeloid-derived suppressor cells. This study suggests that BRONJ pathology is related to N-BP levels in jawbones and demonstrates the potential of HMDP-DNV as an effective BRONJ therapy.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting file. Single cell RNA sequencing data have been deposited in GEO under accession code GSE193110.

The following data sets were generated

Article and author information

Author details

  1. Hiroko Okawa

    Weintraub Center for Reconstructive Biotechnology, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.

  2. Takeru Kondo

    Weintraub Center for Reconstructive Biotechnology, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.

  3. Akishige Hokugo

    Department of Surgery, University of California, Los Angeles, Los Angeles, United States
    For correspondence
    ahokugo@mednet.ucla.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7097-3364

  4. Philip Cherian

    BioVinc, Pasadena, United States
    Competing interests
    Philip Cherian, is an employee in BioVinc LLC..

  5. Jesus J Campagna

    Department of Neurology, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.

  6. Nicholas A Lentini

    Department of Chemistry, University of Southern California, Los Angeles, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1701-0753

  7. Eric C Sung

    Weintraub Center for Reconstructive Biotechnology, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.

  8. Samantha Chiang

    Section of Oral Biology, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.

  9. Yi-Ling Lin

    Section of Oral and Maxillofacial Pathology, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.

  10. Frank H Ebetino

    BioVinc, Pasadena, United States
    Competing interests
    Frank H Ebetino, holds equity in BioVinc LLC and is an employee and has executive management positions in BioVinc LLC..

  11. Varghese John

    Department of Neurology, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.

  12. Shuting Sun

    BioVinc, Pasadena, United States
    For correspondence
    shuting.sun@biovinc.com
    Competing interests
    Shuting Sun, holds equity in BioVinc LLC. SS is an employee and has executive management position in BioVinc LLC..

  13. Charles E McKenna

    Department of Chemistry, University of Southern California, Los Angeles, United States
    For correspondence
    mckenna@usc.edu
    Competing interests
    Charles E McKenna, is a board member and holds equity in Biovinc LLC..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3540-6663

  14. Ichiro Nishimura

    Weintraub Center for Reconstructive Biotechnology, University of California, Los Angeles, Los Angeles, United States
    For correspondence
    inishimura@dentistry.ucla.edu
    Competing interests
    Ichiro Nishimura, was a consultant of BioVinc LLC..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3749-9445

Funding

National Institute of Dental and Craniofacial Research (R01DE022552)

  • Ichiro Nishimura

National Institute of Dental and Craniofacial Research (R44DE025524)

  • Frank H Ebetino
  • Ichiro Nishimura

Tohoku University (Leading young researcher overseas visit program fellowship)

  • Hiroko Okawa

Japan Society for the Promotion of Science (19J117670)

  • Takeru Kondo

National Center for Research Resources (C06RR014529)

  • Ichiro Nishimura

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal experiments were performed at UCLA. All the protocols for animal experiments were approved by the UCLA Animal Research Committee (ARC# 1997-136) and followed the Public Health Service Policy for the Humane Care and Use of Laboratory Animals and the UCLA Animal Care and Use Training Manual guidelines. The C57Bl/6J mice (Jackson Laboratory) were used in this study. Animals consumed gel or regular food for rodents and water ad libitum and were maintained in regular housing conditions with a 12-hour-light/dark cycles at the Division of Laboratory Animal Medicine at UCLA.

Human subjects: This study was not conducted on human subjects. However, the manuscript contains clinical demonstration of human BRONJ obtained from patients of UCLA School of Dentistry clinic with the general consent for educational use. The information was not part of investigator-initiated research.

Copyright

© 2022, Okawa et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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