Mechanism of bisphosphonate-related osteonecrosis of the jaw (BRONJ) revealed by targeted removal of legacy bisphosphonate from jawbone using equilibrium competing inert hydroxymethylene diphosphonate
- University of California, Los Angeles, United States
- BioVinc, United States
- University of Southern California, United States
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.
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Single Cell RNA sequencing of BRONJ disease control and HMDP-treated mouse gingivaNCBI Gene Expression Omnibus, GSE193110.
Article and author information
Author details
Nicholas A Lentini
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.
Reviewing Editor
- Mishaela R Rubin, Columbia University Medical Center, United States
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.
Version history
- Received: December 8, 2021
- Preprint posted: December 29, 2021 (view preprint)
- Accepted: August 25, 2022
- Accepted Manuscript published: August 26, 2022 (version 1)
- Version of Record published: September 20, 2022 (version 2)
- Version of Record updated: September 27, 2022 (version 3)
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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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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