Mechanism of bisphosphonate-related osteonecrosis of the jaw (BRONJ) revealed by targeted removal of legacy bisphosphonate from jawbone using competing inert hydroxymethylene diphosphonate
Hiroko Okawa,
Takeru Kondo,
Akishige Hokugo,
Philip Cherian,
Jesus J Campagna,
Nicholas A Lentini,
Eric C Sung,
Samantha Chiang,
Yi-Ling Lin,
Frank H Ebetino,
Varghese John,
Shuting Sun,
Charles E McKenna,
Ichiro Nishimura
Affiliations
Hiroko Okawa
Weintraub Center for Reconstructive Biotechnology, Division of Regenerative & Reconstructive Sciences, University of California, Los Angeles School of Dentistry, Los Angeles, United States; Division of Molecular & Regenerative Prosthodontics, Tohoku University Graduate School of Dentistry, Sendai, Japan
Takeru Kondo
Weintraub Center for Reconstructive Biotechnology, Division of Regenerative & Reconstructive Sciences, University of California, Los Angeles School of Dentistry, Los Angeles, United States; Division of Molecular & Regenerative Prosthodontics, Tohoku University Graduate School of Dentistry, Sendai, Japan
Weintraub Center for Reconstructive Biotechnology, Division of Regenerative & Reconstructive Sciences, University of California, Los Angeles School of Dentistry, Los Angeles, United States; Regenerative Bioengineering and Repair Laboratory, Division of Plastic and Reconstructive Surgery, Department of Surgery, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, United States
Philip Cherian
BioVinc, LLC, Pasadena, United States
Jesus J Campagna
Department of Neurology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, United States
Department of Chemistry, University of Southern California, Los Angeles, United States
Eric C Sung
Weintraub Center for Reconstructive Biotechnology, Division of Regenerative & Reconstructive Sciences, University of California, Los Angeles School of Dentistry, Los Angeles, United States
Samantha Chiang
Division of Oral & Systemic Health Sciences, University of California, Los Angeles School of Dentistry, Los Angeles, United States
Yi-Ling Lin
Section of Oral & Maxillofacial Pathology, University of California, Los Angeles School of Dentistry, Los Angeles, United States
Frank H Ebetino
BioVinc, LLC, Pasadena, United States
Varghese John
Department of Neurology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, United States
Weintraub Center for Reconstructive Biotechnology, Division of Regenerative & Reconstructive Sciences, University of California, Los Angeles School of Dentistry, Los Angeles, United States; BioVinc, LLC, Pasadena, United States
Weintraub Center for Reconstructive Biotechnology, Division of Regenerative & Reconstructive Sciences, University of California, Los Angeles School of Dentistry, Los Angeles, United States; Division of Oral & Systemic Health Sciences, University of California, Los Angeles School of Dentistry, Los Angeles, United States
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 antiresorptive 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 lesions. Single cell RNA sequencing of mouse gingival cells revealed oral barrier immune dysregulation and unresolved proinflammatory 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.
