title: Spontaneous osteonecrosis of the jaws in the maxilla of mice on antiresorptive treatment: a novel ONJ mouse model.
abstract: Although osteonecrosis of the jaws (ONJ), a serious complication of antiresorptive medications, was reported a decade ago, the exact mechanisms of disease pathophysiology remain elusive. ONJ-like lesions can be induced in animals after antiresorptive treatment and experimental interventions such as tooth extraction or periapical or periodontal disease. However, experimental induction and manipulation of disease progression does not always reflect clinical reality. Interestingly, naturally occurring maxillofacial abscesses, inducing aggressive inflammation of the peri-radicular mucosa with significant osteolysis and alveolar bone expansion, have been reported in mice. Here, we aimed to explore whether osteonecrotic lesions would develop in areas of maxillary peri-radicular infections, in mice on antiresorptive medications with distinct pharmacologic action, thus establishing a novel ONJ animal model. Mice were treated with RANK-Fc or OPG-Fc that bind to RANKL or with the potent bisphosphonate zoledronic acid (ZA). Maxillae were assessed radiographically and histologically. μCT imaging of vehicle mice revealed several maxillae with altered alveolar bone morphology, significant ridge expansion and large lytic areas. However, in RANK-Fc, OPG-Fc and ZA treated animals the extent of bone loss was significantly less, but exuberant bone deposition was noted at the ridge periphery. BV and BV/TV were increased in the diseased site of antiresorptive vs. veh animals. Histologically, extensive inflammation, bone resorption and marginal gingival epithelium migration were seen in the diseased site of vehicle animals. Rank-Fc, OPG-Fc and ZA reduced alveolar bone loss, increased periosteal bone formation, and induced areas of osteonecrosis, and bone exposure that in many animals covered significant part of the alveolar bone. Collectively, our data demonstrate ONJ-like lesions at sites of maxillary peri-radicular infection, indistinguishable in mice treated with RAKL inhibitors vs. zoledronate. This novel mouse model of spontaneous ONJ supports a central role of osteoclast inhibition and infection/inflammation in ONJ pathogenesis and validates and complements existing animal models employing experimental interventions.
authors.affiliation: Division of Diagnostic and Surgical Sciences, UCLA School of Dentistry, Los Angeles, CA 90095, USA; Department of Diagnosis and Surgery, School of Dentistry at Araraquara, São Paulo State University, Araraquara 14801-903, Brazil.
authors.forename: Rafael Scaf
authors.initials: RS
authors.lastname: de Molon
authors.affiliation: Ostrow School of Dentistry, University of Southern California, Los Angeles, CA, USA.
authors.forename: Simon
authors.initials: S
authors.lastname: Cheong
authors.affiliation: Division of Diagnostic and Surgical Sciences, UCLA School of Dentistry, Los Angeles, CA 90095, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Bezouglaia
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Dry
authors.affiliation: Division of Associated Specialties, UCLA School of Dentistry, Los Angeles, CA 90095, USA.
authors.forename: Flavia
authors.initials: F
authors.lastname: Pirih
authors.affiliation: Department of Diagnosis and Surgery, School of Dentistry at Araraquara, São Paulo State University, Araraquara 14801-903, Brazil.
authors.forename: Joni Augusto
authors.initials: JA
authors.lastname: Cirelli
authors.affiliation: Division of Diagnostic and Surgical Sciences, UCLA School of Dentistry, Los Angeles, CA 90095, USA. Electronic address: taghaloo@dentistry.ucla.edu.
authors.forename: Tara L
authors.initials: TL
authors.lastname: Aghaloo
authors.affiliation: Division of Diagnostic and Surgical Sciences, UCLA School of Dentistry, Los Angeles, CA 90095, USA; Molecular Biology Institute, UCLA, Los Angeles, CA 90095, USA. Electronic address: stetradis@dentistry.ucla.edu.
authors.forename: Sotirios
authors.initials: S
authors.lastname: Tetradis
mesh_terms: D000135:Acid Phosphatase / Q000378:metabolism; D000539:Alveolar Process / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D000818:Animals; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw / Q000000981:diagnostic imaging / Q000473:pathology*; D001862:Bone Resorption / Q000188:drug therapy* / Q000473:pathology; D004164:Diphosphonates / Q000009:adverse effects* / Q000627:therapeutic use; D004195:Disease Models, Animal; D007093:Imidazoles / Q000009:adverse effects* / Q000627:therapeutic use; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D008437:Maxilla / Q000187:drug effects / Q000473:pathology*; D008810:Mice, Inbred C57BL; D010519:Periodontium / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D011859:Radiography; D011993:Recombinant Fusion Proteins / Q000494:pharmacology / Q000627:therapeutic use; D000071681:Tartrate-Resistant Acid Phosphatase; D000077211:Zoledronic Acid
chemical_list: D004164:Diphosphonates; D007093:Imidazoles; D007527:Isoenzymes; C517736:Rank-Fc; D011993:Recombinant Fusion Proteins; D000077211:Zoledronic Acid; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase
keywords: Alveolar bone; Antiresorptives; Bisphosphonates; ONJ; Osteoclasts; Osteonecrosis of the jaw
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