title: Osteonecrosis of the Jaw Developed in Mice: DISEASE VARIANTS REGULATED BY γδ T CELLS IN ORAL MUCOSAL BARRIER IMMUNITY.
abstract: Osteonecrosis of the jaw (ONJ), an uncommon co-morbidity in patients treated with bisphosphonates (BP), occurs in the segment of jawbone interfacing oral mucosa. This study aimed to investigate a role of oral mucosal barrier γδ T cells in the pathogenesis of ONJ. Female C57Bl/6J (B6) mice received a bolus zoledronate intravenous injection (ZOL, 540 μg/kg), and their maxillary left first molars were extracted 1 week later. ZOL-treated mice (WT ZOL) delayed oral wound healing with patent open wounds 4 weeks after tooth extraction with characteristic oral epithelial hyperplasia. γδ T cells appeared within the tooth extraction site and hyperplastic epithelium in WT ZOL mice. In ZOL-treated γδ T cell null (Tcrd(-/-) ZOL) mice, the tooth extraction open wound progressively closed; however, histological ONJ-like lesions were identified in 75 and 60% of WT ZOL and Tcrd(-/-) ZOL mice, respectively. Although the bone exposure phenotype of ONJ was predominantly observed in WT ZOL mice, Tcrd(-/-) ZOL mice developed the pustule/fistula disease phenotype. We further addressed the role of γδ T cells from human peripheral blood (h-γδ T cells). When co-cultured with ZOL-pretreated human osteoclasts in vitro, h-γδ T cells exhibited rapid expansion and robust IFN-γ secretion. When h-γδ T cells were injected into ZOL-treated immunodeficient (Rag2(-/-) ZOL) mice, the oral epithelial hyperplasia developed. However, Rag2(-/-) ZOL mice did not develop osteonecrosis. The results indicate that γδ T cells are unlikely to influence the core osteonecrosis mechanism; however, they may serve as a critical modifier contributing to the different oral mucosal disease variations of ONJ.
authors.affiliation: From the Weintraub Center for Reconstructive Biotechnology, Division of Advanced Prosthodontics and Division of Oral Biology and Medicine, UCLA School of Dentistry, Los Angeles, California 90095.
authors.forename: Sil
authors.initials: S
authors.lastname: Park
authors.affiliation: From the Weintraub Center for Reconstructive Biotechnology, Division of Advanced Prosthodontics and the Department of Periodontology, Asahi University School of Dentistry, Gifu 501-0296, Japan, and.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Kanayama
authors.affiliation: Division of Oral Biology and Medicine, UCLA School of Dentistry, Los Angeles, California 90095.
authors.forename: Kawaljit
authors.initials: K
authors.lastname: Kaur
authors.affiliation: Division of Oral Biology and Medicine, UCLA School of Dentistry, Los Angeles, California 90095.
authors.forename: Han-Ching Helen
authors.initials: HC
authors.lastname: Tseng
authors.affiliation: From the Weintraub Center for Reconstructive Biotechnology, Division of Advanced Prosthodontics and.
authors.forename: Sina
authors.initials: S
authors.lastname: Banankhah
authors.affiliation: From the Weintraub Center for Reconstructive Biotechnology, Division of Advanced Prosthodontics and.
authors.forename: Davood Talebi
authors.initials: DT
authors.lastname: Quje
authors.affiliation: the Department of Biostatistics, UCLA Fielding School of Public Health, Los Angeles, California 90095.
authors.forename: James W
authors.initials: JW
authors.lastname: Sayre
authors.affiliation: Division of Oral Biology and Medicine, UCLA School of Dentistry, Los Angeles, California 90095.
authors.forename: Anahid
authors.initials: A
authors.lastname: Jewett
authors.affiliation: From the Weintraub Center for Reconstructive Biotechnology, Division of Advanced Prosthodontics and Division of Oral Biology and Medicine, UCLA School of Dentistry, Los Angeles, California 90095, inishimura@dentistry.ucla.edu.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Nishimura
mesh_terms: D000818:Animals; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D050071:Bone Density Conservation Agents / Q000009:adverse effects; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D004164:Diphosphonates / Q000009:adverse effects; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects; D018928:Immunity, Mucosal; D066298:In Vitro Techniques; D007568:Jaw / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009061:Mouth Mucosa / Q000276:immunology* / Q000473:pathology; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000172:deficiency / Q000235:genetics; D012307:Risk Factors; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000473:pathology; D014081:Tooth Extraction / Q000009:adverse effects; D014945:Wound Healing / Q000187:drug effects / Q000276:immunology; D055114:X-Ray Microtomography; D000077211:Zoledronic Acid
chemical_list: D050071:Bone Density Conservation Agents; D004268:DNA-Binding Proteins; D004164:Diphosphonates; D007093:Imidazoles; C499308:Rag2 protein, mouse; D016692:Receptors, Antigen, T-Cell, gamma-delta; D000077211:Zoledronic Acid
keywords: ONJ; T cell; bisphosphonate; mouse; mucosal immunology; osteonecrosis; pathogenesis; wound healing; γδ T cells