title: Impaired bone resorption and woven bone formation are associated with development of osteonecrosis of the jaw-like lesions by bisphosphonate and anti-receptor activator of NF-κB ligand antibody in mice.
abstract: Drug-induced osteonecrosis of the jaw (ONJ) is a detrimental intraoral lesion that often occurs after dental-related interventions in patients undergoing treatment with bisphosphonates or denosumab, the neutralizing human anti-receptor activator of NF-κB ligand (RANKL) antibody (Ab). The cause of ONJ by these drugs has been speculated to their direct effects on osteoclasts. However, the extent to which osteoclasts contribute to ONJ pathogenesis remains controversial. Herein, by using a tooth-extraction mouse model with i.v. administration of mouse anti-RANKL Ab or the bisphosphonate zoledronate (ZOL), we show that unresorbed bone due to impaired formation or suppressed functions of osteoclasts, respectively, is associated with ONJ development. After tooth extraction, ONJ-like lesions developed 50% in the anti-RANKL Ab-treated mice and 30% in the ZOL-treated mice. Nonviable and unresorbed bone was found more in anti-RANKL Ab-treated mice compared with mice receiving ZOL. All mice receiving anti-RANKL Ab had an undetectable tartrate-resistant acid phosphatase (TRAP) level in the serum and no TRAP-positive osteoclasts at the extracted sockets, whereas ZOL-treated mice had a decreased TRAP level without altering the numbers of TRAP-positive osteoclasts. Interestingly, the absence of newly formed woven bone in the extracted sockets was evident in ONJ-like lesions from both anti-RANKL Ab- and ZOL-treated mice. Our study suggests that the lack of osteoclasts' bone-resorptive functions by these drugs and suppression of woven bone formation after dental trauma may be associated with ONJ development.
authors.affiliation: School of Dentistry, University of California at Los Angeles, Los Angeles, California.
authors.forename: Drake W
authors.initials: DW
authors.lastname: Williams
authors.affiliation: School of Dentistry, University of California at Los Angeles, Los Angeles, California.
authors.forename: Cindy
authors.initials: C
authors.lastname: Lee
authors.affiliation: School of Dentistry, University of California at Los Angeles, Los Angeles, California.
authors.forename: Terresa
authors.initials: T
authors.lastname: Kim
authors.affiliation: Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.affiliation: State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
authors.forename: Hongkun
authors.initials: H
authors.lastname: Wu
authors.affiliation: School of Dentistry, University of California at Los Angeles, Los Angeles, California.
authors.forename: Sil
authors.initials: S
authors.lastname: Park
authors.affiliation: School of Dentistry, University of California at Los Angeles, Los Angeles, California.
authors.forename: Paul
authors.initials: P
authors.lastname: Yang
authors.affiliation: School of Dentistry, University of California at Los Angeles, Los Angeles, California; David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California; Fielding School of Public Health, University of California at Los Angeles, Los Angeles, California.
authors.forename: Honghu
authors.initials: H
authors.lastname: Liu
authors.affiliation: Center for Craniofacial Molecular Biology, School of Dentistry, University of Southern California, Los Angeles, California.
authors.forename: Songtao
authors.initials: S
authors.lastname: Shi
authors.affiliation: School of Dentistry, University of California at Los Angeles, Los Angeles, California; Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, California.
authors.forename: Ki-Hyuk
authors.initials: KH
authors.lastname: Shin
authors.affiliation: School of Dentistry, University of California at Los Angeles, Los Angeles, California; Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, California.
authors.forename: Mo K
authors.initials: MK
authors.lastname: Kang
authors.affiliation: School of Dentistry, University of California at Los Angeles, Los Angeles, California; David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California; Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, California; Kyung Hee University, Seoul, Korea.
authors.forename: No-Hee
authors.initials: NH
authors.lastname: Park
authors.affiliation: School of Dentistry, University of California at Los Angeles, Los Angeles, California; Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, California. Electronic address: rkim@dentistry.ucla.edu.
authors.forename: Reuben H
authors.initials: RH
authors.lastname: Kim
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw / Q000473:pathology*; D001862:Bone Resorption / Q000473:pathology*; D000069448:Denosumab; D004164:Diphosphonates; D004195:Disease Models, Animal; D007093:Imidazoles; D051379:Mice; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology*; D053245:RANK Ligand / Q000037:antagonists & inhibitors*; D000077211:Zoledronic Acid
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D004164:Diphosphonates; D007093:Imidazoles; D053245:RANK Ligand; D000069448:Denosumab; D000077211:Zoledronic Acid