title: Elevation of pro-inflammatory cytokine levels following anti-resorptive drug treatment is required for osteonecrosis development in infectious osteomyelitis.
abstract: Various conditions, including bacterial infection, can promote osteonecrosis. For example, following invasive dental therapy with anti-bone resorptive agents, some patients develop osteonecrosis in the jaw; however, pathological mechanisms underlying these outcomes remain unknown. Here, we show that administration of anti-resorptive agents such as the bisphosphonate alendronate accelerates osteonecrosis promoted by infectious osteomyelitis. Potent suppression of bone turnover by these types of agents is considered critical for osteonecrosis development; however, using mouse models we found that acceleration of bone turnover by teriparatide injection did not prevent osteonecrosis but rather converted osteoclast progenitors to macrophages expressing inflammatory cytokines, which were required for osteonecrosis development. In fact, we demonstrate that TNFα-, IL-1α/β- or IL-6-deficient mice as well as wild-type mice administered a TNFα-inhibitor were significantly resistant to development of osteonecrosis accompanying infectious myelitis, even under bisphosphonate treatment. Our data provide new insight into mechanisms underlying osteonecrosis and suggest new ways to prevent it.
authors.affiliation: Division of Oral and Maxillofacial Surgery, Department of Dentistry and Oral Surgery Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Mayu
authors.initials: M
authors.lastname: Morita
authors.affiliation: Division of Oral and Maxillofacial Surgery, Department of Dentistry and Oral Surgery Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Ryotaro
authors.initials: R
authors.lastname: Iwasaki
authors.affiliation: Department of Orthopedic Surgery Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.|Department of Advanced Therapy for Musculoskeletal Disorders Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Yuiko
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Department of Orthopedic Surgery Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.|Department of Musculoskeletal Reconstruction and Regeneration Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Tami
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: Department of Orthopedic Surgery Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Watanabe
authors.affiliation: Department of Orthopedic Surgery Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Takatsugu
authors.initials: T
authors.lastname: Oike
authors.affiliation: Department of Orthopedic Surgery Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nakamura
authors.affiliation: Department of Orthopedic Surgery Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Keneko
authors.affiliation: Department of Orthopedic Surgery Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Kana
authors.initials: K
authors.lastname: Miyamoto
authors.affiliation: Department of Microbiology, Tokyo Dental College, 2-9-18 Misakicho Ciyoda-ku, Tokyo, 101-0061, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Ishihara
authors.affiliation: Division of Experimental Animal Immunology, Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda-shi, Chiba 278-8510, Japan.
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.affiliation: Department of Orthopedic Surgery Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Ishii
authors.affiliation: Department of Orthopedic Surgery Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Morio
authors.initials: M
authors.lastname: Matsumoto
authors.affiliation: Department of Orthopedic Surgery Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Division of Oral and Maxillofacial Surgery, Department of Dentistry and Oral Surgery Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Hiromasa
authors.initials: H
authors.lastname: Kawana
authors.affiliation: Division of Oral and Maxillofacial Surgery, Department of Dentistry and Oral Surgery Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Taneaki
authors.initials: T
authors.lastname: Nakagawa
authors.affiliation: Department of Orthopedic Surgery Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.|Department of Advanced Therapy for Musculoskeletal Disorders Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Miyamoto
mesh_terms: D019386:Alendronate / Q000009:adverse effects; D000818:Animals; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D050071:Bone Density Conservation Agents / Q000009:adverse effects; D016723:Bone Remodeling; D002478:Cells, Cultured; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D010006:Osteoblasts / Q000187:drug effects; D010019:Osteomyelitis / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D050071:Bone Density Conservation Agents; D007378:Interleukins; D014409:Tumor Necrosis Factor-alpha; D019386:Alendronate