title: Interleukin-1 receptor-associated kinase-4 (IRAK4) promotes inflammatory osteolysis by activating osteoclasts and inhibiting formation of foreign body giant cells.
abstract: Formation of foreign body giant cells (FBGCs) occurs following implantation of medical devices such as artificial joints and is implicated in implant failure associated with inflammation or microbial infection. Two major macrophage subpopulations, M1 and M2, play different roles in inflammation and wound healing, respectively. Therefore, M1/M2 polarization is crucial for the development of various inflammation-related diseases. Here, we show that FBGCs do not resorb bone but rather express M2 macrophage-like wound healing and inflammation-terminating molecules in vitro. We also found that FBGC formation was significantly inhibited by inflammatory cytokines or infection mimetics in vitro. Interleukin-1 receptor-associated kinase-4 (IRAK4) deficiency did not alter osteoclast formation in vitro, and IRAK4-deficient mice showed normal bone mineral density in vivo. However, IRAK4-deficient mice were protected from excessive osteoclastogenesis induced by IL-1β in vitro or by LPS, an infection mimetic of Gram-negative bacteria, in vivo. Furthermore, IRAK4 deficiency restored FBGC formation and expression of M2 macrophage markers inhibited by inflammatory cytokines in vitro or by LPS in vivo. Our results demonstrate that osteoclasts and FBGCs are reciprocally regulated and identify IRAK4 as a potential therapeutic target to inhibit stimulated osteoclastogenesis and rescue inhibited FBGC formation under inflammatory and infectious conditions without altering physiological bone resorption.
authors.affiliation: From the Departments of Orthopedic Surgery.
authors.forename: Eri
authors.initials: E
authors.lastname: Katsuyama
authors.affiliation: From the Departments of Orthopedic Surgery.
authors.forename: Hiroya
authors.initials: H
authors.lastname: Miyamoto
authors.affiliation: From the Departments of Orthopedic Surgery, Integrated Bone Metabolism and Immunology.
authors.forename: Tami
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: From the Departments of Orthopedic Surgery, Musculoskeletal Reconstruction and Regeneration Surgery, and.
authors.forename: Yuiko
authors.initials: Y
authors.lastname: Sato
authors.affiliation: From the Departments of Orthopedic Surgery.
authors.forename: Wu
authors.initials: W
authors.lastname: Hao
authors.affiliation: From the Departments of Orthopedic Surgery.
authors.forename: Hiroya
authors.initials: H
authors.lastname: Kanagawa
authors.affiliation: From the Departments of Orthopedic Surgery.
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Fujie
authors.affiliation: From the Departments of Orthopedic Surgery.
authors.forename: Toshimi
authors.initials: T
authors.lastname: Tando
authors.affiliation: From the Departments of Orthopedic Surgery.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Watanabe
authors.affiliation: 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: From the Departments of Orthopedic Surgery.
authors.forename: Kana
authors.initials: K
authors.lastname: Miyamoto
authors.affiliation: From the Departments of Orthopedic Surgery.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Niki
authors.affiliation: From the Departments of Orthopedic Surgery.
authors.forename: Hideo
authors.initials: H
authors.lastname: Morioka
authors.affiliation: From the Departments of Orthopedic Surgery.
authors.forename: Morio
authors.initials: M
authors.lastname: Matsumoto
authors.affiliation: From the Departments of Orthopedic Surgery.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Toyama
authors.affiliation: From the Departments of Orthopedic Surgery, Integrated Bone Metabolism and Immunology, miyamoto@z5.keio.jp.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Miyamoto
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D015743:Giant Cells, Foreign-Body / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics* / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D010010:Osteoclasts / Q000378:metabolism; D010014:Osteolysis / Q000235:genetics / Q000473:pathology
chemical_list: D053592:Interleukin-1 Receptor-Associated Kinases; C507774:Irak4 protein, mouse
keywords: Bone; Cell Biology; Differentiation; Gene Expression; Osteoclast