title: Immune complexes regulate bone metabolism through FcRγ signalling.
abstract: Autoantibody production and immune complex (IC) formation are frequently observed in autoimmune diseases associated with bone loss. However, it has been poorly understood whether ICs regulate bone metabolism directly. Here we show that the level of osteoclastogenesis is determined by the strength of FcRγ signalling, which is dependent on the relative expression of positive and negative FcγRs (FcγRI/III/IV and IIB, respectively) as well as the availability of their ligands, ICs. Under physiological conditions, unexpectedly, FcγRIII inhibits osteoclastogenesis by depriving other osteoclastogenic Ig-like receptors of FcRγ. Fcgr2b(-/-) mice lose bone upon the onset of a hypergammaglobulinemia or the administration of IgG1 ICs, which act mainly through FcγRIII. The IgG2 IC activates osteoclastogenesis by binding to FcγRI and FcγRIV, which is induced under inflammatory conditions. These results demonstrate a link between the adaptive immunity and bone, suggesting a regulatory role for ICs in bone resorption in general, and not only in inflammatory diseases.
authors.affiliation: Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.|Japan Science and Technology Agency (JST), Exploratory Research for Advanced Technology (ERATO) Program, Takayanagi Osteonetwork Project, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Negishi-Koga
authors.affiliation: Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8549, Japan.
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Gober
authors.affiliation: Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Eriko
authors.initials: E
authors.lastname: Sumiya
authors.affiliation: Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.|Japan Science and Technology Agency (JST), Exploratory Research for Advanced Technology (ERATO) Program, Takayanagi Osteonetwork Project, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Komatsu
authors.affiliation: Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.|Japan Science and Technology Agency (JST), Exploratory Research for Advanced Technology (ERATO) Program, Takayanagi Osteonetwork Project, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Okamoto
authors.affiliation: Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.|Japan Science and Technology Agency (JST), Exploratory Research for Advanced Technology (ERATO) Program, Takayanagi Osteonetwork Project, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Sawa
authors.affiliation: Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Suematsu
authors.affiliation: Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.|Japan Science and Technology Agency (JST), Exploratory Research for Advanced Technology (ERATO) Program, Takayanagi Osteonetwork Project, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Suda
authors.affiliation: Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8549, Japan.
authors.forename: Kojiro
authors.initials: K
authors.lastname: Sato
authors.affiliation: Department of Experimental Immunology, Institute of Development, Aging, and Cancer, Tohoku University, Seiryo 4-1, Aoba-ku, Sendai 980-8575, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Takai
authors.affiliation: Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.|Japan Science and Technology Agency (JST), Exploratory Research for Advanced Technology (ERATO) Program, Takayanagi Osteonetwork Project, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.|Centre for Orthopaedic Research, School of Surgery, The University of Western Australia, 35 Stirling Highway, Crawley, Perth, Western Australia 6009, Australia.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takayanagi
mesh_terms: D000818:Animals; D000936:Antigen-Antibody Complex / Q000276:immunology* / Q000378:metabolism; D001323:Autoantibodies / Q000276:immunology; D001327:Autoimmune Diseases / Q000276:immunology*; D001862:Bone Resorption / Q000235:genetics / Q000276:immunology*; D001842:Bone and Bones / Q000276:immunology* / Q000378:metabolism; D006942:Hypergammaglobulinemia / Q000276:immunology / Q000378:metabolism; D007074:Immunoglobulin G / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D010010:Osteoclasts / Q000378:metabolism*; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D000936:Antigen-Antibody Complex; D001323:Autoantibodies; C485701:Fcgr1 protein, mouse; C499172:Fcgr2b protein, mouse; C485700:Fcgr3 protein, mouse; C522404:Fcgr4 protein, mouse; D007074:Immunoglobulin G; D017452:Receptors, IgG
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