TY - JOUR
T1 - Immune complexes regulate bone metabolism through FcRγ signalling
AU - Negishi-Koga, Takako
AU - Gober, Hans Jürgen
AU - Sumiya, Eriko
AU - Komatsu, Noriko
AU - Okamoto, Kazuo
AU - Sawa, Shinichiro
AU - Suematsu, Ayako
AU - Suda, Tomomi
AU - Sato, Kojiro
AU - Takai, Toshiyuki
AU - Takayanagi, Hiroshi
N1 - Funding Information:
We thank J.V. Ravetch for providing a-FcgRIV antibody. We also thank M. Shinohara, M. Ohora, T. Nakashima, K. Okamoto, S. Sawa, T. Ando, Y. Ogiwara and N. Otsuka for discussion and assistance. This work was supported in part by a grant for ERATO, the Takayanagi Osteonetwork Project from the JST to H.T. (No. 110575) and by Astellas Foundation for Research on Metabolic Disorders to T.N.-K.
Publisher Copyright:
© 2015 Macmillan Publishers Limited. All rights reserved.
PY - 2015/3/31
Y1 - 2015/3/31
N2 - 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.
AB - 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.
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U2 - 10.1038/ncomms7637
DO - 10.1038/ncomms7637
M3 - Article
C2 - 25824719
AN - SCOPUS:84926314110
SN - 2041-1723
VL - 6
JO - Nature Communications
JF - Nature Communications
M1 - 6637
ER -