Immune complexes regulate bone metabolism through FcRγ signalling

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 FcR gamma signalling, which is dependent on the relative expression of positive and negative Fc gamma Rs (Fc gamma RI/III/IV and IIB, respectively) as well as the availability of their ligands, ICs. Under physiological conditions, unexpectedly, Fc gamma RIII inhibits osteoclastogenesis by depriving other osteoclastogenic Ig-like receptors of FcR gamma. Fcgr2b(-/-) mice lose bone upon the onset of a hypergammaglobulinemia or the administration of IgG1 ICs, which act mainly through Fc gamma RIII. The IgG2 IC activates osteoclastogenesis by binding to Fc gamma RI and Fc gamma RIV, 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.