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.
Highlights
Autoantibody production and immune complex (IC) formation are frequently observed in autoimmune diseases associated with bone loss
The immunoreceptor tyrosine-based activation motif (ITAM)-bearing adaptor proteins, Fc receptor common g subunit (FcRg, which is encoded by Fcer1g) and DNAX-activating protein 12 kDa (DAP12, which is encoded by Tyrobp), play a crucial role in the transduction of the co-stimulatory signals for RANK6,7
The role of FcgRs has been explored in arthritis models[14,15,16,17,18]; it has been difficult to observe their direct effects on bone metabolism due to their central contribution to the onset of autoimmune disease and inflammation
Summary
Autoantibody production and immune complex (IC) formation are frequently observed in autoimmune diseases associated with bone loss It has been poorly understood whether ICs regulate bone metabolism directly. The IgG2 IC activates osteoclastogenesis by binding to FcgRI and FcgRIV, 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 in inflammatory diseases. FcRg acts as the common subunit of the activating FcgRs expressed in essentially all innate immune cells, including monocyte/macrophage lineage cells[9,10]; the function of FcgRs in the regulation of osteoclastogenesis is only poorly understood. The direct regulation of bone homeostasis by IgG immune complexes (ICs) has not been established
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