Inflammatory activation of the Fc gamma R and IFN gamma R pathways co-influences the differentiation and activity of osteoclasts

Osteoclasts are polykaryons formed by cell-cell fusion of highly motile progenitors of the myeloid lineage. Osteoclast activity can preserve skeletal strength and bone homeostasis. However, osteoclasts are responsible for bone destruction in rheumatoid arthritis (RA). Fc receptors activated by IgG immune complexes (IC) can boost osteoclast differentiation and bone loss in the course of RA. In contrast, interferon (IFN) gamma secreted by immune cells blocks osteoclast activation. Despite their hypothetical importance in the regulation of osteoclast differentiation in RA, the interconnection between the two pathways has not been described so far. Here, we show by total internal reflection fluorescence (TIRF) microscopy that Fc gamma R3 and IFN gamma receptor (IFN gamma R) locate at close vicinity to each other on the human osteoclast surface. Moreover, the average distance increases during the differentiation process. Interestingly, Fc gamma R and IFN gamma R activation shapes the position of both receptors to each other. Surprisingly, the inhibitory action of IFN gamma on in-vitro human osteoclast differentiation depends on the osteoclast differentiation stage. Indeed, IFN gamma R activation in early osteoclast precursors completely inhibits the formation of polynucleated osteoclasts, while in premature osteoclasts, it further enhanced their fusion. In addition, gene expression analyses showed that IFN gamma R activation on early precursor cells but not on premature osteoclasts could induce Fc gamma R expression, suggesting a co-regulation of both receptors on human osteoclast precursors. Phosphokinase array data of precursor cells demonstrate that the observed divergence of IFN gamma R signaling is dependent on the mitogen-activated protein kinase (MAPK) downstream signaling pathway. Overall, our data indicate that Fc gamma R and IFN gamma R signaling pathways co-influence the differentiation and activity of osteoclasts dependent on the differentiation state, which might reflect the different stages in RA.