FcγRs are involved in regulation of synovial activation and bone destruction during immune complex (IC)-mediated arthritis. The balance between activating FcγRs (FcγRI,III and IV) and inhibiting FcγRII determines synovial activation. Here we investigated the particular role of activating FcγRIV in bone erosion in IC-mediated antigen induced arthritis (AIA) by comparing FcγRI,II,III,IV-/- mice, FcγRI,II,III-/- mice and wild type controls (WT).Material and methods
AIA was induced by injection of mBSA into knee joints of mice previously immunised with mBSA/CFA. Joint inflammation, bone destruction, number of TRAP+ osteoclasts and S100A8/A9 positive cells was determined using histology and immunohistochemistry. In vitro osteoclastogenesis was assessed using TRAP staining.Results
Seven days after induction of AIA, we observed decreased inflammation and bone erosion in the knee joints of FcγRI,II,III,IV-/- mice compared to WT. The ability of bone marrow cells of FcγRI,II,III,IV-/- mice to differentiate into osteoclasts in vitro was comparable to the one of WT controls. Moreover, we observed comparable numbers of TRAP+ osteoclasts on the bone surface of FcγRI/II/III/IV-/- and WT arthritic mice, suggesting that the observed decrease in bone erosion is mainly caused by a reduced osteoclast activity, rather than decreased osteoclast number. However, in contrast to FcγRI/II/III/IV-/-, AIA induction in knee joints of FcγRI/II/III -/- resulted in increased bone erosion and inflammation compared to WT, highlighting the possible crucial role of FcγRIV in the pathology. Interestingly, the increased cell influx in FcγRI/II/III-/- mainly consisted of PMNs, whereas induction of AIA resulted in decreased PMN number in FcγRI/II/III/IV-/-, compared to their WT controls. This observation suggests that particularly FcγRIV is involved in regulating influx of PMNs. PMNs are potent producers of alarmins S100A8/A9 which are described to promote osteoclast activity. In line the number of S100A8/A9 positive cells in synovium was increased in FcγRI/II/III-/- while decreased in FcγRI/II/III/IV-/-, compared to their WT control.Conclusions
FcγRIV promotes bone erosion in AIA by enhancing influx of PMNs within the synovium. PMNs are potent producers of S100A8/A9 which has been described to induce osteoclast activity.