Activating FC[GAMMA] RECEPTORS mediate immune complex-induced inhibition of osteoclastogenesis

• Published in: Annals of the rheumatic diseases Vol. 71; p. A71
• Main Authors: Grevers, LC, van Lent, PLEM, de Vries, T J, Everts, V, van den Berg, W B
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group LTD 01.02.2012
• ISSN: 0003-4967; 1468-2060
• DOI: 10.1136/annrheumdis-2011-201237.25

Background Rheumatoid arthritis is characterised by osteoclast-mediated bone loss. Co-stimulatory signalling via ITAM- and ITIM-coupled receptors is essential for osteoclast formation and function. The ITAM- and ITIM-coupled Fc[GAMMA] receptors (Fc[GAMMA]R) play a crucial role in mediating inflammation and cartilage destruction in experimental arthritis, but their role in osteoclast-mediated bone loss is unknown. Objectives To investigate the role of Fc[GAMMA]Rs in osteoclastogenesis and osteoclast function. Materials and methods Bone destruction was analysed in arthritic knee joints of Fc[GAMMA]RIIB-deficient, FcR[GAMMA]-chain-/- (lacking expression of activating Fc[GAMMA]Rs), and wild type mice. Bone marrow-derived osteoclast precursors were differentiated in vitro towards osteoclasts in the absence or presence of immune complexes (ICs) and stimulated thereafter for 24 h with or without TNFα or LPS. Additionally, mature osteoclasts were stimulated with ICs. Experiments were analysed for osteoclast formation, bone resorption, and the expression of Fc[GAMMA]Rs and osteoclast markers. Results Bone erosions and cathepsin K-positive osteoclast numbers were significantly increased during antigen-induced arthritis in the knee joints of Fc[GAMMA]RIIB-deficient mice. All Fc[GAMMA]R classes were highly expressed on bone marrow-derived osteoclast progenitors. On mature osteoclasts, as compared to macrophages, expression of the inhibitory Fc[GAMMA]RIIB was similar, whereas expression of activating Fc[GAMMA]Rs was significantly lower. IC stimulation of mature osteoclasts neither affected their number nor their bone resorptive capacity. Differentiation of bone marrow-derived precursors in the presence of ICs significantly inhibited osteoclast formation, bone resorption, and expression of the osteoclast markers cathepsin K, CTR, DC-STAMP and NFATc1. In the presence of ICs, osteoclastogenesis of Fc[GAMMA]RIIB-/- precursors and bone resorption remained inhibited. In contrast, ICs could not inhibit osteoclast formation or bone resorption of FcR[GAMMA]-chain-/- precursors. When IC-inhibited osteoclastogenesis was followed by stimulation with TNFα or LPS, the inhibitory effects of ICs were overruled. Conclusions Activating Fc[GAMMA]Rs, but not the inhibitory Fc[GAMMA]RIIB, mediate IC-induced inhibition of osteoclastogenesis. In the presence of pro-inflammatory mediators like TNFα and LPS the inhibitory effect might be overruled. This suggests that the balance of Fc[GAMMA]R-mediated induction of inflammation, through pro-inflammatory cytokine production, as well as the direct inhibitory effect of ICs on osteoclastogenesis determines the net effect on bone loss.