Background/Purpose: Rheumatoid arthritis is characterized by chronic inflammation and 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 Fcγ receptors (FcγR) play a crucial role in mediating inflammation and cartilage destruction in experimental arthritis, but their role in osteoclast-mediated bone loss is unknown. The aim of the present study was to investigate the role of FcγRs in osteoclastogenesis and osteoclast function.

Methods: Bone destruction was analyzed in arthritic knee joints of FcγRIIB-deficient, FcRγ-chain^−/− (lacking expression of activating FcγRs), 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 hrs with or without TNFα or LPS. Experiments were analyzed for the expression of FcγRs and osteoclast markers, osteoclast formation, and resorption pit formation on bone.

Results: Bone erosions and cathepsin K-positive osteoclast numbers were significantly increased (>2.6 fold) during antigen-induced arthritis in the knee joints of FcγRIIB-deficient mice. All FcγR classes were highly expressed on osteoclast precursors. Differentiation of osteoclast precursors in the presence of ICs significantly reduced osteoclast formation (37%), bone resorption (68%), and expression of the osteoclast markers cathepsin K, TRAP, CTR, DC-STAMP, and NFATc1. In the presence of ICs, osteoclastogenesis of FcγRIIB^−/− precursors and bone resorption remained inhibited. In contrast, ICs could not inhibit osteoclast formation or bone resorption of FcRγ-chain^−/−precursors. When IC-inhibited osteoclastogenesis was followed by stimulation with TNFα or LPS, the inhibitory effects of ICs were overruled, resulting in significantly increased osteoclast numbers and resorption levels as compared to unstimulated controls.

Conclusion: Activating FcγRs mediate IC-induced inhibition of osteoclastogenesis, which can be overruled in the presence of pro-inflammatory mediators like TNFα and LPS. This suggests that the balance of FcγR-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.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/osteoclastogenesis-is-inhibited-by-immune-complexes-through-activating-fc%ce%b3-receptors/