Immune complex-induced inhibition of osteoclastogenesis is mediated via activating but not inhibitory Fcγ receptors on myeloid precursor cells

Objective To investigate the role of Fc gamma receptors (Fc gamma Rs) in osteoclastogenesis and osteoclast function. Methods Bone destruction was analysed in arthritic knee joints of several Fc gamma R-knockout mouse strains. Unfractionated bone marrow cells were differentiated in vitro towards osteoclasts in the absence or presence of immune complexes (ICs) and stimulated thereafter for 24 h with tumour necrosis factor alpha (TNF alpha) or lipopolysaccharide (LPS). In addition, 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 destruction was significantly increased in arthritic knee joints of Fc gamma RIIB-deficient mice. All Fc gamma R classes were highly expressed on osteoclast precursors. Expression of the inhibitory Fc gamma RIIB was similar on mature osteoclasts compared to macrophages, whereas activating Fc gamma R levels were significantly lower. IC stimulation of mature osteoclasts did not affect their number or their bone resorptive capacity. ICs significantly inhibited differentiation of unfractionated bone marrow cells towards osteoclasts, bone resorption and expression of osteoclast markers. 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 TNF alpha or LPS, the inhibitory effects of ICs were overruled. Conclusion Activating Fc gamma Rs mediate IC-induced inhibition of osteoclastogenesis, which might be overruled in the presence of proinflammatory mediators. This suggests that the balance of Fc gamma R-mediated inflammation, through proinflammatory cytokine production, as well as the direct inhibitory effect of ICs on osteoclastogenesis determines the net effect on bone loss.