Immune complex-induced inhibition of osteoclastogenesis is mediated via activating but not inhibitory Fcγ receptors on myeloid precursor cells
Immune complex-induced inhibition of osteoclastogenesis is mediated via activating but not inhibitory Fcγ receptors on myeloid precursor cells
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DOI：
10.1136/annrheumdis-2012-201568
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发表时间：
2013-02-01
影响因子：
27.4
通讯作者：
van Lent, Peter L. E. M.
中科院分区：
文献类型：
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作者：
Grevers, Lilyanne C.;de Vries, Teun J.;van Lent, Peter L. E. M.
目的探讨Fc γ受体（Fc γ R）在破骨细胞生成和功能中的作用。未分级的骨髓细胞在体外分化为破骨细胞在免疫复合物（IC）的存在或不存在下，刺激24小时后，与肿瘤坏死因子α（TNF α）或脂多糖（LPS）。此外，成熟的破骨细胞刺激与IC。实验分析破骨细胞的形成，骨吸收和表达的Fc γ Rs和破骨细胞marker.Results骨破坏显着增加，关节炎的Fc γ RIIB缺陷小鼠膝关节。所有Fc γ R类在破骨细胞前体上高度表达。与巨噬细胞相比，成熟破骨细胞上抑制性Fc γ RIIB的表达相似，而活化性Fc γ R水平显著较低。IC刺激成熟破骨细胞并不影响其数量或骨吸收能力。ICs显著抑制未分级骨髓细胞向破骨细胞的分化、骨吸收和破骨细胞标志物的表达。在存在IC的情况下，Fc γ RIIB-/-前体的破骨细胞生成和骨吸收仍然受到抑制。相反，ICs不能抑制破骨细胞的形成或FcR γ链（-/-）前体的骨吸收。当IC抑制破骨细胞生成后，刺激与TNF α或LPS，IC的抑制作用被推翻。结论激活Fc γ R介导IC诱导的抑制破骨细胞生成，这可能是推翻在促炎介质的存在。这表明Fc γ R介导的炎症通过促炎细胞因子产生的平衡以及IC对破骨细胞生成的直接抑制作用决定了对骨丢失的净效应。
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.