Department of Rheumatology Research and Advanced Therapeutics, Radboud University Nijmegen Medical Centre, Geert Grooteplein 28, 272, Nijmegen 6525 GA, The Netherlands.
Ann Rheum Dis. 2013 Feb;72(2):278-85. doi: 10.1136/annrheumdis-2012-201568. Epub 2012 Aug 23.
To investigate the role of Fcγ receptors (FcγRs) in osteoclastogenesis and osteoclast function.
Bone destruction was analysed in arthritic knee joints of several FcγR-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 α (TNFα) or lipopolysaccharide (LPS). In addition, mature osteoclasts were stimulated with ICs. Experiments were analysed for osteoclast formation, bone resorption and the expression of FcγRs and osteoclast markers.
Bone destruction was significantly increased in arthritic knee joints of FcγRIIB-deficient mice. All FcγR classes were highly expressed on osteoclast precursors. Expression of the inhibitory FcγRIIB was similar on mature osteoclasts compared to macrophages, whereas activating FcγR 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 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.
Activating FcγRs mediate IC-induced inhibition of osteoclastogenesis, which might be overruled in the presence of proinflammatory mediators. This suggests that the balance of FcγR-mediated inflammation, through proinflammatory cytokine production, as well as the direct inhibitory effect of ICs on osteoclastogenesis determines the net effect on bone loss.
探讨 Fcγ 受体（FcγRs）在破骨细胞生成和破骨细胞功能中的作用。
分析几种 FcγR 敲除小鼠品系关节炎膝关节中的骨破坏情况。在不存在或存在免疫复合物（ICs）的情况下，将未分馏的骨髓细胞在体外向破骨细胞分化，然后用肿瘤坏死因子 α（TNFα）或脂多糖（LPS）刺激 24 小时。此外，用 ICs 刺激成熟破骨细胞。分析破骨细胞形成、骨吸收以及 FcγR 和破骨细胞标志物的表达情况。
FcγRIIB 缺陷型小鼠关节炎膝关节中的骨破坏明显增加。所有 FcγR 类均在破骨细胞前体上高度表达。与巨噬细胞相比，抑制性 FcγRIIB 的表达在成熟破骨细胞上相似，而激活型 FcγR 水平则明显降低。IC 刺激成熟破骨细胞不会影响其数量或骨吸收能力。ICs 显著抑制未分馏骨髓细胞向破骨细胞分化、骨吸收和破骨细胞标志物的表达。在存在 IC 的情况下，FcγRIIB(-/-)前体的破骨细胞生成和骨吸收仍然受到抑制。相比之下，ICs 不能抑制 FcRγ 链(-/-)前体的破骨细胞形成或骨吸收。当 IC 抑制的破骨细胞生成后用 TNFα 或 LPS 刺激时，IC 的抑制作用被推翻。
激活型 FcγRs 介导 IC 诱导的破骨细胞生成抑制，而在存在促炎介质的情况下，这种抑制作用可能被推翻。这表明 FcγR 介导的炎症的平衡，通过促炎细胞因子的产生，以及 ICs 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。
