The impact of ACPA on bone loss in patients with rheumatoid arthritis

抗瓜氨酸蛋白自身抗体(ACPA)是类风湿性关节炎(RA)的高度特异性抗体，比临床发病早几年，是骨丢失的最大危险因素。我们最近发现，针对瓜氨酸波形蛋白的ACPA通过直接与破骨细胞前体相互作用来诱导骨丢失。ACPA也被证明与滑膜中的瓜氨酸蛋白形成免疫复合体。因此，除了ACPA与破骨细胞表面瓜氨酸蛋白的直接结合外，含有ACPA的免疫复合物与破骨细胞上的Fc-γ受体的相互作用可能是ACPA导致RA骨丢失的原因。事实上，我们发现免疫复合体极大地促进了破骨细胞的成熟，这种相互作用依赖于免疫球蛋白的糖基化。因此，在该项目中，我们希望明确ACPA促进破骨细胞作用的机制。在一种临床方法中，我们将检查细微的特异性ACPA、其糖基化模式和Fcγ受体的等位基因变异对RA患者骨丢失的影响。这些研究将得到体外研究的补充，包括单个Fc-γ受体的参与，ACPA攻击破骨前细胞后促破骨基因和细胞因子的信号和表达。

Autoantibodies against citrullinated proteins (ACPA) are highly specific for rheumatoid arthritis (RA), precede the clinical onset of disease by years and are the strongest risk factor for bone loss. We have recently shown that ACPA directed against citrullinated vimentin induce bone loss by direct interaction with osteoclast precursors. ACPA also have been shown to form immune complexes with citrullinated proteins in the synovium. Hence, aside from the direct binding of ACPA to citrullinated proteins on the surface of the osteoclasts, the interaction of ACPA containing immune complexes with Fc gamma receptors on osteoclasts may explain ACPA-induced bone loss in RA. Indeed, we found that immune complexes dramatically foster the maturation of osteoclasts and that this interaction is dependent on IgG glycosylation. In the proposed project we thus want to specify the mechanisms of the osteoclast promoting effect of ACPA. In a clinical approach we will examine the impact of the fine specificity ACPA, their glycosylation pattern and allelic variants of the Fc gamma receptors on bone loss in RA patients. These studies will be complemented by in vitro investigations of the involvement of individual Fc-gamma-receptors, signalling and expression of pro-osteoclastic genes and cytokines after challenging preosteoclasts with ACPA.