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

抗瓜氨酸化蛋白（ACPA）的自身抗体对类风湿性关节炎（RA）具有高度特异性，在疾病临床发作前数年出现，是骨丢失的最强风险因素。我们最近的研究表明，抗瓜氨酸波形蛋白的ACPA通过与破骨细胞前体直接相互作用诱导骨丢失。ACPA还显示与滑膜中的瓜氨酸化蛋白形成免疫复合物。因此，除了ACPA与破骨细胞表面的瓜氨酸化蛋白直接结合外，含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解释ACPA诱导的RA骨丢失。事实上，我们发现，免疫复合物显着促进破骨细胞的成熟，这种相互作用是依赖于IgG糖基化。因此，在拟议的项目中，我们希望详细说明ACPA促进破骨细胞作用的机制。在临床方法中，我们将检查精细特异性ACPA、其糖基化模式和Fc γ受体的等位基因变体对RA患者骨丢失的影响。这些研究将通过体外研究来补充，这些体外研究涉及单个Fc-γ受体、用ACPA挑战破骨细胞前体后前骨细胞基因和细胞因子的信号传导和表达。

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.