The role of extracellular calcium and the calcium receptors CaSR and GPRC6A in the pathogenesis of rheumatoid arthritis

风湿性关节炎是一种慢性炎症性关节疾病，其特征在于滑膜炎症和骨破坏。在炎症期间发生细胞活化和细胞坏死，这导致细胞外间隙中钙离子浓度的增加。RA患者的骨质侵蚀可能导致额外的局部钙浓度增加。单核细胞/巨噬细胞通过两种G蛋白偶联受体CaSR和GPRC 6A感知细胞外钙浓度的增加。这导致单核细胞活化并产生大量Nlrp 3依赖性细胞因子IL-1和IL-18以及其他促炎细胞因子如TNF和IL-6。该项目的目的是确定细胞外钙浓度增加的作用以及钙受体CaSR和GPRC 6A在RA发病机制中的作用。在初步工作中，我们能够检测到RA患者滑液中钙浓度的增加。在此基础上，我们对类风湿关节炎患者的滑膜组织、滑液和外周血以及关节炎小鼠骨髓中的钙离子浓度进行了研究。将使用基因敲除小鼠和两种不同的关节炎模型（CAIA、CIA）研究钙受体CaSR和GPRC 6A的参与。该项目的另一个目标是确定细胞外钙浓度增加的功能后果。我们想研究细胞外钙对Th 17细胞的单核细胞依赖性扩增和单核细胞向巨噬细胞分化的影响。细胞外钙离子能够趋化性地吸引单核细胞，我们希望研究这一过程是否参与单核细胞在滑膜中的迁移，本项目旨在阐明细胞外钙离子的作用以及两种钙受体CaSR和GPRC 6A在RA发病机制中的作用，从而确定一种新的治疗方法来调节单核细胞/巨噬细胞的促炎激活。

Rheumatoid arthritis is a chronic inflammatory joint disorder, which is characterized by the inflammation of the synovial membrane and bone destruction. Cell activation and cell necrosis occurs during inflammation and this leads to an increase in the concentration of calcium ions in the extracellular space. Bone erosions in RA patients might lead to additional local increased calcium concentrations. Monocytes/macrophages sense an increase in the extracellular calcium concentration by two G-protein coupled receptors, CaSR and GPRC6A. This leads to monocyte activation and the production of large amounts of Nlrp3-dependent cytokines IL-1 and IL-18, and other pro-inflammatory cytokines like TNF and IL-6.Aim of the project is to identify the role of an increased extracellular calcium concentration and the role of the calcium receptors CaSR and GPRC6A in the pathogenesis of RA. In preliminary work we were able to detect an increased calcium concentration in the synovial fluid of RA patients. Based on this result we want to study the calcium concentration in the synovial tissue, synovial fluid and the peripheral blood of RA patients and the bone marrow of arthritic mice. The participation of the calcium receptors CaSR and GPRC6A will be studied using knock-out mice and two different arthritis models (CAIA, CIA). Another goal of the project is the identification of functional consequences of an increased extracellular calcium concentration. We want to study the influence of extracellular calcium on the monocyte-dependent expansion of Th17 cells and on the differentiation of monocytes into macrophages. Extracellular calcium is able to chemotactically attract monocytes and we want to study if this process participates in the migration of monocytes in the synovial membrane.The project is intended to clarify the role of extracellular calcium and the role of the two calcium receptors CaSR and GPRC6A in the pathogenesis of RA and thereby identify a new therapeutic approach to modulate the proinflamamtory activation of monocytes/macrophages.