Cell-cartilage interactions at the articular borders under the influence of steroid hormones and cannabinoids

类风湿性关节炎（RA）的特点是软骨退化和侵袭。这些事件主要由滑膜成纤维细胞（SF）介导。RA-SF响应整合素或细胞因子的激活，产生促炎介质（如基质金属蛋白酶、细胞因子）。在之前的研究中，我们在RA的SCID小鼠模型中证明了皮质醇增加整合素α5的合成，从而增加细胞对纤维连接蛋白的粘附，从而减少RA- sf对软骨的侵袭。由于皮质醇减少了细胞外相关激酶（ERK）的磷酸化，黏附增加并不伴随着整合素信号的增加。在新项目中，我们希望扩展这些激素研究。早期观察到的激素效应可能是由内源性大麻素介导的，因为这种体内平衡系统是由类固醇激素调节的。因此，我们将在RA-SF中分析皮质醇和雌激素化合物如何调节内源性大麻素系统的成分，以及内源性大麻素如何影响RA-SF关节内整合素。这些研究是在体外和体内进行的，使用黏附、迁移和侵袭试验。这些研究将揭示整合素、类固醇激素和内源性大麻素在类风湿性关节炎滑膜炎症中的相互作用。可以预期，新的治疗靶点可以确定。

Rheumatoid arthritis (RA) is characterized by cartilage degradation and invasion. These events are mainly mediated by synovial fibroblasts (SF). RA-SF respond to integrin or cytokine activation with production of proinflammatory mediators (e.g. matrix metalloproteinases, cytokines). In the previous period, we demonstrated that cortisol increased integrin α5 synthesis, which in turn increased cell adhesion to fibronectin leading to reduced invasion of RA-SF into cartilage in the SCID mouse model of RA. Increased adhesion was not accompanied by increased integrin signaling since cortisol diminished extracellular-related kinase (ERK) phosphorylation. Within the new project, we want to extend these hormone studies. The earlier observed hormonal effects might be mediated by endocannabinoids since this homeostatic system is regulated by steroid hormones. Therefore, we will analyze in RA-SF how cortisol and estrogenic compounds regulate the components of the endocannabinoid system and how endocannabinoids exert their effects on RA-SF integrins in the joint. The studies are carried our in vitro and in vivo using assays of adhesion, migration, and invasion. These studies will shed new light on the interaction of integrins, steroid hormones, and endocannabinoids in the context of synovial inflammation in RA. It is to be expected that novel therapeutic targets can be determined.