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

类风湿性关节炎（RA）是一种以软骨退化和侵袭为特征的疾病。这些事件主要由滑膜成纤维细胞（SF）介导。RA-SF对整联蛋白或细胞因子活化作出反应，产生促炎介质（例如基质金属蛋白酶、细胞因子）。在前一阶段，我们证明了皮质醇增加整合素α5的合成，这反过来又增加了细胞与纤连蛋白的粘附，从而减少了RA-SF在RA的SCID小鼠模型中对软骨的侵袭。增加粘附并不伴随着增加整合素信号，因为皮质醇减少细胞外相关激酶（ERK）磷酸化。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，因为这种稳态系统是由类固醇激素调节的。因此，我们将分析在RA-SF皮质醇和雌激素化合物如何调节内源性大麻素系统的组成部分，以及内源性大麻素如何对关节中的RA-SF整合素发挥作用。这些研究在体外和体内使用粘附、迁移和侵袭测定进行。这些研究将揭示整合素，类固醇激素和内源性大麻素在RA滑膜炎症背景下的相互作用。预期可以确定新的治疗靶点。

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.