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

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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.