Combined anti-inflammatory effects of the endocannabinoid system and cortisol in arthritic tissue - a non-neuronal role of endocannabinoids

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RA synovial tissue is characterized by high levels of the endocannabinoid anandamide, expression of all cannabinoid receptors and the major endocannabinoid degrading enzymes fatty acid amide hydrolase and Cox-2. The source of anandamide in synovium is still unclear. In certain brain areas, anandamide levels and cannabinoid receptor 1 levels are controlled by glucocorticoids. Upon prolonged stress, glucocorticoids lead to the synthesis of anandamide which dampens the activity of the hypothalamus-pituitary adrenal axis. In synovial tissue cortisol increases adhesion of synovial fibroblasts to fibronectin by the production of intracellular anandamide. Adhesion is crucial for synovial fibroblasts to initiate migration, cartilage damage and invasion. Anandamide activates cannabinoid receptors 1 and 2 as well as transient receptor potential vanilloid 1 all of which influence adhesion. Since anandamide is abundant in the RA synovium it is likely that synovial fibroblasts are one major source of this endocannabinoid. Extracellular anandamide exerts anti-inflammatory effects via different pathways by down-regulating cytokines/MMPs and inhibiting proliferation in synovial fibroblasts. Until now, it is unknown how cortisol triggers endocannabinoid production and whether this crosstalk can be exploited therapeutically. Furthermore it is unclear how glucocorticoids regulate cannabinoid receptors, which other factors induce endocannabinoid synthesis, how the endocannabinoid system exerts its anti-inflammatory action and how the cannabinoid receptors GPR18, GPR55 and CB2 influence the function of synovial fibroblasts. These points will be answered in this project.