The effect of cannabinoids on IL-1beta induced catabolic pathways in osteoathritic chondrocytes.

A key feature of osteoarthritis (OA) is the loss of articular cartilage. Cartilage breakdown is mediated by complex interactions of proinflammatory cytokines such as interleukin 1beta (IL-1beta) and proteases including matrix metalloproteinases (MMPs). Cannabinoids have been shown to reduce joint damage in animal models of arthritis and have also been shown to prevent IL-1 induced matrix breakdown of collagens and proteoglycans, suggesting a chondroprotective effect of these compounds. Cannabinoids mediate their effects via putative cannabinoid receptors and activation of these receptors has been shown to display antiinflammatory activities and inhibition of destructive factors in human OA chondrocytes and synovial fibroblasts. This thesis demonstrates that the synthetic cannabinoid WIN-55 inhibits the expression of ECM degrading enzymes MMP-3 and MMP-13 both at the mRNA and protein level in human OA chondrocytes. WIN-55 also decreased the expression of MMP inhibitors: tissue inhibitors of matrix metalloproteinases-1 and -2 (TIMP-1 and -2). WIN-55 inhibited IL-beta induced signalling pathways including ERK1/ERK2, c-Jun and IkappaB but not p38, these findings suggest a possible mechanism via which WIN-55 decreases the expression MMPs.The classical cannabinoid receptors cannabinoid receptors 1 and 2 (CB1 and CB2), G protein-coupled receptor 55 (GPR55), G protein-coupled receptor 18 (GPR18), transient receptor potential vanilloid 1 (TRPV1) and peroxisome proliferator activated receptor alpha, delta and gamma (PPARalpha, delta and gamma) were expressed by OA chondrocytes and osteocytes in the underlying bone, with a decrease in GPR18, TPRV1 and PPAR in specific zones of the osteochondral compartment associated with an increase in grade of degeneration.Selective cannabinoid receptor agonists were used to determine the receptor(s) via which WIN-55 may mediate its effects in human OA chondrocytes. Agonists for CB1, CB2 and PPARalpha, delta and gamma used in combination inhibited IL-1beta induced MMP-3 or -13 mRNA expression, suggesting that WIN-55 may mediate its effects via activation of multiple cannabinoid receptors or via a novel cannabinoid receptor.Pro-inflammatory cytokine IL-1beta is a well-known mediator of cartilage degradation, thus the inhibition of IL-1beta induced expression of MMPs and intracellular signalling pathways shown here by WIN-55 suggests that cannabinoids could provide a model for the development of novel therapeutic agents for arthritis via preventing cartilage degradation.