Proteinases and their receptors in inflammatory arthritis: an overview

Proteinases are enzymes with established roles in physiological and pathological processes such as digestion and the homeostasis, destruction and repair of tissues. Over the past few years, the hormone-like properties of circulating proteinases have become increasingly appreciated. Some proteolytic enzymes trigger cell signalling via proteinase-activated receptors, a family of G protein-coupled receptors that have been implicated in inflammation and pain in inflammatory arthritis. Proteinases can also regulate ion flux owing to the cross-sensitization of transient receptor potential cation channel subfamily V members 1 and 4, which are associated with mechanosensing and pain. In this Review, the idea that proteinases have the potential to orchestrate inflammatory signals by interacting with receptors on cells within the synovial microenvironment of an inflamed joint is revisited in three arthritic diseases: osteoarthritis, spondyloarthritis and rheumatoid arthritis. Unanswered questions are highlighted and the therapeutic potential of modulating this proteinase-receptor axis for the management of disease in patients with these types of arthritis is also discussed.