Role of Cysteine Cathepsins in Joint Inflammation and Destruction in Human Rheumatoid Arthritis and Associated Animal Models

Destruction of bone and articular cartilage during pathogenesis of rheumatoid arthritis (RA) is caused by increased activity of a huge panel of proteases, which are secreted by several cell types of arthritic joint. Besides matrix metalloproteases (MMPs), the papain-like cysteine proteases (clan CA, family C1) have been identified as proteases potentially involved in car‐ tilage and bone destruction as well as in immune response during inflammatory arthritis. Several clinical studies demonstrated that expression and activity of different cysteine cathe‐ psins have been increased frequently in synovial membranes and fluids from RA patients. However, the exact roles of papain-like cysteine proteases have not been fully understood yet. Therefore, their contribution to joint inflammation and destruction has been investigat‐ ed by in vivo and in vitro experiments in the last decades of arthritis research. This chapter focuses on cysteine cathepsins K, B, L, and S the best-studied members of the papain-like protease family in arthritic diseases in order to understand better their impact on inflam‐ matory arthritis in respect to their collagenolytic activities as well as to their contributions to immune response. Latest results about the impact of cysteine cathepsins in different animal models for RA are discussed comprehensively. Furthermore, a short excursion to cathepsin V (= cathepsin L2) an exclusively human cathepsin L-like cysteine cathepsin and its im‐ pact on autoimmune disease progression is included in this review. The chapter clarifies that cathepsins K and S are attractive targets for the development of new highly specific an‐ ti-arthritis drugs.