Matrix Metalloproteinases and Synovial Joint Pathology.

Matrix metalloproteinases (MMPs) are zinc-dependent enzymes. These enzymes play a critical role in the destruction of articular cartilage in rheumatoid arthritis (RA), osteoarthritis (OA), psoriatic arthritis (PsA), and the spondyloarthropathies. MMP gene expression is upregulated in these synovial joint pathologies in response to elevated levels of proinflammatory cytokines and soluble mediators such as tumor necrosis factor-α, interleukin-1 (IL-1), IL-6, IL-17, and interferon-γ. These molecules are capable of activating the mitogen-activated protein kinase and Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathways by binding the cytokine to their respective receptors on immune cells, macrophages, chondrocytes, synoviocytes, and osteocytes leading to increased synthesis of MMPs. Biologic drugs and/or small-molecule inhibitors designed to block cytokine to cytokine receptor interactions or to selectively inhibit JAKs have clinical efficacy in RA, PsA, and ankylosing spondylitis which correlated with a reduction in MMPs. Although there are currently no OA-selective drugs, it is likely that such a drug would have to reduce MMP gene expression to have clinical efficacy.