Pathways involved in the osteoarthritis disease process. The evolution of the osteoarthritis disease process is characterized by cartilage degradation caused, at least in part, by proteolytic breakdown of macromolecules, in which matrix metalloproteases (MMPs) play an important role. Further fibrillation and erosion of the cartilage surface result in the release of molecular breakdown products into the synovial fluid. The phagocytosis of cartilage matrix breakdown products and other materials by synovial macrophages induces an inflammatory reaction in the synovial membrane, thereby resulting in local synthesis of proteases and proinflammatory cytokines. The proteases and cytokines released by the synovium diffuse through the synovial fluid and into the cartilage. They induce additional cartilage breakdown by direct macromolecule proteolysis and by stimulation of chondrocyte cytokine production to increase the synthesis of proteases. There is also an increased level of cytokine receptors on the cell. ICE = interleukin-1β-converting enzyme; IL = interleukin; MT-MMP = membrane-type matrix metalloprotease; TIMP = tissue inhibitor of matrix metalloprotease; u-PA = urokinase plasminogen activator; - refers to inhibition; + to stimulation. A part of this figure was adapted from figure 110.1, stage III in , a figure produced by Amersham Pharmacia Biotech and reproduced with permission from .