Figure 1.

Cellular interactions in cartilage destruction in osteoarthritis. This scheme represents the destruction of the cartilage due to mechanical loading and biological factors. The induction of stress-induced intracellular signals, catabolic cytokines, including interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-α), chemokines, and other inflammatory mediators produced by synovial cells and chondrocytes results in the upregulation of cartilage-degrading enzymes of the matrix metalloproteinase (MMP) and ADAMTS families. Matrix degradation products can feedback regulate these cellular events. Anabolic factors, including bone morphogenetic proteins (BMPs) and transforming growth factor-beta (TGF-β), may also be upregulated and participate in osteophyte formation. In addition to matrix loss, evidence of earlier changes, such as chondrocyte proliferation and hypertrophy, increased cartilage calcification with tidemark advancement, and microfractures with angiogenesis from the subchondral bone possibly mediated by vascular endothelial growth factor (VEGF) can be observed in late osteoarthritis samples obtained from patients after total joint replacement. ADAMTS, a disintegrin and metalloproteinase with thrombospondin-1 domains; C/EBP, CCAAT enhancer-binding protein; ESE1, epithelial-specific ETS; ETS, E26 transformation specific; GADD45β, growth arrest and DNA damage 45 beta; HIF-1α, hypoxia-inducible factor-1-alpha; NF-κB, nuclear factor-kappa-B; PA, plasminogen activator; TIMPs, tissue inhibitors of metalloproteinases.