Figure 1.

Human osteoarthritis onset and progression. Illustration of the relationship of signaling and superficial cell spatial organization (SCSO). Overview about key proteins in relation to changes in the SCSO of human articular cartilage (AC), which is based on the subsequent chapters that provide a detailed review of the individual pathways. In the superficial zone (SZ) of normal human adult AC differentiated chondrocytes are arranged in string patterns embedded in the pericellular matrix (PCM) and mediate extracellular matrix (ECM) maintenance. The onset of osteoarthritis (OA) is characterized by proliferation. During formation of double string patterns, the PCM is progressively degraded, presumably by MMPs and other catabolic factors. Proliferation in early OA is dependent on fibroblast growth factor 2 (FGF2), transforming growth factor β (TGF-β), wingless-type MMTV integration site family (WNT), and notch homolog (NOTCH) signaling, whereas catabolic matrix metalloproteinase (MMP) expression is mediated by FGF2, a switch in TGF-β signaling and inflammatory cytokines including IL-6. Subsequently, the processes maintaining sustained proliferation and ECM degradation lead to formation of cell clusters that develop from double strings. At the stage of SCSO clusters, pronounced inflammation outweighs attenuated growth factor impact. Late stage OA, accompanied by macroscopic ECM erosion, is characterized by senescence and apoptosis of cartilage-inherent cells and predominance of inflammation.