Review Article

Emerging Players at the Intersection of Chondrocyte Loss of Maturational Arrest, Oxidative Stress, Senescence and Low-Grade Inflammation in Osteoarthritis

Figure 3

Macro to micro views of changes occurring in articular cartilage during OA onset and development. Left images indicate healthy joint, joint tissues, and chondrocytes. Resting chondrocytes present functional mitochondria and are surrounded by intact ECM. As a consequence of different risk factors, profound changes occur in all the joint tissues. Right images indicate OA joint, crosstalk among OA joint tissues, and hypertrophic chondrocytes. The latter present dysfunctional mitochondria, increased ROS production, and increased IKKα expression and are surrounded by degraded ECM. ECM degradation products act as damage associated molecular patterns (DAMPs or alarmins) recognized by the pattern recognition receptors (PRR) expressed by the cells. Alarmins are able to trigger both synovial macrophages (via TLR2 and TLR4) and chondrocytes (via TLR2 and TLR4, and RAGE), thus sustaining synovial inflammation and cartilage degradation. DAMPs also include HMGB1 that is highly expressed by both OA synoviocytes and hypertrophic chondrocytes and is able to enhance NF-κB activation and release of chemokines (particularly of MCP-1, highly active in the recruitment of monocytes that are also present in the synovial fluid) and cytokines, as well as of matrix metalloproteinases (MMPs) responsible for ECM remodeling and loss of maturational arrest. Increased oxidative stress is both cause and consequence of mitochondrial dysfunction. Correction of major risk factors and changes in diet and lifestyle can significantly reduce disease progression.