Some aspects of the pathophysiology of rheumatoid arthritis

Abstract

The review is devoted to the analysis of the main mechanisms of development of rheumatoid arthritis (RA). Chronic inflammatory process and local hypoxia of synovial tissues require an increased supply of oxygen, which necessitates the formation of new capillaries. A number of proangiogenic factors are activated, including vascular endothelial growth factor (VEGF), adhesion molecules, proinflammatory cytokines, chemokines, and matrix metalloproteinases. Under their influence, the proliferation of endothelial cells occurs, the formation of tubular structures associated with the basement membrane, and the formation of a new primitive vascular network. Mitochondrial dysfunction (MD) plays an important role in RA. Mitochondria at the site of inflammation provide the cell with increased production of energy and reactive oxygen species (ROS). In RA conditions, hypoxia, increased mitochondrial DNA (mtDNA) mutation rates, and excess ROS production are likely to initiate MD. This leads to the activation of autophagy, the formation of the NLRP3 inflammasome, and the release of aberrant mtDNA into the cytosol through a pore that opens in the outer mitochondrial membrane. Emitted mitochondrial structures are sensed as damage-associated molecular patterns (DAMPs), which activate an autoimmune inflammatory process. Activation of free radical oxidation is of great importance in the pathogenesis of RA. With developing hypoxia in the cells of the inflammatory focus, the balance of oxidative and antioxidant factors shifts towards excessive formation of ROS, which leads to the activation of T- and B-lymphocytes, macrophages, and promotes the formation of extracellular traps of neutrophils. All this significantly stimulates the course of autoimmune inflammation. Stimulation of the functional activity of fibroblast-like synoviocytes by free radicals enhances their production of pro-inflammatory cytokines, increases invasiveness and delays the apoptosis of these cells. In addition, excessive activation of radical oxidation contributes to articular cartilage damage and bone erosion through the activation of enzymes that degrade cartilage and extracellular bone matrix. The resulting imbalance between osteoblasts and osteoclasts in favor of the latter induces the process of bone resection.