Osteoarthritis is primarily characterized by areas of destruction of articular cartilage and by synovitis. Articular damage and synovitis are secondary to local increase of pro-inflammatory cytokines (interleukin-1beta and tumor necrosis factor-alpha), enzymes with proteolytic activity (matrix metalloproteinases), and enzymes with pro-inflammatory activity (cyclooxygenase-2 and nitric oxide synthase-2). Enhanced expression of these proteins in chondrocytes and in synovial membrane appears associated to the activation and nuclear translocation of nuclear factor-kappaB (NF-kappaB). Chondroitin sulfate (CS) prevents joint space narrowing and reduces joint swelling and effusion. To produce these effects, CS elicits an anti-inflammatory effect at the chondral and synovial levels. CS and its disaccharides reduce NF-kappaB nuclear translocation, probably by diminishing extracellular signal-regulated kinase1/2, p38mitogen-activated protein kinase and c-Jun N-terminal kinase activation. This review discusses the evidence supporting that CS pleiotropic effects in chondrocytes and synoviocytes are primarily due to a common mechanism, e.g., the inhibition of NF-kappaB nuclear translocation.
Inflammatory reactions (IRs), both infectious and aseptic, downregulate numerous enzymes of cytochrome P450 (CYP) and ATP-binding cassette transporters. The mechanism involves proinflammatory cytokines and activation of transcription factors, nuclear factor-κB, CCAAT-enhancer-binding protein-β and c-myc, which bind to negative regulatory elements and/or impede the binding of nuclear receptors to promoter elements. Downregulation of CYP enzymes and transporters modulates the kinetics of a drug, resulting in increased plasma and tissue concentrations of the drug and enhanced effect and/or toxicity. Clinical trials have shown that IRs increase the risk of myocardial infarction and stroke. In this article, we speculate that IRs downregulate cardiac and vascular CYP enzymes (CYP2C8/9 and CYP2J2) responsible for the formation of vasorelaxant products. Patients with IRs should be advised that the risk of drug adverse effects and of cardiovascular diseases is increased; therefore, the benefit-risk ratio and use of drugs with narrow therapeutic index should be revaluated, as well as the conditions precipitating cardiovascular events.
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