Introduction Osteoarthritis is a degenerative disease of the join

Introduction Osteoarthritis is a degenerative disease of the joints that is characterized by destruction of articular cartilage, inflammation Z-VAD-FMK molecular weight of the synovial membrane, and remodeling of periarticular bone. Which of these pathogenic processes occurs first is unknown. One proposed scenario is that cartilage breakdown releases components of the damaged extracellular matrix into synovial fluid, and that these ECM components elicit the local produc tion of inflammatory molecules by binding to receptors on resident synovial cells or infiltrating inflammatory cells. The inflammatory molecules produced may in turn stimulate production of cartilage degrading enzymes and recruit inflammatory cells to the affected joint, thus establishing Inhibitors,Modulators,Libraries a vicious cycle of cartilage destruction and inflammation that perpetuates and pro motes the OA pathology.

Therefore, OA has been described Inhibitors,Modulators,Libraries as a chronic wound in which molecules in synovial fluid function as damage associated molecular patterns to effect tissue remodeling. Although the identities of the endogenous mole cules that mediate synovial inflammation have yet to be confirmed in OA patients or animal models, a continu ous supply of DAMPs could perpetuate the early response to injury and thereby damage the joint. Besides ECM components, many other molecules may act as DAMPs. One such molecule is fibrinogen, which stimulates macrophage production of chemokines Inhibitors,Modulators,Libraries in a TLR4 dependent manner. Fibrinogen is present at abnormally high levels in OA synovial fluid, and the amount of fibrin deposited in the synovial membrane corre lates with the severity of OA.

Although classically a plasma Inhibitors,Modulators,Libraries protein, fibrinogen exudes from the vasculature at sites of inflammation, such as the inflamed OA joint, owing to the retraction of inflamed Inhibitors,Modulators,Libraries endothelial cells. Fibrinogen is not the only protein to extravasate at sites of inflammation, however, and several other plasma pro teins have been detected in OA synovial fluid. The extravascular function of most of these plasma pro teins is unclear. It is possible that, like fibrinogen, some of these plasma proteins could have an immunoregula tory role at sites of inflammation or tissue damage. Inflammation is present even in the early stages of OA, and clinical signs of synovitis correlate with radiographic progression of knee OA. Insight into the cause of synovial inflammation is therefore impor tant in understanding the pathogenesis of OA. Here we used proteomic techniques to survey the proteins pre sent in OA synovial fluid and to evaluate levels of inflammatory cytokines in OA serum and synovial fluid. We then determined whether a subset of the identified proteins could promote inflammation by functioning as immunostimulatory DAMPs.

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