Which of these pathogenic processes occurs first is unknown One

Which of these pathogenic processes occurs first is unknown. One proposed scenario selleck chem is that cartilage Inhibitors,Modulators,Libraries 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 Inhibitors,Modulators,Libraries inflammatory cells to the affected joint, thus establishing a vicious cycle of cartilage destruction and inflammation that perpetuates and pro motes the OA pathology. Therefore, OA has been described 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, Inhibitors,Modulators,Libraries many other molecules may act as DAMPs. One such molecule is fibrinogen, which stimulates macrophage production of chemokines 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 protein, fibrinogen exudes from the vasculature at sites of inflammation, such as the inflamed OA joint, owing to the retraction of inflamed 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 Inhibitors,Modulators,Libraries 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 Inhibitors,Modulators,Libraries in OA serum and synovial fluid.

We promotion information then determined whether a subset of the identified proteins could promote inflammation by functioning as immunostimulatory DAMPs. Material and methods Synovial fluid and serum samples Serum and synovial fluid samples were obtained from patients with knee OA, patients with rheumatoid arthri tis, or healthy individuals under protocols approved by the Stanford University Institutional Review Board and with the patients informed consent.

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