Mitogen-activated protein (MAP) kinase activation by cytokines and other soluble mediators in articular chondrocyte cultures was shown to reproduce critical components relevant to cartilage development, synovial joint inflammation as well as human and animal osteoarthritic pathology. MAP kinase activation has been shown to be critical in cartilage formation Cytokines, such as interleukin-1β and tumor necrosis factor-α, soluble mediators, such as nitric oxide, and growth factors, namely fibroblast growth factor, connective tissue growth factor, vascular endothelial growth factor and hepatocyte growth factor activate specific MAP kinases resulting in nuclear factor-κB activation. NF-κB is a transcription factor which regulates matrix metalloproteinase gene expression, induces chondrocyte programmed cell death, up-regulates chondrocyte cytokine gene transcription as well as suppressing extracellular matrix protein biosynthesis, events that are consistent with synovial inflammation and the resultant destruction of articular cartilage in osteoarthritis.
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