Protein Kinase R: A Novel Mediator of Articular Cartilage Degradation in Arthritis
Sophie J. Gilbert,
Victor C. Duance,
Deborah J. Mason.
The protein kinase PKR is a key regulator of stress signalling pathways. We found that the PKR activating protein (PACT) is up-regulated in cartilage at the onset of osteoarthritis. PACT activates PKR in response to various cellular stresses such as TNF-α and IL-1. TNF-α also activates PKR via the sphingolipid second messenger, ceramide. Recent studies have shown that ceramide-induced activation of PKR inhibits protein synthesis as a prelude to cell death. TNF- and ceramide stimulate cartilage degradation and we have demonstrated a role for PKR in TNF-α and ceramideinduced increases in the expression and activation of degradative enzymes in articular cartilage. The known role of PKR in cytokine-induced signalling pathways, together with our data showing cytokine regulation of PKR in chondrocytes, reveals a novel mechanism of cartilage degradation that may be important in the pathogenesis of arthritis. Elucidation of this pathway may enable more subtle control of cytokine-mediated degradation of cartilage and improve upon the efficacy of anti-TNF treatments in arthritis. This review will summarise the known activities of PKR and provide evidence for the involvement of this signalling pathway in cartilage breakdown.
Keywords: Articular cartilage, arthritis, PKR, TNF-α, ceramide, matrix metalloproteinase
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