Figure 7.

The potential role of PKR in cartilage degradation. Results from the current study have led us to hypothesise that TNF-α-induced degradative pathways in cartilage may be mediated via activation of PKR. TNF-α binding to its receptor (TNF-R55) may activate PKR either directly or through ceramide (CER) to increase transcription and activation of MMPs via induction of NFκB and early response genes (c-fos and c-jun). Activation of PKR and subsequent phosphorylation of eIF2α would lead to an inhibition of protein synthesis and increased apoptosis, which may also affect cartilage integrity. Increased expression and activation of MMPs, in the absence of a corresponding increase in their inhibitors, would shift the balance of homeostasis towards matrix catabolism. AP-1, activator protein-1; eIF2α, eukaryotic initiation factor 2α ; IκBα, inhibitor kappa B alpha; MMP, matrix metalloproteinase; NFκB, nuclear factor κB; P, phosphorylated; PACT, PKR-activating protein; PKR, protein kinase R; TIMP, tissue inhibitors of MMP; TNF, tumour necrosis factor; TNF-R55, tumour necrosis factor receptor-55.