677th Meeting

Tumour necrosis factor α up-regulates protein kinase R (PKR)-activating protein (PACT) and increases phosphorylation of PKR and eukaryotic initiation factor 2-α in articular chondrocytes

S. J. Gilbert, V. C. Duance, D. J. Mason


Our previous analysis of the genes regulated in cartilage at the onset of spontaneous osteoarthritis in the guinea pig knee revealed up-regulation of the gene for protein kinase R (PKR)-activating protein (PACT), which encodes the cellular activator of the protein kinase, PKR. PACT and PKR are upstream components of a number of signal transduction and gene transcription pathways used by pro-inflammatory cytokines. We have investigated the role of PACT and PKR in articular cartilage degradation using cytokine treatment of bovine primary chondrocytes and cartilage explants. Tumour necrosis factor α increased expression of PACT protein after 3 h of treatment. Furthermore, increased phosphorylation of PKR and eukaryotic initiation factor 2-α was observed. The known role of PKR in cytokine-induced signalling pathways, together with our data showing cytokine regulation of PACT and PKR in chondrocytes, reveals a novel mechanism of cartilage degradation that may be important in the pathogenesis of arthritic diseases.

  • cartilage degradation
  • elF2-α
  • osteoarthritis
  • TNF-α
  • PKR, protein kinase R
  • PACT, protein kinase R-activating protein
  • OA, osteoarthritis
  • elF2-α, eukaryotic initiation factor 2-α
  • TNF-α, tumour necrosis factor α
  • IL-1, interleukin-1
  • RA, rheumatoid arthritis
  • NF-κB, nuclear factor κB
  • 1KK, inhibitory κB kinase
  • MMP, matrix metalloproteinase