This study investigated whether treatment of articular cartilage chondrocytes with a combination of oncostatin M (OSM) and interleukin-1 (IL-1) could induce a degradative phenotype that was mediated through the protein kinase R (PKR) signalling pathway.High-density monolayer cultures of full depth, bovine chondrocytes were treated with a combination of OSM and IL-1 (OSM+IL-1) for 7 days. To inhibit the activation of PKR, a pharmacological inhibitor of PKR was added to duplicate cultures. Pro- and active matrix metalloproteinase-9 (MMP9) andMMP9mRNA were significantly upregulated by OSM+IL-1 through a PKR dependent mechanism.ADAMTS4andADAMTS5mRNA were also upregulated by OSM+IL-1. The upregulation ofADAMTS4andADAMTS5were, in part, mediated through PKR. OSM+IL-1 resulted in a loss of type II collagen, which could not be rescued by PKR inhibition. OSM+IL-1 reduced the expression ofCOL2A1(type II collagen),COL9A1(type IX collagen),COL11A1(type XI collagen), andACAN(aggrecan) mRNAs. Expression of type II and XI collagen and aggrecan was reduced further when PKR was inhibited. OSM+IL-1 resulted in an 11-fold increase inTNFamRNA which was, in part, mediated through the PKR pathway.This study demonstrates, for the first time, that a number of catabolic and pro-inflammatory effects known to be important in human arthritis and induced by OSM and IL-1, are mediated by the PKR signalling pathway.