Regulation of Expression of Cytokines and Growth Factors in Osteoarthritic Cartilage Explants

Abstract

Osteoarthritis (OA) is a degenerative joint disease characterised by the breakdown of the extracellular matrix of chondrocytes in the affected joints. Cytokines and growth factors which are known to play a role in the synthesis and degradation of cartilage matrix have been shown to be upregulated in osteoarthritic cartilage. This upregulation resulted in two different phenotypes, overexpressing either TNF-α and IL-6 or IL-1β, TGFβ₁, IL-4 and IL-10. To investigate the hierarchy among growth factors and cytokines involved in cartilage metabolism, we analysed osteoarthritic cartilage explants for their responses to human recombinant (rh) cytokines and growth factors. The cytokine expression patterns of the explants before and after in vitro culture were compared by immunohistological staining of cartilage sections. We found a coordinate expression of TNF-α and IL-6 on the one hand, and of IL-1β, TGFβ₁, IL-4 and IL-10 on the other. Although TNF-α and IL-6 stimulated each other’s expression, they downregulated TGF β₁, IL-4 and IL-10 or IL-1β, TGF β₁ and IFNg, respectively. IL-1β upregulated the expression of TGF β₁, IL-4 and IL-10, and jointly these four cytokines and growth factors downregulated IL-6. Both of the expression patterns described for OA cartilage can be explained by these regulatory mechanisms. Interestingly, no cytokine efficiently downregulated TNF-α, and even though IL-1β is upregulated in one of the OA phenotypes, none of the growth factors and cytokines tested – except for IL-1β itself – seemed capable of mediating this upregulation. This unresponsiveness to cytokine stimulation might hint at a genetic cause for the elevated expression in the respective phenotypes.