Tumor necrosis factor α activation of the apoptotic cascade in murine articular chondrocytes is associated with the induction of metalloproteinases and specific pro-resorptive factors

Objective Tumor necrosis factor α (TNFα) blockade provides substantive reduction of the symptoms of rheumatoid arthritis (RA). While the biologic actions of TNFα have been well characterized in immune and synovial cells, which are known to be major contributors to the progression of cartilage destruction in RA, the current studies were designed to assess the direct effects of TNFα on chondrocytes. Methods We examined the expression of several groupings of messenger RNA (mRNA) that define key biologic pathways that have previously been associated with either the general actions of TNFα or cartilage destruction, in murine articular chondrocytes isolated from wild-type mice and TNFα receptor–null (p55/p75−/−) mice. Results TNFα induced the expression of multiple mRNA that facilitate apoptosis and lead to apoptosis-induced cell death. The induction of apoptosis was accompanied by the increased expression of several factors involved in the regulation of skeletal tissue proteolysis and resorption. Quantitative increases from 2-fold to >10-fold were seen for inducible nitric oxide synthase, matrix metalloproteinase 3, macrophage colony-stimulating factor, and osteoprotegerin mRNA expression. The dependence of the induction of these mRNA on TNFα was confirmed by comparison with the effects of TNFα on chondrocytes isolated from receptor-null mice. Conclusion These findings demonstrate that TNFα alters the expression of a complex array of genes within murine chondrocytes that contribute to the destruction of joint surfaces, independent of its actions on synovial and immune cells. Further studies are needed to clarify the biologic actions of TNFα in human cartilage cells.