Tumor necrosis factor-α induces ADAMTS-4 expression in human osteoarthritis chondrocytes

Tumor necrosis factor (TNF)- and a disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS-4) are important in osteoarthritis (OA) cartilage degradation. In the present study, we explored the interaction between the two proteins by examining the effect of TNF- on ADAMTS-4 expression and activity in osteoarthritic chondrocytes. Human osteoarthritic chondrocytes were treated with TNF- in different concentrations (5, 15, 30, 45 and 60 ng/ml) for different lengths of time (1, 6, 12, 18 and 24 h) with or without the TNF receptor 1 (TNFR1) inhibitor SPD304 or different kinase inhibitors. TNF- increased the ADAMTS-4 mRNA level in a statistically significant dose- and time-dependent manner within 18 h, which was reflected in the dose-dependent induction of the ADAMTS-4 promoter activity, ADAMTS-4 protein expression and ADAMTS-4 activity. SPD304 (50 M) and p38 mitogen-activated protein kinase (MAPK) siRNA and inhibitor PD169316 (25 M) completely eradicated the promoting effect of TNF- on ADAMTS-4 expression and activity. TNF- induces ADAMTS-4 expression and activity in human osteoarthritic chondrocytes at the transcriptional level via TNFR1 by a p38 MAPK-dependent mechanism. To the best of our knowledge, this is the first evidence of crosstalk between TNF- and ADAMTS-4 in relation to OA cartilage degradation, which adds novel insight into the pathophysiology of OA and cartilage degradation.