High levels of serum IL-18 promote cartilage loss through suppression of aggrecan synthesis.

Osteoarthritis (OA) is closely related to the function of several inflammatory cytokines. It has been reported that older age is associated with higher serum levels of the inflammatory cytokine IL-18. In the present study, we investigated the long-term role of serum IL-18 in cartilage loss in vivo using a new strain of IL-18 transgenic mouse (Tg) in comparison with wild-type (WT) mice. The IL-18 Tg mouse strain we developed constitutively overproduces soluble mature IL-18 in the lungs but not in other tissues, including joints. These Tg mice showed high levels of serum IL-18, but not IL-1beta. No inflammatory cells, fibrillation or synovitis were observed in the knee joints of either IL-18 Tg or WT mice. However, the cartilage cellularity of the femoral and tibial condyles of IL-18 Tg mice was significantly reduced in comparison with control WT mice. Aggrecan was detected in only a few cells in the deep zone of the articular cartilage of Tg mice. The expression of aggrecan mRNA was also significantly decreased in articular chondrocytes from Tg mice when compared with WT mice. In contrast, endogenous IL-18 mRNA was significantly increased in the chondrocytes of Tg mice in comparison with WT mice. Expression of IFN-gamma was also significantly increased in the Tg mice. Moreover, IL-18 transgene-positive caspase-1-deficient mice showed articular cartilage loss that was independent of endogenous IL-1beta. In cultured chondrocytes isolated from WT mice, the expression of aggrecan mRNA was dosage-dependently suppressed by treatment with recombinant IL-18. In contrast, IL-18 stimulated the expression of mRNA for endogenous IL-18 and IFN-gamma. These results suggest that high levels of serum IL-18 promote the overexpression of endogenous IL-18 in articular chondrocytes, resulting in cartilage loss through suppression of aggrecan synthesis. Thus IL-18 may play an important role in the pathogenesis of articular cartilage loss in osteoarthritis.