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.