Pathways by which interleukin 17 induces articular cartilage breakdown in vitro and in vivo

Overexpression of interleukin (IL-)17 has recently been shown to be associa ted with a number of pathological conditions. Because IL-17 is found at hig h levels in the synovial fluid surrounding cartilage in patients with infla mmatory arthritis, the present study determined the direct effect of IL-17 on articular cartilage. As shown herein, IL-17 was a direct and potent indu cer of matrix breakdown and an inhibitor of matrix synthesis in articular c artilage explants. These effects were mediated in part by leukemia inhibito ry factor (LIF), but did not depend on interleukin-1 activity. The mechanis m whereby IL-17 induced matrix breakdown in cartilage tissue appeared to be due to stimulation of activity of aggrecanase(s), not matrix metalloprotei nase(s). However, IL-17 upregulated expression of matrix metalloproteinase( s) in chondrocytes cultured in monolayer. In vivo, IL-17 induced a phenotyp e similar to inflammatory arthritis when injected into the intra-articular space of mouse knee joints. Furthermore, a related protein, IL-17E, was fou nd to have catabolic activity on human articular cartilage. This study char acterizes the mechanism whereby IL-17 acts directly on cartilage matrix tur nover. Such findings have important implications for the treatment of degen erative joint diseases such as arthritis. (C) 2001 Academic Press.