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 associated with a number of pathological conditions. Because IL-17 is found at high levels in the synovial fluid surrounding cartilage in patients with inflammatory arthritis, the present study determined the direct effect of IL-17 on articular cartilage. As shown herein, IL-17 was a direct and potent inducer of matrix breakdown and an inhibitor of matrix synthesis in articular cartilage explants. These effects were mediated in part by leukemia inhibitory factor (LIF), but did not depend on interleukin-1 activity. The mechanism whereby IL-17 induced matrix breakdown in cartilage tissue appeared to be due to stimulation of activity of aggrecanase(s), not matrix metalloproteinase(s). However, IL-17 upregulated expression of matrix metalloproteinase(s) in chondrocytes cultured in monolayer. In vivo, IL-17 induced a phenotype similar to inflammatory arthritis when injected into the intra-articular space of mouse knee joints. Furthermore, a related protein, IL-17E, was found to have catabolic activity on human articular cartilage. This study characterizes the mechanism whereby IL-17 acts directly on cartilage matrix turnover. Such findings have important implications for the treatment of degenerative joint diseases such as arthritis.
Cai
L
L
Department of Molecular Oncology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Yin
J P
JP
Starovasnik
M A
MA
Hogue
D A
DA
Hillan
K J
KJ
Mort
J S
JS
Filvaroff
E H
EH
D000818:Animals; D015153:Blotting, Western; D002358:Cartilage, Articular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002417:Cattle; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism; D046508:Culture Techniques; D016207:Cytokines / Q000494:pharmacology; D010450:Endopeptidases / Q000378:metabolism; D005260:Female; D007270:Injections, Intra-Articular; D020381:Interleukin-17 / Q000494:pharmacology*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000502:physiology; D010329:Patella / Q000378:metabolism; D011509:Proteoglycans / Q000187:drug effects / Q000378:metabolism; D013552:Swine; D015854:Up-Regulation
D016207:Cytokines; D020381:Interleukin-17; D011509:Proteoglycans; D009569:Nitric Oxide; D010450:Endopeptidases; D020782:Matrix Metalloproteinases; C083641:aggrecanase