Volume 1 Supplement 1
Role of Cytokines in Cartilage Destruction in Experimental Arthritis
- Wim B van den Berg1
© Current Science Ltd 2000
Published: 15 November 1999
Rheumatoid arthritis (RA) is characterized by major destruction of the articular cartilage. The mediators TNFα and IL-1 probably play a major role in RA. Following studies in experimental murine arthritis models, using neutralising antibodies and scavenging receptors, it became clear that TNF is a major inflammatory cytokine, whereas IL-1 is the main destructive cytokine. These observations were recently confirmed using TNF and IL-1 knock-out mice. Remarkably, arthritis in TNF-deficient mice was strongly reduced, and yet ongoing cartilage destruction was still noted. In contrast, cartilage destruction was minimal in IL-1β knock-out mice.
Apart from inhibition of IL-1, major therapeutic benefit can be achieved with IL-4 and IL-10 treatment. These cytokines reduce IL-1 levels and relatively enhance IL-ra. Local gene transfer with adenoviral IL-4 constructs revealed major protection against cartilage and bone erosions in experimental arthritis despite marked inflammation.
Stromelysin seems a pivotal enzyme involved in cartilage breakdown. It is not an essential MMP in the early proteoglycan loss, and a major role for aggrecanase seems obvious. However, stromelysin seems crucial in collagenase activation and collagen breakdown, and irreversible cartilage erosion is markedly reduced in arthritis in stromelysin knock-out mice. Induction of stromelysin-induced neoepitopes and late destruction can be blocked with IL-1 neutralization.
- Van den Berg WB: Joint inflammation and cartilage destruction may occur uncoupled. Springer Semin Immunopathol. 1998, 20: 149-164. 10.1007/BF00832004.PubMedView ArticleGoogle Scholar
- Van Meurs JBJ, van Lent PLEM, Singer II, Bayne EK, van de Loo FAJ, van den Berg WB: IL-1ra prevents expression of the metalloproteinase-generated neoepitope VDIPEN in antigen-induced arthritis. Arthritis Rheum. 1998, 41: 647-656. 10.1002/1529-0131(199804)41:4<647::AID-ART11>3.3.CO;2-K.PubMedView ArticleGoogle Scholar
- Joosten LAB, Helsen MMA, van de Loo FAJ, van den Berg WB: Anti-cytokine treatment of established type II collagen-induced arthritis in DBA/1 mice: a comparative study using anti-TNFα, anti-IL-1α/β, and IL-1ra. Arthritis Rheum. 1996, 39: 797-809.PubMedView ArticleGoogle Scholar
- Lubberts E, Joosten LAB, van den Bersselaar L, et al: Adenoviral vector-mediated overexpression of IL-4 in the knee joint of mice with collagen-induced arthritis prevents cartilage destruction. J Immunol. 1999, 163: 4546-4556.PubMedGoogle Scholar