Role of Cytokines in Cartilage Destruction in Experimental Arthritis

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.