JOINT INFLAMMATION AND CARTILAGE DESTRUCTION MAY OCCUR UNCOUPLED

Chronic arthritis is characterized by a persistent joint inflammation and concomitant joint destruction. Although the joint swelling is a ma jor clinical problem, destruction of bone and cartilage may occur unco upled to inflammation and it is of utmost importance to fully understa nd the elements of the destructive process. TNF and IL-1 are considere d master cytokines in the process of human RA, with a claimed cascade of TNF inducing most of the IL-l production. Studies in experimental m odels revealed that TNF is indeed a pivotal cytokine in joint swelling , yet IL-1 is the dominant cartilage destructive cytokine and its prod uction may occur independent of TNF. This was found with anti-TNF/IL-1 neutralizing antibodies and the observations were re cently backed up with similar data in arthritis models in TNF and IL-1 knockout mice. Apart from the absolute level of IL-1, the destructive potential of an arthritis is determined by the balance with regulatory cytokines and anabolic growth factors. IL-4, IL-6, and IL-10 can promote inflammatio n and tissue fibrosis, yet cartilage destruction is found to be greatl y reduced by these cytokines, linked to a range of pathways which can reduce the IL-1 impact on the articular cartilage. Finally, the presen ce of anabolic growth factors in the inflamed synovium may have a majo r impact on net destruction. Endogenous transforming growth factor-bet a (TGF-beta) is found in inflamed synovia, but local coadministration of TGF-beta further enhanced the degree of synovitis, yet almost fully prevented cartilage damage, providing another example of a major lack of correlation between inflammatory mass and destructive potential. I t is suggested that novel therapy in RA patients should not only focus on reduction of outer signs of joint inflammation, but should also in clude attempts at reduction of cartilage destruction.