Lessons for joint destruction from animal models

Abstract

There is growing evidence that tumor necrosis factor-alpha is involved in onset of arthritis, whereas the cartilage destructive process is mainly interleukin-1 driven. Moreover, direct generation of interleukin-1 may occur in the absence of tumor necrosis factor action. This is shown in various arthritis models using neutralizing antibodies, receptor antagonists, and soluble receptors, and similar proof has been provided in cytokine-targeted transgenic and knockout mice. Further evidence for local impact of interleukin-1 is obtained from gene transfer of interleukin-1 receptor agonist to joint tissues, whereas these experiments also underline the therapeutic applicability of this approach. In addition to tumor necrosis factor-alpha and interleukin-1 action, the destructive process appears to be under the control of mediators such as interleukin-6 and -10. Marked cartilage protection can be achieved with additional treatment with interleukin-4 and -10. These modulatory studies also underline the potential uncoupling of inflammatory and destructive processes. Although T cells may drive arthritic processes, it is clear that fibroblasts can cause major destruction in the absence of T cells. Insight in pivotal enzymes primarily involved in cartilage destruction is still limited.