Signal transduction networks in rheumatoid arthritis.(Report)

Signal transduction pathways regulate cellular responses to stress and play a critical role in inflammation. The complexity and specificity of signalling mechanisms represent major hurdles for developing effective, safe therapeutic interventions that target specific molecules. One approach is to dissect the pathways methodically to determine their hierarchy in various cell types and diseases. This approach contributed to the identification and prioritisation of specific kinases that regulate NF-[kappa]B and the mitogen activated protein (MAP) kinase cascade as especially attractive targets. Although significant issues remain with regard to the discovery of truly selective kinase inhibitors, the risks that accompany inhibition of fundamental signal transduction mechanisms can potentially be decreased by careful dissection of the pathways and rational target selection.

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In the late 1980s, the cytokine profile of rheumatoid arthritis (RA) was considered so complex and redundant that the notion of anticytokine therapy appeared remote. Through the considerable effort of many investigators, the cytokine network of RA was gradually unravelled. A degree of order was introduced with the recognition that certain cytokines were potential targets for therapeutic intervention. Great consternation ensued when contemplating the possibility of blocking key cytokines because of the potential for untoward or even catastrophic sequelae. Perhaps the price of success in RA would be too high if critical cytokines were inhibited? Perhaps the cytokine network would be so redundant that inhibition of single factors would be doomed to failure?

Of course, we now know the answers to some of these questions. Selective inhibitors of specific cytokines, most notably tumour necrosis factor [alpha] (TNF[alpha]), were introduced with considerable success. Attention has now turned to other targets in an effort to build on the success of anticytokine therapy. However, these approaches have generally focused on biological agents that are selective for a single factor and must be parenterally administered. More recently, we have directed efforts towards signal transduction pathways because of the possibility of developing oral agents that can regulate the production of an array of cytokine targets. Like cytokine binding proteins introduced several years ago, significant concerns about safety must be considered. The hope is that careful analysis of the signal transduction networks of RA, like cytokine networks, will disclose an organisational hierarchy that can be addressed by highly selective inhibitors.

Multiple signal transduction pathways have been carefully investigated in RA. For instance, elegant studies in rodent models of arthritis suggest that SOCS or JAK-STAT systems can be targeted with gene constructs that express either wild-type or dominant negative proteins. (1) NF-[kappa]B and mitogen activated protein (MAP) kinases are also attractive pathways for intervention in light of their ability to regulate many genes involved in immune responses. (2 3) The enormous diversity of kinases that modulate these and other transduction mechanisms suggests that complex and interrelated events are involved in inflammatory disease.

NF-[kappa]B AS A THERAPEUTIC TARGET

Proof of concept studies demonstrating the use of signal transduction blockade in RA are still in their formative stage. However, understanding the regulation of NF-[kappa]B is an example of how dissecting the pathway can identify the key proteins that can subsequently be targeted. NF-[kappa]B is abundant in rheumatoid synovium, and immunohistochemical analysis demonstrates p50 and p65 NF-[kappa]B proteins in the nuclei of cells in the synovial intimal lining. (4 5) Although the proteins can also be detected in osteoarthritis (OA) synovium, NF-[kappa]B activation is much greater in RA because of phosphorylation and degradation of its natural inhibitor, IkB, in RA intimal lining cells. Nuclear translocation of NF-[kappa]B in cultured fibroblast-like synoviocytes occurs rapidly after stimulation by interleukin (IL)1 or …