The stressed synovium.

Georg Schett,Günter Steiner,Josef Smolen,Makiyeh Tohidast-Akrad

doi:10.1186/ar144

Abstract

This review focuses on the mechanisms of stress response in the synovial tissue of rheumatoid arthritis. The major stress factors, such as heat stress, shear stress, proinflammatory cytokines and oxidative stress, are discussed and reviewed, focusing on their potential to induce a stress response in the synovial tissue. Several pathways of stress signalling molecules are found to be activated in the synovial membrane of rheumatoid arthritis; of these the most important examples are heat shock proteins, mitogen-activated protein kinases, stress-activated protein kinases and molecules involved in the oxidative stress pathways. The expression of these pathways in vitro and in vivo as well as the consequences of stress signalling in the rheumatoid synovium are discussed. Stress signalling is part of a cellular response to potentially harmful stimuli and thus is essentially involved in the process of synovitis. Stress signalling pathways are therefore new and promising targets of future anti-rheumatic therapies.

Highlights

Patients with rheumatoid arthritis (RA) are confronted with a multitude of stressful events during the course of their disease
We have recently focused our attention on signalling by the mitogen-activated protein kinases (MAPKs)/SAPK pathway, which represents the cellular integration of stress signals, namely cytokines and mitogens
Heat stress, cytokine stress and oxidative stress are the hostile conditions to which cells are exposed in the synovial membrane of RA

Summary

Introduction

Patients with rheumatoid arthritis (RA) are confronted with a multitude of stressful events during the course of their disease. The differential synovial expression of stress signalling pathways (Table 1) underlines the variability of cellular responses to stress factors in different subcompartments of the synovial membrane Cytokines such as TNF, IL-1 and IL-6 have been demonstrated to be the major inducers of all three stress kinases in human synovial cells; several other factors, such as growth factors in ERK signalling, heat stress in p38 signalling, and other cytokines such as fibroblast growth factor and vascular endothelial growth factor might have additional roles. Several mechanisms of antioxidative functions are present in the synovial membrane of RA: metallothioneins are cytosolic proteins protecting cells from metal toxicity and oxidative stress [75], and they are expressed in synovial fibroblasts in the lining layer and to a smaller extent in the sublining regions. These mechanisms might not fully counterbalance oxidative stress in

Conclusion

Hlavacek M

14. Schlesinger MJ