The stressed synovium

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.

Figure 1

Activation of synovial fibroblast-like cells by heat shock factor. Gel mobility-shift assay of heat shock factor (HSF)-1 DNA binding in human synovial fibroblast-like cells. HSF-1/DNA complexes are not present in unstimulated cells (control), whereas shear stress, and also heat stress, lead to a strong increase in the DNA-binding activity of HSF-1. Specific binding can be blocked by an excess of unlabelled oligonucleotide; unlabelled oligonucleotide inhibition (COI) is the ratio of unlabelled to labelled oligonucleotide (50:1, 10:1 and 1:1).

Figure 2

Expression of hsp70 (a) and phosphorylated p38 protein kinase (b) in the synovial-lining layer. Immunohistochemistry of synovial membranes of patients with RA shows a hypertrophic synovial-lining layer. (a) Immunostaining for heat shock protein (HSP)70; (b) staining for phosphorylated p38 protein kinase (brown). Both molecules show strong expression in the synovial-lining layer of patients with RA.

Figure 3

Expression of phosphorylated p38 protein kinase and ERK protein kinase in synovial microvessels. Immunohistochemistry of synovial microvessels of patients with RA show the expression of phosphorylated p38 protein kinase in synovial endothelial cells (a). In contrast, the phosphorylated ERK protein kinase (b) is not expressed by synovial endothelial cells but by cells surrounding the synovial microvessel.

Figure 4

Expression of phosphorylated p38 protein kinase and transcription factor ETS-1 in synovial microvessels and synovial endothelial cells. Immunohistochemistry of synovial microvessels (a,c) and synovial endothelial cells (b,d) of patients with RA shows the expression of phosphorylated p38 protein kinase (a,b) and ETS-1 transcription factor (c,d) in the endothelium of synovial microvessels.