The stressed synovium

Abstract

ERK = extracellular signal-regulated protein kinase; HSF-1 = heat shock factor-1; HSP = heat shock protein; IL = interleukin; JNK = c-Jun aminoterminal kinase; MAPK = mitogen-activated protein kinase; NF-κB = nuclear factor-κB; RA = rheumatoid arthritis; SAPK = stress-activated protein kinase; TNF = tumour necrosis factor. Available online http://arthritis-research.com/content/3/2/080 IntroductionPatients with rheumatoid arthritis (RA) are confronted with a multitude of stressful events during the course of their disease. Flares of disease activity with joint pain, swelling and stiffness, progressive damage and subsequent loss of function are hallmarks of RA. These features of chronic inflammation and destruction lead to a harassed and stressed rather than a relaxed life for the patients and their joints. At the microscopic and molecular level of disease, this 'stressful life' must have its counterparts. Understanding the cellular integration of stressful stimuli is of increasing importance and ought to be undertaken in these days of molecular medicine, because it might constitute at least part of the underlying pathogenetic events and thus permit new insights. Mechanical stressUnder normal physiological conditions the synovial space is one of the most heavily pressured areas in the body. In diseases such as inflammatory arthritis the local conditions can deteriaorate. Several classical stress factors are present in the synovial cavity and these stimuli are likely to influence the function of the cells in the synovial membrane. As in the walls of blood vessels, the synovial cavity is exposed to a high degree of mechanical stress under both normal and pathological conditions. Besides mechanical stress due to the load of body weight, which affects predominantly the joint cartilage, mechanical stress following shear forces is also present. In particular the motion of the synovial fluid during exercise induces shear forces whose biophysics has been studied in detail [1,2]. CommentaryThe stressed synovium AbstractThis 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, mitogenactivated 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.

Increased Levels of IgG Antibodies against Human HSP60 in Patients with Spondyloarthritis

“…Likewise, increased expression of human HSP60 in the synovium of patients with rheumatoid arthritis has been demonstrated [24], [46]. A similar upregulation is likely to happen in the synovium of SpA patients, which could be the explanation of the increased levels of antibodies against human HSP60 in SpA patients compared with healthy controls seen in the current study.…”

Expression of Toll‐like receptors 2 and 4 in rheumatoid synovial tissue and regulation by proinflammatory cytokines interleukin‐12 and interleukin‐18 via interferon‐γ

“…It was recently demonstrated that these endogenous ligands (natural adjuvants) can activate dendritic cells in conditions of cell stress and/or structural cell damage, leading to primary immune responses and initiation of autoimmunity (13, 39, 40). Consistent with this scenario, several pathways of stress‐signaling molecules are found to be activated in the synovial membrane and fluid of RA patients (41). It is conceivable that these local endogenous ligands activate TLR‐2– and TLR‐4–bearing dendritic cells, macrophages, and fibroblasts, which leads to an increased secretion of proinflammatory cytokines such as IL‐12, IL‐18, IL‐1, and TNFα.…”

Molecular and cellular basis of rheumatoid joint destruction

“…These pathways are found to be activated in the synovial tissue of RA patients and induced by pro-inflammatory cytokines [49]. In particular, the p38␣ has been localized in synovial macrophages, but not in RA-SF, which preferentially express the ␤ (in the lining and sublining) and ␦ isoforms (at sites of joint destruction).…”