The stressed synovium
© BioMed Central Ltd on behalf of the copyright holder 2001
Received: 25 October 2000
Accepted: 7 December 2000
Published: 9 January 2001
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.
Keywordsheat shock proteins rheumatoid arthritis stress stress-activated protein kinases
Patients 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.
Under 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]. However, because cells can transduce mechanical stress into biochemical signals, numerous cellular functions can be influenced by the presence of mechanical stress.
Heat stress and heat shock protein
Heat is another physical stress factor present in the inflamed synovial membrane. Flares of disease activity based on an increased inflammatory activity lead to hyperaemia and the release of pyrogenic substances. Thus, hyperthermia is a frequent and long-known symptom of arthritis. Heat stress can induce matrix metalloproteinases , for example, which participate in tissue destruction during RA. Transduction of heat to biochemical signals has been studied for several decades and the heat shock response of cells has become a favored topic during recent years [13,14]. HSFs were discovered as signal transducers of heat stress and HSPs as the effector molecules that allow cellular adaptation to heat . The function of HSPs is to protect the folding of nascent proteins, the refolding of denatured proteins and the solubilization of protein aggregates especially under conditions of heat stress . Several multimember families of HSPs have been discovered and are characterized by their molecular mass and intracellular localization. Although heat is the most typical inducer of HSPs, other stress factors such as shear stress , oxidative stress  and proinflammatory cytokines  can also induce certain types of HSP. In comparison with the large number of investigations on autoimmunity against HSPs in RA , studies on the expression of HSPs in the synovial membrane and on the factors leading to synovial HSP expression have been rare.
HSP60 is the human homologue of mycobacterial HSP65, and the cellular and humoral autoimmune responses to both isoforms have been studied for many years in RA [21,22]. HSP60 is expressed in the synovial membrane of patients with RA  and juvenile RA ; however, the synovial tissues of normal and osteoarthritis patients also express a considerable amount of HSP60 . The predominant localizations are the synovial lining, the synovial endothelium and the cartilage–pannus junction ; in addition, synovial lymphocytes also express HSP60 . The factors leading to synovial HSP60 expression are not known, but heat is obviously not the only factor because normal and osteoarthritic synovial membranes also express this stress protein. Shear stress, for example, has been identified as an inducer of HSP60 in endothelial cells  and it is conceivable that shear stress might have a role in HSP60 expression in the synovial lining and endothelium.
The expression of HSP60 in the synovial membrane is likely to exert a protective role on stressed cells. Interestingly, rat strains resistant to adjuvant arthritis express HSP60 abundantly in the synovial membrane, whereas arthritis-prone Lewis rats fail to show a significant expression of HSP60, an observation that suggests a protective role of this molecule against arthritis . Overexpression of HSP60 might also explain the development of an autoimmune response to this protein because overexpression might go along with altered localization of this normally mitochondria-localized protein [28,29]. Similarly to HSP60 expression, the presence of an autoimmune response directed to HSP60 is associated with a protective rather than a pathogenic effect in both adjuvant and human arthritis [30,31,32].
Cytokine stress and stress-activated protein kinases
As well as physical stress factors, the synovial membrane is targeted by a number of proinflammatory cytokines, which trigger and fuel the chronic inflammatory process in the synovium by governing a variety of pathophysiological processes including cell activation, cell proliferation, tissue resorption and chemotaxis [39,40,41]. In particular, TNF-α and IL-1 have been identified as major pathogenic mediators in RA, inducing and propagating a chronic inflammatory process in the synovial membrane . Both cytokines and their receptors are overexpressed in the synovial tissue of patients with RA in comparison with degenerative joint disease [43,44,45,46], and inhibition of their action has proved to be a useful therapeutic strategy [47,48]. There is a wide range of cellular responses to TNF-α, some of which, such as proinflammatory cytokines [49,50] and metalloproteinase synthesis , chemotaxis  and the induction of apoptotic cell death , are likely to be involved in synovitis. As a consequence, the signalling pathways of TNF-α and IL-1 are complex, and several groups of intracellular signal transduction molecules participate in them. The most important of these are the NF-κB pathway , the caspase cascade  and the mitogen- and stress-activated protein kinases (MAPK/SAPKs) [56,57]. The functions of NF-κB activation and of the caspase cascades in the synovial membrane have already been described elsewhere  and will therefore not be reviewed here. We have recently focused our attention on signalling by the MAPK/SAPK pathway, which represents the cellular integration of stress signals, namely cytokines and mitogens.
Differential activation of MAPK/SAPK in the synovial subcompartments of RA
As regards the activation of JNK, its expression by mononuclear cells might reflect the production of IL-6, IL-8 and matrix metalloproteinases in situ by these cells, because JNK signals the transcriptional activation of these proteins [69,70]. In contrast, JNK activation in synovial T cells might mirror the fact that JNK is essential for T cell effector function and stimulates T cells to differentiate into a T helper 1 type . The fact that recent progress in pharmacological research has led to the development of selective inhibitors of all three MAPK/SAPK pathways will provide further insights into the role of each of these pathways in the pathogenesis of RA. Their therapeutic use is under investigation and might prove to be a new and fascinating targeted therapy .
Finally, there is experimental evidence for the presence of oxidative stress in the synovial tissue of RA. An example is thioredoxin, a cellular catalyst induced by oxidative stress, which is overexpressed in synovial cells and tissue of patients with RA . Thioredoxin, which is induced by TNF-α, acts as a co-stimulatory factor for the TNF-α-induced synthesis of IL-6 and IL-8 by synovial fibroblast-like cells . Furthermore, thioredoxin acts in a proinflammatory manner by activating the NF-κB pathway . However, 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 , and they are expressed particularly in synovial fibroblasts in the lining layer and to a smaller extent in the sublining regions. Thioredoxin reductase is an antagonist of proinflammatory thioredoxin and is also produced in situ in the synovial membrane of RA, thus counterbalancing the effects of oxidative stress and thioredoxin . As a third regulatory system, the activity of glutathione reductase is also increased in patients with RA . However, these mechanisms might not fully counterbalance oxidative stress in the synovial membrane of RA and therefore might not prevent the exposure of synovial cells to reactive oxygen products . There is experimental evidence that oxidative stress can induce mutations of key regulatory genes, including the p53 tumour suppressor gene [77,78,79]. These mutations could be part of the self-perpetuation process by which RA becomes a chronic condition.
Shear stress, heat stress, cytokine stress and oxidative stress are the hostile conditions to which cells are exposed in the synovial membrane of RA. Given that the rate of apoptotic cell death in the synovial membrane is rather low, it is obvious that synovial cells have adapted to these stressful conditions and manage to survive. Thus, the cellular response to the stress factors in the joint in general is not cell death, but instead cellular activation, proliferation and participation in a chronic inflammatory process. Signalling systems such as the p38 stress kinase pathway can drive cells into apoptotic death; however, in RA, p38 is likely to be centrally involved in synovitis, thus signalling inflammation and tissue proliferation. The resistance of synovial cells to stress is an important observation and might be associated with the expression of HSPs in the synovial tissue, which can protect the cells from apoptotic death. It seems that this balance between stress factors and the cellular stress response influences the course of synovitis to a similar extent to the balance of pro-inflammatory and anti-inflammatory mechanisms. Thus, the stress response might be an integral part in, and a significant cause of, the chronic nature of RA. Investigations into the molecular actions of stress in the inflamed joint are therefore of great importance to our better understanding of the events taking place in the synovial membrane in RA. Targeting stress pathways by specific therapies, such as inhibition of the p38 pathway, might become increasingly important and represent new and potentially effective therapeutic tools.
= extracellular signal-regulated protein kinase
= heat shock factor-1
= heat shock protein
= c-Jun amino-terminalkinase
= mitogen-activated protein kinase
= nuclear factor-κB
= rheumatoid arthritis
= stress-activated proteinkinase
= tumour necrosis factor.
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