This is the first study demonstrating the expression of resistin in synovial tissue. The intensity of resistin expression was significantly higher in the synovial sublining layer from patients with rheumatoid arthritis than those with osteoarthritis. Resistin was expressed by numerous different cell types including synovial fibroblasts, and several types of inflammatory cells residing in rheumatoid arthritis synovium such as macrophages, B lymphocytes and plasma cells, but not T lymphocytes. On the basis of both in vivo and ex vivo experiments, we could demonstrate that resistin is a secreted protein, and its increased serum levels may be directly linked to an enhanced inflammatory as well as disease activity status of patients with rheumatoid arthritis.
In mice and rats, adipose tissue and adipocytes are the major site of resistin production, whereas other tissues such as gastrointestinal tract, adrenal gland and skeletal muscles contribute less significantly.3,15
Our preliminary data on transgenic lipoatrophic A‐ZIP mice that lack white adipose tissue show that their resistin levels are markedly reduced in contrast with both wild‐type and morbidly obese ob/ob
mice (Haluzík et al
, unpublished data).16
In contrast with rodents, macrophages seem to be a major producer of resistin in humans.4
Recently, it has been suggested that resistin secreted from macrophages may represent a novel link between metabolic signals, inflammation and atherosclerosis,10,17
although some studies including our data failed to confirm this association.18
In our study, similar staining patterns and intensity for resistin were detected in the synovial lining layer in rheumatoid arthritis and osteoarthritis tissue samples, whereas there was a strikingly increased expression of resistin in the synovial sublining layer in the case of rheumatoid arthritis. We suggest that markedly increased resistin expression in rheumatoid arthritis synovium is a result of abundant accumulation of inflammatory cells in the rheumatoid arthritis synovial tissue. It has to be determined whether increased local expression of resistin precedes the development of joint inflammation in patients with rheumatoid arthritis and whether its circulating levels, synovial fluid levels and/or synovial tissue expression can be influenced by the treatment of the disease. It has been demonstrated previously that circulating levels of other adipocytokines such as leptin and adiponectin in patients with rheumatoid arthritis were not affected by treatment with biologicals.19
Resistin was expressed in numerous cell types within the synovial tissue in our study, including macrophages, which have been identified as a source of resistin by Jung et al
Here we demonstrate that other cell types such as plasma cells, B lymphocytes and synovial fibroblasts can also produce resistin. Moreover, in an ex vivo setting, we were able to show much higher resistin levels in eluates from rheumatoid arthritis in contrast with osteoarthritis synovial tissue samples when incubated with PBS. These findings support the idea that resistin may represent a novel secreted signalling molecule, that could be involved in the activation of the above‐mentioned cell types during chronic inflammatory processes such as rheumatoid arthritis. We have previously shown that other inflammatory conditions such as hepatitis C or B also significantly increase circulating resistin levels.20
Resistin was originally discovered as a potential link between obesity and insulin resistance in rodents, and its role, especially in the development of liver insulin resistance has been clearly documented by later experimental studies.21
On the contrary, its exact pathophysiological role in humans is still a matter of debate. Our data, together with previously published papers, suggest that in humans resistin is more directly related to inflammation, whereas its relationship with insulin resistance has been documented only in some but not in all studies. For example, it was shown that, in vitro, resistin expression can be upregulated upon proinflammatory stimuli.9,12
Moreover, several inflammatory markers correlated well with plasma resistin levels in patients with metabolic disorders.10
In our study, serum resistin postitively correlated with ESR and CRP, but not with other pro‐inflammatory cytokines such as IL6, IL8, TNFα or MCP‐1. While synovial fluid resistin levels in patients with rheumatoid arthritis were markedly higher than its serum counterparts, the opposite was true for another adipocytokine leptin. Leptin concentrations were higher in systemic circulation than locally in synovial fluid, and it was related neither to resistin levels nor to other proinflammatory markers in body fluids from patients with rheumatoid arthritis. In agreement with Schäffler et al
we found significantly higher levels of resistin in the synovial fluid in the case of rheumatoid arthritis than in the case of osteoarthritis. Interestingly, we also detected higher serum resistin levels in patients with rheumatoid arthritis in contrast with control patients with osteoarthritis. This finding is in disagreement with recently published data12,22
showing no significant difference in blood resistin levels between patients with rheumatoid arthritis and healthy controls. The explanation for higher resistin levels in patients with rheumatoid arthritis from our study group may lie in the fact that our group consisted of patients with rheumatoid arthritis with more severe disease course as measured by acute‐phase reactants and disease activity score. This is further supported by our finding that serum resistin levels correlated not only with inflammatory status (ESR, CRP) but also with the clinical disease activity (DAS28) in patients with rheumatoid arthritis. On the other hand, we did not see a significant relationship between increased synovial fluid resistin and inflammatory markers as shown previously.11,12
Furthermore, we did not confirm speculations that serum resistin levels would be reflected by those in synovial fluid in inflammatory arthritides.23
Taken together, it can be concluded that the joint compartment represents a major site of resistin production in patients with rheumatoid arthritis. Resistin levels in synovial fluid might reflect both the intensity of the inflammatory infiltrates within synovial tissue and the number of inflammatory cells within the synovial fluid. Since rheumatoid arthritis represents a condition with polyarticular involvement, we suggest that serum resistin levels could be more relevant to systemic inflammation and/or disease activity, whereas synovial fluid resistin reflects the particular inflammatory process of the affected joint.
Adipose tissue in males expresses higher levels of resistin than in females as shown in animal models.3
However, we did not find any influence of sex or age with regard to the resistin levels in human body fluids, which is in agreement with the previous study by Schäffler et al
Although we observed no influence of BMI on resistin levels, it can support the idea that resistin may be the link to inflammatory processes rather than to obesity or insulin resistance in humans. Moreover, numerous hormonal factors including glucocorticoids can regulate resistin levels. As glucocorticoids can increase resistin production,25
we could speculate that the increased resistin level in patients with rheumatoid arthritis is the result of glucocorticoid treatment. To further assess the possible influence of glucocorticoids on resistin level, we compared the subgroups with and without glucocorticoid treatment and found no significant differences between these two groups in terms of resistin levels. We thus suggest that mechanism(s) other than stimulation by exogenous glucocorticoids is (are) responsible for the increase of resistin levels in patients with rheumatoid arthritis. With regard to the recently published data by Bokarewa et al
the role of proinflammatory cytokines and a positive feedback loop (resistin itself) can be hypothesised as a cause for the upregulation of resistin under inflammatory conditions such as rheumatoid arthritis. Furthermore, exogenous resistin induced NF‐κB activation, resulting in a strong upregulation of proinflammatory cytokines such as TNFα or IL6, and, when injected into healthy murine joints, induced synovial pannus formation and cartilage destruction.12
It has to be noted that the present study has several limitations. Firstly, it was designed as a cross‐sectional study with a relatively low number of enrolled patients, and hence the role of DMARDs on the resistin levels in follow‐up could not be determined due to this cross‐sectional character. Secondly, the synovial tissue samples were obtained at the time of both arthroscopy and open joint surgery in our study. As recent work showed increased cell infiltration, expression of proinflammatory cytokines, matrix‐degrading enzymes and growth factors in synovium obtained by arthroscopy in contrast with end stage destructive rheumatoid arthritis synovium obtained by total joint replacement,26
the possible influence of the tissue harvesting procedure on resistin expression has also to be taken into account.
In summary, we have shown markedly increased production of resistin at local sites of inflammation such as synovial tissue and synovial fluid in patients with rheumatoid arthritis. This local overproduction of resistin was also reflected by increased circulating resistin levels in patients with rheumatoid arthritis compared with those with osteoarthritis. Resistin was produced not only by activated macrophages but also by synovial fibroblasts and several other inflammatory cell types. The link between increased serum resistin, inflammation and disease activity of rheumatoid arthritis suggests a role of resistin as a novel proinflammatory mediator and supports the idea that, except for adiponectin,27
resistin may also play a role in chronic joint inflammatory diseases.