Introduction

Rheumatoid arthritis (RA) is a chronic systemic autoim- mune and destructive disorder characterized by synovial hyperplasia and progressive damage to the articular struc- ture in most patients, which can lead to deformity and dys- function [1]. Inflammatory cell recruitment and high con-n centrations of proinflammatory cytokines in the synovial fluid and circulation of RA patients are some crucial path- ogenic causes [2]. Numerous etiologies including genetic and environmental factors are responsible for this disease [3]. As atherosclerosis occurs faster than usual or sooner than expected in RA patients, factors like adipocytokine have been considered in its pathogenesis. Adiponectin is a multifunction cytokine that is secreted from adipocytes. It plays a central metabolic role by its insulin sensitivity and anti-atherogenic effects. On the other hand, the influence of adiponectin on immune response is still controversial because of its pro- and anti-inflammatory properties [3]. Recently, several studies have suggested that adipocytes have the potential to secrete proinflammatory  molecules, complement factors, signaling molecules, growth factors, and adhesion molecules [4-7] which can cause tissue in-] flammation. Adiponectin may have an important role in the pathogenesis of RA because of the similarity of its  two receptors with tumor necrosis factor alpha (TNF_a) [8,9]. Serum and synovial levels of adiponectin were in-e creased in RA patients. It has been shown that adiponectin has a positive correlation with the serum levels of certain inflammatory cytokines such as VEGF, MMP, TNF-a, IL-1ß, IL-6, and IL-8 which are secreted from synovial fibroblasts because of the proinflammatory effect of adi- ponectin on creating synovitis and its dissociative effect in the intracellular matrix in RA [10,11]. However, the exact role of adiponectin in RA remains unknown because of conflicting reports about its function [10,  12-15].

With regard to the proinflammatory effects of adiponec- tin, in this study, adiponectin levels in the serum and syn- ovial fluid of RA patients were measured and compared with those of OA patients as the control  group.

Table 1. Clinical and Demographic Parameters in Patients with RA and OA

Table 2. Correlation between serum and synovial fluid adiponectin levels and their clinical and laboratory data in RA and OA patients.

Discussion

The majority of research investigating the role of ad- iponectin in inflammation has pointed out that the level  of this cytokine increases during an inflammatory process [13-17]. However, other studies have reported paradoxical effects of adiponectin on inflammation [18-20]. The presa- ent study determined the concentration of adiponectin in matched serum and synovial fluid samples of patients with rheumatoid arthritis and compared them with the same val- ues in individuals with osteoarthritis to evaluate its role in RA. The results demonstrated increased adiponectin levels in the serum and synovial fluid of RA patients compared to OA patients, which is in agreement with most similar studies [13-17]. It was also found that in RA patients, adA- iponectin concentration was markedly higher in serum than in synovial fluid. This could be justified by the higher amounts of peripheral fat stores which secrete adiponectin into the blood stream [14].

In accordance with the study of Schaffler et al. [13], the current study found adiponectin levels in the synovial fluid of RA patients were around seven times higher than those in OA patients. However, the serum level of adiponectin in RA patients was twice as high as that of the controls. This difference may be due to the greater production of this factor in synovial fluid than in serum under inflam- matory conditions. In vitro studies have shown that under inflammatory conditions, besides fat tissue, adiponectin can be produced by all knee structures, including the in- frapatellar adipose tissue, osteophytes, cartilage, and bone [14]. The main cells that are responsible for the secretion of adiponectin are adipocytes, osteoblasts, synovial fibro- blasts, and skeletal muscle cells [21-23]. Furthermore, the most important factor in adiponectin secretion is the stim- ulation of inflammatory cytokines and oxidative stress in those aforementioned parts  [14]. Lee et al. demonstrated that adiponectin and IL-1β may act synergistically on the production of proinflammatory mediators such as IL-6, IL-8, and PGE2 in inflammatory arthritic joints [4]. In their recent study, they suggested that the role of adiponectin is more important than that of IL-1β in the production of IL-6 and IL-8 in endothelial cells at their physiological concentrations [7]. The assessment of DAS activity in RA patients showed no correlation between adiponectin levels and disease ac- tivity; this could be due to the small number of patients in each group. Corresponding to the present findings, Targonska et   al. [10] in 2010 reported a positive correlation between serum and synovial fluid adiponectin levels and disease duration in RA patients. Different factors may have a role in the rise of adiponectin level in long term RA, e.g. rheumatoid cachexia, early atherosclerosis, and progression of the disease [24]. On the other hand, some investigations indicate that the rise in adiponectin level in RA acts as a protecting factor against the atherosclerotic effects of longstanding disease [25-28].

Similar to the current findings, several studies have re- ported no correlation between adiponectin levels and BMI in RA patients [14, 25, 26]. This may be related to the ex-s clusion of patients with a BMI>30 from the current study. Moreover, certain investigations on different inflammato- ry and autoimmune diseases have shown no relationship between adiponectin level and BMI [14]. This result can also suggest that the regulation of the serum level of adi- ponectin is complex, and weight is not the only major reg- ulatory factor. Nevertheless, no association between adiponectin and systemic inflammatory markers such as CRP or ESR was observed in the current study, which is in agreement with other related studies [14, 15, 21, 22]. Moreover, no corre- lation between adiponectin levels and ACPA was found in the current study, which may be due to the higher produc- tion of adiponectin in synovial fluid rather than serum with a smaller effect on systemic factors.

In their study, Honsawek and Chayanupatkul also meas- ured adiponectin concentrations in plasma and synovial fluid of patients with knee OA and examined the correla- tion between adiponectin levels and disease severity. They discovered that adiponectin levels in both plasma and syn- ovial fluid were reduced significantly as the severity of OA increased. These findings imply that adiponectin may have a protective role in OA. More studies are needed in order to gain further understanding of the potential utili-  ty of adiponectin as a biochemical determinant of disease progression and prognosis  [29].

In conclusion, the present study showed higher amounts of adiponectin in systemic circulation compared to synovi- al fluid. However, its higher level in the synovial fluid of RA patients compared with OA patients suggests that local inflammation may have a role in this elevation. On the other hand, its high level in the synovial fluid of RA patients might be due to the high serum levels and dis- ease activity. Therefore, it could not be proven with cer- tainty that adiponectin is a marker of local inflammation in RA. In comparison to OA, this study suggested a higher Sf/serum ratio of adiponectin in RA samples. That finding could be a consequence of higher inflammation or the in- flammatory role of adiponectin in RA. To date, different clinical and experimental studies have been performed on adiponectin activity, and our knowledge regarding this factor is increasing. A better understanding of the genetic basis of adiponectin in different diseases and the cellular events developing in these conditions can enhance our knowledge leading to the administration of new methods and better treatment of such cases. Larger studies are still needed to further clarify the poten- tial influence of adiponectin on disease outcome.