Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease with approximately 1 % prevalence among adults [
55]. It is characterized by symmetrical synovitis, pannus formation, joint pain, stiffness, swelling, and destruction. The presence of RA is associated with an increased risk of the development of cardiovascular, neurological, and metabolic disorders [
56]. Although, in recent years, the state of knowledge concerning the pathogenesis of RA has dramatically increased, the detailed mechanisms underlying this disease remain poorly understood, and therefore, the factors responsible for the onset and progression of this disorder are the subject of intense research. Undoubtedly, an important role is played by pro-inflammatory cytokines, particularly by TNFα, IL-1β, and IL-6 [
55]. Taking into consideration the fact that articular and synovial AT is an inseparable component of human joints, local and systemic dysfunction in the synthesis, release, and receptor action of adipocyte-derived proteins was the aim of some recently published studies.
Leptin
It is assumed that Th1/Th2 imbalance plays an important role in the development of RA with a postulated detrimental role of an increased Th1 response in this disorder [
57]. Leptin has been suggested to participate in modulating inflammation response through the induction of Th1 production of pro-inflammatory cytokines. Nevertheless, it is still poorly investigated whether leptin directly induces adipose tissue resident macrophages to release cytokines. On the other hand, pro-inflammatory cytokines raise circulating leptin levels, while in animal models leptin enhances the release of IL-6, IL-12, and TNFα from peritoneal macrophages [
13], and TNFα from synovium, which suggests the existence of a local positive feedback between cytokines and leptin in joint tissues [
58].
Most of the experimental studies conducted to date suggest a pro-inflammatory rather than protective action of leptin in joint inflammatory disorders (Table
1). Several studies confirm the protective impact of leptin deficiency on antigen-induced arthritis and a stimulatory effect of leptin on NO production [
14,
58,
59]. Taking into consideration a well-documented degenerative effect of NO on joint cartilage, evoking the loss of chondrocyte phenotype, inducing chondrocyte apoptosis, and increasing activation of metalloproteases [
60], an increase in leptin levels may deteriorate joint inflammation via the local generation of excessive amounts of NO. Surprisingly, the finding that the administration of exogenous leptin elevates IGF-1 and TGFβ secretion by rat knee joint cartilage may suggest that increased plasma leptin levels in obesity protect cartilage against degeneration [
12]. Treatment with leptin in animal models of septic arthritis reduced the severity of joint damage, which may indicate that leptin in the synovial cavity exerts a protective effect against RA-induced joint destruction [
61]. Regrettably, the results of the latter study were affected by a number of problems limiting their interpretation, that is, cross-sectional character of the study, which did not provide any information on the role of leptin in the course of the disease; assessment of the disease activity based only on plasma CRP levels; and lack of information about the body mass index of the subjects studied [
62].
Table 1
Effect of adipokines on arthritis and non-arthritis joint tissues
Leptin | Leptin deficient ob/ob mice with antigen-induced arthritis | Less severe arthritis compared with control mice | |
Reduction of T cell proliferation |
Decrease in interferon-γ production |
Lower levels of IL-1β and TNFα mRNA in the synovium of arthritis knees |
ATDC5 mouse embryonic cells and human articular chondrocytes | Induction of NO-synthase expression and NO production in articular cartilage and synovium during treatment with leptin and interferon-γ | |
Induction of NO production after leptin and IL-1 administration (mediated by PI-3 kinase, MEK-1, and p-38 kinase pathways) | |
Adiponectin | Rheumatoid synovial cells culture | Strong expression of adiponectin mRNA in synovial fibroblasts and articular adipose tissue | |
Induction of IL-8 expression | |
Resistin | NMRI mice with intra-articularly injected resistin | Development of arthritis with hypertrophy of the synovial layer and pannus formation | |
Despite generally consistent results of animal investigations, suggesting pro-inflammatory implications of leptin in the pathogenesis of RA, the data obtained from clinical studies are not so unambiguous. There are several studies that showed significantly elevated concentrations of leptin in patients with RA [
61,
63‐
66]. Otero et al. [
55] observed that plasma leptin levels increased markedly in patients with RA, independently of BMI value, while Targonska-Stepniak et al. [
65] noted elevated leptin serum concentrations in patients with higher disease activity evaluated by DAS 28, ESR, and the number of tender joints. Also, Bokarewa et al. [
66] reported elevated plasma leptin in RA, though no adjustment for BMI was made in this study. It was also noted that plasma concentrations of leptin were significantly higher than synovial fluid leptin, and this difference was particularly evident in non-erosive arthritis [
66].
Although the majority of studies revealed high systemic and local leptin levels in patients and animals with RA, some other studies did not support these results. Anders et al. [
67] found no differences between serum levels of this adipokine in RA and healthy subjects. A fasting-induced decrease in circulating leptin in RA patients was associated with CD4+ lymphocyte hyporeactivity and increased IL-4 serum concentration [
68]. Reduced serum leptin levels in fasting RA patients resulted in a potentially beneficial shift toward Th2 cytokine production [
7], increased insulin sensitivity, and rise in glucagon and glucocorticoid synthesis [
69].
A study by Popa et al. [
70] demonstrated the existence of an inverse correlation between severity of inflammation and circulating leptin levels in active RA, suggesting contribution of chronic inflammation to lowering plasma leptin concentration. Striking is the fact that this study did not reveal differences in leptinemia between the whole group of RA patients and healthy controls, which was explained by low inflammatory parameters at the time of inquiry.
According to the aforementioned investigations [
67,
68], we may assume that improvements of symptoms may be related to a significant decrease in plasma leptin levels due to weight loss in the course of the disease. Nonetheless, it is not obvious whether the increase of plasma leptin in RA is just an effect of weight changes or it is rather a cause or a consequence of pathology in RA.
Adiponectin
The first report showing the existence of a correlation between adiponectin and RA was published in 2003 by Schaffler et al. [
71]. The authors demonstrated that synovial fluid concentrations of adiponectin were significantly higher in patients with RA than in those with osteoarthritis (OA). In 2004, Berner et al. [
72] evidenced that adiponectin is also expressed and secreted by osteoblasts, which corroborated previous opinions about the role of adiponectin in bone homeostasis. Elevation of synovial adiponectin in RA was later confirmed by other studies [
72,
73]. Ehling et al. [
74] demonstrated a strong expression of adiponectin mRNA in synovial fibroblasts and articular adipocytes of RA and OA patients. The same study showed that adiponectin induced, via p38 mitogen-activated protein kinase (MAPK) pathway, the synthesis of IL-6 and pro-matrix metalloproteinase-1 (pro-MMP-1). What is worth mentioning is that neutralization of TNFα activity by etanercept and adalimumab resulted in a marked reduction of IL-6 and pro-MMP-1. As the specific binding of entanercept and adalimumab to adiponectin was excluded, pro-inflammatory effects of adiponectin in the synovium were, at least in part, mediated by TNFα [
74]. As TNFα was found to stimulate the p38 MAPK pathway, TNFα-directed therapy may modulate adiponectin action on the level of this signaling pathway [
75].
Also, in other studies, adiponectin stimulated IL-6 production [
29] and, in opposition to leptin and resistin, induced IL-8 expression [
76] in rheumatoid synovial fibroblasts and chondrocytes [
77] (Table
1). At the level of chondrocytes, adiponectin was found to exert pro-inflammatory effects by inducing the expression of inducible NO synthase and by stimulating the release of IL-6, MMP-3, MMP-9, and MCP-1 [
78]. Another study reported that the mean levels of adiponectin and type 1 adiponectin receptor were higher in the synovial fluid of RA compared with OA patients. Interestingly, there were no statistically significant differences in serum adiponectin and the type 1 adiponectin receptor content between RA, OA, or healthy control subjects [
79], while in endothelial cells adiponectin reduced the expression of TNFα-induced IL-8 [
80]. Furthermore, in recent research by Kusunoki et al. [
81], adiponectin enhanced production of prostaglandin E
2 in synovial tissues obtained from patients with RA. All these results may suggest that adiponectin locally produced in joint tissues induces inflammation, which is consistent with previous opinions that adiponectin may exhibit some pro-inflammatory properties [
82,
83]. This pro-inflammatory action of adiponectin may be limited to selected tissues, which would explain why, despite local changes in adiponectin levels, serum levels of adiponectin and adiponectin type 1 receptor did not differ between RA, OA, or healthy subjects. If this hypothesis is correct, plasma adiponectin levels may not reflect precisely the activity of this AT product in particular tissues. Alternatively, increased adiponectin production in autoimmune/chronic inflammatory conditions might be secondary to inflammation-induced catabolic responses occurring in RA, which are absent in inflammation associated with obesity [
24,
84].
There are some reports indicating that locally abnormal activity of adiponectin in joint tissues is not only associated with the presence, but also determines the severity of RA. Recent research by Ebina et al. [
85] has shown that serum adiponectin levels were higher in patients with severe RA than in mild RA and control groups (RA was graded on the basis of the extent of joint destruction). It should be underlined that the difference in adiponectin levels between subjects with severe and mild RA did exist, despite higher CRP levels and the use of a higher dose of oral prednisolone by the patients with mild RA [
85] (both CRP and corticosteroids have been reported to markedly inhibit adiponectin [
86]). Similarly, there was a strong positive correlation between serum adiponectin levels and progression of radiographic joint destruction, including enhanced radiographic erosions, and joint space narrowing [
87,
88] As a recent study by Klein-Wieringa et al. [
89] shows, baseline serum levels of adiponectin can predict radiographic progression independently of the presence of anti-cyclic citrullinated peptide antibodies and BMI. These findings suggest that circulating adiponectin and/or adiponectin produced locally by intra-articular adipocytes may play a role in the degradation of extracellular matrix components. These local pro-inflammatory and erosive effects of adiponectin may result from the stimulation of the NF-κB pathway [
29] and/or osteoclastogenesis [
90], respectively. On the other hand, as suggested by Fantuzzi [
24], the catabolic state accompanied by joint destruction, especially in large joints, may be a significant determinant of hyperadiponectinemia.
The results presented above suggest that adiponectin may be a target for the treatment of RA. However, adiponectin would not be called “a controversial hormone” if there were no contradictory opinions about its function. Despite many data suggesting the pro-inflammatory action of adiponectin in joints [
29,
74,
78], it cannot be completely excluded that high local and systemic levels of adiponectin help suppress inflammation in patients with RA. In accordance with this hypothesis, in collagen-induced arthritis mice and RA synovial fibroblasts, intra-articularly injected adiponectin significantly mitigated the severity of the arthritis and histopathological findings indicative of RA [
91].
Unfortunately, one of the serious limitations of the studies conducted to date is that they measured almost exclusively total adiponectin. The ambiguous impact of this adipokine on arthritis [
29,
74,
78,
91] may, in part, be explained by different biologic functions of various adiponectin isoforms. The latest findings by Chedid et al. [
92] are in line with this assumption. The authors have demonstrated that adiponectin and its globular fragment differentially modulated the oxidative burst of primary human phagocytes. Contrary to full-length adiponectin, its globular form, constituting about 25 % of adiponectin in synovial fluid, enhanced reactive oxygen species production and phagocytic NADPH oxidase-2 expression in the plasma membrane, with a concomitant increase in p47(phox) phosphorylation. Interestingly, the same study has shown that LMW adiponectin was more abundant in synovial fluid than in serum from RA patients [
92], and these findings suggest that joint inflammation in RA may be associated with an imbalance between different isoforms of adiponectin.
Although at present, the number of premises indicating pro-inflammatory function of adiponectin in RA patients seems to prevail over data showing its protective action, the association between adiponectin and RA is far from being completely understood. Because no firm conclusions can be drawn; more research in this field is undoubtedly required, particularly with reference to the role of adiponectin isoforms.
Resistin
Although most reports concerning resistin focused on its function in the metabolic syndrome, obesity, and IR, there is some evidence on its role in RA and other inflammatory diseases. The pioneering work by Schaffler et al. [
71] from 2003 showed that not only adiponectin is elevated in the synovial fluid of RA patients, but also resistin levels in the synovium are about 10 times higher than in OA subjects. Resistin, as it was shown by Bokarewa et al. [
34], accumulates locally in the inflamed joints of RA patients. Furthermore, the hypothesis of pro-inflammatory resistin function was confirmed by the development of arthritis after resistin injection into the joints of healthy mice [
34] (Table
1). Interestingly, plasma resistin concentrations remained low, suggesting the local intra-articular action of this agent. Although, there are reports showing no difference in serum resistin levels between RA patients and healthy subjects [
64], two successive studies reported a positive correlation between circulating resistin levels and the severity of inflammation in RA [
93,
94]. Furthermore, Migita et al. [
93] observed correlations between serum resistin and CRP, ESR and TNFα in patients with RA, which is consistent with earlier findings by Schaffler et al. [
71] and a recent report by Forsblad d’Elia et al. [
94]. This study also revealed a strong positive correlation between resistin and IL-1 receptor antagonist, the serum level of which is elevated in many rheumatic diseases [
95], whereas bone mineral density was inversely correlated with serum resistin. The fact that in humans resistin levels positively correlated with coronary atherosclerosis occurrence may suggest a role of resistin in the inflammation-based etiology of atherosclerosis in RA [
94]. Various resistin levels in serum and synovial fluid of RA patients [
34,
64,
71,
93,
94] may be due to or may contribute to differences in RA disease activity.
Other adipokines
The role of the remaining adipokines in the development and progression of RA is even less understood than the role of adiponectin, leptin, and resistin.
Plasma levels of visfatin were found increased in patients with RA [
64]. Visfatin was evidenced to induce chemotaxis and the production of IL-1, TNFα, IL-6, together with costimulatory molecules by CD14C monocytes, and to increase monocyte ability to induce alloproliferative responses in lymphocytes [
96,
97]. These features may suggest that increased visfatin production contributes to the pathogenesis of RA. Because visfatin is suggested to be a part of a compensatory mechanism facilitating lipid accumulation in intra-abdominal depots, it may protect the patient against the development of rheumatoid cachexia [
64].
In a study by Senolt et al. [
48], synovial fluid vaspin levels were higher, while omentin levels were lower in RA patients than in OA patients. Synovial fluid vaspin tended to correlate with the activity of RA assessed by DAS28, but not with serum CRP or a number of leukocytes in synovial fluid. On the other hand, synovial fluid levels of omentin correlated with serum anti-citrullinated peptide antibodies and with IgM-rheumatoid factor [
48]. Elevated serum vaspin levels in RA patients have also been recently demonstrated by Ozgen et al. [
98].
In light of latest research, it seems that novel adipokines, such as chemerin, LCN 2, and SAA3, may also play some role in the development and progression of rheumatic diseases. These adipose tissue proteins are partially produced by murine and human chondrocytes [
53] and their production is up-regulated by pro-inflammatory cytokines and lipopolysaccharide [
52].
Chemerin stimulates leukocyte migration to sites of inflammation. It induces the release of C–C chemokine ligand 2 and enhances the expression of toll-like receptor 4, which is a well-known inhibitor of cartilage biosynthetic activity [
52]. A recent study by Eisinger et al. [
99] showed that chemerin is present in synovial fluids of RA, OA, and psoriatic arthritis patients. Although the significance of chemerin in innate immune system–associated joint inflammation seems probable, its role in the pathogenesis of rheumatic diseases is still unknown.
LCN 2 forms molecular complexes with MMP-9 and, by protecting this MMP from autodegradation [
100], may contribute to the degeneration of cartilage. LCN 2 is highly susceptible to upregulation by IL-1β and, therefore, arouses interest as a potential biomarker of cartilage degeneration in arthritic diseases.
SAA3 increases MMP-1 secretion in rabbit fibroblasts, while the human analogue of SAA3 (A-SSA) can induce MMP-1 and MMP-13 in human chondrocytes [
101]. Significant is the finding that high concentrations of A-SSA have been detected in the inflamed synovium of RA and OA patients, which suggests that SAA3 is involved in cartilage degeneration in rheumatic diseases [
101].