Adipocytokines as driving forces in rheumatoid arthritis and related inflammatory diseases?



Adipose tissue is ubiquitously present in the human organism. It is a structural component of many organs including the skin, the intestinal tract, and the joints. Besides its central function in energy metabolism, adipose tissue usually serves as a bolster in gaps or intersections between tissues. The dominant cell type, adipocytes, secretes highly bioactive substances, the so-called adipokines or adipocytokines (Table 1). Adipokines include a growing number of pluripotent factors such as adiponectin, resistin, leptin, and visfatin/pre–B cell colony-enhancing factor (PBEF) (1, 2). Table 2 provides an overview of several characteristics of these adipokines, and their respective functional aspects are discussed below. There is also increasing evidence that adipocytes actively secrete additional proinflammatory factors operative in the pathophysiology of inflamed joints, such as tumor necrosis factor α (TNFα), interleukin-6 (IL-6), factors of the complement system, growth factors, and adhesion molecules (2–4). Moreover, adipokines are able to actively modulate inflammation and the innate immune system (1, 5). In this review, the current knowledge about the influence of central adipokines in rheumatic diseases, highlighting several aspects of the role of adipokines in chronic inflammation, is summarized.

Table 1. Bioactive substances synthesized and released in adipose tissue
Class of moleculesKey examples
CytokinesTumor necrosis factor α, interleukin-6
Chemokines and growth factorsPlasminogen activator inhibitor 1, macrophage migration inhibitory factor, macrophage colony-stimulating factor
AdipokinesLeptin, adiponectin, resistin, visfatin/pre–B cell colony-enhancing factor, omentin, cartducin (CORS26)
ComplementC1 inhibitor, C3, factor B, factor D
Table 2. Characteristics of some of the adipokines involved in inflammatory diseases*
  • *

    LMW = low molecular weight; HMW = high molecular weight; TNF = tumor necrosis factor; BMI = body mass index; PPARδ = peroxisome proliferator–activated receptor; IL-6 = interleukin-6; LPS = lipopolysaccharide.

Cellular sources and tissue localizationMainly secreted by differentiated adipocytes; accounts for 0.05% of total serum protein in humans (78, 79); dominant isoforms in human serum are LMW and HMW (8)Produced by several tissues including adipose tissue, skeletal muscle, bone marrow, and liver; secreted by early B lymphocytes (80)Monocytes and macrophages are main source in adults; in contrast to mice, only low expression in humans (81); present as hexamer and trimer in human circulation (82)Pleiotropic, i.e., can be produced by numerous cell types (e.g., white adipose tissue cells, endothelial cells, T cells, bone marrow cells, spleen cells) (83)
Homologies and structural propertiesHomologous to C1q complement family and TNF ligand family; monomer is collagen triple helix with a C-terminal globular gC1q domainDimeric type II phosphoribosyltransferase enzymeFamily member of cysteine-rich secretory proteins termed resistin-like molecules (RELM) or FIZZ (found in inflammatory zone) proteinsFamily member of long-chain helical cytokines
Isoforms1) Trimer (LMW); 2) hexamer (middle molecular weight); 3) HMW; 4) globular isoform formed by proteolytic cleavage of the monomer (Figure 1 and ref.8)Two isoforms of different lengths, one full-length transcript and an isoform shorter by 3 exons (84)Multimeric structures (85) including a homodimer, a trimer, and a hexamer (82)Different isoforms with identical extracellular ligand-binding domains but differences at the carboxyterminal end of the molecule or the cytoplasmic portion (83)
ReceptorsAdipoR1 and AdipoR2 (8); novel potential receptors are PAQR3 and PAQR10 (86, 87)Insulin receptor with activation mechanism different from that of insulin but affinity similar to that of insulin (21)Not yet identifiedSeveral receptor isoforms, all encoded by leptin receptor (CD295) (2)
Intracellular signalingSignaling involves NF-κB, p38 MAPK, and MAPK (10, 26, 35)Insulin receptor signaling pathwaysIncreases intracellular Ca2+ (88); induces nuclear translocation of NF-κB (19)Signaling via JAK/STAT and MAPK pathways (83)
CorrelationsNegative correlation with BMI, leptin, insulin, and other metabolic parameters (89)Positive correlation with BMI and amount of visceral fat (21)Positive correlation with BMI and amount of visceral fat (90)Positive correlation with BMI and various metabolic parameters (91)
Factors affecting expressionInduced by endothelin-1 (92) and PPARδ agonist (93); repressed by glucocorticoids (94) and proinflammatory factors such as IL-6 and TNF (2)Induction of synthesis by proinflammatory cytokines such as TNF, IL-1β, IL-6, and LPS as well as by hypoxia (95)Induction of synthesis by glucocorticoids and proinflammatory agents such as TNF, IL-6, and LPS; inhibition by thiazolidinediones (96)Induction of synthesis by proinflammatory cytokines such as TNF and IL-1β; inhibition by long-term in vitro TNF stimulation (2)
Figure 1.

Adiponectin isoforms. Three adiponectin monomers form the trimeric adiponectin isoform, also called the low molecular weight (LMW) isoform. Adiponectin hexamers form the middle molecular weight (MMW) isoform. The high molecular weight (HMW) isoform consists of 12–18 monomers. Globular adiponectin consists of the globular head domain of adiponectin formed after proteolytic cleavage.

General immunologic functions


As shown in Table 2, adiponectin exists in various isoforms (Figure 1). There is increasing evidence that the respective adiponectin isoforms exert different and sometimes counteracting functions (6–8) and induce specific intracellular signaling cascades via selective receptor binding (8–10). The high molecular weight adiponectin, for example, induces IL-6 in human monocytes but does not suppress lipopolysaccharide (LPS)–induced IL-6 secretion. In contrast, low molecular weight (LMW) adiponectin reduces LPS-induced IL-6 secretion and induces IL-10 in these cells (6). Of note, only the LMW isoform appears to have antiapoptotic properties (11). At present, two adiponectin receptors have been described (AdipoR1 and AdipoR2), and the actual adiponectin bioactivity is determined by oligomerization and the expression levels of the receptors (8, 12, 13).

Besides its metabolic functions, adiponectin is involved in several immunomodulatory pathways (2). Adiponectin inhibits cellular growth and functions (e.g., growth of myelomonocytic progenitor cells and macrophage function). In addition, the TNFα-induced monocyte adhesion as well as the expression of adhesion molecules is reduced by adiponectin (2). These and other observations, e.g., that proinflammatory factors such as IL-6 and TNFα inhibit the synthesis of adiponectin in adipocytes, led to the idea that adiponectin has predominantly antiinflammatory and antiadhesive effects.

An interesting feature of adiponectin regarding rheumatic diseases is its ability to stimulate proliferation and RANKL expression in osteoblasts, whereas osteoprotegerin expression is inhibited (14). However, adiponectin had no direct effect on osteoclast differentiation, and suppression of AdipoR1 abolished the adiponectin-induced effects in osteoblasts (14). Adenoviral application of adiponectin in mice increased trabecular bone mass and reduced the number of osteoclasts and markers of bone erosion in vivo (15). In vitro, adiponectin inhibited osteoclastogenesis and the bone-resorptive activity of osteoclasts but increased mineralization activity in MC3T3-E1 osteoblasts (15). A more detailed approach showed that globular adiponectin strongly inhibits TNF/RANKL-induced osteoclastogenesis (16) as well as osteoclast formation induced by Toll-like receptor 4 (TLR-4) ligand and RANKL (17). Therefore, adiponectin appears to influence bone metabolism substantially.

It should be noted that at higher concentrations, commercially available recombinant adiponectin may contain levels of LPS that are sufficient for the induction of LPS-mediated effects or to induce LPS tolerance in different cells. For example, adiponectin is able to induce tolerance to TLR ligands in macrophages, and an LPS antagonist substantially inhibited the adiponectin-mediated induction of tolerance (18). Therefore, potential LPS contaminations and LPS-mediated effects have to be taken into account in experimental settings using adiponectin. However, nearly all studies considering potential LPS contamination in their recombinant proteins showed that it was not responsible for the adipokine-dependent effects that were observed.


Primarily, resistin has been identified in the mouse as a protein involved in adipocyte differentiation. Similar to adiponectin, resistin seems to have immunomodulatory potential. Recombinant human resistin increases the secretion of proinflammatory cytokines such as TNFα, IL-6, and IL-12 in murine and human macrophages (4, 19). In addition, human endothelial cells are activated by recombinant human resistin (4), leading to increased expression of endothelin 1 and several adhesion molecules as well as chemokines in these cells. These findings stimulated the hypothesis of a potential proinflammatory effect of resistin in contrast to adiponectin that, depending on the respective environmental conditions, can be both antiinflammatory and proinflammatory.


The metabolic and endocrine functions of leptin have been extensively described. In addition, leptin has immunoregulatory functions (2). Leptin is an important factor for T cell proliferation and can induce Th1 immune reactions (2). Furthermore, leptin is involved in proliferation and activation of inflammatory cells such as monocytes (2) and neutrophils (20). Serum levels of leptin are increased in some chronic inflammatory diseases, and leptin is most likely induced during acute and initial proinflammatory responses.


Visfatin/PBEF exerts insulin-mimetic effects in vivo and in vitro (21). Visfatin/PBEF is also called Nampt (NAmPRTase) because of its nicotinamide phosphoribosyltransferase activity and is involved in the synthesis of NAD, an essential cofactor of cell metabolism (22). However, it is also a pleiotropic protein with immunomodulatory potential. For example, visfatin/PBEF is able to activate human leukocytes and induce costimulatory molecules on the cell surface. In monocytes, it can induce proinflammatory cytokines such as IL-1, TNF, and IL-6 (23). In addition, visfatin/PBEF protects fibroblasts and neutrophils from apoptosis (24). During polyclonal immune responses, visfatin/PBEF production is increased in lymphocytes and stimulates their proliferation (25).

Adipokines in rheumatic diseases

In contrast to knowledge about the role of adipokines in endocrine and cardiovascular diseases, less is known about the role of adipokines in chronic inflammatory rheumatic diseases such as systemic sclerosis (SSc) or rheumatoid arthritis (RA). However, there is increasing evidence that adipokines actively take part in inflammatory, matrix-destructive, and fibrotic processes in rheumatic diseases. Primarily, increased production of adipokines could be detected in the synovial fluid of patients with RA. Because adipokine levels were also shown to be altered in the serum of patients with other rheumatic diseases, these findings stimulated research to understand the interactions between adipose tissue, adipokines, and inflammatory joint diseases.

Adipokines in rheumatoid arthritis

Adipokines such as adiponectin, leptin, resistin, and visfatin/PBEF are actively produced by local cells of the arthritic joint and the periarticular adipose tissue (26, 27) (Figure 2). The effects of adipokines on different effector cell types have been studied in the past, and some of the effects of adipokines in the synovium are already known.

Figure 2.

Adipocytokines in rheumatoid arthritis. A variety of factors are produced by adipose tissue, including proinflammatory cytokines, chemokines, adiponectin, visfatin/pre–B cell colony-enhancing factor (PBEF), leptin, and others. These factors were collectively called adipo(cyto)kines. Factors that were thought to be predominantly produced by adipose tissue, the classic adipokines, such as adiponectin, visfatin/PBEF, resistin, leptin, and others are shown with a light blue background. Factors produced primarily intraarticularly are marked with a red frame, while factors produced at various sites are marked with a purple frame. It has been shown in the past that other cells besides adipocytes are able to produce these factors, including cells of the hyperplastic synovium of rheumatoid arthritis patients, such as fibroblast-like synoviocytes. IL-1 = interleukin-1; TNF = tumor necrosis factor; MCP-1 = monocyte chemoattractant protein 1; PAI-1 = plasminogen activator inhibitor 1; RBP4 = RNA binding protein 4.

Adiponectin in RA.

The amount of adiponectin is increased in the synovial fluid of patients with RA compared with patients with osteoarthritis (OA) (28, 29). Adiponectin serum levels are also increased in patients with RA compared with control subjects (29, 30). Higher adiponectin levels were also detectable in erosive versus mild RA, and mean adiponectin levels did not significantly change during a followup period of 2.5 years (30). In addition, serum levels of adiponectin correlated with joint erosion (30, 31), and plasma levels of adiponectin were higher in chronic RA compared with early RA (32). In some studies, however, plasma levels were shown to be lower than or similar to the levels in patients with OA, illustrating the problem of using systemic levels as an approximation of local levels of proinflammatory molecules (29, 32).

Analysis of adiponectin in the synovial tissue of patients with RA showed that adiponectin is locally expressed in the lining layer, the perivascular area, and in several cells in the sublining (26). Because adiponectin is also expressed at sites of cartilage destruction, synovial angiogenesis, and inflammation (Figure 3), modulation of adiponectin, e.g., by inhibiting or overexpressing specific adiponectin isoforms or receptors, may be of interest for future therapeutic interventions.

Figure 3.

Adiponectin in rheumatoid arthritis (RA). Adiponectin is expressed at sites of cartilage invasion, in lymphocyte infiltrates, perivascularly, and in the lining layer of the synovium of patients with RA. Adiponectin induces chemokines and proinflammatory cytokines and may contribute to chronic inflammation as well as recruitment of additional inflammatory cells into the synovium and to accumulation of RA synovial fibroblasts (RASFs) at the site of cartilage invasion.

When stimulated with adiponectin, synovial fibroblasts (SFs), the central cells of cartilage destruction in RA, secrete increased amounts of proinflammatory cytokines such as IL-6, a variety of chemokines including IL-8 and growth-related oncogene α, proangiogenic factors such as vascular endothelial growth factor (VEGF), and matrix-degrading proteins including matrix metalloproteinase 1 (MMP-1) and MMP-13 (26, 33–36). Of note, adiponectin serum levels in patients with RA but not in patients with OA correlate with VEGF levels (33). Interestingly, other key factors driving arthritis such as TNFα and IL-1β were not induced by adiponectin in RASFs (26). However, this stimulatory capacity of adiponectin is not restricted to RASFs. In endothelial cells, chondrocytes and lymphocyte subpopulations, proinflammatory factors, and chemokines were also induced by adiponectin (36). Additionally, adiponectin increased the expression of MMPs in chondrocytes and that of adhesion molecules in endothelial cells (36). Thus, adiponectin exerts proinflammatory and prodestructive properties in the majority of cells involved in cartilage destruction in RA.

In contrast to the results in vitro, in the primarily inflammation-driven arthritis model of collagen-induced arthritis (CIA), gene transfer or intraarticular injection of adiponectin resulted in a reduction in the severity of arthritis in mice with CIA (37, 38). When the adenoviral vector was applied prior to progression of arthritis, the histology scores for inflammation and joint erosion were significantly decreased without alteration of the anticollagen levels (37). Of note, induction of arthritis in rats using Freund's complete adjuvant resulted in decreased white adipose tissue as well as adiponectin and leptin serum levels during chronic inflammation (39), which, in part, are reflected by the serum levels in humans.

The discrepancy of the data obtained from rodent models versus the data generated in vitro using human cells may be attributable to the individual models and cell types as well as the individual adiponectin protein used. Adiponectin may have different effects on different effector cells, and cellular interactions may also be relevant. However, cellular interactions are difficult to study in vitro. Furthermore, it has become more obvious in the past years that human adiponectin consists of different isoforms, and that glycosylation and oligomerization, which differ between species, are very important for the functional effects of adiponectin. Because most experiments in animal models are performed using a “wild-type” mix containing all isoforms, it is not yet possible to determine which isoforms are dominant in RA synovial tissue at sites of cartilage degradation and inflammation. In addition, a shift of local adiponectin isoform levels and specific glycosylation and oligomerization patterns may be important for the outcome of the individual experiment.

Being a part of the inflammatory cascade, serum adiponectin is altered by inflammation-modulating treatment including biologic agents such as TNF inhibitors. Methotrexate appears to increase adiponectin levels in humans (32), and a cyclooxygenase 2 inhibitor increased adiponectin in an animal model of arthritis (39). However, it is not clear how anti-TNF therapy influences adiponectin levels in humans. Although adiponectin resembles TNF in its tertiary structure, and experimental treatment with anti-TNF antibodies significantly down-regulated adiponectin-dependent stimulation of SFs (26), the effect of therapeutic TNF inhibitors on adiponectin expression in clinical studies resulted in diverging adiponectin serum levels. Recent findings on the effects of these and other therapeutic treatments are summarized in Table 3.

Table 3. Effects of RA treatment on adipokine expression in different studies
Adipokine, disease, treatment*SettingEffect on serum levelsRef.
  • *

    RA = rheumatoid arthritis; MTX = methotrexate; COX-2 = cyclooxygenase 2; anti-TNF = anti–tumor necrosis factor; PsA = psoriatic arthritis.

  MTXHuman, 28 weeks of treatmentIncreased32
  COX-2 inhibitorRat, adjuvant-induced arthritisIncreased39
  Anti-TNFHuman, 6 weeks of treatmentIncreased97
 Human, 1 year of treatmentIncreased98
 Human, 6 months of treatmentDecreased99
 Human, 2, 6, or 12 weeks of treatmentNot regulated45
 PsA/RA, anti-TNFHumanNot regulated100
Resistin, RA, anti-TNFHumanDecreased101
Leptin, RA, anti-TNFHumanNot regulated45, 99

The observed lack of correlation of anti-TNF treatment effectiveness with adiponectin serum levels suggests that systemic inhibition of inflammation does not directly affect adiponectin serum levels. However, these findings underline the importance of tissue- or compartment-dependent synthesis of adiponectin.

Resistin in RA.

Resistin serum concentrations are increased in patients with RA compared with patients with OA or healthy control subjects and correlate with markers of inflammation in these patients (40–42). Resistin is also increased in the synovial fluid of patients with RA compared with patients with OA and healthy control subjects (4, 28, 42). The resistin concentration in synovial fluid has been shown to be higher than that in plasma from the same patients (4, 28), and resistin concentrations correlate positively with markers of inflammation, including the C-reactive protein (CRP) level, the erythrocyte sedimentation rate, and levels of IL-1 receptor antagonist and TNFα (28, 41, 43). Resistin expression and secretion are also increased in RA synovial tissue, especially in the lining layer in patients with RA compared with patients with OA. Similar to adiponectin, resistin is expressed by different cells in the rheumatoid synovium such as macrophages, B cells, and plasma cells (42).

In vitro, stimulation of murine and human macrophages with recombinant human resistin increased the secretion of proinflammatory cytokines such as TNFα, IL-6, and IL-12 (4, 19). Resistin also induced the production of proinflammatory cytokines such as IL-6 and TNFα in peripheral blood mononuclear cells (PBMCs). Resistin, in turn, is inducible by TNFα, IL-6, and IL-1β in PBMCs, resulting in a positive feedback mechanism of inflammation (4). These effects can be reduced by blocking NF-κB, leading to the idea that resistin-induced inflammation is NF-κB dependent (4).

Because these results led to the hypothesis that resistin supports primarily proinflammatory pathways in RA, it was most interesting to observe that intraarticular injection of recombinant resistin induced joint inflammation in a mouse model similar to that observed in human arthritis (4). In contrast to the challenges of adiponectin research in RA, resistin clearly appears to be prodestructive and proinflammatory in in vivo models as well as in vitro. Along this line, anti-TNF treatment of patients with RA seems to reduce resistin serum levels as well as CRP levels, in contrast to adiponectin (Table 3).

Leptin in RA.

Leptin concentrations were shown to be increased in the synovial fluid of patients with RA (44, 45). The question of whether serum levels of leptin are increased in RA is controversial (27, 46–49). However, serum levels of leptin seem to be higher than the levels in synovial fluid (44). Although leptin is positively correlated with body fat content (46, 50), a correlation between plasma concentration of leptin, body mass index (BMI) (46–48, 50, 51), and markers of inflammation is still debated (47–52). An interesting feature is the finding that serum levels of leptin are higher in active RA than in less-active RA (51), and differences in leptin levels between plasma and synovial fluid were greater in nonerosive than in erosive arthritis (44). In leptin-deficient ob/ob mice, the arthritis that developed was less severe than that in wild-type mice (53). In zymosan-induced arthritis, which is independent on adaptive immunity, a delayed resolution of acute inflammation was observed in leptin-deficient ob/ob mice (54). In addition, anti-TNF therapy for patients with RA did not influence leptin concentrations (Table 3).

It is well known that leptin has an influence on inflammatory processes and especially on T cells. However, although the proinflammatory as well as the antiinflammatory effects of leptin have been described (48, 55–57), determination of the exact role and effects of leptin on inflammatory processes in joint destruction in RA still needs further evaluation. In addition, information on the effects of leptin on central effector cells of cartilage and bone erosion is very limited. Because leptin levels are correlated to disease progression and erosion, leptin may be involved in the destructive processes in RA FLS–mediated cartilage erosion or osteoclast-mediated bone erosion.

Visfatin/PBEF in RA.

The level of visfatin/PBEF is increased in both the synovial fluid and serum of patients with RA (26, 27, 58). Visfatin/PBEF is produced by adipose tissue not only in the synovial tissue but also in the lining layer, in the subintima, in lymphocyte aggregates, and by vascular endothelial cells (59). The proinflammatory potential of visfatin/PBEF in RA has been demonstrated by different groups of investigators. It activates human leukocytes, induces costimulatory molecules on the cell surface of monocytes, and induces proinflammatory cytokines such as IL-1, TNF, and IL-6 in these cells (23, 59). Visfatin/PBEF is induced by IL-6, oncostatin M, and TLR (59), e.g., in synovial fibroblasts, and seems to be involved in IL-6 trans-signaling (58). In addition, fibroblasts and neutrophils are protected from apoptosis by visfatin/PBEF (24, 60). These data show that visfatin/PBEF not only is induced by proinflammatory factors but also induces inflammation and destruction-mediating factors in central cells relevant in RA pathophysiology as well as survival of inflammatory cells.

In vivo, a specific competitive inhibitor of visfatin/PBEF was able to reduce the severity of arthritis and reduced the intracellular NAD concentration in inflammatory cells and circulating TNF levels in the CIA model (22). Therefore, visfatin/PBEF has proinflammatory and prodestructive properties in RA in vivo and in vitro, similar to those of resistin.

Adipokines in other rheumatic diseases

In other rheumatic diseases, mainly the presence and expression levels of adipokines in serum (or, when applicable, in synovial fluid) have been investigated, but data on the effects of adipokines on the respective disease-specific effector cells are available only to a limited extent (e.g., regarding the effects of adipokines on inflammatory, destructive, or profibrotic effector cells).

Systemic lupus erythematosus (SLE).

Plasma and urine adiponectin levels appear to be increased in patients with SLE, especially in those with inflammatory glomerulonephritis (61). Interestingly, full-length (containing all isoforms) but not globular adiponectin induced IL-8 and monocyte chemoattractant protein 1 in microvascular endothelial cells and monocytes (62). This is consistent with the observations in RA and illustrates both the potential proinflammatory role of adiponectin in chronic inflammation and the need to differentiate between the effects of the different adiponectin isoforms.

Serum levels of leptin were negatively correlated to androstenedione levels not only in patients with SLE but also in patients with RA (63). Due to its known antiandrogenic effects, leptin may also be involved in hypoandrogenicity in SLE and RA. In contrast, serum resistin levels in patients with SLE did not differ from those in healthy control subjects but were correlated with systemic inflammation (64). However, no data on the effects of adipokines on SLE-affected tissues, including disease-causing effector cells, are available at present.


Although studies to understand the role of adipokines in OA are limited, OA cells and conditions are often used as controls in studies of chronic inflammatory diseases. However, there are some interesting studies analyzing specifically the role of adipokines in OA. Increased adiponectin serum levels seem to be associated with erosive versus nonerosive OA (65), and serum levels have been shown to be increased in patients with OA compared with healthy individuals. In OA synovial tissue, adiponectin is present in the lining layer and around vessels (26). Adiponectin is, to some extent, also able to induce proinflammatory factors, chemokines, and MMPs in SFs from patients with OA (36).

Visfatin/PBEF is produced by different synovial cells within the OA synovium, including chondrocytes, and can be induced by proinflammatory cytokines such as IL-1 (66). Interestingly, in OA chondrocytes, visfatin/PBEF was also able to trigger prostaglandin E2 (PGE2) release via increased microsomal PGE synthase 1 synthesis and decreased 15-hydroxyprostaglandin dehydrogenase synthesis. The knockout of visfatin/PBEF in these cells resulted in reduced IL-1–mediated PGE2 release (66). Furthermore, visfatin/PBEF induced the expression and synthesis of matrix-degrading enzymes in murine articular chondrocytes (66). Therefore, MMPs are induced not only by visfatin/PBEF in OASFs but also by chondrocytes themselves, leading to increased cartilage degradation. In another study, alteration of the Nampt (visfatin/PBEF) pathway resulted in changes in NAD levels, sirtuin activity, and cartilage-specific gene expression, inducing the expression of matrix proteins in chondrocytes derived from patients with OA (67).


In patients with spondylarthritides in general, synovial fluid levels of resistin were not as elevated as those in patients with RA or OA (42), but serum levels of resistin in patients with ankylosing spondylitis (AS) were increased compared with the levels in patients with OA (42).

In contrast to resistin, leptin levels in patients with AS were lower than those in control subjects, even after adjustment for body fat content, while serum levels of adiponectin did not differ between patients and control subjects (68). This is consistent with data from another study showing decreased leptin levels in patients with AS compared with control subjects (69). In the latter study, body fat content, CRP levels, and the Bath Ankylosing Spondylitis Metrology Index score (70) were significantly correlated with serum levels of leptin. In contrast to these findings, serum levels of leptin were significantly increased compared with those in control subjects, with or without BMI adjustment (71), and in this study the correlation of leptin levels with the CRP concentration could be confirmed and correlated also with the Bath Ankylosing Spondylitis Disease Activity Index (72), IL-6 levels, and disease activity. Interestingly, leptin had proinflammatory effects on PBMCs from patients with AS (73). Leptin, IL-6, and TNF messenger RNA expression levels and secretion were higher in PBMCs from patients with AS than in PBMCs from control subjects. Stimulation with exogenous leptin of PBMCs from patients with AS significantly increased IL-6 and TNF production in a dose-dependent manner.

Although the data on adipokines in disease progression and inflammation in patients with AS are not completely elucidated, the leptin-induced production of proinflammatory cytokines in PBMCs from patients with AS compared with that in PBMCs from control subjects shows the immunomodulatory properties of leptin in AS. However, the role of leptin in local inflammation as well as the effector cells contributing to AS, e.g., osteoclasts and osteoblasts, as wells as the contribution of other adipokines remain to be determined.

Other rheumatic diseases.

Very limited information is available on the role of adipokines in other rheumatic diseases such as SSc. Serum levels of leptin seem to be decreased in patients with SSc (74). However, the number of patients included in this study was limited, and additional investigations are required to determine the role of leptin and other adipokines in SSc. In patients with antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis, leptin levels were significantly lower than those in healthy control subjects, with or without BMI correction, and leptin levels significantly increased after 6 months and 12 months (75). In the current study, the leptin levels were negatively correlated with disease activity. In Behçet's disease, serum leptin concentrations seemed to be increased in comparison with those in healthy control subjects (76). In the current study, leptin concentrations were increased during active disease compared with periods of inactive disease. Furthermore, patients with longer disease duration had higher leptin concentrations than did patients with a shorter disease duration. Similarly, serum levels of resistin and IL-6 were significantly higher in patients with Behçet's disease compared with those in healthy control subjects (77).

In summary, leptin levels are decreased in fibrotic SSc and ANCA-associated vasculitis, whereas they are increased in Behçet's disease, which can most likely be attributed to different pathophysiologic mechanisms. Due to the lack of information on levels of other adipokines and local adipokine expression, the role of adipokines in these rheumatic diseases remains unclear but is probably associated with inflammation in a manner similar to that for the other previously described rheumatic diseases.


The effects of adipokines in chronic inflammatory rheumatic diseases as well as their role in matrix remodeling are one of the most interesting current topics in rheumatology, gastroenterology, and endocrinology. Owing to the pluripotent functions of adipokines, basic research groups are increasing their efforts to analyze the distinct role of the individual adipokines in rheumatic conditions. Especially in RA, there is evidence that adipokines such as resistin, visfatin/PBEF, and, most likely, adiponectin (including its isoforms) exert proinflammatory and prodestructive effects on the different effector cells.

Given the strong immunomodulatory potential of adipokines, therapeutic intervention by altering the synthesis or function of adipokines appears to be of substantial interest not only in RA. However, adipokines are also central factors involved in metabolism, and systemic inhibition or overexpression may instigate heretofore unknown side effects. A potential solution to this problem might be the modulation of specific isoforms or isoform-specific receptors to change the local response to these isoforms. Nonetheless, a variety of interesting and promising new insights regarding the pathophysiology of rheumatic diseases will most likely be provided by adipokine-oriented research in the near future and on a continuous basis.


All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published.