Adiponectin: A biomarker for rheumatoid arthritis?

Cytokine & Growth Factor Reviews 24 (2013) 83–89

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Adiponectin: A biomarker for rheumatoid arthritis? Xiuping Chen a,b,*, Jinjian Lu a, Jiaolin Bao a, Jiajie Guo a, Jingshan Shi b, Yitao Wang a,* a b

State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China Department of Pharmacology and Key Lab of Basic Pharmacology of Guizhou, Zunyi Medical College, Zunyi, China

A R T I C L E I N F O

A B S T R A C T

Article history: Available online 19 August 2012

Recent achievements in the biology and the function of adipose tissue have regarded white adipose tissue (WAT) as an important endocrine and secretory organ. Releasing a series of multiple-function mediators, WAT is involved in a wide spectrum of diseases, including not only cardiovascular and metabolic complications, such as atherosclerosis and type 2 diabetes, but also inflammatory- and immune-related disorders, such as rheumatoid arthritis (RA) and osteoarthritis (OA). A large number of these mediators, called adipokines, such as tumor necrosis factor alpha (TNF-a), leptin, adiponectin, resistin, chemerin, interleukin-6 (IL-6), visfatin, and so on have been identified and studied widely. Important advances related to these proteins shed new insights into the pathophysiological mechanisms of many complicated diseases, although details of which remain unclear. Adiponectin, one of the most widely investigated adipokine, has been shown to possess both anti- and pro-inflammatory effects. RA is a chronic systemic inflammatory-related autoimmune disease. Accumulated evidence has demonstrated that cytokines and adipokines play an important role in the pathogenesis of RA. In this review, we have summarized the most recent advances in adiponectin research in the context of RA, focusing primarily on its effect on RA-related cells, its regulation on pro-inflammatory cytokines, as well as its validation as a biomarker for RA. ß 2012 Elsevier Ltd. All rights reserved.

Keywords: Adiponectin Rheumatoid arthritis Biomarker Inflammation

1. Introduction The discovery of the secretion functions of adipose tissue, as evidenced by the biological investigation of numerous adipokines, has demolished a previously held doctrine that adipose tissue was simply for energy storage. Since the identification of leptin in 1994, various types of adipokines from white adipose tissue (WAT) have been reported and studied. The rapidly increasing knowledge of their biology and function reveals that these amazing proteins are active participants in the regulation of physiological and pathological processes, such as inflammation, metabolism, immunity, and so on [1,2]. Rheumatoid arthritis (RA) is a chronic systemic autoimmune disorder characterized by synovitis, as well as progressive damage to the articular cartilage and the subchondral bone [3]. RA is a common form of arthritis with 1% prevalence worldwide, but its exact pathophysiology is poorly understood. Recent advances have highlighted the important role of cytokines and adipokines, such as

* Corresponding authors at: Institute of Chinese Medical Sciences, University of Macau, Av. Padre Tomas Pereira S.J., Taipa, Macau, China. Tel.: +00 853 83974873; fax: +00 853 28841358. E-mail addresses: [email protected] (X. Chen), [email protected] (Y. Wang). 1359-6101/$ – see front matter ß 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.cytogfr.2012.07.004

the tumor necrosis factor alpha (TNF-a) and the interleukins (IL-1, -6, -12, -15, -17, -18, and -23) in the pathogenesis of RA [4–6], which provides potential therapeutic targets for the clinical interference of RA [7,8]. The important role of adipokines in inflammation provides novel links between adipose tissues, adipokines, and inflammatory-related disorders, including RA, thus attracting the interest of both basic researchers and clinical physicians. Recent findings have demonstrated that adipokines exert potent modulatory actions on tissues and cells involved in RA, including cartilage, synovium, bone, and various immune cells [9]. In this review, the role of adiponectin in RA was described with the aim of providing basic insights on its clinical relevance for future investigations. 2. Adiponectin biology Adiponectin is an adipose tissue-derived hormone of interest to scientists studying obesity, atherosclerosis, diabetes, and metabolic syndrome, among others. Publications related to its biology and functions have increased rapidly in the last ten years, with more than 4200 papers that could be retrieved in PubMed when searching for ‘‘adiponectin’’ as a keyword. Adiponectin has numerous beneficial biological functions from head to toe [10]

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and is involved in obesity [11], metabolic syndrome [12], atherosclerosis [13], type 2 diabetes [12], cancer [14], polycystic ovary syndrome [15], and so on. Adiponectin, also called Acrp30, adipoQ, ApM1, and GBP28, is a 28–30 kDa collagen-like protein secreted mainly by adipocytes. Insulin, angiotensin II, the inflammatory cytokines TNF-a, IL-6, and IL-1b, and interferon-g (IFN-g), as well ascertained pathological states, can regulate the expression and the secretion of adiponectin [16]. Five configurations of adiponectin (isoforms) have been identified, with globular adiponectin (gAPN) and full-length adiponectin (fAPN) as the main configurations of interest. Compared with other adipokines, the circulating concentrations of adiponectin in normal healthy subjects are surprisingly high, with the mean value ranging between 0.5 and 30 mg/L (or 3– 30 mg/L, 5–30 mg/L), accounting for about 0.01% of all plasma proteins in humans and 0.05% in rodents, respectively [17]. Three receptors for adiponectin have been identified, with its action mediated mainly by two of the following: adiponectin receptor 1 (AdipoR1) and adiponectin receptor 2 (AdipoR2). In human and mouse, AdipoR1 and AdipoR2 share 96.8% and 95.2% identity respectively. They are highly related structurally and share 67.5% identity of protein sequence and are conserved from yeast to human [18]. Both are integral membrane proteins that contain seven transmembrane domains, but are structurally and functionally distinct from classical G protein-coupled receptors. The former is expressed abundantly in skeletal muscles and has high-affinity for gAPN, whereas the latter is expressed predominantly in the liver and shows an intermediate degree of affinity for both gAPN and fAPN [19–21]. The signaling transduction pathways of adiponectin and its receptors are rather complicated, which have been well summarized and reviewed recently [10,19,22–25]. APLL1, an adaptor protein with multiple functional domains, is the first identified protein that interacts directly with adiponectin receptors [22]. Activated protein kinase C1, endoplasmic reticulum protein 46 (ERp46) and protein kinase CK2b subunit are newly identified proteins which could form a complex with AdipoR1 in hepatocytes, MCF-7 cells and HeLa cells respectively [23]. Following APPL1-AdipoR1 interaction, adiponectin exerts its effect mainly by activating AMP-activated protein kinase (AMPK), p38 mitogenactivated protein kinase (p38 MAPK), and peroxisome proliferator-activated receptor-a (PPARa) in skeletal muscle and liver, thereby decreasing the level of glucose and lipid in vivo. This effect is mainly through enhanced fatty acid oxidation and glucose uptake in muscle and inhibition of gluconeogenesis in liver mediated by glucose transporter 4 (GLUT4) and acetyl-CoA carboxylase (ACC) [18]. Recent studies showed that APPL1 also functioned as a scaffolding protein and mediates adiponectinstimulated p38 MAPK activation by scaffolding the transforming growth factor-b-activated kinase 1 (TAK1)/mitogen-activated protein kinase 3 (MKK3)/p38 MAPK pathway in C2C12 cells [26]. In endothelial cells, adiponectin activated AMPK prevents endothelial dysfunction by regulating nitric oxide (NO) and reactive oxygen species (ROS) production through AMPK-eNOS, phosphatidylinositol 30 kinase (PI3K)/AKT and cAMP/protein kinase A (PKA) pathways [27–29]. This beneficial effect of adiponectin in vascular complications might also be mediated through regulation of fatty acid oxidation, small G protein activity as well as inflammation and angiogenesis [30]. In dendritic cells, adiponectin induces dendritic cell activation via phospholipase Cg (PLCg)/c-Jun N-terminal kinase (JNK)/nuclear factor kappaB (NF-kB) pathways, leading to enhanced Th1 and Th17 responses [31]. Adiponectin also activates extracellular signal-regulated kinase 1/2 (ERK1/2), NF-kB, janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathways in primary human hepatocytes [32].

3. Adiponectin and RA 3.1. Effect of adiponectin on RA-basic research 3.1.1. Chondrocytes The role of chondrocytes, the only cells found in cartilage, in cartilage destruction in the human rheumatoid joint has not been established fully, but results from in vitro and animal models have provided inferred conclusions. Chondrocytes may participate in the destruction of the cartilage matrix by responding to proinflammatory cytokines released from the synovium [33]. The elevated expression of matrix metalloproteinases (MMPs) has been observed in RA and may contribute to the breakdown of articular cartilage during RA [34]. Both human and murine chondrocytes express functional AdipoR receptors [35]. In cultured chondrocytes, adiponectin treatment leads to a dose-dependent increase in the mRNA expression and secretion of MMP-3 [35–38] through AdipoR1, followed by the activation of AMPK and the p38 MAPK, resulting in the activation of the transcription factor NF-kB by the MMP-3 promoter [36]. Adiponectin dose-dependently induced phosphorylation of AMPK [37], JNK [37,38], ERK1/2 and p38 MAPK [38] in primary chondrocytes isolated from OA cartilage. Increased expression and secretion of MMP-1, 3, 13 were also observed in these studies [37,38]. However, the application of ERK1/2 and JNK inhibitors showed controversial effect on adiponectin induced MMP-1, 3 expression and secretion [37,38]. Interestingly, adiponectin induced MMP-13 secretion could be inhibited by inhibitors of p38 MAPK, AMPK, ERK1/2, JNK but not by inhibitor of NF-kB [37] suggesting that adiponectin induced MMP-13 secretion involves multiple signaling pathways. Furthermore, adiponectin is also able to increase the expression, the secretion, and/or the activity of nitric oxide synthase type II (NOS2/iNOS), IL-6, MMP-9, and the monocyte chemotactic protein MCP-1 in these cells [35]. The pharmacological blockade of PI3K by LY294002 results in a marked reduction of adiponectin induced iNOS expression and NO production, as well as decreased production of IL-6 and MMP-9 suggesting the involvement of PI3K pathway. The partial inhibition of adiponectin-induced MCP1 and MMP-3 by LY294002 also suggests that other alternative pathways may be involved [35]. In primary chondrocytes isolated from OA, increased production of IL-6 and increased expression of iNOS after adiponectin treatment were mediated by p38 MAPK, ERK1/2 and JNK [38] while the increased NO production might be through p38 MAPK, ERK1/2 and JNK [38], AMPK, NF-kB [37]. In addition, adiponectin induced MMP-1, 3, 13 secretion was significantly augmented by nonselective NOS inhibitor, LNMMA and a selective iNOS inhibitor, L-NIL [37], while NO was reported to be able to upregulate the expression or activity of MMPs in articular cartilage [39]. Tissue inhibitors of metalloproteinases (TIMPs) are natural inhibitors of MMPs. Four TIMPs (TIMP-1, TIMP2, TIMP-3, and TIMP-4) have been identified in vertebrates [40]. It seems that adiponectin showed no effect on the expression and secretion of TIMP-1 [35,41] but upregulated TIMP-2 expression [41]. Adiponectin stimulation also induced the mRNA expression of IL-6, regulated upon activation, normal T-cell expressed and secreted (RANTES), and MMP-3 in cultured bovine chondrocytes [42]. However, adiponectin has shown no effect on the release of TNF-a, IL1b, MMP-2, prostaglandin E2 (PGE2), and leukotriene B4 (LTB4) [35]. In human aortic endothelial cells (HAEC), adiponectin inhibited TNFa induced IL-8 synthesis through PKA dependent NF-kB signaling pathway [43] while in human chondrocytes, both adiponectin and leptin could induce the secretion of IL-8, another important cytokine in the pathogenesis of RA [44]. Taken together, these results suggest that adiponectin plays a negative role in the maintenance of cartilage homeostasis and might contribute to cartilage destruction during arthritis. However, in a well-characterized chondrogenic cell line

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Fig. 1. Effect of adiponectin on chondrocytes in RA. Both adiponectin and its receptors have been detected in chondrocytes. Interaction between adiponectin and its receptors results in the increased expression and/or secretion of cytokines, such as IL-6, matrix metalloproteinases, such as MMP-1, 3, 9, 13, chemokines, such as MCP-1, as well as in the production of NO. Pharmacological inhibitors revealed that multiple pathways such as p38 MAPK, AMPK, PI3K, ERK1/2, JNK, and so on were involved.

ATDC5, adiponectin increases chondrocyte proliferation, proteoglycan synthesis, and matrix mineralization, possibly through the upregulation of the signaling molecules Ihh, PTHrP, Ptc1, FGF18, BMP7, IGF1, and p21, as well as the down-regulation of FGF9, suggesting the positive effects of adiponectin on bone development [45]. The effect of adiponectin on chondrocytes is summarized in Fig. 1. 3.1.2. Rheumatoid arthritis synovial fibroblasts RA is characterized by synovial hyperplasia and progressive joint destruction. Rheumatoid arthritis synovial fibroblasts (RASFs) are considered to be the lead cells that drive the persistent, destructive characteristics of the disease [46,47]. The expression of adiponectin and adiponectin receptors in RASFs and synovial biopsies at the mRNA and the protein levels has been documented [48–51]. IL-6, a multifunctional cytokine that regulates immune response, haemopoiesis, the acute phase response, and inflammation, is a potential therapeutic target in RA [52]. The use of monoclonal antibody against the IL-6 receptor has been approved in many countries for the treatment of moderate to severe RA [53]. Ehling et al. [51] reported that adipoenctin increased IL-6 and MMP-1 secretion in a concentration-manner in both RASFs and OA synovial fibroblasts (OASFs). Furthermore, adipoenctin induced IL6 and MMP-1 secretion could be inhibited by p38 MAPK inhibitor (SB203580), anti-adiponectin Abs, and TNF inhibitors (etanercept and adalimumab) suggesting the involvement of p38 MAPK pathway. Subsequent studies confirmed that adiponectin treatment increases IL-6 production in a concentration- and timedependent manner [50,54,55] via the AdipoR1/AMPK/p38MAPK/ IkB kinase ab (IKKab), and the NF-kB signaling pathway [55]. PGE2, transformed from arachidonic acid via cyclooxygenase (COX) enzymes, is a principal mediator of inflammation in diseases such as RA and OA [56]. Adiponectin treatment dose-dependently induces PGE2 production [48,49,54] in both RASFs and OASFs. This was mediated by AdipoR1 in a COX-2-dependent manner as PGE2

production induced by adiponectin was significantly inhibited by siRNA for AdipoR1, nonsteroidal anti-inflammatory drug (NSAID), and selective COX-2 inhibitor [48]. It also involves the regulation of membrane-associated PGE synthase 1 (mPGES-1), one of the key enzymes involved in PGE2 synthesis and expression [49]. Furthermore, physiological concentrations of adiponectin could induce the production of IL-8 [54,57], which could be inhibited by the siRNA for AdipoR2, but not by the siRNA for AdipoR1. These results suggest that the influence of adiponectin on IL-8 is mediated by AdipoR2. The application of pharmacological inhibitors reveal that the adiponectin signaling pathway involves NF-kB and MAPK [57]. In addition, adiponectin was found to stimulate the expression of MMP-1 and MMP-13, which could be suppressed by taurine chloramine through the NF-kB pathway [58]. However, adiponectin had no effects on IL-1b, TNF-a [50,51], IL-4, IL-10, pro-MMP-13, vascular endothelial growth factor (VEGF), TGF-b [51], and MMP-9, but increased the MCP-1 expression [50]. High adiponectin levels are present in inflamed synovium [42] and in the synovial fluids of RA patients [50] which was positively correlated with the production of VEGF. Frommer et al. [42] showed that adiponectin-mediated effects, such as the expression of chemokines, cytokines, and matrix-degrading enzymes in cultured RASFs, were dependent on p38 MAPK and protein kinase C. More recently, the same group further studied the effect of adiponectin on a panel of genes/proteins relevant in RA pathogenesis including chemokines, cytokines, proteinases and peptidases, receptors etc. using affymetrix microarrays in RASFs. The expressions of most tested genes show several to more than one thousand folds of increase after adiponectin treatment. Interestingly, different adiponectin isoforms show different effect on these genes: the high molecular weight/middle molecular weight isoforms and the globular isoform are the most potent isoforms while the least potent isoform is the adiponectin trimer. These results lead to the hypothesis that adiponectin isoforms might serve as a potential therapeutic target for RA [59]. In

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Fig. 2. Effect of adiponectin on RASFs in RA. Both adiponectin and its receptors have been detected in RASFs. The interaction between adiponectin and AdipoR2 activates MAPK resulting in increased production of IL-8 mediated by NF-kB pathway; Adipoenctin upregulates IL-6, MMP-1, 13 expression/secretion through p38 MAPK/AMPK/IKKab/NFkB pathway mediated by AdipoR1; The binding of adiponectin with AdipoR1 also results in increased production of PGE2 through COX-2 and mPGES-1. Furthermore, adiponectin also induces expression of a panel of genes including chemokines, such as MCP-1, 2, 3, RANTES, GRO-a, b, g, IP-10, cytokines, such as IL-6, 11, receptors, such as IL-7R, IL-17RB, matrix metallopeptidases, such as MMP-1, 3, 10, 12, inflammatory molecules, such as PTGES, PTGS2/COX-2, and BST2, STC1, FGF10, and so on. The detailed pathways needs further study to elucidate. GRO-a, growth-related oncogene a (CXCL1); GRO-b, growth-related oncogene b (CXCL2); GRO-g, growth-related oncogene g (CXCL3); IP-10, interferon-inducible protein-10 (CXCL10); IL-7 R, interleukin 7 receptor; IL-17RB, interleukin 17 receptor B; PTGES, prostaglandin E synthase; PTGS2/COX-2, prostaglandin endoperoxide synthase2/cyclooxygenase-2; BST2, bone marrow stromal cell antigen 2; STC1, stanniocalcin 1; FGF10, fibroblast growth factor 10.

addition, adiponectin and IL-1b could synergistically activate IL-6, IL-8, and PGE2 expression in RA fibroblast-like synoviocytes in a NF-kB dependent manner [60]. The effect of adiponectin on RASFs in RA is summarized in Fig. 2. 3.1.3. Animal studies The in vitro data in chondrocytes and RASFs suggested that adiponectin might promoting RA. However, in in vivo models adiponectin exhibited quite different effects. In a DBA/1 mouse model for collagen-induced arthritis (CIA), adiponectin treatment mitigated significantly the severity of arthritis along with a decrease in the expression of TNF-a, IL-1b, and MMP-3 in joint tissues. Furthermore, adiponectin pretreatment inhibited significantly the IL-1b-induced proliferation of synovial fibroblasts from this model but stimulated the IL-6 expression in both the joint tissues and the synovial fibroblasts [61]. Taken together, recent findings have indicated that adiponectin induces gene expression and protein synthesis in both chondrocytes and RASFs, thus supporting its potential role in the pathophysiological modulation of RA. Although adiponectin is generally considered as an anti-inflammatory adipokine [62], its roles in inflammation are still debatable. Adiponectin might act as both anti- and pro-inflammatory mediator [17,63], depending on the different pathophysiological processes. Present data in basic research have demonstrated clearly that adiponectin promotes inflammation by increasing cytokine secretion, promoting MMPs synthesis, inducing chemokines expression and so on. These effects are mediated by adiponectin receptors through multiple pathways including p38 MAPK, AMPK, ERK1/2, PI3K, NF-kB, iNOS/NO and COX-2, etc. in numerous types of cells in RA while the detailed mechanisms need further investigation to dissect. It is worth noting that the only animal study provides positive results for the beneficial effect of adiponectin in RA. Therefore, more in vivo experiments are urgently needed to interpret this inconsistency.

3.2. Adiponectin levels in RA patients Accumulating evidence have demonstrated that low adiponectin levels are associated with type 2 diabetes [64], metabolic syndrome [65], atherosclerosis [13], obesity, cancer [66], hypertension [67], chronic kidney disease [68], and polycystic ovary syndrome [15], among others. Thus, adiponectin could serve as a useful risk biomarker, even though there are some discrepancies in these reports [17]. Multiple studies have determined the adiponectin levels in the serum/plasma and the synovial fluid of RA patients and healthy controls. Surprisingly, most publications have reported increased serum/plasma adiponectin in RA patients. Rho et al. [69] showed that the serum concentrations of adiponectin, visfatin, the C-reactive protein (CRP), and TNF-a were significantly higher in RA patients than in controls. Moreover, this association remained significant even after adjusting for body mass index (BMI), inflammation, or both. Furthermore, disease duration correlated significantly with adiponectin concentrations, but was not associated with decreased radiographic joint damage in obesity because the inverse correlation with BMI remained constant [69]. However, Klein-Wieringa et al. [70] demonstrated that levels of IL-6, TNF-a, visfatin, and adiponectin were positively associated with radiographic progression, but only adiponectin levels retained this significant association when the model was corrected for the presence of anti-cyclic citrullinated peptide antibodies. They concluded that baseline serum adiponectin levels could predict radiographic progression in early RA [70]. TargonskaStepniak et al. [71] found that serum adiponectin concentrations remained within the normal range in RA patients, but significantly higher in patients with disease duration less than 10 years. Serum adiponectin levels correlated positively with age, disease duration, and high-density lipoprotein cholesterol (HDL) levels. While in patients with long-standing RA, there was a negative correlation between adiponectin and numbers of tender, swollen joints.

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Table 1 Adiponectin levels in RA patients. Publication date

Number of C/P

Adiponectin level in C/P (mg/ml)

Main findings serum/plasma adiponectin:

Ref.

2006

23/20

25.57  1.95/37.64  3.77

[72]

2006 2008

18/31 18/18

7.6  0.7/13.56  2.1 9.2(3.5–15.3)/12.3(5.7–21.1)

2008

19/37

13.5  2.7/12.9  5.1 for females; 7.8  4.5/8.6  5.6 for males

2009 2009

91/167 0/197

16.7(9.5–31.1)/22.8 (14.8–38.7) N/30.5 (19.1–40.3)

2009

58/58

2.352  0.266/4.116  0.598 for males; 3.487  0.298/6.017  0.524 for females

2009

30/30

10.9(2.9–27.3)/17.9(3.7–32.6)

2009

42/90

9.1  3.8/16.1  6.8

2010

0/169

2010

0/80

2010

29/56

N/25.0(15.1–39.4) for females; N/20.5(13.8–35.7) for males N/12.7 (6.4) RA <10 years; N/17.7 (11.2) RA >10 years 9.2  3.8/58.9  30.4

2010

22/62

2011

146/141

Higher in RA compared with healthy controls; Negatively associated with the leukocyte count in RA synovial fluid; Not related to age, disease duration, BMI, or disease activity of RA patients Higher in RA patients Higher in RA patients; Increased by etanercept treatment for three months in RA patients In healthy controls did not differ significantly from those of patients with RA at baseline; Increased by both infliximab and etanercept treatment, but only in female patients Higher in RA patients, but not associated with Larsen scores Associated with radiographic damage, which was stronger in patients with longer disease duration Higher in RA patients, which tended to be higher in lean RA patients and not correlate with BMI,disease activity; Not affected by short- or long-term TNF blockade alone Higher in RA patients; Not affected by anti-TNF treatment but significantly decreased in the tertile of patients with the highest baseline after a sixmonth treatment Higher in RA patients and significantly correlated with RA severity; Negatively correlated with BMI, but not correlated with inflammatory markers, bone metabolism markers, DAS28, CRP, or the prednisolone dose Not differ significantly among women and men; Not interact significantly with HOMA Correlated positively both with age and disease duration, and correlated negatively with glomerular filtration rate Higher in RA patients; Not correlated with either the HOMA-IR index or the IMT in RA patients; Correlated with DAS28 and IL-6 level in RA patients Higher in active RA patients Not show difference between inactive RA patients and healthy control; Positively correlated with DAS28, ESR, and RF in active RA patients Significantly higher in female RA patients, but not in male patients; Negatively associated with the CRP level

13.7  2.1 (for control)/15.8  2.6 (for active patients);14.0  2.4 (for inactive patients) 3.6(2.4–7.4)/10.1(4.5–26.8) for females; 2.3/2.6 for males

[79] [89] [90]

[69] [73] [80]

[91]

[82]

[84] [71] [81] [75]

[83]

C/P: number of healthy controls/number of RA patients; N: not detected; BMI: body mass index; TNF: tumor necrosis factor; HOMA: Homoeostasis Model Assessment; IR: insulin resistance; IMT: common carotid intima-media thickness; ESR: erythrocyte sedimentation rate; RF: rheumatoid factor; DAS28: Disease Activity Score 28; CRP: Creactive protein.

However, another study suggested that although both the serum and the synovial fluid have higher adiponectin concentrations, this was not related to age, disease duration, body mass index, or disease activity in RA patients [72]. Giles et al. [73] demonstrated that RA patients have high serum adiponectin levels, which were associated with radiographic damage. Furthermore, RA patients with low levels of visceral fat showed the highest adiponectin levels. The same group also identified the temporality and the dose-responsiveness of the relationship between circulating adiponectin and erosive joint destruction in RA [74]. Liu et al. [75] reported that the levels of serum adiponectin are higher in active RA patients than in inactive patients and healthy volunteers. The elevated levels of adiponectin were correlated with the disease activity score 28 (DAS28), the erythrocyte sedimentation rate (ESR), and the rheumatoid factor (RF) [75] positively. Similarly, higher concentrations of adiponectin were detected in the synovial fluid of RA patients [72,76], which were positively correlated with the synovial fluid white blood cells (WBCs) [77]. Further, adiponectin levels in the synovial fluid were lower than those in the serum [72,77], indicating that peripheral fat stores are major producers of adiponectin in the blood stream [72], as well as implying the chondroprotective role of adiponectin [77]. High serum/plasma levels of adiponectin were also observed by other groups in RA patients [78–82]. Interestingly, Yoshino et al. [83] reported that female RA patients had significantly higher serum adiponectin concentrations than normal female control subjects, but this difference was not observed in males. However, other groups have shown that serum adiponectin concentrations did not differ significantly between women and men [71,84], and that these were not associated with insulin resistance in patients with RA [84].

The clinical examination of adiponectin serum/plasma levels is summarized in Table 1. Taken together, present evidence suggest that RA patients have higher serum/plasma and synovial fluid adiponectin levels, although there are discrepancies regarding their association with age, gender, disease duration, joint damage, body mass index, and so on. The reasons for these inconsistences have yet to be defined clearly. These might be due to the heterogeneity of patients, the small sample sizes, and the bias or errors in the assessment of disease severity and disease activity. In view of the proinflammatory effects of adiponectin and its action on RA-related cells in vitro, adiponectin appears to be a potential driver for RA, whereas some in vivo studies have shown its beneficial effects. The interpretation of these paradoxical results is a big challenge. As both in vitro and in vivo studies in this area are mostly preliminary, with limited data available, further future studies might help resolve inconsistencies in the literature. 4. Conclusions and perspectives Recent advances have demonstrated that adiponectin is an ‘‘almighty’’ adipose tissue-derived protein acting from head to toe. There are consistent reports on its beneficial roles in cardiovascular diseases, diabetes, and so on, but its involvement in inflammation is still controversial. Existing data have established the novel link between adiponectin and RA, as proven by its effect on chondrocytes and RASFs, as well as the changes in its concentration in RA patients. Serum/plasma adiponectin levels can be considered as a useful biomarker for RA. However, increased serum/plasma levels of adiponectin were observed in RA, which are different from those in cardiovascular diseases, diabetes, and obesity. This

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observation, together with inconsistencies in in vitro and in vivo studies, has raised the yet-unsolved debate on the role of adiponectin in inflammation. Inconsistent results on adiponectin levels after anti-TNF intervention in RA [85–88] complicate the issue further. Therefore, more in-depth investigations in basic research and more clinical observations with larger sample sizes are needed urgently to elucidate fully the role and the mechanisms of adiponectin in RA. Conflicts of interests The authors declare that they have no competing interests. Acknowledgments The present study was supported by the National Natural Science Foundation of China (No. 81160048) and the Research Fund of the University of Macau (No. MYRG161(Y2-L2)-ICMS11CXP)). References [1] Chaldakov GN, Stankulov IS, Hristova M, Ghenev PI. Adipobiology of disease: adipokines and adipokine-targeted pharmacology. Current Pharmaceutical Design 2003;9:1023–31. [2] Maury E, Brichard SM. Adipokine dysregulation, adipose tissue inflammation and metabolic syndrome. Molecular and Cellular Endocrinology 2010;314: 1–16. [3] Kontny E, Plebanczyk M, Lisowska B, Olszewska M, Maldyk P, Maslinski W. Comparison of rheumatoid articular adipose and synovial tissue reactivity to proinflammatory stimuli: contribution to adipocytokine network. Annals of Rheumatic Diseases 2012;71:262–7. [4] McInnes IB, Liew FY. Cytokine networks – towards new therapies for rheumatoid arthritis. Nature and Clinical Practice in Rheumatology 2005;1:31–9. [5] Christodoulou C, Choy EH. Joint inflammation and cytokine inhibition in rheumatoid arthritis. Clinical and Experimental Medicine 2006;6:13–9. [6] Bingham 3rd CO. The pathogenesis of rheumatoid arthritis: pivotal cytokines involved in bone degradation and inflammation. Journal of Rheumatology 2002;65(Suppl.):3–9. [7] Asquith DL, McInnes IB. Emerging cytokine targets in rheumatoid arthritis. Current Opinion in Rheumatology 2007;19:246–51. [8] Williams RO, Paleolog E, Feldmann M. Cytokine inhibitors in rheumatoid arthritis and other autoimmune diseases. Current Opinion in Pharmacology 2007;7:412–7. [9] Gomez R, Conde J, Scotece M, Gomez-Reino JJ, Lago F, Gualillo O. What’s new in our understanding of the role of adipokines in rheumatic diseases? Nature Reviews in Rheumatology 2011;7:528–36. [10] Brochu-Gaudreau K, Rehfeldt C, Blouin R, Bordignon V, Murphy BD, Palin MF. Adiponectin action from head to toe. Endocrine 2010;37:11–32. [11] Matsuzawa Y. Adiponectin: a key player in obesity related disorders. Current Pharmaceutical Design 2010;16:1896–901. [12] Kadowaki T, Yamauchi T, Kubota N, Hara K, Ueki K, Tobe K. Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. Journal of Clinical Investigation 2006;116:1784–92. [13] Behre CJ. Adiponectin obesity and atherosclerosis. Scandinavian Journal of Clinical and Laboratory Investigation 2007;67:449–58. [14] Jarde T, Perrier S, Vasson MP, Caldefie-Chezet F. Molecular mechanisms of leptin and adiponectin in breast cancer. European Journal of Cancer 2011;47:33–43. [15] Groth SW. Adiponectin and polycystic ovary syndrome. Biological Research for Nursing 2010;12:62–72. [16] Chen X, Wang Y. Adiponectin and breast cancer. Medical Oncology 2011;28: 1288–95. [17] Sun Y, Xun K, Wang C, Zhao H, Bi H, Chen X, et al. Adiponectin, an unlocking adipocytokine. Cardiovascular Therapy 2009;27:59–75. [18] Yamauchi T, Kamon J, Ito Y, Tsuchida A, Yokomizo T, Kita S, et al. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature 2003;423:762–9. [19] Kadowaki T, Yamauchi T. Adiponectin and adiponectin receptors. Endocrine Reviews 2005;26:439–51. [20] Yamauchi T, Nio Y, Maki T, Kobayashi M, Takazawa T, Iwabu M, et al. Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions. Nature Medicine 2007;13:332–9. [21] Kadowaki T, Yamauchi T, Waki H, Iwabu M, Okada-Iwabu M, Nakamura M. Adiponectin, adiponectin receptors, and epigenetic regulation of adipogenesis. Cold Spring Harbor Symposia on Quantitative Biology 2011;76:257–65. [22] Deepa SS, Dong LQ. APPL1: role in adiponectin signaling and beyond. American Journal of Physiology – Endocrinology and Metabolism 2009;296:E22–36.

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Dr. Xiuping Chen Xiuping Chen graduated from Peking Union Medical College and was a post-doctoral fellow of Dr. Cuihua Zhang’s lab in cardiovascular pharmacology at Texas A&M University and University of MissouriColumbia. Then he move to University of Macau and serves as an assistant professor in University of Macau from 2010. He has published more than 50 peer reviewed articles. His research now is in the fields of cardiovascular pharmacology and natural products including traditional Chinese medicine. The primary focus has been the role of cytokines in the pathogenesis of cardiovascular system inflammatory disorders such as atherosclerosis and the effect of natural products on these processes.