Rheumatic Diseases and Obesity: Adipocytokines as Potential Comorbidity Biomarkers for Cardiovascular Diseases

Scrivo, Rossana; Vasile, Massimiliano; Müller-Ladner, Ulf; Neumann, Elena; Valesini, Guido

doi:https://doi.org/10.1155/2013/808125

Mediators of Inflammation

On this page

Abstract Introduction Conclusions References Copyright Related Articles

Review Article | Open Access

Volume 2013 | Article ID 808125 | https://doi.org/10.1155/2013/808125

Rheumatic Diseases and Obesity: Adipocytokines as Potential Comorbidity Biomarkers for Cardiovascular Diseases

Rossana Scrivo,¹Massimiliano Vasile,^1,2Ulf Müller-Ladner,²Elena Neumann,²and Guido Valesini¹

Academic Editor: Eric F. Morand

Received15 May 2013

Revised29 Oct 2013

Accepted30 Oct 2013

Published26 Nov 2013

Abstract

Inflammation has been recognized as a common trait in the pathogenesis of multifactorial diseases including obesity, where a low-grade inflammation has been established and may be responsible for the cardiovascular risk related to the disease. Obesity has also been associated with the increased incidence and a worse outcome of rheumatoid arthritis (RA) and osteoarthritis (OA). RA is characterized by systemic inflammation, which is thought to play a key role in accelerated atherosclerosis and in the increased incidence of cardiovascular disease, an important comorbidity in patients with RA. The inflammatory process underlying the cardiovascular risk both in obesity and RA may be mediated by adipocytokines, a heterogeneous group of soluble proteins mainly secreted by the adipocytes. Many adipocytokines are mainly produced by white adipose tissue. Adipocytokines may also be involved in the pathogenesis of OA since a positive association with obesity has been found for weight-bearing and nonweight-bearing joints, suggesting that, in addition to local overload, systemic factors may contribute to joint damage. In this review we summarize the current knowledge on experimental models and clinical studies in which adipocytokines were examined in obesity, RA, and OA and discuss the potential of adipocytokines as comorbidity biomarkers for cardiovascular risk.

1. Introduction

Adipocytokines are a very heterogeneous group of soluble proteins showing pro- or anti-inflammatory effects. Many adipocytokines are mainly secreted by the adipocytes of white adipose tissue (WAT), which is nowadays considered a major endocrine organ through the capability of secreting adipocytokines [1]. The most widely studied adipocytokines are leptin, adiponectin, resistin, and visfatin. Leptin plays a key role in the regulation of appetite and body weight and in the modulation of immune responses. Circulating leptin concentrations are increased in obesity, and these increased levels are associated with the development of inflammation, insulin resistance, and subclinical coronary atherosclerosis [2, 3]. Elevations in resistin and visfatin are also associated with increased inflammation, insulin resistance, and cardiovascular risk [2, 4]. In contrast, adiponectin is an anti-inflammatory adipocytokine, and increased concentrations are inversely associated with obesity, insulin resistance, and cardiovascular risk [2]. Hence, all of these adipocytokines are actively involved in obesity, but the precise mechanism needs to be defined. Interestingly, WAT hosts a special microenvironment during obesity, enriched with many immune cell populations interacting with adipocytes [1], and this strict interaction may sustain the pathways linking metabolism and the immune system. Indeed, when adipose tissue inflammation and dysfunction have developed, adipokine secretion is significantly changed towards a proinflammatory, diabetogenic, and atherogenic pattern [5, 6]. Recently, the identification of biomarkers gained increased attention in many fields of medicine, including rheumatology. Per the definition of the working group of the National Institutes of Health (NIH), a biomarker is assumed to be “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention” [7]. These features may help physicians to recognize disease susceptibility, prognosis, and therapeutic response that are vital issues when assessing chronic diseases, including rheumatic conditions. However, some biomarkers may be disease related, such as anti-citrullinated protein/peptide antibodies (ACPA) in rheumatoid arthritis (RA), while others appear to be inflammation dependent, and in this perspective we may consider several adipocytokines. Since obesity may be associated with other chronic conditions, including RA, whose onset and outcome are affected by obesity [8, 9], and osteoarthritis (OA) [10], the purpose of this review is to summarize the literature related to adipocytokines in obesity, RA, and OA and to discuss whether they may be considered as comorbidity biomarkers for cardiovascular risk, potentially worsening the outcome of these diseases. The literature search relied on PubMed (from January 1, 1990, through March 31, 2013) and was limited to original research involving animal models and human subjects published in English and having abstracts. The articles were identified using headings consisting of a combination of at least two among “rheumatoid arthritis, osteoarthritis, obesity, cardiovascular risk, adipocytokine, biomarker, adiponectin, leptin, resistin, and visfatin.”

2. Obesity

Overweight and obesity are defined by the World Health Organization (WHO) as abnormal or excessive fat that accumulates and presents a risk to health [11]. Over the past years, obesity has become epidemic in many countries and has been recognized as a challenge for public health since it may contribute, together with abdominal fat distribution, to the individual risk for type 2 diabetes, dyslipidemia, fatty liver disease, chronic subclinical inflammation, hypertension, and cardiovascular disease [12–14]. In the past decades, advances in obesity research have led to the recognition that adipose tissue is an active endocrine organ that secretes several bioactive proteins termed adipocytokines [1]. In an autocrine and paracrine manner, adipocytokines contribute to the modulation of adipogenesis, immune cell migration into adipose tissue, and adipocyte metabolism and function [5, 6]. Hence, they may be involved in the pathogenesis of obesity and the role of some of them (leptin, adiponectin, resistin, and visfatin) has been extensively studied in the disease. The main findings related to these studies are summarized in Table 1.

2.1. Experimental Models

Leptin mRNA levels were increased in mice adipose tissue after the exposure to proinflammatory cytokines [15]. In addition, leptin has been shown to acutely decrease in mice with caloric restriction and increase with refeeding and also induces anorexigenic factors [16]. Also adiponectin seems to regulate metabolic pathways in animal models. In fact, treatment with adiponectin decreases hyperglycaemia and plasma levels of free fatty acids and improves insulin sensitivity in obese animals [17], while adiponectin-deficient mice develop diet-induced insulin resistance on a high-fat, high-sucrose diet [18].

Differently from leptin and adiponectin which are mainly produced by adipocytes, visfatin and resistin are primarily secreted by the cells of immune system [19, 20]. Visfatin is a product of the pre-B cell colony enhancing factor (PBEF) gene, subsequently identified as the extracellular form of the enzyme nicotinamide phosphoribosyltransferase (NAMPT), believed to mimic insulin function [21]. Plasma visfatin concentration was increased during the development of obesity in an experimental model of obesity-associated insulin resistance [22]. Resistin is a 12 kDa polypeptide that was initially implicated in the pathogenesis of obesity-associated insulin resistance and type 2 diabetes mellitus in mouse models [23]. Mice with chronic hyperresistinemia exhibit modest fasting hyperglycemia and glucose intolerance, associated with increased hepatic glucose production in the setting of hyperinsulinemia, suggesting that chronic hyperresistinemia leads to impairment of glucose homeostasis [24].

2.2. Clinical Studies

In humans, leptin primarily acts on hypothalamic neurons resulting in anorexia and weight reduction [25]; in particular, serum levels decrease with fasting [26, 27] and increase during hyperinsulinemia [28]. Furthermore, there may be a direct link between circulating leptin concentrations and increased cardiovascular risk since this adipocytokine may enhance platelet aggregation and arterial thrombosis, promote angiogenesis, impair arterial distensibility, and induce proliferation and migration of vascular smooth muscle cells [29]. In contrast, circulating adiponectin levels tend to be low in morbidly obese patients and increase with weight loss and with the use of thiazolidinediones, which enhance the sensitivity to insulin [30, 31]. However, different isoforms of adiponectin have been recognized [32], which may have different effects: low, middle, and high molecular weight isoforms (LMW, MMW, and HMW) and globular adiponectin. A protective role of HMW adiponectin against the development of obesity, insulin resistance, glucose intolerance, diabetes mellitus, hypertension, metabolic syndrome, atherosclerosis, and cardiovascular disease [33–37] and a negative role of LMW adiponectin on diabetes mellitus and cardiovascular disease have been described [38–41]. In humans, circulating visfatin levels are increased in diabetic subjects and are closely correlated with WAT accumulation [22, 42]. However, the current data on visfatin levels in humans are controversial in many aspects: the effective cellular source of visfatin in visceral fat in obese individuals, the possible influence of gender in its production, the association between visfatin mRNA expression in visceral fat mass with the body mass index (BMI), and the correlation between plasma levels with the total amount of visceral fat and plasma lipids [21]. A possible explanation for these conflicting findings may reside in the fact that, although visceral fat may be a central source of visfatin, the producing cells may be mainly other cells of the adipose tissue, not adipocytes. There could also be a stronger influence of inflammatory cells/stage on systemic visfatin level than on other adipocytokines, but also polymorphisms in coding regions of the genes may be responsible for different effects in the different population considered. Regarding the gender differences, hormones or even the different dispositions of adiposity in male and female may play a role, while the influence on lipid profile is probably linked to intracellular enzymatic function in nicotinamide adenine dinucleotide (NAD) synthesis [43]. Similarly, studies in humans have shown conflicting results when examining resistin levels in obese and lean subjects, the adipose resistin expression, or the role of resistin in the development of insulin resistance [44–51]. In one of these, serum resistin levels were higher in female patients than in males [45]. Hence, as for visfatin, additional research is necessary to better define its role in the pathogenesis of obesity. Considering that visfatin and resistin share a common origin, mainly linked to the cells of the immune system and not adipocytes, it is likely that their prevalent activity is devoted to immunomodulation rather than control of metabolism and lipid profile. This may sustain the mixed results so far obtained.

Overall, it has been demonstrated that adiposity is associated with increased production of proinflammatory molecules, whereas reduced adiposity is associated with decreased concentration of proinflammatory and increased concentration of anti-inflammatory molecules [52]. All these findings suggest that altered adipocytokine secretion may represent a link between adipose tissue dysfunction in obesity and metabolic and cardiovascular obesity-related disorders. Leptin, adiponectin, visfatin, and resistin are important modulators of glucose metabolism because they may primarily contribute to altered appetite and satiety, impaired insulin sensitivity or secretion, and to inflammation. Hotamisligil et al. first discovered the existence of an inflammatory state involving adipose tissue and its potential role in obesity by demonstrating the secretion of TNF by the adipose tissue [53]. In addition to adipocytes, macrophages in human adipose tissue may contribute to enhancing the obesity-related “low-grade’’ chronic inflammation [14]. The action of the inflammatory molecules may represent the molecular link between adipose tissue and the cardiovascular complications of obesity [14]. Despite these considerations, we believe that adipocytokines cannot still be included as biomarkers of cardiovascular risk in obese subjects: although they may have a clinical relevance as biomarkers for fat mass, more focused studies are needed to evaluate their potential in the assessment of cardiovascular function in obese individuals.

3. Rheumatoid Arthritis

RA is an autoimmune disease affecting 0.5–1% of the adult population with potential destructive effects on diarthrodial joints and often burdened by comorbidities, particularly in the cardiovascular system. Indeed, people with RA die prematurely, mostly due to higher rates of cardiovascular events [54]. Concentrations of adipocytokines have generally been reported to be higher in patients with RA than in control subjects [55–57], and it is supposable that they may also play a role in the increased cardiovascular risk since obesity is also associated with this unfavorable outcome [58]. Here we summarize the available experimental and clinical data in which adipocytokines were examined, discussing their potential role as biomarkers of cardiovascular risk. In addition, an overview of the central findings of these studies is reported in Table 2.

3.1. Experimental Models

Adiponectin is one of the most studied adipocytokines in the context of this review. It has been shown to be secreted not only by WAT, but also locally by osteoblasts and hepatocytes during inflammatory processes [59–61] and by RA synovial fibroblasts (RASF) [62]. In contrast to findings in other inflammatory diseases [18, 63], both RA synovial tissue and articular adipose tissue were a significant source of adiponectin, capable of stimulating RASF to produce IL-6 and prometalloproteinase-1, a finding that supports an active role of this adipocytokine in the pathogenesis of RA [62]. These results were confirmed in recent studies, where adiponectin stimulation induced the secretion of chemokines and proinflammatory cytokines by fibroblasts and other immune cells and of matrix metalloproteinases (MMP) by fibroblasts and chondrocytes in synovial tissue from RA patients [32, 64]. Furthermore, several findings in vitro suggest that adiponectin may actively promote RA progression as it induces the secretion of proinflammatory molecules (e.g., IL-6, COX-2), chemokines (e.g., IL-8, MCP-1), and matrix-degrading enzymes (e.g., MMP-3) in vitro [64, 65]. Hence, adiponectin seems to have a strong proinflammatory effect in RA, which may also sustain the increased cardiovascular risk observed in some patients. In particular, increased levels of proinflammatory cytokines, including IL-6, may directly contribute to the mechanisms of change in the insulin sensitivity in different adipose depots [14]. Interestingly, insulin resistance is increased in patients with RA and is associated with accelerated coronary atherosclerosis [66].

The other well-known adipocytokines, leptin, resistin, and visfatin show also predominantly proinflammatory properties similar to the local effects described for adiponectin. In antigen-induced arthritis models, leptin-deficient mice developed less severe arthritis with lower mRNA levels of proinflammatory cytokines compared with control mice and had reduced inflammation [67]. Furthermore, mice with a mutation in the gene encoding leptin or the gene encoding the leptin receptor both displayed obese phenotypes and various defects in cell-mediated and humoral immunity [68], thus providing a molecular mechanism sustained by leptin linking metabolic processes and immune dysfunctions.

Resistin showed a strong upregulation of TNF and IL-6 expression by human peripheral blood mononuclear cells. It induced arthritis onset after injection into the joints of healthy mice, and the frequency of arthritis increased in a dose-dependent manner [69]. Visfatin was shown to be involved in RASF activation by triggering fibroblast motility and promoting high amounts of chemokines, proinflammatory cytokines, and MMPs synthesis by these cells [70]. These results show a strong contribution of visfatin to synovial inflammation in RA, suggesting that this may be a potential biomarker for RA.

3.2. Clinical Studies

In patients with RA a low BMI appears to be associated with a significant risk of cardiovascular death, even after adjustment for cardiac history, smoking, diabetes mellitus, hypertension and malignancy [71]. This may be due to the state of rheumatoid cachexia, typical for RA patients, which show characteristic low muscle and high fat mass. In addition, considering that increased central adiposity is common in RA [72] and is associated with insulin resistance [73], the role of adipocytokines in RA inflammation appears captivating. In fact, most evidence suggests that classic risk factors do not explain excess vascular disease in RA, and systemic inflammation independently predicts cardiovascular events in men and women with or without existing heart disease [74].

The diverse isoforms of adiponectin have different potencies to modulate gene expression of RASF [32] or in part even contrary effects [75, 76].

Available data on RA suggest that adiponectin is associated with disease progression [77–79], probably because adiponectin may stimulate osteoclast differentiation via increasing RANKL and decreasing osteoprotegerin [80] and may up-regulate vascular endothelial growth factor and MMPs [65]. Another possible underlying mechanism could be the effect of IL-6 on ACPA-producing B cells, because IL-6 is a well-known growth factor for B cells and has been shown to play a role in mouse models of antibody-mediated arthritis [81, 82]. However, adiponectin and leptin serum levels from RA patients were neither associated with clinical and serological features of inflammation nor were they down-regulated after 12 weeks of anti-TNF treatment [83], in contrast with findings shown in vitro [62, 64, 65]. Furthermore, early and chronic RA patients had higher plasma adiponectin levels compared to healthy controls, but they were lower than those of patients with OA [84]. A possible explanation for the discrepancy of experimental and clinical findings could be due to relevance of metabolic and systemic regulation of adiponectin over the local phenomenon. It may also be a consequence of the individual adiponectin isoforms with different potencies to modulate gene expression of RASF locally as well as systemically, suggesting that some of them are more detrimental in RA than others, even if no opposing effects in the setting of RA pathophysiology were found [32]. While adiponectin levels were associated with radiographic damage and RA progression [78, 84], the levels decreased as visceral fat area increased. Hence, this adipocytokine might be a mediator of the inverse association of visceral fat with radiographic damage [85]. Consistent with these results showing an inverse relation between severity of RA and adipose tissue, a high BMI was inversely associated with the amount of joint destruction in patients with early RA, although only in those with a positive ACPA status [86]. A peculiar feature of adiponectin physiology is that circulating levels diminish as adiposity increases, with the highest levels in subjects with the lowest fat mass [87]. Hence, considering the detrimental effects on the joint, adiponectin becomes an excellent candidate to mediate the inverse relationship between increasing adiposity and radiographic damage.

Data on leptin in RA are likewise controversial regarding serum levels: in some studies RA patients and controls with a similar body fat content and BMI or when adjusted for BMI did not differ with respect to systemic leptin concentrations [88–91], while in others they were higher than controls [55, 92–96]. Furthermore, these ambiguous results were not limited to serum/plasma concentrations since higher leptin levels correlated with disease activity or clinical features [55, 56, 95, 96], whereas other studies did not confirm these findings [90, 91, 94]. Moreover, in one report an inverse correlation with C-reactive protein (CRP) and IL-6 levels was described [89]. However, leptin may have a protective effect against joint damage in RA, as it was hypothesized in the study by Rho et al. [95]. Here, leptin concentrations were found to be associated with reduced radiographic joint damage, particularly after adjustment for measures of inflammation (disease activity score 28, IL-6, CRP). Recently, a similar conclusion was made from the observation that synovial fluid (SF) leptin levels were lower in nonerosive patients, suggesting that a local leptin consumption may be protective against erosions [96], as previously described [69]. In favour of this suggestion is the knowledge that leptin induces IL-1 receptor antagonist production [97], and treatment of RA patients with IL-1 receptor antagonist has been proved to stop the joint destructive process [98]. Higher leptin levels were also associated with insulin resistance in RA, although they paradoxically attenuated the effect of insulin resistance on severity of coronary calcification [99]. This finding was interpreted by the authors as an overall effect of leptin on atherosclerosis mediated through interactions with other risk factors for atherosclerosis, rather than an independent effect in RA. Alternatively, high leptin concentrations could reflect a feedback mechanism to improve insulin resistance and also ameliorate its effects on atherosclerosis in RA [99].

Resistin levels were found to be increased in the serum and accumulated in the inflamed joints of RA patients [57, 69, 100]. Furthermore, they were found to be predictive with regard to radiological damage, irrespective of CRP levels or ACPA status, in a cohort of patients treated with adalimumab. In this study resistin levels declined after long-term adalimumab or glucocorticoid treatment in parallel with a decrease of inflammatory markers and also the lipid profile was ameliorated [101]. Hence, resistin seems to have a definite pathophysiological role in RA inflammation and damage, while the potential involvement in cardiovascular risk in these patients has not been investigated.

In conclusion, both experimental and clinical data show a strong proinflammatory potential for these adipocytokines in RA, although many data remain controversial. Adiponectin and leptin are the two adipocytokines showing a potential for being comorbidity biomarkers of cardiovascular risk in RA patients (see Figure 1). Adiponectin levels were associated with radiographic damage and RA progression. However, adiponectin seems to be a mediator of the inverse association of visceral fat with radiographic damage that may be related to the state of rheumatoid cachexia, characterized by low muscle mass and high fat mass. Indeed, it was observed that serum adiponectin concentration decreased as visceral fat area increased, leading to the inhibition of radiographic damage progression [78, 85]. Also leptin may be involved in cardiovascular risk, due to the association of serum levels with insulin resistance and the effect on atherosclerosis [99].

Figure 1

The white adipose tissue (WAT) is considered a major endocrine organ through the capability of secreting adipocytokines. In obese individuals, WAT hosts many immune cell populations interacting with adipocytes. Obesity is a risk factor for both rheumatoid arthritis (RA) and osteoarthritis (OA), and it is likely that some adipocytokines are involved in the pathogenesis of these two diseases. In RA, serum adiponectin levels were associated with radiographic damage and decreased as visceral fat area increased; leptin levels were associated with insulin resistance. In OA, leptin levels were associated with increased levels of bone formation biomarkers and erosive disease, and a positive correlation with the body mass index was also observed. These adipocytokines may be involved in the increased cardiovascular risk observed in RA and OA patients. Conversely, the role of resistin and visfatin is still controversial.

4. Osteoarthritis

OA in general develops progressively over several years, although symptoms might remain stable for long periods, and indeed it becomes more common with age. The diagnosis relies on clinical and radiological features since nearly half of the patients with radiological features have no symptoms and vice versa [102]. The disease is characterized by biomechanical and biochemical changes in the cartilage, subchondral bone, and synovial tissue [102]. Obesity is doubtless a very relevant etiologic factor for OA due to the overload effect on joint cartilage. In fact, chondrocytes and osteoblasts are sensitive to pressure through the presence of mechanoreceptors [103], whose activation may trigger both the inhibition of matrix synthesis and cartilage degradation. However, a positive association between OA and obesity has also been found for non-weight-bearing joints [104] suggesting that, in addition to local overload, systemic factors contribute to joint damage. The central role of inflammatory processes in OA supports this view, and it is relevant to note that the risk of hand OA is about 2-fold in obese people as compared with normal-weight subjects [105]. The inflammatory mediators responsible for this observation in OA probably also include adipocytokines. Therefore, they were recently investigated for their utility in providing diagnostic or prognostic clues as biomarkers for OA. An overview of the key findings of studies investigating adipocytokines in OA is reported in Table 3.

4.1. Experimental Models

Leptin is the most studied adipocytokine in OA experimental models, with recent studies supporting its pathogenetic role. It was demonstrated that leptin has a catabolic role on cartilage metabolism, inducing collagen release from bovine cartilage and stimulating MMP expression in chondrocytes cultured with WAT-conditioned media taken from fat pads from OA patients [106]. Other findings support a role of leptin in cytoskeletal remodeling, which is also implicated in OA pathogenesis, since leptin-treated human chondrocytes showed an activated Rho/ROCK pathway signaling leading to change of cell shape and stress fiber formation [107]. However, these data are not consistent with a previous study in which physiologic doses of leptin were not able to affect matrix biosynthesis, proteoglycan breakdown, or nitric oxide production in vitro in cartilage explants from mice with OA [108]. Hence, leptin may be a secondary mediator of cartilage degeneration in OA. Indeed, the proinflammatory effects of leptin are apparent at superphysiologic concentrations: OA increases the expression of leptin and leptin receptors in chondrocytes from OA samples [109], suggesting that physiologic levels of leptin may mediate the production of inflammatory mediators in osteoarthritic but not normal tissue.

As in RA, adiponectin seems to drive proinflammatory effects in RASF and adipose tissue adipocytes [62]. Recently, an increased secretion of MMP-3 in cultured human chondrocytes through its receptor AdipoR1 was found, contributing to cartilage destruction [110]. Furthermore, the pro-destructive effect of adiponectin in OA was shown in another study, in which both AdipoR1 and AdipoR2 were significantly higher in lesional than in nonlesional areas of cartilage obtained from OA patients at the time of knee-replacement surgery [111]. In addition, adiponectin was shown to induce nitric oxide synthase, IL-6, MMP-3, MMP-9, and MCP-1 in murine ATDC5 chondrogenic cell lines [112]. Only one report demonstrated a protective effect of adiponectin through the upregulation of tissue inhibitor of metalloproteinase (TIMP)-2 and downregulation of IL-1β-induced MMP-13 in chondrocytes [113]. In the same study, the percentage of HMW per total adiponectin in SF was lower than that in plasma, while that of the examer form (MMW) in SF and plasma, and the trimer form (LMW) was higher in SF [113]. Indeed, adiponectin stimulation increased protein secretion in OA fibroblasts to a much lesser extent than in RA [32, 64] suggesting that, as observed in RA, some adiponectin isoforms may be more detrimental than others, but also that OA fibroblasts show in general a weaker response to adiponectin stimuli than RASF. Also visfatin was shown to be involved in OA catabolism: chondrocytes produce visfatin, and stimulation of normal chondrocytes with visfatin decreases the synthesis of prostaglandins [114]. However, in human OA chondrocytes, visfatin inhibits the function of IGF-1, a well-known growth factor for several matrix components, producing a resistance to IGF-1 which negatively regulates matrix synthesis [115]. Limited data are available for resistin. The levels of this adipocytokine were measured in paired SF and serum samples from patients following joint injury and its expression was studied and found by immunohistochemistry in synovial tissue from healthy and OA donors [116]. Considering these data, we can conclude that especially adiponectin, leptin, and visfatin can promote cartilage catabolism and may have a role in the pathophysiology of OA. Current evidence is too scant for resistin to draw definite conclusions.

4.2. Clinical Studies

There is some evidence that the infrapatellar fat pad, also known as Hoffa’s fat pad, is an important source of several central adipocytokines such as leptin, adiponectin, and resistin in OA patients [117]. In particular, the stimulation of human infrapatellar fat pad obtained from OA patients with IL-1β induced a 10-fold increase in leptin mRNA expression [118]. Furthermore, in patients with knee OA studied for 2 years, baseline serum levels of leptin were associated with increased levels of bone formation biomarkers [119]. The soluble receptor of leptin was associated with reduced levels of bone formation biomarkers and increased cartilage volume loss assessed by magnetic resonance imaging. In this study, adiponectin and resistin were not significantly associated with bone formation biomarkers [119]. In addition, leptin seems to be locally involved in joint erosion in OA since SF concentrations were significantly higher in OA patients compared to controls. Importantly, leptin levels were highest in patients with more severe disease [120], suggesting that SF levels could be used as an effective biomarker for quantitative detection of OA. Recent findings showed the association of higher serum leptin levels with increased odds of both prevalent and incident knee OA in a cohort of mid-life women [121]. Furthermore, a positive correlation between the BMI of OA patients and serum levels of leptin was found, whereas no correlation was detectable with age, disease duration, and visual analogue pain scale for the lower-limb afflicted patients and stage of disease [91]. All these findings strongly support a major role of leptin in the pathogenesis of OA and the potential utility as a biomarker for OA risk.

As observed in experimental models, also in humans the role of adiponectin appears controversial in OA. In patients with knee OA, plasma concentrations of adiponectin were significantly higher than those in SF and both plasma and SF levels inversely correlated with disease severity [122]. These results, showing a protective effect, were indirectly confirmed by the observation that patients with the highest levels of adiponectin had a decreased risk of hand OA progression while no association for leptin and resistin was found [123]. On the other hand, plasma adiponectin levels were found to be significantly higher in OA patients than in healthy controls in another study [84], and higher levels were also observed in female patients with erosive hand OA in comparison to those with nonerosive disease [124]. Finally, plasma adiponectin levels were higher in patients undergoing total knee replacement surgery than in patients with less severe disease [125].

Along this line, higher serum levels of resistin but not adiponectin were found in patients with radiographic subchondral erosion than in nonradiographic hand OA patients [126], while in another study involving 172 subjects no association between resistin and adiponectin serum levels with cartilage damage was found [127]. Therefore, data on adiponectin and resistin are conflicting, making the possibility to consider them as valuable biomarkers of OA hard, while data on leptin in this regard are consistent. Since leptin is almost exclusively secreted from adipocytes and obesity is associated with increased leptin serum concentrations which potentially contribute to insulin resistance and metabolic syndrome [29], this adipocytokine deserves further attention as potential comorbidity biomarker of cardiovascular risk (see Figure 1).

5. Conclusions

RA and OA are two epidemiologically relevant diseases leading to articular damage and disability, whose outcome can be heavily affected by comorbidities, particularly in the cardiovascular system. On the other hand, obesity is suggested to be the underlying cause of the metabolic syndrome which results in a 2- to 3-fold increase in cardiovascular risk. Obesity is also a risk factor for RA and OA, and this observation has captured attention on WAT as an immunomodulatory endocrine organ, due to the capability of secreting adipocytokines. Some of these are probably involved in the pathogenesis of RA and a possible role in the increased cardiovascular risk observed in these patients cannot be excluded, considering that increased central adiposity is common in RA. Likewise, OA does not cause death directly, but, limiting mobility and physical activity, it increases the risk of obesity and cardiovascular disease. Again, the role of adipocytokines, acting independently of mechanical stress, may be relevant and influence the prognosis.

Despite these considerations, studies evaluating adipocytokines in RA and OA have shown controversial results both in experimental models and human diseases with regard to serum/plasma levels and association with severity of disease. Focusing on the context of this review, related to the implication of adipocytokines for the cardiovascular risk, the only speculations may be done on adiponectin and leptin (see Figure 1): in RA, the first was shown to be reduced in obese patients or in those with rheumatoid cachexia and inversely correlated with radiographic damage [78, 84]; the latter was associated with insulin resistance [99], but the consequences of these association have not been further studied. Leptin seems to be a promising biomarker also for OA patients, due to its involvement in disease pathogenesis and obesity.

Hence, we believe that adipocytokines cannot be currently included in the clinical practice evaluation of RA and OA patients. Although their potential use as comorbidity biomarkers of cardiovascular risk may be of interest, a specific investigation is required due to the limitations of the data currently available.

Conflict of Interests

The authors declared that they have no conflict of interests.

Acknowledgment

The authors wish to thank Dr. Soheila Rezai for inspiring Figure 1.

References

S. P. Weisberg, D. McCann, M. Desai, M. Rosenbaum, R. L. Leibel, and A. W. Ferrante Jr., “Obesity is associated with macrophage accumulation in adipose tissue,” Journal of Clinical Investigation, vol. 112, no. 12, pp. 1796–1808, 2003.
View at: Publisher Site | Google Scholar
H. Tilg and A. R. Moschen, “Adipocytokines: mediators linking adipose tissue, inflammation and immunity,” Nature Reviews Immunology, vol. 6, no. 10, pp. 772–783, 2006.
View at: Publisher Site | Google Scholar
S. S. Martin, A. Qasim, and M. P. Reilly, “Leptin resistance. A possible interface of inflammation and metabolism in obesity-related cardiovascular disease,” Journal of the American College of Cardiology, vol. 52, no. 15, pp. 1201–1210, 2008.
View at: Publisher Site | Google Scholar
T. Luk, Z. Malam, and J. C. Marshall, “Pre-B cell colony-enhancing factor (PBEF)/visfatin: a novel mediator of innate immunity,” Journal of Leukocyte Biology, vol. 83, no. 4, pp. 804–816, 2008.
View at: Publisher Site | Google Scholar
M. Blüher, “Do adipokines link obesity to its related metabolic and cardiovascular diseases?” Clinical Lipidology, vol. 5, no. 1, pp. 95–107, 2010.
View at: Publisher Site | Google Scholar
H. E. Bays, “‘Sick fat,’ metabolic disease, and atherosclerosis,” The American Journal of Medicine, vol. 122, supplement 1, pp. S26–S37, 2009.
View at: Publisher Site | Google Scholar
M. Jenkins, A. Flynn, T. Smart et al., “A statistician's perspective on biomarkers in drug development,” Pharmaceutical Statistics, vol. 10, no. 6, pp. 494–507, 2011.
View at: Publisher Site | Google Scholar
C. S. Crowson, E. L. Matteson, J. M. Davis III, and S. E. Gabriel, “Contribution of obesity to the rise in incidence of rheumatoid arthritis,” Arthritis Care and Research, vol. 65, no. 1, pp. 71–77, 2013.
View at: Publisher Site | Google Scholar
Ajeganova, M. L. Andersson, I. Hafström, and BARFOT Study Group, “Obesity is associated with worse disease severity in rheumatoid arthritis as well as with co-morbidities—a long-term follow-up from disease onset,” Arthritis Care and Research, vol. 65, no. 1, pp. 78–87, 2013.
View at: Publisher Site | Google Scholar
L. S. Lohmander, M. G. de Verdier, J. Rollof, P. M. Nilsson, and G. Engström, “Incidence of severe knee and hip osteoarthritis in relation to different measures of body mass: a population-based prospective cohort study,” Annals of the Rheumatic Diseases, vol. 68, no. 4, pp. 490–496, 2009.
View at: Publisher Site | Google Scholar
World Health Organization, Health Topics: Obesity, World Health Organization, Geneva, Switzerland, 2011, http://www.who.int/topics/obesity/en/.
L. F. van Gaal, I. L. Mertens, and C. E. de Block, “Mechanisms linking obesity with cardiovascular disease,” Nature, vol. 444, no. 7121, pp. 875–880, 2006.
View at: Publisher Site | Google Scholar
D. Leroith, R. Novosyadlyy, E. J. Gallagher, D. Lann, A. Vljayakumar, and S. Yakar, “Obesity and Type 2 diabetes are associated with an increased risk of developing cancer and a worse prognosis; epidemiological and mechanistic evidence,” Experimental and Clinical Endocrinology and Diabetes, vol. 116, supplement 1, pp. S4–S6, 2008.
View at: Publisher Site | Google Scholar
M. Blüher, “Adipose tissue dysfunction in obesity,” Experimental and Clinical Endocrinology and Diabetes, vol. 117, no. 6, pp. 241–250, 2009.
View at: Publisher Site | Google Scholar
P. Sarraf, R. C. Frederich, E. M. Turner et al., “Multiple cytokines and acute inflammation raise mouse leptin levels: potential role in inflammatory anorexia,” Journal of Experimental Medicine, vol. 185, no. 1, pp. 171–175, 1997.
View at: Publisher Site | Google Scholar
R. S. Ahima, D. Prabakaran, C. Mantzoros et al., “Role of leptin in the neuroendocrine response to fasting,” Nature, vol. 382, no. 6588, pp. 250–252, 1996.
View at: Publisher Site | Google Scholar
K. Hotta, T. Funahashi, N. L. Bodkin et al., “Circulating concentrations of the adipocyte protein adiponectin are decreased in parallel with reduced insulin sensitivity during the progression to type 2 diabetes in rhesus monkeys,” Diabetes, vol. 50, no. 5, pp. 1126–1133, 2001.
View at: Google Scholar
N. Maeda, I. Shimomura, K. Kishida et al., “Diet-induced insulin resistance in mice lacking adiponectin/ACRP30,” Nature Medicine, vol. 8, no. 7, pp. 731–737, 2002.
View at: Publisher Site | Google Scholar
L. Patel, A. C. Buckels, I. J. Kinghorn et al., “Resistin is expressed in human macrophages and directly regulated by PPARγ activators,” Biochemical and Biophysical Research Communications, vol. 300, no. 2, pp. 472–476, 2003.
View at: Publisher Site | Google Scholar
C. A. Curat, V. Wegner, C. Sengenès et al., “Macrophages in human visceral adipose tissue: increased accumulation in obesity and a source of resistin and visfatin,” Diabetologia, vol. 49, no. 4, pp. 744–747, 2006.
View at: Publisher Site | Google Scholar
J. Stastny, J. Bienertova-Vasku, and A. Vasku, “Visfatin and its role in obesity development,” Diabetes and Metabolic Syndrome, vol. 6, no. 2, pp. 120–124, 2012.
View at: Publisher Site | Google Scholar
M. P. Chen, F. M. Chung, D. M. Chang et al., “Elevated plasma level of visfatin/pre-B cell colony-enhancing factor in patients with type 2 diabetes mellitus,” Journal of Clinical Endocrinology and Metabolism, vol. 91, no. 1, pp. 295–299, 2006.
View at: Publisher Site | Google Scholar
C. M. Steppan, S. T. Bailey, S. Bhat et al., “The hormone resistin links obesity to diabetes,” Nature, vol. 409, no. 6818, pp. 307–312, 2001.
View at: Publisher Site | Google Scholar
S. M. Rangwala, A. S. Rich, B. Rhoades et al., “Abnormal glucose homeostasis due to chronic hyperresistinemia,” Diabetes, vol. 53, no. 8, pp. 1937–1941, 2004.
View at: Publisher Site | Google Scholar
J. M. Friedman, “Leptin and the regulation of body weight,” Keio Journal of Medicine, vol. 60, no. 1, pp. 1–9, 2011.
View at: Publisher Site | Google Scholar
G. Boden, X. Chen, M. Mozzoli, and I. Ryan, “Effect of fasting on serum leptin in normal human subjects,” Journal of Clinical Endocrinology and Metabolism, vol. 81, no. 9, pp. 3419–3423, 1996.
View at: Publisher Site | Google Scholar
J. W. Kolaczynski, J. P. Ohannesian, R. V. Considine, C. C. Marco, and J. F. Caro, “Response of leptin to short-term and prolonged overfeeding in humans,” Journal of Clinical Endocrinology and Metabolism, vol. 81, no. 11, pp. 4162–4165, 1996.
View at: Publisher Site | Google Scholar
G. Boden, X. Chen, J. W. Kolaczynski, and M. Polansky, “Effects of prolonged hyperinsulinemia on serum leptin in normal human subjects,” Journal of Clinical Investigation, vol. 100, no. 5, pp. 1107–1113, 1997.
View at: Google Scholar
R. S. Ahima and J. S. Flier, “Leptin,” Annual Review of Physiology, vol. 62, pp. 413–437, 2000.
View at: Publisher Site | Google Scholar
N. Maeda, M. Takahashi, T. Funahashi et al., “PPARγ ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein,” Diabetes, vol. 50, no. 9, pp. 2094–2099, 2001.
View at: Google Scholar
Y. Arita, S. Kihara, N. Ouchi et al., “Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity,” Biochemical and Biophysical Research Communications, vol. 257, no. 1, pp. 79–83, 1999.
View at: Publisher Site | Google Scholar
K. W. Frommer, A. Schäffler, C. Büchler et al., “Adiponectin isoforms: a potential therapeutic target in rheumatoid arthritis?” Annals of the Rheumatic Diseases, vol. 71, no. 10, pp. 1724–1732, 2012.
View at: Publisher Site | Google Scholar
R. Baratta, S. Amato, C. Degano et al., “Adiponectin relationship with lipid metabolism is independent of body fat mass: evidence from both cross-sectional and intervention studies,” Journal of Clinical Endocrinology and Metabolism, vol. 89, no. 6, pp. 2665–2671, 2004.
View at: Publisher Site | Google Scholar
J. Hung, B. M. McQuillan, P. L. Thompson, and J. P. Beilby, “Circulating adiponectin levels associate with inflammatory markers, insulin resistance and metabolic syndrome independent of obesity,” International Journal of Obesity, vol. 32, no. 5, pp. 772–779, 2008.
View at: Publisher Site | Google Scholar
J. M. Dekker, T. Funahashi, G. Nijpels et al., “Prognostic value of adiponectin for cardiovascular disease and mortality,” Journal of Clinical Endocrinology and Metabolism, vol. 93, no. 4, pp. 1489–1496, 2008.
View at: Publisher Site | Google Scholar
S. Li, H. J. Shin, E. L. Ding, and R. M. van Dam, “Adiponectin levels and risk of type 2 diabetes: a systematic review and meta-analysis,” The Journal of the American Medical Association, vol. 302, no. 2, pp. 179–188, 2009.
View at: Publisher Site | Google Scholar
K. Tucholski and E. Otto-Buczkowska, “The role of leptin in the regulation of carbohydrate metabolism,” Polish Journal of Endocrinology, vol. 62, no. 3, pp. 258–262, 2011.
View at: Google Scholar
Y. Tabara, H. Osawa, R. Kawamoto et al., “Reduced high-molecular-weight adiponectin and elevated high-sensitivity C-reactive protein are synergistic risk factors for metabolic syndrome in a large-scale middle-aged to elderly population: the Shimanami health promoting program study,” Journal of Clinical Endocrinology and Metabolism, vol. 93, no. 3, pp. 715–722, 2008.
View at: Publisher Site | Google Scholar
S. Rizza, F. Gigli, A. Galli et al., “Adiponectin isoforms in elderly patients with or without coronary artery disease,” Journal of the American Geriatrics Society, vol. 58, no. 4, pp. 702–706, 2010.
View at: Publisher Site | Google Scholar
R. Nakashima, K. Yamane, N. Kamei, S. Nakanishi, and N. Kohno, “Low serum levels of total and high-molecular-weight adiponectin predict the development of metabolic syndrome in Japanese-Americans,” Journal of Endocrinological Investigation, vol. 34, no. 8, pp. 615–619, 2011.
View at: Publisher Site | Google Scholar
J. Graessler, M. Gruber, R. Radke et al., “Type 2 diabetes in octogenarians is associated with decreased low molecular weight adiponectin,” Gerontology, vol. 57, no. 4, pp. 316–326, 2011.
View at: Publisher Site | Google Scholar
A. R. Moschen, A. Kaser, B. Enrich et al., “Visfatin, an adipocytokine with proinflammatory and immunomodulating properties,” Journal of Immunology, vol. 178, no. 3, pp. 1748–1758, 2007.
View at: Google Scholar
P. Wang, M. M. J. van Greevenbroek, F. G. Bouwman et al., “The circulating PBEF/NAMPT/visfatin level is associated with a beneficial blood lipid profile,” Pflügers Archiv, vol. 454, no. 6, pp. 971–976, 2007.
View at: Publisher Site | Google Scholar
F. Sentinelli, S. Romeo, M. Arca et al., “Human resistin gene, obesity, and type 2 diabetes: mutation analysis and population study,” Diabetes, vol. 51, no. 3, pp. 860–862, 2002.
View at: Google Scholar
M. Degawa-Yamauchi, J. E. Bovenkerk, B. E. Juliar et al., “Serum resistin (FIZZ3) protein is increased in obese humans,” Journal of Clinical Endocrinology and Metabolism, vol. 88, no. 11, pp. 5452–5455, 2003.
View at: Publisher Site | Google Scholar
J. H. Lee, J. L. Chan, N. Yiannakouris et al., “Circulating resistin levels are not associated with obesity or insulin resistance in humans and are not regulated by fasting or leptin administration: cross-sectional and interventional studies in normal, insulin-resistant, and diabetic subjects,” Journal of Clinical Endocrinology and Metabolism, vol. 88, no. 10, pp. 4848–4856, 2003.
View at: Publisher Site | Google Scholar
L. K. Heilbronn, J. Rood, L. Janderova et al., “Relationship between serum resistin concentrations and insulin resistance in nonobese, obese, and obese diabetic subjects,” Journal of Clinical Endocrinology and Metabolism, vol. 89, no. 4, pp. 1844–1848, 2004.
View at: Publisher Site | Google Scholar
B. Vozarova de Courten, M. Degawa-Yamauchi, R. V. Considine, and P. A. Tataranni, “High serum resistin is associated with an increase in adiposity but not a worsening of insulin resistance in Pima Indians,” Diabetes, vol. 53, no. 5, pp. 1279–1284, 2004.
View at: Google Scholar
M. P. Reilly, M. Lehrke, M. L. Wolfe, A. Rohatgi, M. A. Lazar, and D. J. Rader, “Resistin is an inflammatory marker of atherosclerosis in humans,” Circulation, vol. 111, no. 7, pp. 932–939, 2005.
View at: Publisher Site | Google Scholar
M. F. Hivert, L. M. Sullivan, C. S. Fox et al., “Associations of adiponectin, resistin, and tumor necrosis factor-α with insulin resistance,” Journal of Clinical Endocrinology and Metabolism, vol. 93, no. 8, pp. 3165–3172, 2008.
View at: Publisher Site | Google Scholar
S. Beckers, D. Zegers, J. K. van Camp et al., “Resistin polymorphisms show associations with obesity, but not with bone parameters in men: results from the odense androgen study,” Molecular Biology Reports, vol. 40, no. 3, pp. 2467–2472, 2013.
View at: Publisher Site | Google Scholar
E. J. B. Ramos, Y. Xu, I. Romanova et al., “Is obesity an inflammatory disease?” Surgery, vol. 134, no. 2, pp. 329–335, 2003.
View at: Publisher Site | Google Scholar
G. S. Hotamisligil, N. S. Shargill, and B. M. Spiegelman, “Adipose expression of tumor necrosis factor-α: direct role in obesity-linked insulin resistance,” Science, vol. 259, no. 5091, pp. 87–91, 1993.
View at: Google Scholar
J. A. Aviña-Zubieta, H. K. Choi, M. Sadatsafavi, M. Etminan, J. M. Esdaile, and D. Lacaille, “Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta-analysis of observational studies,” Arthritis Care and Research, vol. 59, no. 12, pp. 1690–1697, 2008.
View at: Publisher Site | Google Scholar
M. Otero, R. Logo, R. Gomez et al., “Changes in plasma levels of fat-derived hormones adiponectin, leptin, resistin and visfatin in patients with rheumatoid arthritis,” Annals of the Rheumatic Diseases, vol. 65, no. 9, pp. 1198–1201, 2006.
View at: Publisher Site | Google Scholar
S. W. Lee, M. C. Park, Y. B. Park, and S. K. Lee, “Measurement of the serum leptin level could assist disease activity monitoring in rheumatoid arthritis,” Rheumatology International, vol. 27, no. 6, pp. 537–540, 2007.
View at: Publisher Site | Google Scholar
A. Schäffler, A. Ehling, E. Neumann et al., “Adipocytokines in synovial fluid,” The Journal of the American Medical Association, vol. 290, no. 13, pp. 1709–1710, 2003.
View at: Publisher Site | Google Scholar
S. Kenchaiah, J. C. Evans, D. Levy et al., “Obesity and the risk of heart failure,” The New England Journal of Medicine, vol. 347, no. 5, pp. 305–313, 2002.
View at: Publisher Site | Google Scholar
M. Yoda-Murakami, M. Taniguchi, K. Takahashi et al., “Change in expression of GBP28/adiponectin in carbon tetrachloride-administrated mouse liver,” Biochemical and Biophysical Research Communications, vol. 285, no. 2, pp. 372–377, 2001.
View at: Publisher Site | Google Scholar
H. S. Berner, S. P. Lyngstadaas, A. Spahr et al., “Adiponectin and its receptors are expressed in bone-forming cells,” Bone, vol. 35, no. 4, pp. 842–849, 2004.
View at: Publisher Site | Google Scholar
A. M. Delaigle, J. Jonas, I. B. Bauche, O. Cornu, and S. M. Brichard, “Induction of adiponectin in skeletal muscle by inflammatory cytokines: in vivo and in vitro studies,” Endocrinology, vol. 145, no. 12, pp. 5589–5597, 2004.
View at: Publisher Site | Google Scholar
A. Ehling, A. Schäffler, H. Herfarth et al., “The potential of adiponectin in driving arthritis,” Journal of Immunology, vol. 176, no. 7, pp. 4468–4478, 2006.
View at: Google Scholar
N. Ouchi, S. Kihara, Y. Arita et al., “Novel modulator for endothelial adhesion molecules: adipocyte-derived plasma protein adiponectin,” Circulation, vol. 100, no. 25, pp. 2473–2476, 1999.
View at: Google Scholar
K. W. Frommer, B. Zimmermann, F. M. P. Meier et al., “Adiponectin-mediated changes in effector cells involved in the pathophysiology of rheumatoid arthritis,” Arthritis and Rheumatism, vol. 62, no. 10, pp. 2886–2899, 2010.
View at: Publisher Site | Google Scholar
H. M. Choi, Y. A. Lee, S. H. Lee et al., “Adiponectin may contribute to synovitis and joint destruction in rheumatoid arthritis by stimulating vascular endothelial growth factor, matrix metalloproteinase-1, and matrix metalloproteinase-13 expression in fibroblast-like synoviocytes more than proinflammatory mediators,” Arthritis Research and Therapy, vol. 11, no. 6, article R161, 2009.
View at: Publisher Site | Google Scholar
C. P. Chung, A. Oeser, J. F. Solus et al., “Inflammation-associated insulin resistance: differential effects in rheumatoid arthritis and systemic lupus erythematosus define potential mechanisms,” Arthritis and Rheumatism, vol. 58, no. 7, pp. 2105–2112, 2008.
View at: Publisher Site | Google Scholar
N. Busso, A. So, V. Chobaz-Péclat et al., “Leptin signaling deficiency impairs humoral and cellular immune responses and attenuates experimental arthritis,” Journal of Immunology, vol. 168, no. 2, pp. 875–882, 2002.
View at: Google Scholar
G. M. Lord, G. Matarese, J. K. Howard, R. J. Baker, S. R. Bloom, and R. I. Lechler, “Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression,” Nature, vol. 394, no. 6696, pp. 897–901, 1998.
View at: Publisher Site | Google Scholar
M. Bokarewa, I. Nagaev, L. Dahlberg, U. Smith, and A. Tarkowski, “Resistin, an adipokine with potent proinflammatory properties,” Journal of Immunology, vol. 174, no. 9, pp. 5789–5795, 2005.
View at: Google Scholar
F. M. Meier, K. W. Frommer, M. A. Peters et al., “Visfatin/pre-B cell colony-enhancing factor (PBEF): a proinflammatory and cell motility-changing factor in rheumatoid arthritis,” The Journal of Biological Chemistry, vol. 287, no. 34, pp. 28378–28385, 2012.
View at: Publisher Site | Google Scholar
A. Escalante, R. W. Haas, and I. del Rincón, “Paradoxical effect of body mass index on survival in rheumatoid arthritis: role of comorbidity and systemic inflammation,” Archives of Internal Medicine, vol. 165, no. 14, pp. 1624–1629, 2005.
View at: Publisher Site | Google Scholar
A. C. Elkan, I. L. Engvall, T. Cederholm, and I. Hafström, “Rheumatoid cachexia, central obesity and malnutrition in patients with low-active rheumatoid arthritis: feasibility of anthropometry, mini nutritional assessment and body composition techniques,” European Journal of Nutrition, vol. 48, no. 5, pp. 315–322, 2009.
View at: Publisher Site | Google Scholar
P. H. Dessein and B. I. Joffe, “Insulin resistance and impaired beta cell function in rheumatoid arthritis,” Arthritis and Rheumatism, vol. 54, no. 9, pp. 2765–2775, 2006.
View at: Publisher Site | Google Scholar
T. A. Pearson, G. A. Mensah, R. W. Alexander et al., “Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the centers for disease control and prevention and the American heart association,” Circulation, vol. 107, no. 3, pp. 499–511, 2003.
View at: Publisher Site | Google Scholar
A. Tomizawa, Y. Hattori, K. Kasai, and Y. Nakano, “Adiponectin induces NF-κB activation that leads to suppression of cytokine-induced NF-κB activation in vascular endothelial cells: globular adiponectin versus high molecular weight adiponectin,” Diabetes and Vascular Disease Research, vol. 5, no. 2, pp. 123–127, 2008.
View at: Publisher Site | Google Scholar
Y. Hattori, Y. Nakano, S. Hattori, A. Tomizawa, K. Inukai, and K. Kasai, “High molecular weight adiponectin activates AMPK and suppresses cytokine-induced NF-κB activation in vascular endothelial cells,” FEBS Letters, vol. 582, no. 12, pp. 1719–1724, 2008.
View at: Publisher Site | Google Scholar
K. Ebina, A. Fukuhara, W. Ando et al., “Serum adiponectin concentrations correlate with severity of rheumatoid arthritis evaluated by extent of joint destruction,” Clinical Rheumatology, vol. 28, no. 4, pp. 445–451, 2009.
View at: Publisher Site | Google Scholar
J. T. Giles, D. M. van der Heijde, and J. M. Bathon, “Association of circulating adiponectin levels with progression of radiographic joint destruction in rheumatoid arthritis,” Annals of the Rheumatic Diseases, vol. 70, no. 9, pp. 1562–1568, 2011.
View at: Publisher Site | Google Scholar
I. R. Klein-Wieringa, M. P. M. van der Linden, R. Knevel et al., “Baseline serum adipokine levels predict radiographic progression in early rheumatoid arthritis,” Arthritis and Rheumatism, vol. 63, no. 9, pp. 2567–2574, 2011.
View at: Publisher Site | Google Scholar
X. H. Luo, L. J. Guo, H. Xie et al., “Adiponectin stimulates RANKL and inhibits OPG expression in human osteoblasts through the MAPK signaling pathway,” Journal of Bone and Mineral Research, vol. 21, no. 10, pp. 1648–1656, 2006.
View at: Publisher Site | Google Scholar
T. Alonzi, E. Fattori, D. Lazzaro et al., “Interleukin 6 is required for the development of collagen-induced arthritis,” Journal of Experimental Medicine, vol. 187, no. 4, pp. 461–468, 1998.
View at: Publisher Site | Google Scholar
C. Gabay, “Interleukin-6 and chronic inflammation,” Arthritis Research and Therapy, vol. 8, supplement 2, article S3, 2006.
View at: Publisher Site | Google Scholar
P. Härle, P. Sarzi-Puttini, M. Cutolo, and R. H. Straub, “No change of serum levels of leptin and adiponectin during anti-tumour necrosis factor antibody treatment with adalimumab in patients with rheumatoid arthritis,” Annals of the Rheumatic Diseases, vol. 65, no. 7, pp. 970–971, 2006.
View at: Publisher Site | Google Scholar
T. B. Laurberg, J. Frystyk, T. Ellingsen et al., “Plasma adiponectin in patients with active, early, and chronic rheumatoid arthritis who are steroid- and disease-modifying antirheumatic drug-naive compared with patients with osteoarthritis and controls,” Journal of Rheumatology, vol. 36, no. 9, pp. 1885–1891, 2009.
View at: Publisher Site | Google Scholar
J. T. Giles, M. Allison, C. O. Bingham III, W. M. Scott Jr., and J. M. Bathon, “Adiponectin is a mediator of the inverse association of adiposity with radiographic damage in rheumatoid arthritis,” Arthritis Care and Research, vol. 61, no. 9, pp. 1248–1256, 2009.
View at: Publisher Site | Google Scholar
A. H. M. van der Helm-van Mil, S. M. van der Kooij, C. F. Allaart, R. E. M. Toes, and T. W. J. Huizinga, “A high body mass index has a protective effect on the amount of joint destruction in small joints in early rheumatoid arthritis,” Annals of the Rheumatic Diseases, vol. 67, no. 6, pp. 769–774, 2008.
View at: Publisher Site | Google Scholar
H. P. Kopp, K. Krzyzanowska, M. Möhlig, J. Spranger, A. F. H. Pfeiffer, and G. Schernthaner, “Effects of marked weight loss on plasma levels of adiponectin, markers of chronic subclinical inflammation and insulin resistance in morbidly obese women,” International Journal of Obesity, vol. 29, no. 7, pp. 766–771, 2005.
View at: Publisher Site | Google Scholar
H. J. Anders, M. Rihl, A. Heufelder, O. Loch, and M. Schattenkirchner, “Leptin serum levels are not correlated with disease activity in patients with rheumatoid arthritis,” Metabolism, vol. 48, no. 6, pp. 745–748, 1999.
View at: Publisher Site | Google Scholar
C. Popa, M. G. Netea, T. R. D. S. Radstake, P. L. van Riel, P. Barrera, and J. W. M. van der Meer, “Markers of inflammation are negatively correlated with serum leptin in rheumatoid arthritis,” Annals of the Rheumatic Diseases, vol. 64, no. 8, pp. 1195–1198, 2005.
View at: Publisher Site | Google Scholar
S. Hizmetli, M. Kisa, N. Gokalp, and M. Z. Bakici, “Are plasma and synovial fluid leptin levels correlated with disease activity in rheumatoid arthritis?” Rheumatology International, vol. 27, no. 4, pp. 335–338, 2007.
View at: Publisher Site | Google Scholar
M. Wisłowska, M. Rok, B. Jaszczyk, K. Stȩpień, and M. Cicha, “Serum leptin in rheumatoid arthritis,” Rheumatology International, vol. 27, no. 10, pp. 947–954, 2007.
View at: Publisher Site | Google Scholar
M. Salazar-Páramo, M. González-Ortiz, L. González-López et al., “Serum leptin levels in patients with rheumatoid arthritis,” Journal of Clinical Rheumatology, vol. 7, no. 1, pp. 57–59, 2001.
View at: Google Scholar
M. Bokarewa, D. Bokarew, O. Hultgren, and A. Tarkowski, “Leptin consumption in the inflamed joints of patients with rheumatoid arthritis,” Annals of the Rheumatic Diseases, vol. 62, no. 10, pp. 952–956, 2003.
View at: Publisher Site | Google Scholar
É. Toussirot, N. U. Nguyen, G. Dumoulin, F. Aubin, J. Cédoz, and D. Wendling, “Relationship between growth hormone-IGF-I-IGFBP-3 axis and serum leptin levels with bone mass and body composition in patients with rheumatoid arthritis,” Rheumatology, vol. 44, no. 1, pp. 120–125, 2005.
View at: Publisher Site | Google Scholar
Y. H. Rho, J. Solus, T. Sokka et al., “Adipocytokines are associated with radiographic joint damage in rheumatoid arthritis,” Arthritis and Rheumatism, vol. 60, no. 7, pp. 1906–1914, 2009.
View at: Publisher Site | Google Scholar
S. M. Olama, M. K. Senna, and M. Elarman, “Synovial/serum leptin ratio in rheumatoid arthritis: the association with activity and erosion,” Rheumatology International, vol. 32, no. 3, pp. 683–690, 2012.
View at: Publisher Site | Google Scholar
C. Gabay, M. G. Dreyer, N. Pellegrinelli, R. Chicheportiche, and C. A. Meier, “Leptin directly induces the secretion of interleukin 1 receptor antagonist in human monocytes,” Journal of Clinical Endocrinology and Metabolism, vol. 86, no. 2, pp. 783–791, 2001.
View at: Publisher Site | Google Scholar
S. Cohen, E. Hurd, J. Cush et al., “Treatment of rheumatoid arthritis with anakinra, a recombinant human interleukin-1 receptor antagonist, in combination with methotrexate: results of a twenty-four-week, multicenter, randomized, double-blind, placebo-controlled trial,” Arthritis and Rheumatism, vol. 46, no. 3, pp. 614–624, 2002.
View at: Publisher Site | Google Scholar
Y. H. Rho, C. P. Chung, J. F. Solus et al., “Adipocytokines, insulin resistance, and coronary atherosclerosis in rheumatoid arthritis,” Arthritis and Rheumatism, vol. 62, no. 5, pp. 1259–1264, 2010.
View at: Publisher Site | Google Scholar
L. Šenolt, D. Housa, Z. Vernerová et al., “Resistin in rheumatoid arthritis synovial tissue, synovial fluid and serum,” Annals of the Rheumatic Diseases, vol. 66, no. 4, pp. 458–463, 2007.
View at: Publisher Site | Google Scholar
R. Klaasen, M. M. J. Herenius, C. A. Wijbrandts et al., “Treatment-specific changes in circulating adipocytokines: a comparison between tumour necrosis factor blockade and glucocorticoid treatment for rheumatoid arthritis,” Annals of the Rheumatic Diseases, vol. 71, no. 9, pp. 1510–1516, 2012.
View at: Publisher Site | Google Scholar
J. W. J. Bijlsma, F. Berenbaum, and F. P. J. G. Lafeber, “Osteoarthritis: an update with relevance for clinical practice,” The Lancet, vol. 377, no. 9783, pp. 2115–2126, 2011.
View at: Publisher Site | Google Scholar
L. G. Alexopoulos, I. Youn, P. Bonaldo, and F. Guilak, “Developmental and osteoarthritic changes in Col6a1-knockout mice: biomechanics of type VI collagen in the cartilage pericellular matrix,” Arthritis and Rheumatism, vol. 60, no. 3, pp. 771–779, 2009.
View at: Publisher Site | Google Scholar
D. Iliopoulos, K. N. Malizos, and A. Tsezou, “Epigenetic regulation of leptin affects MMP-13 expression in osteoarthritic chondrocytes: possible molecular target for osteoarthritis therapeutic intervention,” Annals of the Rheumatic Diseases, vol. 66, no. 12, pp. 1616–1621, 2007.
View at: Publisher Site | Google Scholar
E. Yusuf, R. G. Nelissen, A. Ioan-Facsinay et al., “Association between weight or body mass index and hand osteoarthritis: a systematic review,” Annals of the Rheumatic Diseases, vol. 69, no. 4, pp. 761–765, 2010.
View at: Publisher Site | Google Scholar
W. Hui, G. J. Litherland, M. S. Elias et al., “Leptin produced by joint white adipose tissue induces cartilage degradation via upregulation and activation of matrix metalloproteinases,” Annals of the Rheumatic Diseases, vol. 71, no. 3, pp. 455–462, 2012.
View at: Publisher Site | Google Scholar
J. Liang, J. Feng, W. K. K. Wu et al., “Leptin-mediated cytoskeletal remodeling in chondrocytes occurs via the RhoA/ROCK pathway,” Journal of Orthopaedic Research, vol. 29, no. 3, pp. 369–374, 2011.
View at: Publisher Site | Google Scholar
T. M. Griffin, B. Fermor, J. L. Huebner et al., “Diet-induced obesity differentially regulates behavioral, biomechanical, and molecular risk factors for osteoarthritis in mice,” Arthritis Research and Therapy, vol. 12, no. 4, article R130, 2010.
View at: Publisher Site | Google Scholar
T. Simopoulou, K. N. Malizos, D. Iliopoulos et al., “Differential expression of leptin and leptin's receptor isoform (Ob-Rb) mRNA between advanced and minimally affected osteoarthritic cartilage; effect on cartilage metabolism,” Osteoarthritis and Cartilage, vol. 15, no. 8, pp. 872–883, 2007.
View at: Publisher Site | Google Scholar
K. M. Tong, C. P. Chen, K. C. Huang et al., “Adiponectin increases MMP-3 expression in human chondrocytes through adipor1 signaling pathway,” Journal of Cellular Biochemistry, vol. 112, no. 5, pp. 1431–1440, 2011.
View at: Publisher Site | Google Scholar
E. H. Kang, Y. J. Lee, T. K. Kim et al., “Adiponectin is a potential catabolic mediator in osteoarthritis cartilage,” Arthritis Research and Therapy, vol. 12, no. 6, article R231, 2010.
View at: Publisher Site | Google Scholar
R. Lago, R. Gomez, M. Otero et al., “A new player in cartilage homeostasis: adiponectin induces nitric oxide synthase type II and pro-inflammatory cytokines in chondrocytes,” Osteoarthritis and Cartilage, vol. 16, no. 9, pp. 1101–1109, 2008.
View at: Publisher Site | Google Scholar
T. H. Chen, L. Chen, M. S. Hsieh, C. P. Chang, D. T. Chou, and S. H. Tsai, “Evidence for a protective role for adiponectin in osteoarthritis,” Biochimica et Biophysica Acta, vol. 1762, no. 8, pp. 711–718, 2006.
View at: Publisher Site | Google Scholar
M. Gosset, F. Berenbaum, C. Salvat et al., “Crucial role of visfatin/pre-B cell colony-enhancing factor in matrix degradation and prostaglandin E2 synthesis in chondrocytes: possible influence on osteoarthritis,” Arthritis and Rheumatism, vol. 58, no. 5, pp. 1399–1409, 2008.
View at: Publisher Site | Google Scholar
R. R. Yammani and R. F. Loeser, “Extracellular nicotinamide phosphoribosyltransferase (NAMPT/visfatin) inhibits insulin-like growth factor-1 signaling and proteoglycan synthesis in human articular chondrocytes,” Arthritis Research and Therapy, vol. 14, no. 1, article R23, 2012.
View at: Publisher Site | Google Scholar
J. H. Lee, T. Ort, K. Ma et al., “Resistin is elevated following traumatic joint injury and causes matrix degradation and release of inflammatory cytokines from articular cartilage in vitro,” Osteoarthritis and Cartilage, vol. 17, no. 5, pp. 613–620, 2009.
View at: Publisher Site | Google Scholar
I. R. Klein-Wieringa, M. Kloppenburg, Y. M. Bastiaansen-Jenniskens et al., “The infrapatellar fat pad of patients with osteoarthritis has an inflammatory phenotype,” Annals of the Rheumatic Diseases, vol. 70, no. 5, pp. 851–857, 2011.
View at: Publisher Site | Google Scholar
S. Clockaerts, Y. M. Bastiaansen-Jenniskens, C. Feijt et al., “Cytokine production by infrapatellar fat pad can be stimulated by interleukin 1β and inhibited by peroxisome proliferator activated receptor α agonist,” Annals of the Rheumatic Diseases, vol. 71, no. 6, pp. 1012–1018, 2012.
View at: Publisher Site | Google Scholar
P. A. Berry, S. W. Jones, F. M. Cicuttini, A. E. Wluka, and R. A. MacIewicz, “Temporal relationship between serum adipokines, biomarkers of bone and cartilage turnover, and cartilage volume loss in a population with clinical knee osteoarthritis,” Arthritis and Rheumatism, vol. 63, no. 3, pp. 700–707, 2011.
View at: Publisher Site | Google Scholar
J. H. Ku, C. K. Lee, B. S. Joo et al., “Correlation of synovial fluid leptin concentrations with the severity of osteoarthritis,” Clinical Rheumatology, vol. 28, no. 12, pp. 1431–1435, 2009.
View at: Publisher Site | Google Scholar
C. A. Karvonen-Gutierrez, S. D. Harlow, P. Mancuso, J. Jacobson, C. F. M. de Leon, and B. Nan, “Association of leptin levels with radiographic knee osteoarthritis among a cohort of midlife women,” Arthritis Care and Research, vol. 65, no. 6, pp. 936–944, 2013.
View at: Publisher Site | Google Scholar
S. Honsawek and M. Chayanupatkul, “Correlation of plasma and synovial fluid adiponectin with knee osteoarthritis severity,” Archives of Medical Research, vol. 41, no. 8, pp. 593–598, 2010.
View at: Publisher Site | Google Scholar
E. Yusuf, A. Ioan-Facsinay, J. Bijsterbosch et al., “Association between leptin, adiponectin and resistin and long-term progression of hand osteoarthritis,” Annals of the Rheumatic Diseases, vol. 70, no. 7, pp. 1282–1284, 2011.
View at: Publisher Site | Google Scholar
M. Filková, M. Lisková, H. Hulejová et al., “Increased serum adiponectin levels in female patients with erosive compared with non-erosive osteoarthritis,” Annals of the Rheumatic Diseases, vol. 68, no. 2, pp. 295–296, 2009.
View at: Publisher Site | Google Scholar
A. Koskinen, S. Juslin, R. Nieminen, T. Moilanen, K. Vuolteenaho, and E. Moilanen, “Adiponectin associates with markers of cartilage degradation in osteoarthritis and induces production of proinflammatory and catabolic factors through mitogen-activated protein kinase pathways,” Arthritis Research and Therapy, vol. 13, no. 6, article R184, 2011.
View at: Publisher Site | Google Scholar
J. Y. Choe, J. Bae, H. Y. Jung, S. H. Park, H. J. Lee, and S. K. Kim, “Serum resistin level is associated with radiographic changes in hand osteoarthritis: cross-sectional study,” Joint Bone Spine, vol. 79, no. 2, pp. 160–165, 2012.
View at: Publisher Site | Google Scholar
T. N. de Boer, W. E. van Spil, A. M. Huisman et al., “Serum adipokines in osteoarthritis, comparison with controls and relationship with local parameters of synovial inflammation and cartilage damage,” Osteoarthritis and Cartilage, vol. 20, no. 8, pp. 846–853, 2012.
View at: Publisher Site | Google Scholar

Copyright

Copyright © 2013 Rossana Scrivo et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PDF Download Citation

Download other formats

Order printed copies

Views

2525

Downloads

1622

Citations