An update on the association between metabolic syndrome and osteoarthritis and on the potential role of leptin in osteoarthritis

Cytokine 129 (2020) 155043

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Review article

An update on the association between metabolic syndrome and osteoarthritis and on the potential role of leptin in osteoarthritis

T

Yu-Hang Gaoa, Cheng-Wu Zhaob, Bo Liuc, Ning Dongd, Lu Dinga, Ye-Ran Lia, Jian-Guo Liua, ⁎ ⁎⁎ Wei Fenga, Xin Qia, , Xian-Hua Jine, a

Department of Orthopaedic Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, China Department of Sports Medicine, The First Hospital of Jilin University, Changchun, Jilin 130021, China c Department of Ultrasound, The First Hospital of Jilin University, Changchun, Jilin 130021, China d Department of Pediatric Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, China e Department of Dermatology, The Second Hospital of Jilin University, Changchun, Jilin 130022, China b

A R T I C LE I N FO

A B S T R A C T

Keywords: Metabolic syndrome Osteoarthritis Epidemiology Leptin Pathophysiology

Metabolic syndrome (MetS) has been associated with osteoarthritis (OA). Leptin, which is one of the markers of MetS, has been associated with OA pathophysiology. This study aimed to provide an update on the association between MetS and OA and on the potential role of leptin in OA. In this review, we summarized the current knowledge of the association between MetS and OA and updated the evidence on the potential role of leptin in OA. Clinical studies have investigated the epidemiologic association between MetS or its components and OA. Results suggested strong epidemiologic associations between MetS and OA, especially in the Asian population. Animal studies also indicated that metabolic dysregulation may lead to OA pathogenesis. The systemic role of MetS in OA pathophysiology is associated with obesity-related inflammation, the beneficial role of n-3 polyunsaturated fatty acids and deleterious role of cholesterol, physical inactivity, hypertension-induced subchondral ischemia, dyslipidemia-induced ectopic lipid deposition in chondrocytes, hyperglycemia-induced local effects of oxidative stress and advanced glycation end-products, low-grade systemic inflammation, and obesityrelated adipokines by inducing the expression of proinflammtory factors. Leptin levels in serum/plasma and synovial fluid were associated with joint pain, radiographic progression, bone formation biomarkers, cartilage volume, knee OA incidence, and total joint arthroplasty in OA patients. Elevated leptin expression and increased effect of leptin on infrapatellar fat pad, synovium, articular cartilage, and bone were also involved in the pathogenesis of OA. Current knowledge indicates a convincing epidemiologic association between MetS and OA, especially in the Asian population. Animal studies have also shown that metabolic dysregulation may lead to OA pathogenesis. Accumulating evidence suggests that leptin may play a potential role in OA pathogenesis. Therefore, leptin and its receptor may be an emerging target for intervention in metabolic-associated OA.

1. Introduction

subgroups, which are defined based on the main disease driver, one of which is a distinct metabolic phenotype [3]. Thus, interest in the metabolic-associated OA phenotype is increasing. MetS refers to a cluster of metabolic abnormalities, including obesity, insulin resistance, dyslipidemia, hyperglycemia, and hypertension [4]. Epidemiological studies highlight the link between MetS and OA and the effect of interplay between immunological and metabolic processes is getting increasing emphasis because of to the discovery that metabolic syndrome is implicated in OA pathogenesis and progression [5]. Type 2 diabetes mellitus (T2DM) mediates synovial inflammation and insulin resistance may play a role in the pathogenesis OA [6]. The

Osteoarthritis (OA) is a leading cause of disability and a source of societal cost in older adults. With an ageing and increasingly obese population worldwide, OA incidence could increase [1]. Recently, advances in epidemiology and basic research have changed our perspectives on this disease. We could now clearly identify the role of systemic inflammation in OA progression and differentiate clinical phenotypes based on the following risk factors: aging, trauma, heredity, obesity, and metabolic syndrome (MetS) [2]. Moreover, evidence suggested that patients with OA could be classified into multiple phenotypic

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Corresponding author. Corresponding author. E-mail addresses: [email protected] (X. Qi), [email protected] (X.-H. Jin).

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https://doi.org/10.1016/j.cyto.2020.155043 Received 23 October 2019; Received in revised form 22 January 2020; Accepted 11 February 2020 1043-4666/ © 2020 Elsevier Ltd. All rights reserved.

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development of knee OA and severe knee OA in Korea women. In addition, dose-response relationships were observed between MetS components and knee OA in women [16]. Yasuda et al. reported that symptomatic OA severity is significantly associated with hypertension, dyslipidemia, and the number of MetS factors after adjustment for age, body mass index (BMI), knee extensor strength, and Kellgren-Lawrence (KL) grade among female Japanese patients with knee OA diagnosed using radiographic criteria [17]. Xie et al. showed a positive association between the prevalence of MetS and knee OA. Moreover, MetS components (e.g., overweight, hypertension, and dyslipidemia) were also associated with radiographic knee OA prevalence after adjustment for some confounding factors. In addition, knee OA prevalence increased with the accumulation of MetS components. MetS is also associated with a higher prevalence of knee osteophyte (Xiangya Hospital Health Management Center Study, China) [18]. Askari et al. revealed that metabolic markers are strongly associated with OA, and the addition of each MetS component significantly increases the risk of developing OA (Fasa Osteoarthritis Registry, Iran) [19]. Afifi et al. demonstrated that knee OA is prevalent in a sample of Egyptian patients with MetS, and MetS was associated with worse pain and functional impairment score and advanced radiographic changes [20]. Yerima et al. revealed a significant association of BMI with pain and KL grade, whereas MetS was not associated with pain, function, or KL grade in patients with knee OA in a tertiary hospital in Nigeria [21]. Sanchez-Santos et al. reported a significant association of the presence and the number of MetS components with painful knee OA after adjustment for age; however, the association disappeared when BMI was included in the model. By contrast, the presence and the number of MetS components were associated with painful interphalangeal (IPJ) OA after adjustment for both age and BMI. Four MetS components, including triglycerides, highdensity lipoprotein cholesterol, hypertension, and glucose, were associated with painful IPJ OA (The Chingford 1000 Women, North London, UK) [22]. Niu et al. assessed OA among the Framingham Study subjects and found that MetS and most of its components are associated with both incident radiographic OA and symptomatic OA; however, after adjustment for BMI, almost all of the associations were attenuated weak and no longer significant. An association of high blood pressure, especially diastolic pressure, with OA outcomes persisted in both men and women [23]. Strand et al. reported that MetS is not associated with the incidence of hand OA and change in KL sum score, whereas a significant association between hypertension and change in KL sum score was found. Furthermore, hypertension was not significantly associated with hand OA incidence, and no significant associations were found between MetS and erosive hand OA in a previous study (Participants were from Framingham Heart Study) [24]. Hellevik et al. found an increased risk of total knee replacement (TKR) in men < 50 years with hypertension and individuals < 70 years with an increased waist circumference. Moreover, neither MetS nor its components were associated with increased risk of TKR due to primary OA (The HUNT Study and The Norwegian Arthroplasty Register) [25]. Based on the aforementioned findings, the epidemiologic association between MetS and OA is stronger in the Asian population (Table 1). While some studies supported the association between MetS and OA, other studies showed conflicting evidence. A systemic review identified seven eligible studies on knee OA, three on hip OA, and three on hand OA. In studies that adjusted for BMI or weight, MetS was not significantly associated with the risk of knee OA. No significant associations were reported for hip OA. For hand OA, the data were sparse and insufficient to reach a conclusion. However, the authors also noted that the studies were mostly cross-sectional, exposure included only one time measurement, few studies had incident outcomes, and covariate adjustment was often insufficient. Thus, future longitudinal studies with incident OA cases, repeated measurement of MetS, and appropriate covariate adjustment are needed [26]. In addition, the heterogeneity of different study populations was possibly underestimated. Gandhi et al. indicated that MetS is a risk factor for OA, and Asians

risk of dyslipidemia was twofold greater with than without OA, such a result supports the individualisation of the Metabolic-associated OA phenotype [7]. Metabolic-associated OA is a clinical phenotype that is defined by obesity and MetS as risk factors and by chronic low-grade inflammation; adipose tissue’s endocrine production of proinflammatory mediators (i.e., cytokines, adipokines, fatty acids, and reactive oxygen species) could adversely affect joint tissues [8]. It has been showed that adipocytokines produced by visceral adipose tissue other than mechanical loading might play a role in the development and progression of knee OA; it also has been demonstrated that infrapatellar fat pad (IFP) is a local producer of adipokines and cytokines [9]. Adipokines are a set of metabolites, lipids, and bioactive peptides released by adipocytes, precursors, endothelial and immune cells, fibroblasts, and others. Adipokines contribute to the regulation of appetite and satiety, fat distribution, insulin secretion and sensitivity, energy expenditure, endothelial function, inflammation, blood pressure, and hemostasis [10]. In addition, adipokines also played an emerging role in the modulation of the immune system, MetS and arthritic diseases including OA [11]. Adipokines, including leptin, visfatin, adiponectin, resistin and others, are demonstrated to have metabolic implications in the pathogenesis and progression in obesityinduced OA by modulating the pro/anti-inflammatory and anabolic/ catabolic balance, apoptosis, matrix remodeling and subchondral bone ossification [12]. Among the adipokines, leptin has been investigated for its role in lipodystrophy, and its interaction with metabolic dysfunctions of obesity has been evaluated [13]. Moreover, leptin may also contribute to the pathogenesis and/or progression of OA [14]. A previous review has briefly introduced leptin as a significant modulator of inflammation, cartilage catabolic activity, and cartilage and bone remodeling, which are all associated with OA pathophysiology [11]. There were several published review articles regarding the relationship between MetS and OA, as well as the relationship between leptin and OA. However, few review has systematically summarized the relationship between MetS and OA from both clinical and animal studies. In addition, no recent literature has focused on the relationship between leptin and OA, evidence needs to be updated systematically to further elucidate the role of leptin in OA. Hence, this review aimed to update the current knowledge of the association between MetS and OA as well as the potential role of leptin in OA. 2. Methods We performed a systematic review of the PubMed and Web of Science databases for all English language articles, containing the terms “metabolic syndrome” and“osteoarthritis” for the first issue of the association between MetS and OA (osteoarthritis[Title/Abstract] AND metabolic syndrome[Title/Abstract]), and “leptin” and “osteoarthritis” for the second issue of potential role of leptin in OA (osteoarthritis [Title/Abstract] AND leptin[Title/Abstract]). The repetition were excluded. Two reviewers were assigned to the determination of enrollment of related articles. When they cannot reach a consensus, the third reviewer would determine the enrolment. This study was exempt from institutional review board approval, and no external funding was received for this project. 3. Current knowledge of the association between MetS and OA 3.1. Evidence on clinical studies Numerous clinical studies have investigated the epidemiologic association between MetS or its components and OA. MetS has a cumulative and negative effect on hand OA, independent of weight [15]. However, the results of recent published literatures from different regions appear conflicting. Lee et al. indicated that MetS affects the 2

Cytokine 129 (2020) 155043

demonstrate a greater MetS prevalence than whites and blacks [27]. This result is consistent with our finding on the association of MetS with OA in the Asian population. 3.2. Evidence on animal studies

Knee, hip

Numerous animal studies have been conducted to explore the underlying mechanism of the association between MetS and OA. Using weight-matched mice and multivariate models, Wu et al. found that OA is significantly associated with dietary fatty acid content but not with body weight [28]. Collins et al. found that OA damage in obese contralateral limbs is similar to mechanically perturbed limbs, suggesting that obesity may induce OA in a non-mechanical manner [29]. Griffin et al. suggested that high susceptibility to dietary obesity is associated with increased osteoarthritic changes in the knee and impaired musculoskeletal force generation and motor function compared with controls. A high-fat diet also induced symptomatic characteristics of OA, including hyperalgesia and anxiety-like behaviors [30]. Sekar et al. showed that longer-chain dietary saturated fatty acids in rats induce both MetS and OA-like knee changes [31]. Siriarchavatana et al. demonstrated that rats fed a high-fat/high-sugar (HFHS) diet developed metabolic dysregulation and obesity. Visible damage to knee joint cartilage was minimal; however, plasma levels of C-telopeptide of type II collagen (CTX-II), which is a biomarker of cartilage degradation, were markedly higher in HFHS-fed rats than in control-fed rats [32]. Collins et al. reported that rats with diet-induced obesity had greater modified Mankin OA scores than chow rats, and a significant relationship between body fat, but not body mass, and Modified Mankin OA score was found [33]. They also suggested that systemic inflammatory alterations due to diet-induced obesity in a rat model in the absence of trauma may result in a higher risk of knee, shoulder, and multi-joint damage with a high-fat/high-sucrose diet [34]. In another study, numerous systemic and limited synovial fluid (SF) inflammatory markers were increased at 12-weeks in animals with diet-induced obesity compared to chow, and at 28-weeks, limited systemic differences but marked increases in local SF inflammatory marker concentrations were observed, thereby suggesting that metabolic OA may manifest from an initial systemic inflammatory disturbance [35]. Larranaga-Vera et al. also indicated that a high-fat diet is an aggravating factor for synovial membrane inflammation during OA, guided by increased macrophage infiltration and adipose tissue removal, together with a remarkable presence of proinflammatory factors [36]. De Visser et al. reported that a dysmetabolic state due to surgically induced cartilage damage with inflammatory responses and increased CD68 expressing cells localized on the synovial membrane and osteophytes clearly accelerates OA progression [37]. Sun et al. showed that obesity induced by a high-carbohydrate, high-fat diet is associated with spontaneous and local inflammation of the synovial membranes in rats even before cartilage degradation, which is was followed by increased synovitis and increased macrophage infiltration into the synovium and a predominant elevation of proinflammatory M1 macrophages. In addition, bone marrow-derived macrophages, which were cultured with SF and obtained from the knees of obese rats, exhibited a proinflammatory M1 macrophage phenotype [38]. Rios et al. indicated that a prebiotic fiber supplementation, aerobic exercise, and the combination of the two interventions completely prevent knee joint damage [39]. Griffin et al. also showed that wheel-running exercise reduced the OA progression in the medial femur of obese mice [40]. Using a mouse model, Triantaphyllidou et al. reported that reduced high-density lipoprotein, which is a component of MetS, could be a key component in OA pathogenesis [41]. All these results possibly indicate that metabolic dysregulation could lead to OA pathogenesis. However, recently, Guss et al. suggested that severe adiposity and systemic inflammation could increase load-induced cartilage damage after six weeks of loading, while milder adiposity and metabolic abnormalities in Toll-like receptor-5-deficient mice do not worsen OA

Longitudinal Cohort Hellevik et al., 2018 [25]

Norway

Hand Longitudinal Cohort Strand et al., 2018 [24]

USA

Knee Longitudinal Cohort Niu et al., 2017 [23]

USA

Knee, hip Knee Knee Knee, hand Case-control Case-control Cross-sectional Cross-sectional Askari et al., 2017 [19] Afifi et al., 2018 [20] Yerima et al., 2017 [21] Sanchez-Santos et al., 2019 [22]

Iran Egypt Nigeria UK

Knee Cross-sectional Xie et al., 2017 [18]

China

Cross-sectional Yasuda et al., 2018 [17]

Japan

Knee

MetS affects the development of knee OA and severe knee OA in women. In addition, dose-response relationships were observed between MetS components and knee OA in women Symptomatic OA severity is significantly associated with hypertension, dyslipidemia, and the number of MetS factors after adjustment for age, body mass index, knee extensor strength, and Kellgren-Lawrence grade among female patients with knee OA diagnosed using radiographic criteria A positive association between the prevalence of MetS and knee OA. Moreover, MetS components were also associated with radiographic knee OA prevalence after adjustment for some confounding factors. In addition, knee OA prevalence increased with the accumulation of MetS components. MetS is also associated with a higher prevalence of knee osteophyte Metabolic markers are strongly associated with OA, and the addition of each MetS component significantly increases the risk of developing OA Knee OA is prevalent in patients with MetS, and MetS was associated with worse pain and functional impairment score and advanced radiographic changes A significant association of BMI with pain and KL grade, whereas MetS was not associated with pain, function, or KL grade in patients with knee OA A significant association of the presence and the number of MetS components with painful knee OA after adjustment for age; however, the association disappeared when BMI was included in the model. By contrast, the presence and the number of MetS components were associated with painful interphalangeal OA after adjustment for both age and BMI. Four MetS components, including triglycerides, high-density lipoprotein cholesterol, hypertension, and glucose, were associated with painful interphalangeal OA MetS and most of its components are associated with both incident radiographic OA and symptomatic OA; however, after adjustment for BMI, almost all of the associations were attenuated weak and no longer significant. An association of high blood pressure, especially diastolic pressure, with OA outcomes persisted in both men and women. MetS is not associated with the incidence of hand OA and change in KL sum score, whereas a significant association between hypertension and change in KL sum score was found. Furthermore, hypertension was not significantly associated with hand OA incidence, and no significant associations were found between MetS and erosive hand OA An increased risk of total knee replacement (TKR) in men < 50 years with hypertension and individuals < 70 years with an increased waist circumference. Moreover, neither MetS nor its components were associated with increased risk of TKR due to primary OA Knee Cross-sectional Lee et al., 2019 [16]

Korea

Joint Region Type of study Authors, year

Table 1 Summary of clinical studies on the association between MetS and OA.

Results

Y.-H. Gao, et al.

3

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Table 2 Summary of animal studies on the association between MetS and OA. Authors, year

Animal

Results

Wu et al. 2015 [28] Collins et al. 2015 [29] Griffin et al. 2010 [30]

mice rat mice

Sekar et al. 2017 [31] Siriarchavatana et al. 2019 [32]

rat rat

Collins et al. 2015 [33]

rat

Collins et al. 2018 [34]

rat

Collins et al. 2016 [35]

rat

Larranaga-Vera wt al. 2017 [36]

rabbit

de Visser et al. 2018 [37]

rat

Sun et al. 2017 [38]

rat

Rios et al. 2019 [39]

rat

Griffin et al. 2012 [40] Triantaphyllidou et al. [41] Guss et al. 2019 [42]

mice mice mice

Louer et al. 2012 [43] Mooney et al. 2011 [44]

mice mice

OA is significantly associated with dietary fatty acid content but not with body weight OA damage in obese contralateral limbs is similar to mechanically perturbed limbs High susceptibility to dietary obesity is associated with increased osteoarthritic changes in the knee and impaired musculoskeletal force generation and motor function compared with controls. A high-fat diet also induced symptomatic characteristics of OA, including hyperalgesia and anxiety-like behaviors Longer-chain dietary saturated fatty acids in rats induce both MetS and OA-like knee changes Rats fed a high-fat/high-sugar (HFHS) diet developed metabolic dysregulation and obesity. Visible damage to knee joint cartilage was minimal; plasma levels of C-telopeptide of type II collagen (CTX-II), were markedly higher in HFHS-fed rats than in control-fed rats Rats with diet-induced obesity had greater modified Mankin OA scores than chow rats, and a significant relationship between body fat, but not body mass, and Modified Mankin OA score was found Systemic inflammatory alterations due to diet-induced obesity in a rat model in the absence of trauma may result in a higher risk of knee, shoulder, and multi-joint damage with a high-fat/high-sucrose diet Numerous systemic and limited synovial fluid (SF) inflammatory markers were increased at 12-weeks in animals with diet-induced obesity compared to chow, and at 28-weeks, limited systemic differences but marked increases in local SF inflammatory marker concentrations were observed A high-fat diet is an aggravating factor for synovial membrane inflammation during OA, guided by increased macrophage infiltration and adipose tissue removal, together with a remarkable presence of proinflammatory factors A dysmetabolic state due to surgically induced cartilage damage with inflammatory responses and increased CD68 expressing cells localized on the synovial membrane and osteophytes clearly accelerates OA progression Obesity induced by a high-carbohydrate, high-fat diet is associated with spontaneous and local inflammation of the synovial membranes in rats even before cartilage degradation, which is was followed by increased synovitis and increased macrophage infiltration into the synovium and a predominant elevation of proinflammatory M1 macrophages A prebiotic fiber supplementation, aerobic exercise, and the combination of the two interventions completely prevent knee joint damage Wheel-running exercise reduced the OA progression in the medial femur of obese mice Reduced high-density lipoprotein, which is a component of MetS, could be a key component in OA pathogenesis Severe adiposity and systemic inflammation could increase load-induced cartilage damage after six weeks of loading, while milder adiposity and metabolic abnormalities in Toll-like receptor-5-deficient mice do not worsen OA pathology Diet-induced obesity significantly increased the severity of OA following intraarticular fracture the High-fat diet accelerates progression of OA in a type 2 diabetic mouse model without correlation to weight gain

subchondral bone remodeling [45].

pathology. Furthermore, the effects of systemic inflammation/obesity on cartilage damage depend on the mechanical loading duration [42]. However, the authors also admitted that early studies have indicated that high-fat diet (HFD) models develop both increased severity and accelerated progression of OA [43,44]. Therefore, they also suggested that it is possible that if the current study extended beyond six weeks, OA cartilage pathology in other groups might become as severe as in HFD mice [42] (Table 2).

3.4. Evidences on the relationship between leptin and MetS Adipokines play important physiological roles in metabolic activities contributing to the pathogenesis of MetS, and are also involved in the regulation of autoimmune and/or inflammatory processes associated with arthritic diseases such like OA [11]. Leptin, as one of adipokines, is a 16 kDa nonglycosylated hormone that belongs to the class 1 cytokine superfamily and exerts its biological actions through the activation of OB-Rb long-form isoform receptors encoded by the diabetes (db) gene. Leptin is primarily involved in regulating food intake, body weight and energy homeostasis through neuroendocrine functions. Contemporary research suggests that leptin also influences insulin sensitivity and lipid metabolism [46]. It was associated with MetS: Subjects with MetS had higher leptin levels compared with individuals without MetS [47]. Furthermore, Franks et al. have suggested that leptin predicted the development of the MetS independently of baseline obesity. This association was specifically related to the development of glucose intolerance and insulin resistance [48]. Chiu et al. also have observed leptin levels were associated with MetS score in both men and women in Taiwanese adults [49]. Ghadge and Khaire recently have reviewed that leptin acted as a key a signaling molecule of metabolic status and mediates various metabolic processes such as energy homeostasis and neuroendocrine functions, hyperleptinemia and leptin resistance were closely associated with pathological conditions such as obesity and diabetes, therefore suggested that leptin may act as a predictive marker for MetS [46]. These evidences may indicate the relationship between leptin and MetS.

3.3. Possible pathogenic mechanisms The systemic role of MetS in OA pathophysiology is now better understood. Obesity-associated inflammation could affect OA progression independent of mechanical stress due to excess weight. Fat intake could also influence knee OA progression independent of weight (i.e., the possible beneficial role of n-3 polyunsaturated fatty acids and deleterious effect of cholesterol). Risk of cardiovascular diseases is increased with OA mainly because of physical inactivity and also possibly because of low-grade inflammation [15]. Moreover, links have been discovered between this OA phenotype and MetS (both individual MetS component and MetS as a whole). Hypertension is associated with OA through subchondral ischemia, which could compromise nutrient exchange in the articular cartilage and trigger bone remodeling. Ectopic lipid deposition in chondrocytes induced by dyslipidemia may initiate OA development, which is exacerbated by deregulated cellular lipid metabolism in joint tissues. Hyperglycemia and OA interact at both local and systemic levels; local effects of oxidative stress and advanced glycation end-products are implicated in cartilage damage, while lowgrade systemic inflammation results from glucose accumulation and contributes to a toxic internal environment that may in turn exacerbate OA. Obesity-related metabolic factors, particularly altered adipokine levels, contribute to OA development by inducing the expression of proinflammtory factors as well as degradative enzymes, thereby leading to the inhibition of cartilage matrix synthesis and stimulation of 4

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Table 3 Summary of evidence based on serum/plasma and SF. Authors, year

Sample

Results

Miller et al. 2004 [50]

Serum

Lubbeke et al. 2013 [51]

SF

Perruccio et al. 2014 [52] Ku et al. 2009 [53] Stannus et al. 2010 [54] de Boer et al. 2012 [55] Karvonen-Gutierrez et al. 2012 [56]

Plasma SF Serum Serum Serum

Kroon et al. 2019 [57] Dumond et al. 2003 [58]

Serum SF

Simopoulou et al. 2007 [59] Beekhuizen et al. 2013[60] Staikos et al. 2013 [61]

Serum, SF SF Plasma, SF

Bas et al. 2014 [62]

Serum, SF

Dong et al. 2018 [63] Ding et al. 2008 [64] King et al. 2015 [65] Martel-Pelletier et al. 2016 [66] Stannus et al. 2015 [67]

Plasma, SF Serum Plasma Serum Serum

Nelson et al. 2015 [68] Karvonen-Gutierrez et al. 2013 [69]

Serum, SF Serum

Saluk et al. 2017 [70] Presle et al. 2006 [71]

Plasma Serum, SF

Hooshmand et al. 2015 [72] Berry et al. 2011 [73]

SF Serum

Calvet et al. 2016 [74]

SF

Calvet et al. 2018 [75]

SF

Decreases in serum leptin may be one mechanism by which weight loss improves physical function and symptoms in OA patients Joint pain is associated with SF leptin concentrations. Increased pre-operative pain observed in women and obese may be related to high intra-articular leptin levels Higher leptin was associated with greater painful joint burden among women SF leptin concentrations were closely related to the radiographic severity of OA Hip joint-space narrowing was associated with serum levels of leptin Leptin were associated with female gender and body mass index Among obese women, a 5-μg/L higher leptin was associated with nearly 30% higher odds of having knee OA. Among men, odds ratios for the association of leptin and knee OA were in the opposite direction. Serum leptin levels were associated with OA, and partially mediated the association between adiposity and OA Leptin was observed in SF obtained from human OA-affected joints, and leptin concentrations correlated with the body mass index Leptin is significantly increased in SF compared with serum samples Leptin levels were higher in OA SF than in control SF Plasma leptin positively correlated with the severity of knee OA. The ratio of SF to plasma leptin might be a marker related to the severity of knee OA SF Leptin tended to be higher in the knee than in the hip. In both hip and knee OA, median serum concentrations of leptin exceeded those in SF, worse pain was significantly associated with high SF leptin Leptin level is higher in patients with knee OA with MetS than in those without MetS, independent of body mass index Cartilage volume loss with obesity and female sex is related to leptin Decrease in leptin was associated with reduced loss of medial femoral volume and lateral femoral volume Leptin predict greater cartilage volume loss over time in the lateral and medial compartment Serum levels of leptin are associated with reduced cartilage thickness. In addition, the associations between adiposity measures and cartilage thickness are mediated by leptin Both serum and SF samples showed significant decreases for leptin in the oral hyaluronic acid preparation group. Serum leptin levels were associated with prevalent and incident knee OA. Women with incident knee OA during the 10-year followup period had consistently higher serum leptin levels as compared to women with no knee OA during followup Levels of leptin were significantly elevated in patients undergoing total joint arthroplasty compared to normal. The sOb-R deficiency found in SF further increased the difference in the bioactive leptin levels between serum and SF. A gender-specific difference was observed with women exhibiting the highest level of free leptin in the joint. Leptin concentrations in SF showed significantly elevated levels in women with knee OA but not in men Baseline leptin was associated with increased levels of bone formation biomarkers (osteocalcin and PINP) over 2 years, while sOB-Rb was associated with reduced levels of osteocalcin. Baseline sOB-Rb was associated with reduced levels of the cartilage formation biomarker PIIANP, an increased cartilage defects score, and increased cartilage volume loss over 2 years. Leptin was not independently associated with Lequesne index after adjustment for clinical confounders (age, symptom duration, and radiology) Leptin was associated with pain and function; however, the association was not statistically significant after adjustment for potential confounders

4. The potential role of leptin in OA

associated with reduced cartilage thickness (cross-sectionally and longitudinally). In addition, the associations between adiposity measures and cartilage thickness are mediated by leptin [67]. Nelson et al. studied the effect of an oral preparation containing hyaluronic acid on patients with knee OA with obesity and showed statistically significant improvements in pain and function. Both serum and SF samples showed significant decreases in the majority of inflammatory cytokines, including leptin, in the oral hyaluronic acid preparation group [68]. Karvonen-Gutierrez et al. reported that women with incident knee OA had consistently higher serum leptin levels than those without knee OA during the 10-year follow-up period [69]. Saluk et al. suggested that leptin levels are significantly elevated in patients undergoing total joint arthroplasty [70]. Furthermore, Presle et al. reported that the soluble leptin receptor (sOb-R) deficiency found in SF further increases the difference in the bioactive leptin levels between serum and SF [71]. On the other hand, leptin levels increase in SF of women but not in men with OA versus those without OA [72]. Therefore, these studies suggested a genderspecific distribution of leptin [12]. Since the prevalence of OA is higher in females than in males, leptin in relation to obesity and metabolic abnormalities may attribute more effect to the pathogenesis of OA in females. In a study with over 2 years of follow-up, Berry et al. reported that baseline leptin is associated with increased levels of bone formation biomarkers, while sOb-R is associated with reduced osteocalcin levels; moreover, baseline sOb-R is associated with reduced levels of the cartilage formation biomarkers (cartilage oligomeric matrix protein, Nterminal type IIA procollagen propeptide, and type II collagen cleavage fragments), an increased cartilage defect score, and increased cartilage

4.1. Evidence based on Serum/Plasma and SF Numerous studies investigated leptin levels in serum/plasma and SF, which were obtained during routine clinical procedures, to explore its potential role in OA. Both serum and SF leptin levels were associated with physical function, OA symptoms such as joint pain, and radiographic severity of OA [50–54]. In addition, serum leptin levels were distinctly higher in OA patients than in controls and were associated with female sex and BMI [55,56]. In a large cross-sectional analysis, Kroon et al. reported that serum leptin levels partially mediate the association between adiposity and OA [57]. Dumond et al. firstly reported that leptin exists in SF obtained from human OA-affected joints and that leptin concentrations are correlated with BMI [58]. Simopoulou et al. revealed that leptin is significantly increased in SF compared with serum samples [59]. Beekhuizen et al. indicated that leptin levels were higher in OA SF than in control SF [60]. Staikos et al. and Bas et al. also suggested that the ratio of SF to plasma leptin could be a marker related to knee OA severity [61,62]. Recently, our group investigated the differential expression of adipokines in patients with knee OA with and without MetS and found that leptin level is higher in patients with knee OA with MetS than in those without MetS, independent of BMI [63]. In addition, serum leptin is associated with cartilage volume loss with obesity and female sex [64,65]. Martel-Pelletier et al. demonstrated that serum leptin predicts greater cartilage volume loss in the lateral and medial compartments over time [66]. Stannus et al. reported that serum levels of leptin are independently and consistently 5

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inhibited by peroxisome proliferator-activated receptor α agonist [90]. However, in an HFD-induced obesity model, the IFP does not recapitulate classic abdominal adipose tissue inflammation during the early stages of knee OA. These findings do not support the hypothesis that IFP inflammation is an initiating factor of obesity-induced knee OA. Furthermore, the profibrotic and antihypertrophic responses of IFP adipocytes to HFD suggest that intraarticular adipocytes are subject to distinct spatiotemporal structural and metabolic regulation [91]. Gross et al. also suggested that IFP may trigger both cartilage destruction and synovium inflammation, but not through leptin [92]. Therefore, current evidence suggested that IFP may play a deleterious role in OA, but was insufficient to support the idea that leptin in IFP plays a role in OA pathogenesis, further studies need to be conducted to elucidate the effect of leptin in deleterious role of IFP on the pathogenesis of OA.

volume loss, independent of age, sex, and BMI [73]. However, in Calvet et al.’s cross-sectional study including female patients with symptomatic primary knee OA with ultrasound-confirmed joint effusion, high leptin level was related to knee OA severity. Nevertheless, leptin was not independently associated with Lequesne index after adjustment for clinical confounders (age, symptom duration, and radiology) [74]. Furthermore, leptin was associated with pain and function; however, the association was not statistically significant after adjustment for potential confounders [75]. The conflicting results of these clinical studies could be attributed to the heterogeneity of clinical confounders of the different study populations, as previously mentioned [27]. Thus, a well-designed, prospective, and multi-center research with a large group of patients may be warranted (Table 3). 4.2. Evidence based on intraarticular tissues 4.2.1. Involved intraarticular tissues Synovial joints are surrounded by articular cartilage and a fibrous capsule, including the inner lining of the synovium [76]. The knee joint is one of the most commonly affected joints in OA [77,78]. The IFP differentiates the knee joint from other articular joints [79]. The IFP is composed of a fibrous scaffold, on which fat tissue is embedded. This adipose structure is in close contact with the articular cartilage, bone, and synovium [80–82]. Thus, IFP, synovium, articular cartilage, and bone are often investigated in both observational and interventional studies. (Fig. 1) To be noted, IFP may play a deleterious role in OA by affecting joint homeostasis because of their inflammatory phenotype and their close interaction with synovium in the same functional unit, therefore the two structures may be considered a morpho-functional unit [83,84].

4.2.3. Leptin in the synovium Malaise et al. demonstrated that OA synovial fibroblasts spontaneously produce leptin in vitro [93]. Tong et al. suggested that leptin increases IL-8 production in synovial fibroblast via the leptin receptor long form (OBRl)/JAK2/STAT3 pathway as well as the activation of IRS1/PI3K/Akt/NF-kappaB-dependent pathway and the subsequent recruitment of p300 [94]. Yang et al. showed that leptin activates the OBRl receptor, which in turn activates IRS-1, PI3K, Akt, and AP-1 pathways, thereby leading to the upregulation of IL-6 expression in OA synovial fibroblasts [95]. Our group previously evaluated the expression levels of leptin in the synovium in OA patients with and without MetS and found that the synovium in the MetS-OA group secreted more leptin than that in the non-MetS-OA group [96]. These results suggest that leptin in the synovium may play a proinflammtory role in OA pathogenesis.

4.2.2. Leptin in IFP IFPs and synovial membranes of patients with OA are more inflamed, vascularized, and fibrous than those of patients without OA [85]. Increased fat tissue in joints could be attributed to MetS [86]. IFP dimension is conserved during extreme white adipose tissue states: obesity, MetS, lipodystrophy, and cachexia [87]. In addition, the IFP serves as a source of local inflammatory factors in the knee joint [88]. Presle et al. suggested that synovium and IFP are the major sources of adipokines in the knee joint [71]. Gandhi et al. examined differences in genes involved in fat metabolism, energy homeostasis, adipogenesis, and inflammation between end-stage and early-stage knee OA IFP; 29 IFPs demonstrated an elevated leptin expression [89]. Clockaerts et al. showed that leptin production by IFP could be stimulated by IL-1β and

4.2.4. Leptin in the articular cartilage Dumond et al. firstly reported a marked leptin expression of the protein in OA cartilage and in osteophytes; in a normal cartilage, few chondrocytes produced leptin. Furthermore, the pattern and level of leptin expression were related to the degree of cartilage destruction and paralleled those of growth factors (i.e., IGF-1 and TGFbeta1). Animal studies showed that leptin strongly stimulates the anabolic functions of chondrocytes and induces the synthesis of IGF-1 and TGFbeta1 in the cartilage at both the messenger RNA and protein levels [58]. Koskinen et al. indicated that leptin upregulates matrix metalloproteinase (MMP)-1 and MMP-3 production in human OA cartilage and correlates positively to MMP-1 and MMP-3 in SF from patients with OA [97]. Bao et al. reported that leptin significantly increases both gene and protein

Fig. 1. The roles of leptin in different OA joint tissues. 6

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Scotece et al. showed that the exposure of activated CD4 + T cells to leptin modulates IL-6, IL-8, and CCL-3 production. In addition, production of key extracellular matrix macromolecules (aggrecan and collagen-2) and MMP-13 in co-cultured chondrocytes with activated CD4 + T cells was altered [113]. Sanchez et al. demonstrated that hypotonic shock results in a pH increase in human articular chondrocytes from both healthy and osteoarthritic cartilages, although the increase was significantly smaller in osteoarthritic cartilage. Leptin could attenuate this response [114]. Pallu also showed that the characteristics of patients with OA, especially obesity, may affect the responsiveness of cultured chondrocytes to leptin [115]. Thus, these results may indicate that leptin has both direct and indirect pathway to play catabolic and proinflammtory functions in OA cartilage.

levels of MMP-2, MMP-9, cathepsin D, and collagen II in the cartilage. Moreover, the gene expression of ADAMTS-4 and ADAMTS-5 were markedly increased, and histological assessment showed proteoglycan depletion in the articular cartilage after treatment with leptin [98]. Iliopoulos et al. found that epigenetic mechanisms regulate leptin's expression in chondrocytes affecting its downstream target MMP-13. Small interference RNA against leptin directly deactivates MMP-13, which was upregulated after leptin's epigenetic reactivation [99]. Simopoulou et al. indicated that leptin's and leptin receptor’s (Ob-Rb) expression levels are significantly increased in advanced OA cartilage. The observed intrajoint differences in leptin and Ob-Rb mRNA expression may be related to the degree of cartilage destruction. Moreover, production of IL-1 beta, MMP-9, and MMP-13 by chondrocytes after leptin treatment indicated a proinflammatory and catabolic role of leptin in cartilage metabolism. Furthermore, leptin's mRNA expression was correlated with BMI [59]. By contrast, Lee et al. suggested that the leptin present in the articular joint fluid protects the articular chondrocytes against cumulative mechanical load and detrimental stresses, thereby delaying the onset of degenerative changes in chondrocytes [100]. Griffin et al. suggested that body fat, in and of itself, may not be a risk factor for joint degeneration; in female C57BL/6J mice, adiposity in the absence of leptin signaling is insufficient to induce systemic inflammation and knee OA [101]. Francin et al. reported that leptin promotes the expression of cartilage-specific markers through mitogenactivated protein kinase, Janus kinase, and phosphatidylinositol-3 kinase signaling pathways [102]. Yaykasli et al. demonstrated that leptin treatment increases ADAMTSs expression level and that MAPKs (p38, JNK, and MEK) and NF-ĸB signaling pathways involving leptin trigger ADAMTSs upregulation [103]. Ohba et al. showed that leptin/ObR signaling in articular chondrocytes modulates the expression of canonical Wnt signaling receptors [104]. Liang et al. indicated that leptin activates the RhoA/ROCK/LIMK/cofilin pathway, which results in cytoskeletal reorganization in chondrocytes [105]. Zhang et al. reported that leptin induces apoptosis of chondrocytes in an in vitro model of OA via the JAK2/STAT3 signaling pathway [106]. Huang et al. suggested that leptin promotes apoptosis and inhibits autophagy of chondrocytes by upregulating lysyl oxidase-like 3 during OA pathogenesis [107]. Zhao et al. reported that in knockout mice, high leptin doses decrease the ability of chondrogenic progenitor cells to migrate, inhibit the cells’ chondrogenic potential and increase their osteogenic potential, and induce cell cycle arrest and senescence by activating the p53/p21 pathway and inhibiting the Sirt1 pathway that accelerates cartilage senescence [108]. In addition, the effect of leptin could synergize with interleukins. Conde et al. demonstrated that leptin increases VCAM-1 expression in human and murine chondrocytes and adds to the effect of IL-1β [109]. Vuolteenaho et al. reported that leptin alone or in combination with IL1 enhances the expression of iNOS and COX-2 and the production of NO, PGE (2), IL-6, and IL-8 on human OA cartilage [110]. Hui et al. also reported that leptin, either alone or with IL-1, significantly induces collagen release from bovine cartilage by upregulating collagenolytic and gelatinolytic activities. In chondrocytes, leptin could induce the expression of MMP-1 and MMP-13 with a concomitant activation of STAT1, STAT3, STAT5, MAPK (JNK, Erk, p38), Akt, and NF-kappa B signaling pathways. Selective inhibitor blockade of PI3K, p38, Erk, and Akt pathways significantly reduces MMP-1 and MMP¬-13 expression in chondrocytes and reduces cartilage collagen release induced by leptin or leptin plus IL-1. Conditioned media from cultured white adipose tissue of the OA knee joint fat pads contain leptin, induce cartilage collagen release, and increase MMP-1 and MMP-13 expression in chondrocytes; the latter being partly blocked with an anti-leptin antibody [111]. Pearson et al. reported that leptin enhances IL-6 inflammatory response, which is mediated by a chondrocyte-synovial fibroblast cross-talk [112]. Some indirect effects of leptin on articular cartilage were reported.

4.2.5. Leptin in the bone Chou et al. assessed the gene expression profiling in OA subchondral bone and suggested that leptin is implicated in bone remodeling by osteoblasts [116]. Mutabaruka et al. suggested that abnormal leptin production by abnormal osteoblasts could be responsible, in part, for the elevated phosphatase activity levels, osteocalcin release, and collagen type 1 and TGF-beta1 levels. Leptin also stimulates cell proliferation and Erk 1/2 and p38 signaling [117]. Yang et al. showed that leptin increases oncostatin M expression by downregulating miR-93 through the Akt signaling pathway in osteoblasts [118]. Since the homeostasis of bone in OA was determined on both osteoblasts and osteoclasts, further studies need to be performed on the effect of leptin on osteoclasts to elucidate the role of leptin in the bone of OA. 5. Perspectives Leptin has been considered a marker of MetS [119]. The role of other adipokines in the pathogenesis of OA has also been investigated. Adiponectin is associated with joint pain, while resistin and visfatin are mainly related to function [120]. Adiponectin expression levels are higher in patients with OA than in healthy controls [121], and plasma adiponectin concentrations are associated with clinical and radiological disease severity among patients with knee OA [122]. Moreover, resistin levels in both the serum and SF are higher in patients with OA and RA than in healthy subjects, and generally, resistin levels are much higher in serum than in SF. In human cartilage, resistin induces the expression of proinflammatory factors, such as degradative enzymes, which in turn results in the inhibition of cartilage matrix synthesis [123]. The role of individual adipokines in the pathogenesis of OA has been studied. Gandhi et al. revealed that the correlations between the individual adipokines and the pain scales are low to moderate and consistently lower than that for the corresponding adiponectin/leptin ratio [124]. Thus, changes in the expressions of different adipokines may play a synergistic effect, which was not taken into consideration as most studies focused on one type of adipokine. Although OA risk is influenced by intrinsic factors, such as age and genetics, it is partly a mismatch disease affected by modifiable factors, such as MetS, which indicates a substantial potential for prevention [125]. Six main phenotypes were identified in a previous systematic review [126]. The inflammatory and MetS phenotypes showed similar health outcomes, which could be attributed to the similarity in the hypothesized disease mechanisms. However, these two phenotypes differ in other important characteristics. This suggests that despite the similarity in the outcome, the mechanisms of the disease are different; hence, subjects classified in these phenotypes may benefit from different treatments [127]. Based on the evidence we have presented in this review, an intervention that aims to reduce leptin expression may be a novel approach to delay OA progression in patients with obesity or MetS. Regular and light aerobic exercise could decrease leptin levels in un-trained females; thus, decreases in serum leptin may be one mechanism by which weight loss improves physical function [128]. 7

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Current recommendations only specify that patients with obesity must lose weight and practice regular physical activity in addition to the usual care. In patients with MetS, non-steroidal anti-inflammatory drugs and corticosteroids must be avoided, whereas symptomatic slow acting drugs for OA, such as glucosamine and chondroitin, and some anti-oxidant drugs, including curcumin, may be helpful because of their excellent benefit/risk ratio and their mode of action, which may have a positive effect on both OA and metabolic disorders [129]. Jiang et al. suggested that serum IL-1β and leptin levels are decreased by resveratrol treatment and positively correlate with Mankin scores [130]. Zhou et al. suggested that the upregulation of miR-27 inhibits the OA pathogenesis by targeting leptin and inhibiting the NF-kappa B signaling pathway [131]. A meta-analysis showed that curcumin supplementation is associated with decreased leptin levels, which may be regarded as a potential mechanism of the metabolic effects of curcumin [132]. Moreover, considering that some physical exercises may aggravate joint damage in patients with OA with obesity or MetS, pharmacological intervention that aims to attenuate disease progression by reducing leptin expression should be developed. Nevertheless, further research on the role of leptin and its receptor on the pathogenesis of metabolicassociated OA is warranted.

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