Osteoarthritis and Cardiovascular Diseases: is Meta-Inflammation the Missing Link?

Camille Roubille, Johanne Martel-Pelletier, Jérémie Sellam, Jean-Pierre Pelletier, Jean-Pierre Raynauld, François Roubille

Camille Roubille, Department of Rheumatology, Lapeyronie Hospital, Montpellier, France
Johanne Martel-Pelletier, Jean-Pierre Pelletier, Jean-Pierre Raynauld, Osteoarthritis Research Unit, University of Montreal Hospital Research Centre (CRCHUM), Montreal, Quebec, Canada
Jérémie Sellam, Rheumatology Department, Saint-Antoine Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Sorbonne Universités UPMC Univ Paris 06 and INSERM UMRS_938, DHU i2B, 75012, Paris, France
François Roubille, Cardiology Department, Arnaud de Villeneuve University Hospital, Montpellier, France

Correspondence to: Camille Roubille, Department of Rheumatology, Lapeyronie Hospital, Montpellier, France
Email: c-roubille@chu-montpellier.fr
Telephone: +33-04- 67338710
Fax: +33-04-67337311
Received: November 11, 2014
Revised: December 3, 2014
Accepted: December 8, 2014
Published online: June 10, 2015


Osteoarthritis (OA) was found associated with atherosclerosis, metabolic syndrome, more cardiovascular diseases (CVD) and higher cardiovascular morbidity and mortality. However, it remains unclear whether these conditions only coexist in ageing patients presenting shared traditional cardiovascular risk factors, including age, obesity and disability-related sedentary lifestyle, or are further interconnected. Interestingly, the accumulation of metabolic syndrome components was associated with the development and progression of knee OA, supporting the concept of metabolic OA. Recent research suggests key roles of meta-inflammation, and adipokines in the pathogenesis of OA, metabolic syndrome and CVD. While leptin may be one cornerstone mediator linking obesity, metabolic syndrome, OA, and CVD, the exact role of adiponectin remains controversial in both CVD and OA as it may exert both pro-inflammatory and anti-inflammatory properties. However, the relationship between adipokines and OA as well as CVD is being uncovered and require further investigation. In any case, if meta-inflammation is truly the pivotal link interconnecting OA, metabolic syndrome, and CVD, managing dyslipidemia, hyperglycemia, hypertension and weight in OA patients may be beneficial not only for cardiovascular reasons but also perhaps to delay OA progression.

Key words: Osteoarthritis; Cardiovascular diseases; Meta-inflammation; Adipokines; Metabolic syndrome

© 2015 The Authors. Published by ACT Group Ltd.

Roubille C, Martel-Pelletier J, Sellam J, Pelletier JP, Raynauld JP, Roubille F. Osteoarthritis and Cardiovascular Diseases: is Meta-Inflammation the Missing Link? Journal of Cardiology and Therapy 2015; 2(3): 315-320 Available from: URL: http://www.ghrnet.org/index.php/jct/article/view/1203


Osteoarthritis (OA) is the most common form of arthritis, affecting around 6 million individuals in France, mostly elderly with significant comorbidities including cardiovascular diseases (CVD)[1]. OA of the knee and of the hip is one major cause of pain, disability and functional limitation worldwide, leading to increased morbidity and mortality[2]. OA is characterized by degradation and loss of articular cartilage, hypertrophic bone changes with osteophyte formation, subchondral bone remodeling and inflammation of the synovial membrane. Muscles and ligaments are also altered during the OA process. Currently, OA is considered as a more complex disease than previously assumed as it involves various joints (hip, knee, hands, spine) and multiple phenotypes within a specific joint, as well as underlying pathophysiological factors including aging, injuries, genetics and obesity, to name a few. Increasing evidence suggests that cardiovascular morbidity and mortality are higher in OA populations, especially in knee and hip OA patients with severe disability[2-4]. This disease was also found associated with atherosclerosis, metabolic syndrome and more CVD. However, it remains unclear whether these conditions only coexist in ageing patients presenting shared traditional cardiovascular risk factors, including age, obesity and disability-related sedentary lifestyle, or are further interconnected. Nonetheless, recent research suggests key roles of low-grade systemic inflammation, also termed meta-inflammation, and adipokines in the pathogenesis of OA, metabolic syndrome and CVD.

Relationship between osteoarthritis and cardiovascular diseases

Some studies based on large cohorts have shown an independent association between atherosclerosis and knee OA, as well as hand OA[5], especially distal interphalangeal OA[6]. In the Reykjavik study[5], both carotid plaque severity and coronary calcification were associated with hand OA in women and in the Rotterdam study[7], OA was associated with an increased risk of CVD among both men and women, including an increased risk of angina and heart failure. Conversely, the presence of OA may reduce the potential for rehabilitation after cardiovascular events; for instance, OA-related disability may limit improvement in ambulation level in hemiplegic patients after strokes[8].

Over the past decades, several explanations have been proposed to understand the increased risk of CVD presented by patients with OA. First, by limiting exercise, OA-related disability is a major cause of sedentary lifestyle, which is a well-known cardiovascular risk factor. This is indeed consistent and logical that higher cardiovascular mortality in OA patients appears to be strongly related to walking disability and reduced physical activity[2]. Interestingly, patients with moderate-severe knee and hip OA who underwent total joint replacement were recently found less likely than those who did not, to experience serious cardiovascular events[9]. Second, the symptomatic treatment of OA, which currently consists of analgesics and non-steroidal anti-inflammatory drugs (NSAIDs), has several potential cardiovascular side effects. Cardiovascular side effects of NSAIDs (among others including gastro-intestinal and renal side effects) are clearly well established, including myocardial infarction and hypertension[10], and current OA management guidelines recommend limiting their use to flares. Significant adverse effects of acetaminophen have also been reported including hypertension for doses up to 3 g per day[11]. Moreover, besides these class-related adverse effects, opioids, by reducing patients’ mobility[12], may also reduce life expectancy by increasing cardiovascular risk; however, this relationship has not been clearly established.

In addition to these hypotheses, given that obesity is a well-recognized risk factor for knee OA incidence, the relationship between metabolic syndrome and OA has been largely investigated, leading to focus on the concept of metabolic OA and its potential relationship with CVD[13].

From an association between osteoarthritis and metabolic syndrome to the concept of metabolic osteoarthritis: the role of meta-inflammation

Metabolic syndrome is associated with an increased risk of CVD and its prevalence is increased in OA subjects[14]. In the USA, it affects about 60% of OA populations compared to 23% in non-OA populations[14,15]. However, metabolic syndrome lacks a single definition as several definitions have been proposed[16-19]. Insulin resistance appears to be a major criteria in all definitions, associated with others including obesity (increased waist circumference), dyslipidemia (based on elevated triglyceride levels and/or decreased HDL-cholesterol levels), and hypertension[15]. Notably, the prevalence of metabolic syndrome is increased in OA subjects[14]. Moreover, OA has been associated with several components of metabolic syndrome such as obesity[20], hypertension[21], dyslipidemia[22,23] and type 2 diabetes[24], alone or in combination: for example, diabetes, hypertension and obesity may be synergistic on the risk of hand OA in middle-aged individuals[25]. Moreover, an increased risk of hand OA was also found in overweight individuals. These data have led to the current concept of a “metabolic OA” because of shared underlying pathways[15]. However, although most of the data currently report an impact of metabolic syndrome and its components on OA pathogenesis, one should also consider how OA could in turn influence metabolic syndrome components and contribute to a vicious circle elevating the global cardiovascular risk of OA patients. In this line of thought, low-grade systemic inflammation or meta-inflammation may be the common cornerstone of OA, metabolic syndrome and atherosclerosis. The association between inflammation and cardiovascular risk is well-known and appeared as clinically consistent since the JUPITER trial[26] in which the absolute risk of first major adverse cardiac events was greater with increasing high-sensitivity C-reactive protein (CRP) levels, a measure of systemic inflammation. Although to a lesser extent, low-grade systemic inflammatory was demonstrated to play key roles in metabolic syndrome[27] and OA[28]. Dysregulation in pro-inflammatory cytokines and adipokines released by the adipose tissue may contribute to a certain level of systemic inflammation which may initiate and/or perpetuate the OA process, but also promote insulin resistance and other components of metabolic syndrome. Once activated, OA joint cells might in turn release inflammatory factors into the joint and the bloodstream, increasing the low-grade inflammation[28], which can in turn induce endothelial dysfunction and CVD and reversely promote metabolic syndrome, creating a vicious circle. This concept has to be validated with in vivo models but this holistic vision is appealing.

Among the metabolic syndrome components, obesity is a major risk factor for knee OA incidence. While joint overload has long been considered to account for this relationship, increasing evidence suggests the critical role of metabolic factors. Obesity has been associated with a two-fold increased risk of hand OA[29] yet, obviously, excessive mechanical stress cannot fully explain the link between obesity and OA of non-weight-bearing joints. Hence, showing an increased risk of hand OA in obese patients opened the door to a role of inflammatory mediators such as adipokines. Adipose tissue is now considered an endocrine organ that releases pro-inflammatory cytokines such as TNF-alpha, IL-1 and adipokines. Adipokines (including leptin, adiponectin, visfatin, resistin among others) are cytokines produced by adipose tissue that exert inflammatory and metabolic properties leading to chronic low-grade systemic inflammation - or meta-inflammation - in obese individuals. Adipokines are involved in glucose and lipid metabolism, haemostasis, insulin sensitivity and blood pressure regulation. Individuals with metabolic syndrome have higher levels of leptin, which are related to insulin resistance[30] and can be decreased by weight loss. On the other hand, subjects with metabolic syndrome have also lower levels of adiponectin, which are inversely proportional to insulin resistance and can be increased with weight loss[31]. Adiponectin may be thus considered as a protective adipokine on the cardiovascular system.

Infrapatellar fat pad (in the knee) and synovial membrane are potential sources of adipokines which could contribute to OA pathophysiology via local production of these adipokines[32]. Moreover, as subchondral bone osteoblasts have been reported to produce leptin[33], a local production of leptin in subchondral bone tissue may also contribute to the presence of leptin in articular cartilage. Finally, under inflammatory stimulation, adipokines are also produced by the activated chondrocyte itself.

Associations between adipokine concentrations and OA severity[34], as well as local synovial tissue inflammation, have been described[35]. Some studies reported a role of adipokines in knee OA structural progression[36,37]. Leptin, adiponectin, visfatin and resistin are likely involved in OA pathogenesis with mainly pro-inflammatory activities. Adipokines and inflammatory cytokines promote the activation of the chondrocytes, which in turn contribute to the expression of metalloproteinases (MMPs) and proinflammatory cytokines, initiating a vicious circle. Leptin may promote cartilage loss[38], and serum leptin levels have been reported to correlate with radiographic knee OA severity[39]. Indeed, leptin has mostly catabolic properties, but a role in osteophytes development has been also suggested[40]. It is involved in upregulating the expression of MMPs by chondrocytes, thereby contributing to collagen degradation[41], of insulin-like growth factor 1 (IGF-1), and of transforming growth factor β (TGF-β) by osteoblasts, enhancing osteophyte formation[42]. Serum adiponectin levels may predict radiographic progression of hand OA[34] and increased levels of adiponectin have been reported in women suffering from erosive compared with non-erosive OA of the hands[43]. However, some reports argue for a protective role of adiponectin in OA with an inverse correlation found between adiponectin levels and cartilage damage or OA severity[34]. One hypothesis is that adiponectin might play a different role in OA according to the stage and severity of the disease, and also according to the affected joint (hand OA vs knee or hip OA), but its exact role remains elusive as there are limited in vivo models. Complex equilibrium could also explain at least by part this heterogeneity. Additionally, visfatin has recently been reported to be involved in inflammatory pathways in OA[44].

On the other hand, some studies also reported a pathophysiological role of adipokines in CVD. Increased levels of leptin have been associated with myocardial infarction and stroke[45,46], independent of traditional cardiovascular risk factors. Low levels of adiponectin have been linked to hypertension[47], and high levels to lower risk of myocardial infarction in men[48-50], suggesting a protective vascular role of adiponectin in the general population. By contrast, in patients with coronary artery disease (CAD), elevated levels of adiponectin have been associated with higher mortality and major cardiovascular events[51-53], while inversely associated with an increasing number of traditional cardiovascular risk factors[52]. In patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention, increased levels of adiponectin have been reported to predict all-cause and cardiovascular mortality[54]. Consistently, total adiponectin was also associated with an increased 10-year risk of ischemic stroke among healthy middle-aged men in the PRIME study[55] and with stroke-related mortality in acute stroke patients[56]. As in OA, the exact role of adiponectin in CVD remains unclear; one meta-analysis of 17 prospective studies reported that higher serum adiponectin was related to an increased risk of ischemic stroke, while not related to CAD or CVD[57].

In summary, leptin may be one cornerstone mediator linking obesity, metabolic syndrome, OA, and CVD. The exact role of adiponectin remains controversial in both CVD and OA as it may exert both pro-inflammatory and anti-inflammatory properties, probably due differential effects of its different isoforms (low molecular weight, high molecular weight, globular) on 2 different receptors (adipoR1 and adipor2). Altogether, these data suggest a role of meta-inflammation in both OA and CVD[28] (Figure 1). However, the relationship between adipokines and OA as well as CVD is being uncovered and require further investigation. Moreover, adipokines are a growing family of white adipose tissue-produced factor and, perhaps in the future, other adipokines will be found to have greater impact on these conditions than those known at present.

Interestingly, the accumulation of metabolic syndrome components was associated with the development and progression of knee OA in the Japanese Research on Osteoarthritis/Osteoporosis Against Disability (ROAD) study[58]. Knee OA progression increased with the number of metabolic syndrome components. However, among the metabolic syndrome risk factors, body mass index (BMI) was the only factor that was significantly associated with knee OA occurrence and progression. Although a recent magnetic resonance imaging (MRI) study reported similar data[59], another showed that the accumulation of metabolic syndrome components was associated with the incidence of total knee replacement, independently of BMI[21]. In the latter study, central obesity (increased waist circumference) (hazard ratio 1.59, 95% confidence interval 1.25-2.01) and hypertension (1.24, 1.05-1.48) were the two factors which were associated with the incidence of total knee replacement in multivariate analysis, adjusted on BMI among other factors. Altogether, these data suggest the cumulative impact of metabolic syndrome components on the risk of severe knee OA[60].

Finally, although the link between obesity and OA is well established, the effect of weight loss on OA symptoms and progression remains unclear. Recently, weight loss via bariatric surgery was reported to result in symptomatic improvement in knee OA patients in pain, stiffness, and physical function as assessed by both the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and the Knee injury and Osteoarthritis Outcome Score (KOOS) at 12 months after surgery[61]. Another study using a low-energy diet reported an improvement in WOMAC total score, and pain and physical function subscales. The authors concluded that a weight loss of 10% improved physical function by 28%[62]. Interestingly, these patients, who had lost weight and whose clinical symptoms improved, also experienced a decrease in low-grade systemic inflammation. However, the impact of such weight loss on OA tissue structural changes remains unknown.


Besides weight loss, it remains unknown whether controlling other metabolic syndrome components such as hypertension, diabetes and dyslipidemia might be beneficial for OA. Statins have anti-inflammatory and immuno-modulatory properties and have been expected to show disease-modifying OA drug (DMOAD) effects[63]. However, although recently associated with lower prevalence of generalized OA[64], statin use has so far not been associated with clinical efficacy in OA[65,66]. Nonetheless, the Rotterdam study[67] reported that statin use was associated with reduced incidence and progression of knee OA. Going one step further, this leads to the expectation of benefits of OA management in cardiovascular outcomes in these patients. Reduction of fat mass via modification of lifestyle or any therapeutic intervention can be expected to improve both OA progression and cardiovascular survival. A knee OA trial (www.clinicaltrials.gov; NCT01906281), which is currently recruiting, aims at assessing the impact of adipokines levels on both the inflammatory phenotype of the knee and on carotid atheromatous disease and cardiovascular risk factors. Targeting metabolic syndrome via adipokines may be a future research avenue for both OA and cardiovascular related morbi-mortality. It is suggested that inhibition of leptin expression or intra-articular injection of a leptin antagonist could be a research avenue in DMOAD management, especially in obese patients. However, the pleiotropic function of adipokines could counteract the expected effects.

In any case, the metabolic concept of OA argues for a specific prevention management for CVD and a tight control of cardiovascular risk factors. If meta-inflammation is truly the pivotal link interconnecting OA, metabolic syndrome, and CVD, managing dyslipidemia, hyperglycemia, hypertension and weight in OA patients may be beneficial not only for cardiovascular reasons but also perhaps to delay OA progression.


There are no conflicts of interest with regard to the present study.


1. Sellam J, Berenbaum F. Is osteoarthritis a metabolic disease? Joint, bone, spine : revue du rhumatisme. 2013;80:568-573

2. Nuesch E, Dieppe P, Reichenbach S, Williams S, Iff S, Juni P. All cause and disease specific mortality in patients with knee or hip osteoarthritis: Population based cohort study. BMJ. 2011;342:d1165

3. Hawker GA, Croxford R, Bierman AS, Harvey PJ, Ravi B, Stanaitis I, Lipscombe LL. All-cause mortality and serious cardiovascular events in people with hip and knee osteoarthritis: A population based cohort study. PloS one. 2014;9:e91286

4. Haugen IK, Ramachandran VS, Misra D, Neogi T, Niu J, Yang T, Zhang Y, Felson DT. Hand osteoarthritis in relation to mortality and incidence of cardiovascular disease: Data from the framingham heart study. Annals of the rheumatic diseases. 2013

5. Jonsson H, Helgadottir GP, Aspelund T, Eiriksdottir G, Sigurdsson S, Ingvarsson T, Harris TB, Launer L, Gudnason V. Hand osteoarthritis in older women is associated with carotid and coronary atherosclerosis: The ages reykjavik study. Annals of the rheumatic diseases. 2009;68:1696-1700

6. Hoeven TA, Kavousi M, Clockaerts S, Kerkhof HJ, van Meurs JB, Franco O, Hofman A, Bindels P, Witteman J, Bierma-Zeinstra S. Association of atherosclerosis with presence and progression of osteoarthritis: The rotterdam study. Annals of the rheumatic diseases. 2013;72:646-651

7. Rahman MM, Kopec JA, Cibere J, Goldsmith CH, Anis AH. The relationship between osteoarthritis and cardiovascular disease in a population health survey: A cross-sectional study. BMJ open. 2013;3

8. Doruk P. The impact of knee osteoarthritis on rehabilitation outcomes in hemiparetic stroke patients. Journal of back and musculoskeletal rehabilitation. 2013;26:207-211

9. Ravi B, Croxford R, Austin PC, Lipscombe L, Bierman AS, Harvey PJ, Hawker GA. The relation between total joint arthroplasty and risk for serious cardiovascular events in patients with moderate-severe osteoarthritis: Propensity score matched landmark analysis. Bmj. 2013;347:f6187

10. Trelle S, Reichenbach S, Wandel S, Hildebrand P, Tschannen B, Villiger PM, Egger M, Juni P. Cardiovascular safety of non-steroidal anti-inflammatory drugs: Network meta-analysis. BMJ. 2011;342:c7086

11. Forman JP, Rimm EB, Curhan GC. Frequency of analgesic use and risk of hypertension among men. Archives of internal medicine. 2007;167:394-399

12. Solomon DH, Rassen JA, Glynn RJ, Lee J, Levin R, Schneeweiss S. The comparative safety of analgesics in older adults with arthritis. Archives of internal medicine. 2010;170:1968-1976

13. Bijlsma JW, Berenbaum F, Lafeber FP. Osteoarthritis: An update with relevance for clinical practice. Lancet. 2011;377:2115-2126

14. Puenpatom RA, Victor TW. Increased prevalence of metabolic syndrome in individuals with osteoarthritis: An analysis of nhanes iii data. Postgraduate medicine. 2009;121:9-20

15. Zhuo Q, Yang W, Chen J, Wang Y. Metabolic syndrome meets osteoarthritis. Nature reviews. Rheumatology. 2012;8:729-737

16. Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: Diagnosis and classification of diabetes mellitus provisional report of a who consultation. Diabetic medicine : a journal of the British Diabetic Association. 1998;15:539-553

17. Balkau B, Charles MA. Comment on the provisional report from the who consultation. European group for the study of insulin resistance (egir). Diabetic medicine : a journal of the British Diabetic Association. 1999;16:442-443

18. Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, Gordon DJ, Krauss RM, Savage PJ, Smith SC, Jr., Spertus JA, Fernando C. Diagnosis and management of the metabolic syndrome: An american heart association/national heart, lung, and blood institute scientific statement: Executive summary. Critical pathways in cardiology. 2005;4:198-203

19. Zimmet P, Magliano D, Matsuzawa Y, Alberti G, Shaw J. The metabolic syndrome: A global public health problem and a new definition. Journal of atherosclerosis and thrombosis. 2005;12:295-300

20. Anderson JJ, Felson DT. Factors associated with osteoarthritis of the knee in the first national health and nutrition examination survey (hanes i). Evidence for an association with overweight, race, and physical demands of work. American journal of epidemiology. 1988;128:179-189

21. Monira Hussain S, Wang Y, Cicuttini FM, Simpson JA, Giles GG, Graves S, Wluka AE. Incidence of total knee and hip replacement for osteoarthritis in relation to the metabolic syndrome and its components: A prospective cohort study. Seminars in arthritis and rheumatism. 2014;43:429-436

22. Davies-Tuck ML, Hanna F, Davis SR, Bell RJ, Davison SL, Wluka AE, Adams J, Cicuttini FM. Total cholesterol and triglycerides are associated with the development of new bone marrow lesions in asymptomatic middle-aged women - a prospective cohort study. Arthritis research & therapy. 2009;11:R181

23. Dore D, de Hoog J, Giles G, Ding C, Cicuttini F, Jones G. A longitudinal study of the association between dietary factors, serum lipids, and bone marrow lesions of the knee. Arthritis research & therapy. 2012;14:R13

24. Schett G, Kleyer A, Perricone C, Sahinbegovic E, Iagnocco A, Zwerina J, Lorenzini R, Aschenbrenner F, Berenbaum F, D'Agostino MA, Willeit J, Kiechl S. Diabetes is an independent predictor for severe osteoarthritis: Results from a longitudinal cohort study. Diabetes care. 2013;36:403-409

25. Dahaghin S, Bierma-Zeinstra SM, Koes BW, Hazes JM, Pols HA. Do metabolic factors add to the effect of overweight on hand osteoarthritis? The rotterdam study. Annals of the rheumatic diseases. 2007;66:916-920

26. Ridker PM, MacFadyen J, Libby P, Glynn RJ. Relation of baseline high-sensitivity c-reactive protein level to cardiovascular outcomes with rosuvastatin in the justification for use of statins in prevention: An intervention trial evaluating rosuvastatin (jupiter). The American journal of cardiology. 2010;106:204-209

27. Fuentes E, Fuentes F, Vilahur G, Badimon L, Palomo I. Mechanisms of chronic state of inflammation as mediators that link obese adipose tissue and metabolic syndrome. Mediators of inflammation. 2013;2013:136584

28. Berenbaum F. Osteoarthritis as an inflammatory disease (osteoarthritis is not osteoarthrosis!). Osteoarthritis and cartilage / OARS, Osteoarthritis Research Society. 2013;21:16-21

29. Yusuf E, Nelissen RG, Ioan-Facsinay A, Stojanovic-Susulic V, DeGroot J, van Osch G, Middeldorp S, Huizinga TW, Kloppenburg M. Association between weight or body mass index and hand osteoarthritis: A systematic review. Annals of the rheumatic diseases. 2010;69:761-765

30. Gannage-Yared MH, Khalife S, Semaan M, Fares F, Jambart S, Halaby G. Serum adiponectin and leptin levels in relation to the metabolic syndrome, androgenic profile and somatotropic axis in healthy non-diabetic elderly men. European journal of endocrinology / European Federation of Endocrine Societies. 2006;155:167-176

31. Abella V, Scotece M, Conde J, Lopez V, Lazzaro V, Pino J, Gomez-Reino JJ, Gualillo O. Adipokines, metabolic syndrome and rheumatic diseases. Journal of immunology research. 2014;2014:343746

32. Presle N, Pottie P, Dumond H, Guillaume C, Lapicque F, Pallu S, Mainard D, Netter P, Terlain B. Differential distribution of adipokines between serum and synovial fluid in patients with osteoarthritis. Contribution of joint tissues to their articular production. Osteoarthritis and cartilage / OARS, Osteoarthritis Research Society. 2006;14:690-695

33. Mutabaruka MS, Aoulad Aissa M, Delalandre A, Lavigne M, Lajeunesse D. Local leptin production in osteoarthritis subchondral osteoblasts may be responsible for their abnormal phenotypic expression. Arthritis research & therapy. 2010;12:R20

34. Yusuf E, Ioan-Facsinay A, Bijsterbosch J, Klein-Wieringa I, Kwekkeboom J, Slagboom PE, Huizinga TW, Kloppenburg M. Association between leptin, adiponectin and resistin and long-term progression of hand osteoarthritis. Annals of the rheumatic diseases. 2011;70:1282-1284

35. de Boer TN, van Spil WE, Huisman AM, Polak AA, Bijlsma JW, Lafeber FP, Mastbergen SC. Serum adipokines in osteoarthritis; comparison with controls and relationship with local parameters of synovial inflammation and cartilage damage. Osteoarthritis and cartilage / OARS, Osteoarthritis Research Society. 2012;20:846-853

36. Perruccio AV, Mahomed NN, Chandran V, Gandhi R. Plasma adipokine levels and their association with overall burden of painful joints among individuals with hip and knee osteoarthritis. The Journal of rheumatology. 2014;41:334-337

37. Karvonen-Gutierrez CA, Harlow SD, Mancuso P, Jacobson J, Mendes de Leon CF, Nan B. Association of leptin levels with radiographic knee osteoarthritis among a cohort of midlife women. Arthritis care & research. 2013;65:936-944

38. Ding C, Parameswaran V, Cicuttini F, Burgess J, Zhai G, Quinn S, Jones G. Association between leptin, body composition, sex and knee cartilage morphology in older adults: The tasmanian older adult cohort (tasoac) study. Annals of the rheumatic diseases. 2008;67:1256-1261

39. Staikos C, Ververidis A, Drosos G, Manolopoulos VG, Verettas DA, Tavridou A. The association of adipokine levels in plasma and synovial fluid with the severity of knee osteoarthritis. Rheumatology. 2013;52:1077-1083

40. Terlain B, Presle N, Pottie P, Mainard D, Netter P. [leptin: A link between obesity and osteoarthritis?]. Bulletin de l'Academie nationale de medecine. 2006;190:1421-1435; discussion 1435-1427, 1475-1427

41. Hui W, Litherland GJ, Elias MS, Kitson GI, Cawston TE, Rowan AD, Young DA. Leptin produced by joint white adipose tissue induces cartilage degradation via upregulation and activation of matrix metalloproteinases. Annals of the rheumatic diseases. 2012;71:455-462

42. Lajeunesse D, Pelletier JP, Martel-Pelletier J. Osteoarthritis: A metabolic disease induced by local abnormal leptin activity? Current rheumatology reports. 2005;7:79-81

43. Filkova M, Liskova M, Hulejova H, Haluzik M, Gatterova J, Pavelkova A, Pavelka K, Gay S, Muller-Ladner U, Senolt L. Increased serum adiponectin levels in female patients with erosive compared with non-erosive osteoarthritis. Annals of the rheumatic diseases. 2009;68:295-296

44. Laiguillon MC, Houard X, Bougault C, Gosset M, Nourissat G, Sautet A, Jacques C, Berenbaum F, Sellam J. Expression and function of visfatin (nampt), an adipokine-enzyme involved in inflammatory pathways of osteoarthritis. Arthritis research & therapy. 2014;16:R38

45. Wannamethee SG, Shaper AG, Whincup PH, Lennon L, Sattar N. Adiposity, adipokines, and risk of incident stroke in older men. Stroke; a journal of cerebral circulation. 2013;44:3-8

46. Soderberg S, Stegmayr B, Stenlund H, Sjostrom LG, Agren A, Johansson L, Weinehall L, Olsson T. Leptin, but not adiponectin, predicts stroke in males. Journal of internal medicine. 2004;256:128-136

47. Iwashima Y, Katsuya T, Ishikawa K, Ouchi N, Ohishi M, Sugimoto K, Fu Y, Motone M, Yamamoto K, Matsuo A, Ohashi K, Kihara S, Funahashi T, Rakugi H, Matsuzawa Y, Ogihara T. Hypoadiponectinemia is an independent risk factor for hypertension. Hypertension. 2004;43:1318-1323

48. Pischon T, Girman CJ, Hotamisligil GS, Rifai N, Hu FB, Rimm EB. Plasma adiponectin levels and risk of myocardial infarction in men. JAMA : the journal of the American Medical Association. 2004;291:1730-1737

49. Schulze MB, Shai I, Rimm EB, Li T, Rifai N, Hu FB. Adiponectin and future coronary heart disease events among men with type 2 diabetes. Diabetes. 2005;54:534-539

50. Wolk R, Berger P, Lennon RJ, Brilakis ES, Davison DE, Somers VK. Association between plasma adiponectin levels and unstable coronary syndromes. European heart journal. 2007;28:292-298

51. Beatty AL, Zhang MH, Ku IA, Na B, Schiller NB, Whooley MA. Adiponectin is associated with increased mortality and heart failure in patients with stable ischemic heart disease: Data from the heart and soul study. Atherosclerosis. 2012;220:587-592

52. Lindberg S, Mogelvang R, Pedersen SH, Bjerre M, Frystyk J, Flyvbjerg A, Galatius S, Jensen JS. Relation of serum adiponectin levels to number of traditional atherosclerotic risk factors and all-cause mortality and major adverse cardiovascular events (from the copenhagen city heart study). The American journal of cardiology. 2013;111:1139-1145

53. Wilson SR, Sabatine MS, Wiviott SD, Ray KK, De Lemos JA, Zhou S, Rifai N, Cannon CP, Morrow DA, Group TS. Assessment of adiponectin and the risk of recurrent cardiovascular events in patients presenting with an acute coronary syndrome: Observations from the pravastatin or atorvastatin evaluation and infection trial-thrombolysis in myocardial infarction 22 (prove it-timi 22). American heart journal. 2011;161:1147-1155 e1141

54. Lindberg S, Pedersen SH, Mogelvang R, Bjerre M, Frystyk J, Flyvbjerg A, Galatius S, Jensen JS. Usefulness of adiponectin as a predictor of all cause mortality in patients with st-segment elevation myocardial infarction treated with primary percutaneous coronary intervention. The American journal of cardiology. 2012;109:492-496

55. Prugger C, Luc G, Haas B, Arveiler D, Machez E, Ferrieres J, Ruidavets JB, Bingham A, Montaye M, Amouyel P, Yarnell J, Kee F, Ducimetiere P, Empana JP, Group PS. Adipocytokines and the risk of ischemic stroke: The prime study. Annals of neurology. 2012;71:478-486

56. Nagasawa H, Yokota C, Toyoda K, Ito A, Minematsu K. High level of plasma adiponectin in acute stroke patients is associated with stroke mortality. Journal of the neurological sciences. 2011;304:102-106

57. Hao G, Li W, Guo R, Yang JG, Wang Y, Tian Y, Liu MY, Peng YG, Wang ZW. Serum total adiponectin level and the risk of cardiovascular disease in general population: A meta-analysis of 17 prospective studies. Atherosclerosis. 2013;228:29-35

58. Yoshimura N, Muraki S, Oka H, Tanaka S, Kawaguchi H, Nakamura K, Akune T. Accumulation of metabolic risk factors such as overweight, hypertension, dyslipidaemia, and impaired glucose tolerance raises the risk of occurrence and progression of knee osteoarthritis: A 3-year follow-up of the road study. Osteoarthritis and cartilage / OARS, Osteoarthritis Research Society. 2012;20:1217-1226

59. Jungmann PM, Kraus MS, Alizai H, Nardo L, Baum T, Nevitt MC, McCulloch CE, Joseph GB, Lynch JA, Link TM. Association of metabolic risk factors with cartilage degradation assessed by t2 relaxation time at the knee: Data from the osteoarthritis initiative. Arthritis care & research. 2013;65:1942-1950

60. Visser AW, de Mutsert R, le Cessie S, den Heijer M, Rosendaal FR, Kloppenburg M, for the NEOSG. The relative contribution of mechanical stress and systemic processes in different types of osteoarthritis: The neo study. Annals of the rheumatic diseases. 2014

61. Edwards C, Rogers A, Lynch S, Pylawka T, Silvis M, Chinchilli V, Mosher T, Black K. The effects of bariatric surgery weight loss on knee pain in patients with osteoarthritis of the knee. Arthritis. 2012;2012:504189

62. Christensen R, Astrup A, Bliddal H. Weight loss: The treatment of choice for knee osteoarthritis? A randomized trial. Osteoarthritis and cartilage / OARS, Osteoarthritis Research Society. 2005;13:20-27

63. Baker JF, Walsh P, Mulhall KJ. Statins: A potential role in the management of osteoarthritis? Joint, bone, spine : revue du rhumatisme. 2011;78:31-34

64. Valdes AM, Zhang W, Muir K, Maciewicz RA, Doherty S, Doherty M. Use of statins is associated with a lower prevalence of generalised osteoarthritis. Annals of the rheumatic diseases. 2014;73:943-945

65. Peeters G, Tett SE, Conaghan PG, Mishra GD, Dobson AJ. Is statin use associated with new joint-related symptoms, physical function and quality of life? The australian longitudinal study on women's health. Arthritis care & research. 2014

66. Riddle DL, Moxley G, Dumenci L. Associations between statin use and changes in pain, function and structural progression: A longitudinal study of persons with knee osteoarthritis. Annals of the rheumatic diseases. 2013;72:196-203

67. Clockaerts S, Van Osch GJ, Bastiaansen-Jenniskens YM, Verhaar JA, Van Glabbeek F, Van Meurs JB, Kerkhof HJ, Hofman A, Stricker BH, Bierma-Zeinstra SM. Statin use is associated with reduced incidence and progression of knee osteoarthritis in the rotterdam study. Annals of the rheumatic diseases. 2012;71:642-647

Peer reviewers: Hua He, MD, Department of Cardiovascular Internal Medicine, Beijing Anzhen Hospital, Capital Medical University, Anzhen Road Second, Chaoyang District, Beijing, 100029, People’s Republic of China.


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