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Metabolic triggered inflammation in osteoarthritis

  • X. Wang
    Affiliations
    Menzies Research Institute Tasmania, University of Tasmania, Hobart, Tasmania, Australia
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  • D. Hunter
    Affiliations
    Institute of Bone and Joint Research, Kolling Institute and Royal North Shore Hospital, University of Sydney, Sydney, NSW, Australia
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  • J. Xu
    Affiliations
    Department of Rheumatology and Arthritis Research Institute, 1st Affiliated Hospital, Anhui Medical University, Hefei, China
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  • C. Ding
    Correspondence
    Address correspondence and reprint requests to: C. Ding, Private Bag 23, Hobart, Tasmania 7000, Australia. Tel: 61-3-62267730; Fax: 61-3-62267704.
    Affiliations
    Menzies Research Institute Tasmania, University of Tasmania, Hobart, Tasmania, Australia

    Institute of Bone and Joint Research, Kolling Institute and Royal North Shore Hospital, University of Sydney, Sydney, NSW, Australia

    Department of Rheumatology and Arthritis Research Institute, 1st Affiliated Hospital, Anhui Medical University, Hefei, China
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Open ArchivePublished:October 14, 2014DOI:https://doi.org/10.1016/j.joca.2014.10.002

      Summary

      Osteoarthritis (OA) is a common chronic joint disorder with a multifactorial etiology including genetic and environmental factors. Metabolic triggered inflammation, induced by nutrient overload and metabolic surplus, consists of components such as obesity, pro-inflammatory cytokines and adipokines, abnormal metabolites, acute phase proteins, vitamin D deficiency, and deregulated microRNAs that may play a role in OA pathophysiology. Obesity-related metabolic factors, especially adipokines, contribute to OA development by inducing pro-inflammatory cytokines and degradative enzymes, leading to cartilage matrix impairment and subchondral bone remodeling. Ectopic metabolite deposition and low-grade systemic inflammation can contribute to a toxic internal environment that exacerbates OA. Complement components highly expressed in osteoarthritic joints have also been proposed as causative factors. Vitamin D deficiency has been associated with obesity and is implicated to be associated with cartilage loss in OA. Metabolic microRNAs may explain the inflammatory link between obesity and OA. Therapies targeting metabolic-triggered inflammation and its components are anticipated to have potential for the treatment of OA.

      Keywords

      Introduction

      Osteoarthritis (OA) is a common disease characterized by joint pain, impaired mobility, and synovial joint structural changes
      • Hootman J.M.
      • Helmick C.G.
      Projections of US prevalence of arthritis and associated activity limitations.
      . It is no longer conceived as a simplex disease, but rather has a complex etiology and new discoveries have differentiated OA into several phenotypes, i.e., post-traumatic, ageing-related, genetic and symptomatic
      • Blagojevic M.
      • Jinks C.
      • Jeffery A.
      • Jordan K.P.
      Risk factors for onset of osteoarthritis of the knee in older adults: a systematic review and meta-analysis.
      . A newly defined phenotype of OA, namely ‘metabolic OA’, has been associated with metabolic syndrome (MetS) and obesity
      • Zhuo Q.
      • Yang W.
      • Chen J.
      • Wang Y.
      Metabolic syndrome meets osteoarthritis.
      . Metabolic triggered inflammation (also called meta-inflammation
      • Gregor M.F.
      • Hotamisligil G.S.
      Inflammatory mechanisms in obesity.
      ), which can be a result of abnormalities in body composition, adipokines, cytokines, complements, lipids and vitamin D, has been implicated in the pathogenesis of OA (Fig. 1).
      Figure thumbnail gr1
      Fig. 1Pathogenic role of metabolic triggered inflammation in OA. Abnormal dietary factors (such as lipids and glucose) and dysfunctional fat produce an excess of adipokines (leptin, resistin, visfatin etc.) that are able to increase risk of OA by inducing pro-inflammatory mediators (cytokines, CRP, complements). The levels of lean mass, muscle strength and anti-inflammatory mediators, including IL-10, IL-4 and adiponectin, are decreased in OA. Other common metabolites such as vitamin D not only interact with other inflammatory mediators, but also involve in cartilage and bone development and metabolism. Abnormal expressions of microRNAs are associated with meta-inflammation and joint structural alterations.
      The incidence of obesity worldwide has increased dramatically during recent decades. Accordingly, obesity and associated disorders such as OA now constitute a serious threat to the current and future health of both developed and developing populations. Strategies targeting obesity-related mechanisms, e.g., meta-inflammation, may be effective in preventing and slowing disease progression of OA. The purpose of this narrative review is to examine the link between meta-inflammation and OA, discussing how the components of meta-inflammation contribute to OA, and to propose several potential therapies modifying meta-inflammation in OA.

      Metabolic triggered inflammation

      Meta-inflammation is mainly caused by nutrient overload and metabolic surplus
      • Hotamisligil G.S.
      Inflammation and metabolic disorders.
      . Metabolic overload results in oxidative stress and inflammation, which then triggers vicious stress cycles that lead to cell dysfunction
      • Monteiro R.
      • Azevedo I.
      Chronic inflammation in obesity and the metabolic syndrome.
      . The components that make up the cluster of MetS, such as overweight, dyslipidemia and impaired glucose tolerance, have been involved in meta-inflammation. Other components as summarized in Table I also have roles to play.
      Table IKey components of metabolic triggered inflammation and their roles in OA
      Key componentsRoles in OA
      Body composition
      • Ding C.
      • Stannus O.
      • Cicuttini F.
      • Antony B.
      • Jones G.
      Body fat is associated with increased and lean mass with decreased knee cartilage loss in older adults: a prospective cohort study.
      • Teichtahl A.J.
      • Wang Y.
      • Wluka A.E.
      • Szramka M.
      • English D.R.
      • Giles G.G.
      • et al.
      The longitudinal relationship between body composition and patella cartilage in healthy adults.
      • Berry P.A.
      • Wluka A.E.
      • Davies-Tuck M.L.
      • Wang Y.
      • Strauss B.J.
      • Dixon J.B.
      • et al.
      The relationship between body composition and structural changes at the knee.
      Body fat is associated with more knee cartilage loss; lean mass has an opposite effect; body composition measures were better than BMI in predicting OA
      Adipokines
      • Ding C.
      • Parameswaran V.
      • Cicuttini F.
      • Burgess J.
      • Zhai G.
      • Quinn S.
      • et al.
      Association between leptin, body composition, sex and knee cartilage morphology in older adults: the Tasmanian older adult cohort (TASOAC) study.
      • Gomez R.
      • Conde J.
      • Scotece M.
      • Gomez-Reino J.J.
      • Lago F.
      • Gualillo O.
      What's new in our understanding of the role of adipokines in rheumatic diseases?.
      • de Boer T.
      • Van Spil W.
      • Huisman A.
      • Polak A.
      • Bijlsma J.
      • Lafeber F.
      • et al.
      Serum adipokines in osteoarthritis; comparison with controls and relationship with local parameters of synovial inflammation and cartilage damage.
      • Yusuf E.
      • Ioan-Facsinay A.
      • Bijsterbosch J.
      • Klein-Wieringa I.
      • Kwekkeboom J.
      • Slagboom P.E.
      • et al.
      Association between leptin, adiponectin and resistin and long-term progression of hand osteoarthritis.
      Leptin, resistin and visfatin have emerged as pro-inflammatory and pro-catabolic factors in OA; circulating leptin is associated with increased knee cartilage loss and joint pain; adiponectin may have an anti-inflammatory effect and thus be beneficial on OA
      Cytokines
      • Kapoor M.
      • Martel-Pelletier J.
      • Lajeunesse D.
      • Pelletier J.P.
      • Fahmi H.
      Role of proinflammatory cytokines in the pathophysiology of osteoarthritis.
      • Stannus O.
      • Jones G.
      • Cicuttini F.
      • Parameswaran V.
      • Quinn S.
      • Burgess J.
      • et al.
      Circulating levels of IL-6 and TNF-alpha are associated with knee radiographic osteoarthritis and knee cartilage loss in older adults.
      • Helmark I.C.
      • Mikkelsen U.R.
      • Borglum J.
      • Rothe A.
      • Petersen M.C.
      • Andersen O.
      • et al.
      Exercise increases interleukin-10 levels both intraarticularly and peri-synovially in patients with knee osteoarthritis: a randomized controlled trial.
      Cytokines can be produced by adipose tissue; circulating or local cytokines (IL-6, TNF-α, IL-17, IL-18) were associated with ROA, cartilage loss and/or knee pain. Intervention such as exercise can increase anti-inflammatory cytokine IL-10 in OA.
      Acute-phase inflammatory components
      • Happonen K.E.
      • Heinegard D.
      • Saxne T.
      • Blom A.M.
      Interactions of the complement system with molecules of extracellular matrix: relevance for joint diseases.
      • Wang Q.
      • Rozelle A.L.
      • Lepus C.M.
      • Scanzello C.R.
      • Song J.J.
      • Larsen D.M.
      • et al.
      Identification of a central role for complement in osteoarthritis.
      • Scott J.L.
      • Scanzello C.R.
      • Dragomir C.
      • Crow M.K.
      Complement activation and regulation in early and advanced stage osteoarthritis.
      CRP is associated with decreased knee cartilage volume and increased knee pain. Complements such as C1s, C4A, factor B, C3, C5, MAC and transcripts that encoding complements effectors are all abnormally expressed in OA. COMP-C3b complexes can be found in OA.
      Nutrients
      • Tiku M.L.
      • Shah R.
      • Allison G.T.
      Evidence linking chondrocyte lipid peroxidation to cartilage matrix protein degradation. Possible role in cartilage aging and the pathogenesis of osteoarthritis.
      • Gkretsi V.
      • Simopoulou T.
      • Tsezou A.
      Lipid metabolism and osteoarthritis: lessons from atherosclerosis.
      • Hiraiwa H.
      • Sakai T.
      • Mitsuyama H.
      • Hamada T.
      • Yamamoto R.
      • Omachi T.
      • et al.
      Inflammatory effect of advanced glycation end products on human meniscal cells from osteoarthritic knees.
      Lipids accumulate in cartilage with increasing histological lesion severity; serum cholesterol and triglyceride levels were associated increased risk of osteoarthritic changes, but HDL was associated with decreased risk; statin use in high doses may reduce OA risk.

      Hyperglycaemia has detrimental effects on cartilage; diabetes could be an independent risk factor for OA, leading to the concept of a diabetes-induced OA phenotype.
      Vitamin D deficiency
      • Ding C.
      • Cicuttini F.
      • Parameswaran V.
      • Burgess J.
      • Quinn S.
      • Jones G.
      Serum levels of vitamin D, sunlight exposure, and knee cartilage loss in older adults: the Tasmanian older adult cohort study.
      • Heidari B.
      • Heidari P.
      • Hajian-Tilaki K.
      Association between serum vitamin D deficiency and knee osteoarthritis.
      Vitamin D deficiency can be a result of metabolic triggered inflammation; low serum levels of 25-(OH)D were associated with increased progression of knee ROA and increased cartilage loss.
      Reactive nitrogen and oxygen species
      • Mazzetti I.
      • Grigolo B.
      • Pulsatelli L.
      • Dolzani P.
      • Silvestri T.
      • Roseti L.
      • et al.
      Differential roles of nitric oxide and oxygen radicals in chondrocytes affected by osteoarthritis and rheumatoid arthritis.
      • Davies C.M.
      • Guilak F.
      • Weinberg J.B.
      • Fermor B.
      Reactive nitrogen and oxygen species in interleukin-1-mediated DNA damage associated with osteoarthritis.
      Nitric oxide (NO) and reactive oxygen species are increased in OA, and associated with increased inflammatory cytokines. IL-1-induced OA cartilage damage is inhibited by a NO synthase 2 inhibitor or by superoxide dismutase, but a recent RCT failed to show positive effects of iNOS inhibition on symptoms and disease progression of knee OA.
      MicroRNAs
      • Iliopoulos D.
      • Malizos K.N.
      • Oikonomou P.
      • Tsezou A.
      Integrative microRNA and proteomic approaches identify novel osteoarthritis genes and their collaborative metabolic and inflammatory networks.
      • Miyaki S.
      • Nakasa T.
      • Otsuki S.
      • Grogan S.P.
      • Higashiyama R.
      • Inoue A.
      • et al.
      MicroRNA-140 is expressed in differentiated human articular chondrocytes and modulates interleukin-1 responses.
      • Yamasaki K.
      • Nakasa T.
      • Miyaki S.
      • Ishikawa M.
      • Deie M.
      • Adachi N.
      • et al.
      Expression of MicroRNA-146a in osteoarthritis cartilage.
      MiRNAs is involved in meta-inflammation and the regulation of cartilage development and homeostasis; nine miRNAs up-regulated (i.e., miR-22 and miR-103) and seven down-regulated (i.e., miR29a, miR-140 and miR-25) in osteoarthritic cartilage; the various functions of miRNAs include suppression of inflammatory cytokines, ADAMTS, COX-2, iNOS and MMPs
      Recent studies have found that centrally placed adipose tissues (e.g., visceral fat) is a crucial site in the generation of inflammatory responses and mediators
      • Ouchi N.
      • Parker J.L.
      • Lugus J.J.
      • Walsh K.
      Adipokines in inflammation and metabolic disease.
      . Abdominal (central) obesity is associated with increased incidence of metabolic diseases, which are closely related to chronic inflammation through elevated levels of cytokines, acute-phase inflammatory components (complements and C reactive protein, CRP) and other mediators
      • Monteiro R.
      • Azevedo I.
      Chronic inflammation in obesity and the metabolic syndrome.
      • Emanuela F.
      • Grazia M.
      • Marco de R.
      • Maria Paola L.
      • Giorgio F.
      • Marco B.
      Inflammation as a link between obesity and metabolic syndrome.
      . Furthermore, adipocytes as the key cells that regulate the interactions between endothelial cells (EC) and macrophages also synthesize numerous cytokines such as interleukin (IL)-6, IL-1, and tumor necrosis factor-α (TNF-α) and adipokines such as leptin, adiponectin, resistin, and visfatin
      • Zeyda M.
      • Farmer D.
      • Todoric J.
      • Aszmann O.
      • Speiser M.
      • Gyori G.
      • et al.
      Human adipose tissue macrophages are of an anti-inflammatory phenotype but capable of excessive pro-inflammatory mediator production.
      .
      Excessive metabolites and nutrients such as lipids and glucose could disturb the integration of systemic metabolism, simultaneously leading to inflammatory responses. In addition, a group of acute phase protein such as complement components, stimulated by pro-inflammatory cytokines, could lead to a chronic inflammatory state and metabolic dysfunction
      • Epstein F.H.
      • Gabay C.
      • Kushner I.
      Acute-phase proteins and other systemic responses to inflammation.
      . Individuals with obesity and/or metabolic diseases have low circulating 25-hydroxy-vitamin D (25-(OH)D)
      • Lenders C.M.
      • Feldman H.A.
      • Von Scheven E.
      • Merewood A.
      • Sweeney C.
      • Wilson D.M.
      • et al.
      Relation of body fat indexes to vitamin D status and deficiency among obese adolescents.
      , which can be induced by factors including leptin and IL-6
      • Ding C.
      • Parameswaran V.
      • Blizzard L.
      • Burgess J.
      • Jones G.
      Not a simple fat-soluble vitamin: changes in serum 25-(OH)D levels are predicted by adiposity and adipocytokines in older adults.
      . At the molecular level, microRNAs are differentially expressed in fat depots and can regulate meta-inflammation, which potentially contribute to the pathogenesis of obesity-associated complications
      • Xie H.
      • Lim B.
      • Lodish H.F.
      MicroRNAs induced during adipogenesis that accelerate fat cell development are downregulated in obesity.
      .

      Direct evidence of meta-inflammation in OA

      Body fat may be better than body mass index (BMI) in predicting OA

      Obesity (defined by BMI > 30 kg/m2) is a significant risk factor for the onset and progression of OA
      • Blagojevic M.
      • Jinks C.
      • Jeffery A.
      • Jordan K.P.
      Risk factors for onset of osteoarthritis of the knee in older adults: a systematic review and meta-analysis.
      . BMI was negatively associated with knee cartilage volume and cartilage thickness, and positively associated with tibial bone area and knee cartilage defects
      • Ding C.
      • Parameswaran V.
      • Cicuttini F.
      • Burgess J.
      • Zhai G.
      • Quinn S.
      • et al.
      Association between leptin, body composition, sex and knee cartilage morphology in older adults: the Tasmanian older adult cohort (TASOAC) study.
      • Ding C.
      • Cicuttini F.
      • Scott F.
      • Cooley H.
      • Jones G.
      Knee structural alteration and BMI: a cross-sectional study.
      . However, BMI is only a surrogate measure of obesity that cannot discriminate fat and lean mass, which may have different effects on OA. Indeed, central adiposity, measured by waist-to-hip ratio and waist circumference, were better predictors of OA incidence than BMI
      • Teichtahl A.J.
      • Wang Y.
      • Wluka A.E.
      • Cicuttini F.M.
      Obesity and knee osteoarthritis: new insights provided by body composition studies.
      . Also fat mass and skeletal muscle mass had a better statistical fit than BMI to explain both the odds of having and the severity of knee OA
      • Sowers M.
      • Yosef M.
      • Jamadar D.
      • Jacobson J.
      • Karvonen-Gutierrez C.
      • Jaffe M.
      BMI vs. body composition and radiographically defined osteoarthritis of the knee in women: a 4-year follow-up study.
      . Furthermore, body fat adversely affects knee cartilage loss over time, whereas lean mass is protective, and body fat was better than BMI in predicting tibial cartilage loss
      • Ding C.
      • Stannus O.
      • Cicuttini F.
      • Antony B.
      • Jones G.
      Body fat is associated with increased and lean mass with decreased knee cartilage loss in older adults: a prospective cohort study.
      . Additionally, waist circumference and fat mass were associated with increased knee cartilage defects
      • Teichtahl A.J.
      • Wang Y.
      • Wluka A.E.
      • Szramka M.
      • English D.R.
      • Giles G.G.
      • et al.
      The longitudinal relationship between body composition and patella cartilage in healthy adults.
      , reduced knee cartilage volume and increased bone marrow lesions (BMLs)
      • Berry P.A.
      • Wluka A.E.
      • Davies-Tuck M.L.
      • Wang Y.
      • Strauss B.J.
      • Dixon J.B.
      • et al.
      The relationship between body composition and structural changes at the knee.
      . Total body fat, trunk fat, waist-hip ratio and waist circumference were all associated with increased knee pain over 5 years
      • Ding C.
      • Stannus O.
      • Antony B.
      • Cicuttini F.
      • Jones G.
      Body fat and lean mass have opposite effects on loss of knee cartilage and increase in knee pain in older adults: a prospective cohort study.
      . In addition, some local fat tissues, such as infrapatellar fat pad (IPFP), may act as modulators in OA. IPFP was considered as a source of local inflammatory mediators and thus an active osteoarthritic tissue
      • Clockaerts S.
      • Bastiaansen-Jenniskens Y.M.
      • Runhaar J.
      • Van Osch G.J.
      • Van Offel J.F.
      • Verhaar J.A.
      • et al.
      The infrapatellar fat pad should be considered as an active osteoarthritic joint tissue: a narrative review.
      , but it also has a beneficial effect possibly through biomechanical mechanisms, as supported by a recent study suggesting that IPFP size was negatively associated with OA disease severity independent of BMI and total body fat
      • Han W.
      • Cai S.
      • Liu Z.
      • Jin X.
      • Wang X.
      • Antony B.
      • et al.
      Infrapatellar fat pad in the knee: is local fat good or bad for knee osteoarthritis?.
      . Taken together, all these suggest that it is central adiposity, rather than extra body weight, that may play a major role in the structural and symptomatic changes of OA.

      Adipokines

      Adipose tissue is considered as a metabolic endocrine organ during systematic metabolic process. As obesity develops, adipocytes release active components such as leptin, adiponectin, resistin and visfatin, which lead to metabolic dysfunction in OA patients
      • Gomez R.
      • Conde J.
      • Scotece M.
      • Gomez-Reino J.J.
      • Lago F.
      • Gualillo O.
      What's new in our understanding of the role of adipokines in rheumatic diseases?.
      . Adipokines can disrupt cartilage homeostasis through directly inducing joint structural degradation or regulating local inflammatory processes
      • de Boer T.
      • Van Spil W.
      • Huisman A.
      • Polak A.
      • Bijlsma J.
      • Lafeber F.
      • et al.
      Serum adipokines in osteoarthritis; comparison with controls and relationship with local parameters of synovial inflammation and cartilage damage.
      .

      Leptin

      Leptin, a small (16 kd) polypeptide encoded by the obese (ob) gene, is produced predominantly in white adipose tissue and regulates energy intake and expenditure at the hypothalamic level
      • Masuzaki H.
      • Ogawa Y.
      • Isse N.
      • Satoh N.
      • Okazaki T.
      • Shigemoto M.
      • et al.
      Human obese gene expression. Adipocyte-specific expression and regional differences in the adipose tissue.
      . Leptin was positively correlated with BMI, fat mass and body weight among people with OA
      • Vuolteenaho K.
      • Koskinen A.
      • Nieminen R.
      • Moilanen T.
      • Moilanen E.
      Leptin enhances MMP-1 MMP-3 and MMP-13 production in human osteoarthritis cartilage and correlates with MMP-1 and MMP-3 in synovial fluid from OA patients.
      . The strong synergistic relationship between leptin and pro-inflammatory cytokines has been discovered in OA, as leptin enhanced the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase (COX-2), prostaglandin E2 (PGE2), IL-6 and IL-8 in cartilage
      • Vuolteenaho K.
      • Koskinen A.
      • Kukkonen M.
      • Nieminen R.
      • Paivarinta U.
      • Moilanen T.
      • et al.
      Leptin enhances synthesis of proinflammatory mediators in human osteoarthritic cartilage–mediator role of NO in leptin-induced PGE2, IL-6, and IL-8 production.
      . The elevated expressions of leptin and its receptor isoform (Ob-Rb) had detrimental effects on chondrocyte proliferation by inducing matrix metalloproteinases (MMPs) and IL-1β production
      • Bao J.P.
      • Chen W.P.
      • Feng J.
      • Hu P.F.
      • Shi Z.L.
      • Wu L.D.
      Leptin plays a catabolic role on articular cartilage.
      . Griffin et al. asserted that leptin, rather than obesity per se, was essential for joint cartilage degradation, because impaired leptin signaling was unable to trigger systemic inflammation and knee OA in leptin-deficient (ob/ob) and leptin receptor–deficient (db/db) mice, although adiposity was increased by approximately 10-fold
      • Griffin T.M.
      • Huebner J.L.
      • Kraus V.B.
      • Guilak F.
      Extreme obesity due to impaired leptin signaling in mice does not cause knee osteoarthritis.
      .
      In clinical studies, serum leptin was associated with reduced cartilage volume
      • Ding C.
      • Parameswaran V.
      • Cicuttini F.
      • Burgess J.
      • Zhai G.
      • Quinn S.
      • et al.
      Association between leptin, body composition, sex and knee cartilage morphology in older adults: the Tasmanian older adult cohort (TASOAC) study.
      , increased hip joint space narrowing (JSN)
      • Stannus O.P.
      • Jones G.
      • Quinn S.J.
      • Cicuttini F.M.
      • Dore D.
      • Ding C.
      The association between leptin, interleukin-6, and hip radiographic osteoarthritis in older people: a cross-sectional study.
      and increased loss of cartilage thickness
      • Stannus O.P.
      • Cao Y.
      • Antony B.
      • Blizzard L.
      • Cicuttini F.
      • Jones G.
      • et al.
      Cross-sectional and longitudinal associations between circulating leptin and knee cartilage thickness in older adults.
      , independent of BMI. More interestingly, the significant associations between obesity measures and all the above structural outcomes were largely mediated by leptin
      • Ding C.
      • Parameswaran V.
      • Cicuttini F.
      • Burgess J.
      • Zhai G.
      • Quinn S.
      • et al.
      Association between leptin, body composition, sex and knee cartilage morphology in older adults: the Tasmanian older adult cohort (TASOAC) study.
      • Stannus O.P.
      • Jones G.
      • Quinn S.J.
      • Cicuttini F.M.
      • Dore D.
      • Ding C.
      The association between leptin, interleukin-6, and hip radiographic osteoarthritis in older people: a cross-sectional study.
      • Stannus O.P.
      • Cao Y.
      • Antony B.
      • Blizzard L.
      • Cicuttini F.
      • Jones G.
      • et al.
      Cross-sectional and longitudinal associations between circulating leptin and knee cartilage thickness in older adults.
      , suggesting that metabolic rather than mechanical mechanisms underlie the association between obesity and cartilage loss. Similarly, studies reported that plasma or synovial leptin levels were associated with increased joint pain in OA
      • Lubbeke A.
      • Finckh A.
      • Puskas G.J.
      • Suva D.
      • Ladermann A.
      • Bas S.
      • et al.
      Do synovial leptin levels correlate with pain in end stage arthritis?.
      , and the association between obesity and joint pain was substantially reduced after adjustment for synovial leptin
      • Lubbeke A.
      • Finckh A.
      • Puskas G.J.
      • Suva D.
      • Ladermann A.
      • Bas S.
      • et al.
      Do synovial leptin levels correlate with pain in end stage arthritis?.
      . All these suggest that leptin has a catabolic effect, but it may also exert anabolic activity in chondrocytes by inducing the production of growth factors including insulin-like growth factor-1 (IGF-1) and transforming growth factor-β (TGF-β)
      • Dumond H.
      • Presle N.
      • Terlain B.
      • Mainard D.
      • Loeuille D.
      • Netter P.
      • et al.
      Evidence for a key role of leptin in osteoarthritis.
      . Leptin may have opposite effects on radiographic knee OA in men and women, as a study reported that leptin levels were significantly associated with increased radiographic knee OA among obese and non-obese women, but associated with decreased radiographic knee OA among obese and non-obese men
      • Karvonen-Gutierrez C.A.
      • Sowers M.R.
      • Heeringa S.G.
      Sex dimorphism in the association of cardiometabolic characteristics and osteophytes-defined radiographic knee osteoarthritis among obese and non-obese adults: NHANES III.
      .

      Adiponectin

      Adiponectin is a 244-amino acid protein expressed in adipose tissue that exerts its biological activity through two cell receptors, AdipoR1 and AdipoR2
      • Kang E.H.
      • Lee Y.J.
      • Kim T.K.
      • Chang C.B.
      • Chung J.H.
      • Shin K.
      • et al.
      Adiponectin is a potential catabolic mediator in osteoarthritis cartilage.
      . In cultured chondrocytes, adiponectin is involved in cartilage hemostasis by increasing tissue inhibitor of metalloprotease (TIMP)-2 and decreasing IL-1β-induced MMP-3
      • Chen T.H.
      • Chen L.
      • Hsieh M.S.
      • Chang C.P.
      • Chou D.T.
      • Tsai S.H.
      Evidence for a protective role for adiponectin in osteoarthritis.
      . In addition, adiponectin up-regulates IL-10 in human macrophages to increase TIMP-1 levels and to prevent the extracellular matrix (ECM) degradation
      • Emanuela F.
      • Grazia M.
      • Marco de R.
      • Maria Paola L.
      • Giorgio F.
      • Marco B.
      Inflammation as a link between obesity and metabolic syndrome.
      . An epidemiological study reported that patients in the two higher tertiles of adiponectin had a decreased risk of 70% for hand OA progression in comparison with patients in the lowest tertile over 6 years
      • Yusuf E.
      • Ioan-Facsinay A.
      • Bijsterbosch J.
      • Klein-Wieringa I.
      • Kwekkeboom J.
      • Slagboom P.E.
      • et al.
      Association between leptin, adiponectin and resistin and long-term progression of hand osteoarthritis.
      . The adiponectin/leptin ratio in synovial fluid was associated with reduced knee pain in patients with severe knee OA
      • Gandhi R.
      • Takahashi M.
      • Smith H.
      • Rizek R.
      • Mahomed N.N.
      The synovial fluid adiponectin-leptin ratio predicts pain with knee osteoarthritis.
      . Collectively, these findings indicate that adiponectin may have a beneficial effect on OA. On the other hand, some studies reported that adiponectin induced nitric oxide synthase type II and pro-inflammatory cytokines in chondrocytes
      • Lago R.
      • Gomez R.
      • Otero M.
      • Lago F.
      • Gallego R.
      • Dieguez C.
      • et al.
      A new player in cartilage homeostasis: adiponectin induces nitric oxide synthase type II and pro-inflammatory cytokines in chondrocytes.
      , and its plasma level was associated with increased OA radiographic severity
      • Koskinen A.
      • Juslin S.
      • Nieminen R.
      • Moilanen T.
      • Vuolteenaho K.
      • Moilanen E.
      Adiponectin associates with markers of cartilage degradation in osteoarthritis and induces production of proinflammatory and catabolic factors through mitogen-activated protein kinase pathways.
      . These discrepancies may be due to the existence of different isoforms of adiponectin, which may have different effects on OA
      • Francin P.J.
      • Abot A.
      • Guillaume C.
      • Moulin D.
      • Bianchi A.
      • Gegout-Pottie P.
      • et al.
      Association between adiponectin and cartilage degradation in human osteoarthritis.
      .

      Other adipokines

      Resistin augments the expression of cytokines and chemokines, up-regulates MMP-1 and -13, but down-regulates type II collagen α1 (COL2A1) and aggrecan expressions in human chondrocytes
      • Zhang Z.
      • Xing X.
      • Hensley G.
      • Chang L.W.
      • Liao W.
      • Abu-Amer Y.
      • et al.
      Resistin induces expression of proinflammatory cytokines and chemokines in human articular chondrocytes via transcription and messenger RNA stabilization.
      . Another catabolic adipokine, visfatin, could induce the expression of MMPs and reduce the synthesis of matrix components (for example, low-molecular-weight proteoglycans) in OA chondrocytes
      • Yang S.
      • Ryu J.H.
      • Oh H.
      • Jeon J.
      • Kwak J.S.
      • Kim J.H.
      • et al.
      NAMPT (visfatin), a direct target of hypoxia-inducible factor-2alpha, is an essential catabolic regulator of osteoarthritis.
      . Chemerin is recently described as a chemokine/adipokine that regulates metabolic function and is associated with the severity of knee OA
      • Valcamonica E.
      • Chighizola C.B.
      • Comi D.
      • De Lucia O.
      • Pisoni L.
      • Murgo A.
      • et al.
      Levels of chemerin and interleukin 8 in the synovial fluid of patients with inflammatory arthritides and osteoarthritis.
      . All these suggest that adipokines are important metabolic mediators involved in the inflammatory process of OA.

      Cytokines

      Pro-inflammatory cytokines

      In OA adipose tissue, there are numerous pro-inflammatory cytokines produced by adipocytes and infiltrating macrophages which are modulated by adipokines
      • Lago F.
      • Dieguez C.
      • Gomez-Reino J.
      • Gualillo O.
      Adipokines as emerging mediators of immune response and inflammation.
      . These cytokines induce the release of matrix anabolic enzymes and inhibit the synthesis of ECM components such as proteoglycan and type II collagen
      • Hashimoto M.
      • Nakasa T.
      • Hikata T.
      • Asahara H.
      Molecular network of cartilage homeostasis and osteoarthritis.
      ; subsequently, accelerate cartilage degradation or induce bone reabsorption in OA
      • Hoff P.
      • Buttgereit F.
      • Burmester G.R.
      • Jakstadt M.
      • Gaber T.
      • Andreas K.
      • et al.
      Osteoarthritis synovial fluid activates pro-inflammatory cytokines in primary human chondrocytes.
      . IL-1β, TNF-α and IL-6 appear to be the major cytokines involved in the pathogenesis of OA. Other pro-inflammatory cytokines including IL-15, IL-17, IL-18, leukemia inhibitory factor (LIF) and chemokines such as CC-chemokine ligand (CCL5) and IL-8 are also increased in OA and are significantly associated with increased MMPs or down-regulated proteoglycan levels
      • Kapoor M.
      • Martel-Pelletier J.
      • Lajeunesse D.
      • Pelletier J.P.
      • Fahmi H.
      Role of proinflammatory cytokines in the pathophysiology of osteoarthritis.
      . A single injection of IL-17A into the rat knee joint elicited a slowly developing and long-lasting sensitization of nociceptive C fibers of the joint to mechanical stimuli, which was not attenuated by neutralizing TNF-α or IL-6, suggesting IL-17A has the potential to act as a pain mediator in knee OA
      • Richter F.
      • Natura G.
      • Ebbinghaus M.
      • von Banchet G.S.
      • Hensellek S.
      • Konig C.
      • et al.
      Interleukin-17 sensitizes joint nociceptors to mechanical stimuli and contributes to arthritic pain through neuronal interleukin-17 receptors in rodents.
      .
      Clinical and epidemiological studies have confirmed the roles of cytokines in OA. Livshits et al. reported that serum IL-6 level was a significant predictor in women of radiographic OA (ROA) 5–10 years later
      • Livshits G.
      • Zhai G.
      • Hart D.J.
      • Kato B.S.
      • Wang H.
      • Williams F.M.
      • et al.
      Interleukin-6 is a significant predictor of radiographic knee osteoarthritis: the Chingford Study.
      . Our group reported that higher baseline IL-6 and TNF-α levels were associated with more severe ROA and predicted greater loss of cartilage over 3 years
      • Stannus O.
      • Jones G.
      • Cicuttini F.
      • Parameswaran V.
      • Quinn S.
      • Burgess J.
      • et al.
      Circulating levels of IL-6 and TNF-alpha are associated with knee radiographic osteoarthritis and knee cartilage loss in older adults.
      ; baseline IL-6 and TNF-α levels also predicted an increase in knee pain over 5 years in older adults
      • Stannus O.P.
      • Jones G.
      • Blizzard L.
      • Cicuttini F.M.
      • Ding C.
      Associations between serum levels of inflammatory markers and change in knee pain over 5 years in older adults: a prospective cohort study.
      . Synovial fluid/serum levels of IL-17 were associated with greater ROA and knee pain
      • Chen B.
      • Deng Y.
      • Tan Y.
      • Qin J.
      • Chen L.B.
      Association between severity of knee osteoarthritis and serum and synovial fluid interleukin 17 concentrations.
      . Furthermore, IL-18 and IL-1β in subjects with knee OA were strongly correlated with JSN and osteophytes
      • Denoble A.E.
      • Huffman K.M.
      • Stabler T.V.
      • Kelly S.J.
      • Hershfield M.S.
      • McDaniel G.E.
      • et al.
      Uric acid is a danger signal of increasing risk for osteoarthritis through inflammasome activation.
      . Synovial fluid IL-18 was also positively associated with knee pain and OA severity as measured by bone scintigraphy. Besides this, it also predicted an increase in osteophyte score over 3 years
      • Denoble A.E.
      • Huffman K.M.
      • Stabler T.V.
      • Kelly S.J.
      • Hershfield M.S.
      • McDaniel G.E.
      • et al.
      Uric acid is a danger signal of increasing risk for osteoarthritis through inflammasome activation.
      .

      Anti-inflammatory cytokines

      Apart from pro-inflammatory cytokines, adipose tissue also secrets regulatory cytokines. Anti-inflammatory cytokines such as IL-4, IL-10 and IL-13 were elevated in OA tissues, inhibiting the expression of IL-1β, TNF-α and proteases, and increasing IL-1 receptor antagonist and TIMP production
      • Kapoor M.
      • Martel-Pelletier J.
      • Lajeunesse D.
      • Pelletier J.P.
      • Fahmi H.
      Role of proinflammatory cytokines in the pathophysiology of osteoarthritis.
      . The protective role of IL-10 in cartilage and synovial membrane has been shown to be through counteracting the detrimental effects of pro-inflammatory cytokines, and exercise caused an increase in both intra-articular and peri-synovial concentrations of IL-10 in females with knee OA
      • Helmark I.C.
      • Mikkelsen U.R.
      • Borglum J.
      • Rothe A.
      • Petersen M.C.
      • Andersen O.
      • et al.
      Exercise increases interleukin-10 levels both intraarticularly and peri-synovially in patients with knee osteoarthritis: a randomized controlled trial.
      .

      Acute-phase inflammatory components: hs-CRP and complements

      The key acute phase protein CRP is regulated by pro-inflammatory cytokines and mostly produced by hepatocytes and adipocytes. CRP levels were elevated in obese subjects
      • Choi J.
      • Joseph L.
      • Pilote L.
      Obesity and C-reactive protein in various populations: a systematic review and meta-analysis.
      and had been added into other conventional risk factors for the prediction of age-related diseases
      • Kaptoge S.
      • Di Angelantonio E.
      • Pennells L.
      • Wood A.M.
      • White I.R.
      • Gao P.
      • et al.
      C-reactive protein, fibrinogen, and cardiovascular disease prediction.
      .
      Studies have demonstrated that levels of hs-CRP are associated with decreased cartilage volume and OA progression
      • Hanna F.S.
      • Bell R.J.
      • Cicuttini F.M.
      • Davison S.L.
      • Wluka A.E.
      • Davis S.R.
      High sensitivity C-reactive protein is associated with lower tibial cartilage volume but not lower patella cartilage volume in healthy women at mid-life.
      . In older adults, both baseline and change in hs-CRP were positively associated with change in knee pain particularly inflammatory phenotypes (sitting/lying or nocturnal) over 5 years
      • Stannus O.P.
      • Jones G.
      • Blizzard L.
      • Cicuttini F.M.
      • Ding C.
      Associations between serum levels of inflammatory markers and change in knee pain over 5 years in older adults: a prospective cohort study.
      . Furthermore, the plasma level of hs-CRP in hip or knee OA patients with inflammatory infiltrates in synovial membrane was significantly higher than those without inflammation
      • Pearle A.D.
      • Scanzello C.R.
      • George S.
      • Mandl L.A.
      • DiCarlo E.F.
      • Peterson M.
      • et al.
      Elevated high-sensitivity C-reactive protein levels are associated with local inflammatory findings in patients with osteoarthritis.
      . Plasma hs-CRP was significantly associated with synovial fluid IL-6, degree of synovial inflammatory infiltration and BMI, suggesting that systemic hs-CRP levels may reflect synovial inflammation in OA patients, presumably by means of synovial IL-6 production
      • Pearle A.D.
      • Scanzello C.R.
      • George S.
      • Mandl L.A.
      • DiCarlo E.F.
      • Peterson M.
      • et al.
      Elevated high-sensitivity C-reactive protein levels are associated with local inflammatory findings in patients with osteoarthritis.
      .
      Recently we performed a meta-analysis to systematically review the literature for the relationship between circulating hs-CRP and OA phenotypes
      • Jin X.
      • Beguerie J.
      • Zhang W.
      • Blizzard L.
      • Otahal P.
      • Jones G.
      • et al.
      Circulating C-reactive protein in osteoarthritis: a systematic review and meta-analysis.
      . We found that hs-CRP levels in OA were modestly higher than controls, and associated with increased pain and decreased physical function. All these associations appeared to be independent of BMI. In contrast, there was no significant association between hs-CRP and ROA, suggesting low-grade systemic inflammation may play a greater role in symptoms rather than radiographic changes of OA.
      Pathological complement activation can occur in the affected joints propagating a disease process leading to tissue destruction in rheumatoid arthritis and OA
      • Happonen K.E.
      • Heinegard D.
      • Saxne T.
      • Blom A.M.
      Interactions of the complement system with molecules of extracellular matrix: relevance for joint diseases.
      . To identify the role of complements in the inflammatory cascades of OA, Wang et al. reported that components of the classical pathway (C1s and C4A), the alternative pathway (factor B) and the central components C3 and C5 were all abnormally expressed in synovial fluid of human osteoarthritic joints
      • Wang Q.
      • Rozelle A.L.
      • Lepus C.M.
      • Scanzello C.R.
      • Song J.J.
      • Larsen D.M.
      • et al.
      Identification of a central role for complement in osteoarthritis.
      . They also discovered that membrane attack complex (MAC), which comprised the complement effector C5b-9, were aberrantly expressed in synovial fluids from individuals with OA. Furthermore, MAC can also induce chondrocyte expression of pro-inflammatory cytokines, COX 2 and cartilage-degrading enzymes
      • Wang Q.
      • Rozelle A.L.
      • Lepus C.M.
      • Scanzello C.R.
      • Song J.J.
      • Larsen D.M.
      • et al.
      Identification of a central role for complement in osteoarthritis.
      . In addition, the expression of properdin, a positive regulator of the alternative complement pathway, and CD59, an inhibitor of MAC formation, were significantly up-regulated in early OA synovium compared with advanced stage
      • Scott J.L.
      • Scanzello C.R.
      • Dragomir C.
      • Crow M.K.
      Complement activation and regulation in early and advanced stage osteoarthritis.
      .
      In an OA model induced by medial meniscectomy, C5-deficient mice had less cartilage loss, osteophyte formation and synovitis than C5-sufficient wide-type mice. Targeting C5 using a neutralizing monoclonal antibody or a fusion protein attenuated the development of OA in wild-type mice
      • Wang Q.
      • Rozelle A.L.
      • Lepus C.M.
      • Scanzello C.R.
      • Song J.J.
      • Larsen D.M.
      • et al.
      Identification of a central role for complement in osteoarthritis.
      . Mice deficient in C6, an integral component of the MAC, also developed less OA and synovitis, whereas mice deficient in CD59a developed more
      • Wang Q.
      • Rozelle A.L.
      • Lepus C.M.
      • Scanzello C.R.
      • Song J.J.
      • Larsen D.M.
      • et al.
      Identification of a central role for complement in osteoarthritis.
      . Emerging evidence has shown that osteoarthritic cartilage or components of cartilage ECM (i.e., fibromodulin, cartilage oligomeric matrix protein (COMP)) can activate complements such as C5b-9, C1q and C3b
      • Wang Q.
      • Rozelle A.L.
      • Lepus C.M.
      • Scanzello C.R.
      • Song J.J.
      • Larsen D.M.
      • et al.
      Identification of a central role for complement in osteoarthritis.
      , and subsequently trigger the complement cascade which promotes joint pathology of OA. COMP-C3b complexes can be found in patients with joint diseases
      • Wang Q.
      • Rozelle A.L.
      • Lepus C.M.
      • Scanzello C.R.
      • Song J.J.
      • Larsen D.M.
      • et al.
      Identification of a central role for complement in osteoarthritis.
      .

      Nutrients

      Altered nutrition metabolism such as abnormal lipids, cholesterol and glucose may be one of the underlying causes of OA. In OA cartilage, accumulation of lipid, total fatty acids and arachidonic acid were elevated with increasing histological lesion severity
      • Masuko K.
      • Murata M.
      • Suematsu N.
      • Okamoto K.
      • Yudoh K.
      • Nakamura H.
      • et al.
      A metabolic aspect of osteoarthritis: lipid as a possible contributor to the pathogenesis of cartilage degradation.
      . Lipid peroxidation in chondrocytes or synoviocytes was linked to cartilage matrix protein oxidation and degradation, supporting the role of lipid metabolism in the pathogenesis of cartilage aging
      • Tiku M.L.
      • Shah R.
      • Allison G.T.
      Evidence linking chondrocyte lipid peroxidation to cartilage matrix protein degradation. Possible role in cartilage aging and the pathogenesis of osteoarthritis.
      . Interestingly, the genetic expressions of cholesterol efflux, which can decrease lipid deposits in the chondrocytes, were significantly lower in osteoarthritic cartilage, suggesting that impaired expression of cholesterol regulatory genes may be a critical player in OA
      • Tsezou A.
      • Iliopoulos D.
      • Malizos K.N.
      • Simopoulou T.
      Impaired expression of genes regulating cholesterol efflux in human osteoarthritic chondrocytes.
      . Proteomic analyses in isolated chondrocytes and osteoarthritic cartilage have also shown that some proteins, such as peroxisome proliferators-activated receptors (PPAR) and apolipoproteins, were relevant to lipid metabolism
      • Gkretsi V.
      • Simopoulou T.
      • Tsezou A.
      Lipid metabolism and osteoarthritis: lessons from atherosclerosis.
      .
      Some epidemiological studies have shown serum cholesterol to be a risk factor for OA development
      • Gkretsi V.
      • Simopoulou T.
      • Tsezou A.
      Lipid metabolism and osteoarthritis: lessons from atherosclerosis.
      , and two recent studies reported that while serum cholesterol and triglyceride levels were associated with the incidence of knee subchondral BMLs over 2 years
      • Davies-Tuck M.L.
      • Hanna F.
      • Davis S.R.
      • Bell R.J.
      • Davison S.L.
      • Wluka A.E.
      • et al.
      Total cholesterol and triglycerides are associated with the development of new bone marrow lesions in asymptomatic middle-aged women - a prospective cohort study.
      , high-density lipoprotein (HDL) cholesterol was protective against BML change
      • 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.
      .
      Long-chain omega-3 polyunsaturated fatty acids (PUFAs) could decrease inflammatory eicosanoids, cytokines and reactive oxygen species
      • Masuko K.
      • Murata M.
      • Suematsu N.
      • Okamoto K.
      • Yudoh K.
      • Nakamura H.
      • et al.
      A metabolic aspect of osteoarthritis: lipid as a possible contributor to the pathogenesis of cartilage degradation.
      . A recent animal study showed that small amounts of omega-3 PUFAs in a high-fat diet were sufficient to mitigate injury-induced OA, decrease leptin and resistin levels and enhance wound repair, while saturated fatty acids (SFAs) or omega-6 PUFAs independently increased OA severity, synovitis and osteophyte formation
      • Wu C.L.
      • Jain D.
      • McNeill J.N.
      • Little D.
      • Anderson J.A.
      • Huebner J.L.
      • et al.
      Dietary fatty acid content regulates wound repair and the pathogenesis of osteoarthritis following joint injury.
      . In the Multi-center OA Study, subjects with higher levels of total omega-3 PUFAs had lower patellofemoral cartilage loss, but subjects with higher levels of omega-6 PUFAs tended to have higher synovitis
      • Baker K.R.
      • Matthan N.R.
      • Lichtenstein A.H.
      • Niu J.
      • Guermazi A.
      • Roemer F.
      • et al.
      Association of plasma n-6 and n-3 polyunsaturated fatty acids with synovitis in the knee: the MOST study.
      .
      Hyperglycaemia can trigger a low-grade systemic inflammation that may have an impact on the progression of OA. Indeed, several epidemiological studies reported that diabetes could be an independent risk factor for OA, leading to the concept of a diabetes-induced OA phenotype
      • Berenbaum F.
      Diabetes-induced osteoarthritis: from a new paradigm to a new phenotype.
      . Hyperglycaemia has detrimental effects on cartilage and these effects are mediated by oxidative stress and advanced glycation end-products (AGEs), which induce chondrocyte dysfunction, matrix stiffness and subchondral bone destruction
      • Hiraiwa H.
      • Sakai T.
      • Mitsuyama H.
      • Hamada T.
      • Yamamoto R.
      • Omachi T.
      • et al.
      Inflammatory effect of advanced glycation end products on human meniscal cells from osteoarthritic knees.
      . Increased fasting serum glucose concentration in a non-diabetic female population was associated with greater loss of knee cartilage and higher incidence of BMLs
      • Stannus O.
      • Jones G.
      • Cicuttini F.
      • Parameswaran V.
      • Quinn S.
      • Burgess J.
      • et al.
      Circulating levels of IL-6 and TNF-alpha are associated with knee radiographic osteoarthritis and knee cartilage loss in older adults.
      • Davies-Tuck M.L.
      • Wang Y.
      • Wluka A.E.
      • Berry P.A.
      • Giles G.G.
      • English D.R.
      • et al.
      Increased fasting serum glucose concentration is associated with adverse knee structural changes in adults with no knee symptoms and diabetes.
      , supporting the potential role of hyperglycaemia in OA.

      Complementary evidence of meta-inflammation in OA

      Vitamin D deficiency

      Change in 25-(OH)D levels per annum was negatively predicted by baseline body fat, leptin, IL-6 and total cholesterol/high-density lipoprotein (HDL) ratio
      • Ding C.
      • Parameswaran V.
      • Blizzard L.
      • Burgess J.
      • Jones G.
      Not a simple fat-soluble vitamin: changes in serum 25-(OH)D levels are predicted by adiposity and adipocytokines in older adults.
      , suggesting vitamin D deficiency is involved in the meta-inflammation. Vitamin D deficiency (25-(OH)D < 50 nmol/L) was found to be positively associated with the development and worsening of knee OA, including cartilage loss, increased JSN
      • Ding C.
      • Cicuttini F.
      • Parameswaran V.
      • Burgess J.
      • Quinn S.
      • Jones G.
      Serum levels of vitamin D, sunlight exposure, and knee cartilage loss in older adults: the Tasmanian older adult cohort study.
      • Heidari B.
      • Heidari P.
      • Hajian-Tilaki K.
      Association between serum vitamin D deficiency and knee osteoarthritis.
      and pain
      • Laslett L.L.
      • Quinn S.
      • Burgess J.R.
      • Parameswaran V.
      • Winzenberg T.M.
      • Jones G.
      • et al.
      Moderate vitamin D deficiency is associated with changes in knee and hip pain in older adults: a 5-year longitudinal study.
      . In a systematic review, we reported that there was moderate evidence showing that low levels of 25-(OH)D were associated with increased progression of knee ROA. Strong evidence for an association between 25-(OH)D and knee cartilage loss was apparent when JSN and changes in cartilage volume were considered collectively as knee cartilage loss.

      MicroRNAs in OA

      MicroRNAs (miRNAs) are a class of non-coding endogenous RNA molecules, only 18–25 nucleotides in length, which have been shown to possess significant modulatory effects in biological and pathological processes including adipocyte differentiation, apoptosis, metabolic regulation and inflammation
      • Heneghan H.M.
      • Miller N.
      • Kerin M.J.
      Role of microRNAs in obesity and the metabolic syndrome.
      , and are thus involved in the process of meta-inflammation. Indeed, a study reported there were a series of significant correlations between miRNAs expression in omental adipose tissue and serum inflammatory/metabolic biomarkers
      • Kloting N.
      • Berthold S.
      • Kovacs P.
      • Schon M.R.
      • Fasshauer M.
      • Ruschke K.
      • et al.
      MicroRNA expression in human omental and subcutaneous adipose tissue.
      .
      Iliopoulos et al. investigated expressions of 365 miRNAs in articular cartilage of OA patients undergoing knee replacement surgery. They identified 16 miRNAs differentially expressed in osteoarthritic in contrast to normal cartilage with nine up-regulated (i.e., miR-22 and miR-103) and seven down-regulated (i.e., miR29a, miR-140 and miR-25). Furthermore, the expressions of miR-22 and miR-103 in cartilage were positively correlated with BMI in OA patients, but miR-25, miR-337 and miR-29a were the opposite
      • Iliopoulos D.
      • Malizos K.N.
      • Oikonomou P.
      • Tsezou A.
      Integrative microRNA and proteomic approaches identify novel osteoarthritis genes and their collaborative metabolic and inflammatory networks.
      . By matching miRNA and protein data, Iliopoulos et al. reported that miRNA-gene target pairs were involved in cartilage homeostasis (i.e., miR-140-ADAMTS-5) and in metabolic pathways (i.e., miR-29a-leptin)
      • Iliopoulos D.
      • Malizos K.N.
      • Oikonomou P.
      • Tsezou A.
      Integrative microRNA and proteomic approaches identify novel osteoarthritis genes and their collaborative metabolic and inflammatory networks.
      . Moreover, inhibition of miR-22 in osteoarthritic chondrocytes could block the inflammatory process and up-regulate the expression of cartilage repair protein aggrecan
      • Iliopoulos D.
      • Malizos K.N.
      • Oikonomou P.
      • Tsezou A.
      Integrative microRNA and proteomic approaches identify novel osteoarthritis genes and their collaborative metabolic and inflammatory networks.
      . Miyaki et al. reported that expression of miR-140 was significantly reduced in OA than normal cartilage
      • Miyaki S.
      • Nakasa T.
      • Otsuki S.
      • Grogan S.P.
      • Higashiyama R.
      • Inoue A.
      • et al.
      MicroRNA-140 is expressed in differentiated human articular chondrocytes and modulates interleukin-1 responses.
      . Yamasaki et al. showed that miR-146a was expressed intensely in cartilage with a low osteoarthritic grade and its expression was decreased in parallel with the levels of MMP-13
      • Yamasaki K.
      • Nakasa T.
      • Miyaki S.
      • Ishikawa M.
      • Deie M.
      • Adachi N.
      • et al.
      Expression of MicroRNA-146a in osteoarthritis cartilage.
      . Recently, Vonk et al. reported that overexpression of hsa-miR-148a in osteoarthritic chondrocytes increased the production of type II collagen and proteoglycans, and inhibited MMP-13 and ADAMTS-5 gene expression
      • Vonk L.A.
      • Kragten A.H.
      • Dhert W.J.
      • Saris D.B.
      • Creemers L.B.
      Overexpression of hsa-miR-148a promotes cartilage production and inhibits cartilage degradation by osteoarthritic chondrocytes.
      . These findings have confirmed that miRNAs most likely modulate cartilage metabolism through metabolic and inflammatory mechanisms in OA.

      Modification of meta-inflammation in OA

      Weight loss and exercise

      As weight loss and exercise have been strongly recommended for the management of knee OA symptoms, the underlying mechanisms may partly be due to modification of meta-inflammation. Among overweight and/or obese adults with knee OA, intensive weight loss induced by diet and exercise resulted in significant improvements in knee pain, function, quality of life, muscle strength and endurance, as well as reductions in body fat, trunk fat, plasma IL-6 levels, leptin, leptin: adiponectin ratio and/or lipids
      • Messier S.P.
      • Mihalko S.L.
      • Legault C.
      • Miller G.D.
      • Nicklas B.J.
      • DeVita P.
      • et al.
      Effects of intensive diet and exercise on knee joint loads, inflammation, and clinical outcomes among overweight and obese adults with knee osteoarthritis: the IDEA randomized clinical trial.
      • Miller G.D.
      • Jenks M.Z.
      • Vendela M.
      • Norris J.L.
      • Muday G.K.
      Influence of weight loss, body composition, and lifestyle behaviors on plasma adipokines: a randomized weight loss trial in older men and women with symptomatic knee osteoarthritis.
      . Intensive weight loss induced by a gastric surgery
      • Richette P.
      • Poitou C.
      • Garnero P.
      • Vicaut E.
      • Bouillot J.L.
      • Lacorte J.M.
      • et al.
      Benefits of massive weight loss on symptoms, systemic inflammation and cartilage turnover in obese patients with knee osteoarthritis.
      or diet
      • Nicklas B.J.
      • Ambrosius W.
      • Messier S.P.
      • Miller G.D.
      • Penninx B.W.
      • Loeser R.F.
      • et al.
      Diet-induced weight loss, exercise, and chronic inflammation in older, obese adults: a randomized controlled clinical trial.
      in obese knee OA patients also resulted in significant relief of knee pain as well as decreases in IL-6, hs-CRP and/or COMP. While muscle strength training alone showed significant improvements in leptin levels as well as knee pain, disability, muscle strength and functional performance
      • Durmus D.
      • Alayli G.
      • Aliyazicioglu Y.
      • Buyukakincak O.
      • Canturk F.
      Effects of glucosamine sulfate and exercise therapy on serum leptin levels in patients with knee osteoarthritis: preliminary results of randomized controlled clinical trial.
      , acute resistance exercise caused an increase in intraarticular and peri-synovial IL-10 and a decrease in intraarticular COMP in women with knee OA
      • Helmark I.C.
      • Mikkelsen U.R.
      • Borglum J.
      • Rothe A.
      • Petersen M.C.
      • Andersen O.
      • et al.
      Exercise increases interleukin-10 levels both intraarticularly and peri-synovially in patients with knee osteoarthritis: a randomized controlled trial.
      .

      Anti-cytokine/adipokine therapies

      IL-1 and TNF-α are the pivotal cytokines involved in OA physiopathology; hence, strategies targeting these inflammatory cytokines seem to be rational therapies for OA. However, the results from clinical trials are not promising so far. A randomized controlled trial (RCT) showed that one single intra-articular injection of anakinra (a recombinant IL-1Ra) was not associated with improvements in OA symptoms compared with placebo in 12 weeks of follow-up
      • Chevalier X.
      • Goupille P.
      • Beaulieu A.D.
      • Burch F.X.
      • Bensen W.G.
      • Conrozier T.
      • et al.
      Intraarticular injection of anakinra in osteoarthritis of the knee: a multicenter, randomized, double-blind, placebo-controlled study.
      . Another RCT reported that subcutaneously administration of a monoclonal antibody (AMG 108) against the functional type 1 receptor of IL-1 did not significantly relieve knee pain compared with placebo after 12 weeks treatment despite the numerical differences favoring efficacy of AMG 108
      • Cohen S.B.
      • Proudman S.
      • Kivitz A.J.
      • Burch F.X.
      • Donohue J.P.
      • Burstein D.
      • et al.
      A randomized, double-blind study of AMG 108 (a fully human monoclonal antibody to IL-1R1) in patients with osteoarthritis of the knee.
      . Diacerein, an anthraquinone that interferes with IL-1, has been confirmed by a recent systematic review to have minimal benefits on knee symptoms and JSN in OA
      • Fidelix T.S.
      • Macedo C.R.
      • Maxwell L.J.
      • Fernandes Moca Trevisani V.
      Diacerein for osteoarthritis.
      .
      Similarly, TNF-α antagonists, such as adalimumab and infliximab, have shown inconsistent clinical efficacies in OA. A recent RCT reported that adalimumab was not superior to placebo to alleviate pain in patients with hand OA not responding to analgesics and NSAIDs
      • Chevalier X.
      • Ravaud P.
      • Maheu E.
      • Baron G.
      • Rialland A.
      • Vergnaud P.
      • et al.
      Adalimumab in patients with hand osteoarthritis refractory to analgesics and NSAIDs: a randomised, multicentre, double-blind, placebo-controlled trial.
      , but it significantly halted the progression of joint damage compared to placebo in hand OA patients with palpable soft tissue swelling
      • Verbruggen G.
      • Wittoek R.
      • Vander Cruyssen B.
      • Elewaut D.
      Tumour necrosis factor blockade for the treatment of erosive osteoarthritis of the interphalangeal finger joints: a double blind, randomised trial on structure modification.
      . An open-label trial reported that adalimumab treatment for 12 weeks significantly improved knee pain, stiffness, function, joint swelling in knee OA patients with evidence of effusion
      • Maksymowych W.P.
      • Russell A.S.
      • Chiu P.
      • Yan A.
      • Jones N.
      • Clare T.
      • et al.
      Targeting tumour necrosis factor alleviates signs and symptoms of inflammatory osteoarthritis of the knee.
      .
      These inconsistent results may be due to variations in factors such as small sample size, heterogeneous samples (inflammatory phenotype would be more responsive to anti-inflammatory therapy), and a short treatment period. Adipokines (e.g., leptin) and other cytokines (e.g., IL-6 and IL-17) are closely related to OA, but there are no clinical trials reporting efficacies of anti-IL-6, 17 or leptin therapies on OA so far. Further well-designed RCTs using sensitive measures such as MRI are required to test if anti-cytokine/adipokine therapies will relieve symptoms and slow disease progression of OA.

      Metabolite modulators

      Lipid-lowering drugs, e.g., statins, may have the potential for OA treatment. Use of statins was associated with more than a 50% reduction in overall progression of knee OA over 6.5 years
      • Clockaerts S.
      • Van Osch G.J.
      • Bastiaansen-Jenniskens Y.M.
      • Verhaar J.A.
      • Van Glabbeek F.
      • Van Meurs J.B.
      • et al.
      Statin use is associated with reduced incidence and progression of knee osteoarthritis in the Rotterdam study.
      . Although it is reported that statin use was not associated with improvements in knee pain, function or structural progression over a 4-year study period
      • Riddle D.L.
      • Moxley G.
      • Dumenci L.
      Associations between statin use and changes in pain, function and structural progression: a longitudinal study of persons with knee osteoarthritis.
      , a 10-year observational study indicated that only a higher therapeutic dose of statin (>18 mg daily), with a treatment-duration of at least 2 years, was associated with a significant reduction in clinical OA compared to non-statin use
      • Kadam U.T.
      • Blagojevic M.
      • Belcher J.
      Statin use and clinical osteoarthritis in the general population: a longitudinal study.
      . Currently a RCT is being performed to examine if atorvastatin has a disease-modifying effect in symptomatic knee OA in Australia ( National Health & Medical Research Council Project Grant 1048581 ).

      Vitamin D supplementation

      Vitamin D supplementation significantly reduced serum levels of IL-6 and decreased leptin: adiponectin ratio in obese objects
      • Belenchia A.M.
      • Tosh A.K.
      • Hillman L.S.
      • Peterson C.A.
      Correcting vitamin D insufficiency improves insulin sensitivity in obese adolescents: a randomized controlled trial.
      , and thus may affect OA through modifying meta-inflammation. A RCT showed that vitamin D supplementation for 2 years at a dose sufficient to elevate 25-(OH)D plasma levels to higher than 36 ng/ml did not reduce knee pain or cartilage volume loss in patients with symptomatic OA. However, in those with low baseline 25-(OH)D (<15 ng/ml), vitamin D supplementation had larger effects on knee pain and change in cartilage volume than in those who received placebo, although these were not significant due to the small sample size
      • McAlindon T.
      • LaValley M.
      • Schneider E.
      • Nuite M.
      • Lee J.Y.
      • Price L.L.
      • et al.
      Effect of vitamin D supplementation on progression of knee pain and cartilage volume loss in patients with symptomatic osteoarthritis: a randomized controlled trial.
      . In another RCT, knee OA patients with vitamin D deficiency were included and it was found that vitamin D supplementation significantly improved knee pain and function compared to placebo, but had no effect on progression of ROA, possibly due to a short follow-up period
      • Sanghi D.
      • Mishra A.
      • Sharma A.C.
      • Singh A.
      • Natu S.M.
      • Agarwal S.
      • et al.
      Does vitamin D improve osteoarthritis of the knee: a randomized controlled pilot trial.
      . It is most likely that vitamin D supplementation is only effective in those with vitamin D deficiency patients. Further well-designed RCTs are required to determine whether vitamin D supplementation can reduce symptoms and disease progression of OA
      • Cao Y.
      • Jones G.
      • Cicuttini F.
      • Winzenberg T.
      • Wluka A.
      • Sharman J.
      • et al.
      Vitamin D supplementation in the management of knee osteoarthritis: study protocol for a randomized controlled trial.
      .

      Modification of miRNAs

      In recent years, anti-miRNAs or miRNA-mimics have emerged as useful tools for inhibiting/over-expressing the function of miRNAs, and thus may be used for the treatment of miRNAs-related diseases such as OA. Some pre-clinical studies have provided promising evidence. Transfection with ds-miR-140 in chondrocytes down-regulated IL-1β-induced a disintegrin and metalloprotease with thrombospondin motifs (ADAMTS)-5 expression and rescued the IL-1β-dependent repression of aggrecan gene expression
      • Miyaki S.
      • Nakasa T.
      • Otsuki S.
      • Grogan S.P.
      • Higashiyama R.
      • Inoue A.
      • et al.
      MicroRNA-140 is expressed in differentiated human articular chondrocytes and modulates interleukin-1 responses.
      . Transfection of synthetic miR-146a showed that IL-1 induced expression of MMP-13 and ADAMTS-5 were suppressed in human knee chondrocytes, and inflammatory cytokines (IL-6, IL-8) were inhibited in synovial cells
      • Li X.
      • Gibson G.
      • Kim J.S.
      • Kroin J.
      • Xu S.
      • van Wijnen A.J.
      • et al.
      MicroRNA-146a is linked to pain-related pathophysiology of osteoarthritis.
      . Besides, exogenous supplementation of synthesis miR-146a prominently decreased inflammatory cytokines and pain-related molecules in human glial cells, such as TNF-α, COX-2, iNOS, IL-6 and IL-8
      • Li X.
      • Gibson G.
      • Kim J.S.
      • Kroin J.
      • Xu S.
      • van Wijnen A.J.
      • et al.
      MicroRNA-146a is linked to pain-related pathophysiology of osteoarthritis.
      .

      Conclusion

      As discussed above, OA, inflammation and MetS are well correlated, and meta-inflammation plays an important role in the pathogenesis of OA. Obesity induced chronic, low-grade inflammatory responses initiated by excess nutrients in metabolic cells results in a series of pro-inflammatory changes in OA. Targeting components of meta-inflammation, such as body fat, adipokines, cytokines, acute-phase inflammatory components, excessive metabolites or nutrients, vitamin D deficiency and miRNAs, would constitute novel ways for the prevention and treatment of OA, especially those with metabolic phenotype. So far, OA patients who lose weight have shown improvements in pain and physical function, with decreased low-grade inflammation; however, strategies aiming at reducing body fat and increasing muscle mass or strength would be more effective. NO inhibitors and antioxidants may modulate meta-inflammation, but so far their clinical efficacies for the treatment of OA are not promising. Other strategies that can regulate meta-inflammation, such as anti-cytokine therapies, lipid-modification by statins, vitamin D supplementation, progressive resistance training and anti-miRNAs/miRNA-mimics, are under extensive investigation. These therapies may prove to be effective, and can provide innovative approaches for OA management.

      Contributorship

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

      Ethics approval

      No human subjects involved in this study.

      Fundings

      National Natural Science Foundation of China (NSFC) 81172865 .

      Conflict of interest

      David Hunter reports receiving royalties from DJO for a patellofemoral brace patent.

      Patient consent

      No human subjects involved in this study.

      Data sharing statement

      None.

      Provenance and peer review

      Not commissioned; extremely peer reviewer.
      Abbreviation: ADAMTS, a disintegrin-like and metalloproteinase with thrombospondin type 1 motifs.

      Acknowledgments

      None.

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