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Metabolic syndrome meets osteoarthritis

Abstract

Metabolic osteoarthritis (OA) has now been characterized as a subtype of OA, and links have been discovered between this phenotype and metabolic syndrome (MetS)—both with individual MetS components and with MetS as a whole. Hypertension associates with OA through subchondral ischaemia, which can compromise nutrient exchange into articular cartilage and trigger bone remodelling. Ectopic lipid deposition in chondrocytes induced by dyslipidemia might initiate OA development, exacerbated by deregulated cellular lipid metabolism in joint tissues. Hyperglycaemia and OA interact at both local and systemic levels; local effects of oxidative stress and advanced glycation end-products are implicated in cartilage damage, whereas low-grade systemic inflammation results from glucose accumulation and contributes to a toxic internal environment that can exacerbate OA. Obesity-related metabolic factors, particularly altered levels of adipokines, contribute to OA development by inducing the expression of proinflammatory factors as well as degradative enzymes, leading to the inhibition of cartilage matrix synthesis and stimulation of subchondral bone remodelling. In this Review, we summarize the shared mechanisms of inflammation, oxidative stress, common metabolites and endothelial dysfunction that characterize the aetiologies of OA and MetS, and nominate metabolic OA as the fifth component of MetS. We also describe therapeutic opportunities that might arise from uniting these concepts.

Key Points

  • Osteoarthritis (OA) is a heterogeneous disease; the metabolic subtype is distinguishable by the presence of its major causative features, adipokines, hyperglycaemia and hormonal imbalance, and its prevalence in middle-aged people

  • The link between hypertension and OA centres on subchondral ischaemia, which can compromise nutrient exchange into the articular cartilage and trigger bone remodelling

  • Dyslipidemia-induced deregulation of cellular lipid metabolism in joint tissues might initiate OA development

  • Hyperglycaemia leads to local accumulation of advanced glycation end-products, which contribute to a toxic internal environment that facilitates OA pathogenesis

  • Obesity-altered adipokine levels induce the expression of proinflammatory factors and degradative enzymes, leading to the inhibition of cartilage matrix synthesis and stimulation of subchondral bone remodelling

  • Metabolic OA and MetS share mechanisms of inflammation, oxidative stress, common metabolites and endothelial dysfunction in their aetiologies

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Figure 1: Metabolic OA—the 5th component of MetS? OA is linked to individual components of MetS, and to MetS as a whole.

References

  1. Altman, R. et al. Development of criteria for the classification and reporting of osteoarthritis. Classification of osteoarthritis of the knee. Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association. Arthritis Rheum. 29, 1039–1049 (1986).

    Article  CAS  PubMed  Google Scholar 

  2. Symmons, D., Mathers, C. & Pfleger, B. Global burden of osteoarthritis in the year 2000. World Health Organization [online] (2003).

    Google Scholar 

  3. Bijlsma, J. W., Berenbaum, F. & Lafeber, F. P. Osteoarthritis: an update with relevance for clinical practice. Lancet 377, 2115–2126 (2011).

    Article  PubMed  Google Scholar 

  4. Alberti, K. G. & Zimmet, P. Z. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet. Med. 15, 539–553 (1998).

    Article  CAS  PubMed  Google Scholar 

  5. Balkau, B. & Charles, M. A. Comment on the provisional report from the WHO consultation. European Group for the study of Insulin Resistance (EGIR). Diabet. Med. 16, 442–443 (1999).

    Article  CAS  PubMed  Google Scholar 

  6. Grundy, S. M. et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute scientific statement: Executive Summary. Crit. Pathw. Cardiol. 4, 198–203 (2005).

    Article  PubMed  Google Scholar 

  7. Zimmet, P., Magliano, D., Matsuzawa, Y., Alberti, G. & Shaw, J. The metabolic syndrome: a global public health problem and a new definition. J. Atheroscler. Thromb. 12, 295–300 (2005).

    Article  CAS  PubMed  Google Scholar 

  8. Huang, P. L. A comprehensive definition for metabolic syndrome. Dis. Model. Mech. 2, 231–237 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Singh, G., Miller, J. D., Lee, F. H., Pettitt, D. & Russell, M. W. Prevalence of cardiovascular disease risk factors among US adults with self-reported osteoarthritis: data from the Third National Health and Nutrition Examination Survey. Am. J. Manag. Care 8, S383–S391 (2002).

    PubMed  Google Scholar 

  10. Puenpatom, R. A. & Victor, T. W. Increased prevalence of metabolic syndrome in individuals with osteoarthritis: an analysis of NHANES III data. Postgrad. Med. 121, 9–20 (2009).

    Article  PubMed  Google Scholar 

  11. Engstrom, G., Gerhardsson de Verdier, M., Rollof, J., Nilsson, P. M. & Lohmander, L. S. C-reactive protein, metabolic syndrome and incidence of severe hip and knee osteoarthritis. A population-based cohort study. Osteoarthritis Cartilage 17, 168–173 (2009).

    Article  CAS  PubMed  Google Scholar 

  12. Marks, R. & Allegrante, J. P. Comorbid disease profiles of adults with end-stage hip osteoarthritis. Med. Sci. Monit. 8, CR305–CR309 (2002).

    PubMed  Google Scholar 

  13. Conaghan, P. G., Vanharanta, H. & Dieppe, P. A. Is progressive osteoarthritis an atheromatous vascular disease? Ann. Rheum. Dis. 64, 1539–1541 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Brown, C. D. et al. Body mass index and the prevalence of hypertension and dyslipidemia. Obes. Res. 8, 605–619 (2000).

    Article  CAS  PubMed  Google Scholar 

  15. Colin Bell, A., Adair, L. S. & Popkin, B. M. Ethnic differences in the association between body mass index and hypertension. Am. J. Epidemiol. 155, 346–353 (2002).

    Article  CAS  PubMed  Google Scholar 

  16. Felmeden, D. C. et al. Endothelial damage and angiogenesis in hypertensive patients: relationship to cardiovascular risk factors and risk factor management. Am. J. Hypertens. 16, 11–20 (2003).

    Article  CAS  PubMed  Google Scholar 

  17. Kiefer, F. N. et al. Hypertension and angiogenesis. Curr. Pharm. Des. 9, 1733–1744 (2003).

    Article  CAS  PubMed  Google Scholar 

  18. Karter, Y. et al. Endothelium and angiogenesis in white coat hypertension. J. Hum. Hypertens. 18, 809–814 (2004).

    Article  CAS  PubMed  Google Scholar 

  19. Findlay, D. M. Vascular pathology and osteoarthritis. Rheumatology (Oxford) 46, 1763–1768 (2007).

    Article  CAS  Google Scholar 

  20. Imhof, H. et al. Subchondral bone and cartilage disease: a rediscovered functional unit. Invest. Radiol. 35, 581–588 (2000).

    Article  CAS  PubMed  Google Scholar 

  21. Berger, C. E., Kroner, A. H., Minai-Pour, M. B., Ogris, E. & Engel, A. Biochemical markers of bone metabolism in bone marrow edema syndrome of the hip. Bone 33, 346–351 (2003).

    Article  CAS  PubMed  Google Scholar 

  22. Hamerman, D. & Stanley, E. R. Implications of increased bone density in osteoarthritis. J. Bone Miner. Res. 11, 1205–1208 (1996).

    Article  CAS  PubMed  Google Scholar 

  23. Shibahara, M. et al. Increased osteocyte apoptosis during the development of femoral head osteonecrosis in spontaneously hypertensive rats. Acta Med. Okayama 54, 67–74 (2000).

    CAS  PubMed  Google Scholar 

  24. Kerachian, M. A. et al. A rat model of early stage osteonecrosis induced by glucocorticoids. J. Orthop. Surg. Res. 6, 62 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Lippiello, L., Walsh, T. & Fienhold, M. The association of lipid abnormalities with tissue pathology in human osteoarthritic articular cartilage. Metabolism 40, 571–576 (1991).

    Article  CAS  PubMed  Google Scholar 

  26. Kellgren, J. H. Osteoarthrosis in patients and populations. Br. Med. J. 2, 1–6 (1961).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Sturmer, T. et al. Serum cholesterol and osteoarthritis. The baseline examination of the Ulm Osteoarthritis Study. J. Rheumatol. 25, 1827–1832 (1998).

    CAS  PubMed  Google Scholar 

  28. Al-Arfaj, A. S. Radiographic osteoarthritis and serum cholesterol. Saudi Med. J. 24, 745–747 (2003).

    PubMed  Google Scholar 

  29. Hart, D. J., Doyle, D. V. & Spector, T. D. Association between metabolic factors and knee osteoarthritis in women: the Chingford Study. J. Rheumatol. 22, 1118–1123 (1995).

    CAS  PubMed  Google Scholar 

  30. Lippiello, L., Walsh, T. & Fienhold, M. The association of lipid abnormalities with tissue pathology in human osteoarthritic articular cartilage. Metabolism 40, 571–576 (1991).

    Article  CAS  PubMed  Google Scholar 

  31. Oliviero, F. et al. Apolipoprotein A-I and cholesterol in synovial fluid of patients with rheumatoid arthritis, psoriatic arthritis and osteoarthritis. Clin. Exp. Rheumatol. 27, 79–83 (2009).

    CAS  PubMed  Google Scholar 

  32. Gkretsi, V., Simopoulou, T. & Tsezou, A. Lipid metabolism and osteoarthritis: lessons from atherosclerosis. Prog. Lipid Res. 50, 133–140 (2011).

    Article  CAS  PubMed  Google Scholar 

  33. Gobezie, R. et al. High abundance synovial fluid proteome: distinct profiles in health and osteoarthritis. Arthritis Res. Ther. 9, R36 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ruiz-Romero, C., Lopez-Armada, M. J. & Blanco, F. J. Proteomic characterization of human normal articular chondrocytes: a novel tool for the study of osteoarthritis and other rheumatic diseases. Proteomics 5, 3048–3059 (2005).

    Article  CAS  PubMed  Google Scholar 

  35. Wu, J. et al. Comparative proteomic characterization of articular cartilage tissue from normal donors and patients with osteoarthritis. Arthritis Rheum. 56, 3675–3684 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. 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. PLoS ONE 3, e3740 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Simopoulou, T., Malizos, K. N. & Tsezou, A. Lectin-like oxidized low density lipoprotein receptor 1 (LOX-1) expression in human articular chondrocytes. Clin. Exp. Rheumatol. 25, 605–612 (2007).

    CAS  PubMed  Google Scholar 

  38. Tsezou, A., Iliopoulos, D., Malizos, K. N. & Simopoulou, T. Impaired expression of genes regulating cholesterol efflux in human osteoarthritic chondrocytes. J. Orthop. Res. 28, 1033–1039 (2010).

    CAS  PubMed  Google Scholar 

  39. Collins-Racie, L. A. et al. Global analysis of nuclear receptor expression and dysregulation in human osteoarthritic articular cartilage: reduced LXR signaling contributes to catabolic metabolism typical of osteoarthritis. Osteoarthritis Cartilage 17, 832–842 (2009).

    Article  CAS  PubMed  Google Scholar 

  40. Aspden, R. M., Scheven, B. A. & Hutchison, J. D. Osteoarthritis as a systemic disorder including stromal cell differentiation and lipid metabolism. Lancet 357, 1118–1120 (2001).

    Article  CAS  PubMed  Google Scholar 

  41. Waine, H., Nevinny, D., Rosenthal, J. & Joffe, I. B. Association of osteoarthritis and diabetes mellitus. Tufts Folia Med. 7, 13–19 (1961).

    CAS  PubMed  Google Scholar 

  42. Sturmer, T., Brenner, H., Brenner, R. E. & Gunther, K. P. Non-insulin dependent diabetes mellitus (NIDDM) and patterns of osteoarthritis. The Ulm osteoarthritis study. Scand. J. Rheumatol. 30, 169–171 (2001).

    Article  CAS  PubMed  Google Scholar 

  43. Cimmino, M. A. & Cutolo, M. Plasma glucose concentration in symptomatic osteoarthritis: a clinical and epidemiological survey. Clin. Exp. Rheumatol. 8, 251–257 (1990).

    CAS  PubMed  Google Scholar 

  44. Schett, G. et al. Vascular cell adhesion molecule 1 as a predictor of severe osteoarthritis of the hip and knee joints. Arthritis Rheum. 60, 2381–2389 (2009).

    Article  CAS  PubMed  Google Scholar 

  45. Frey, M. I., Barrett-Connor, E., Sledge, P. A., Schneider, D. L. & Weisman, M. H. The effect of noninsulin dependent diabetes mellitus on the prevalence of clinical osteoarthritis. A population based study. J. Rheumatol. 23, 716–722 (1996).

    CAS  PubMed  Google Scholar 

  46. Anderson, J. J. & Felson, D. T. 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. Am. J. Epidemiol. 128, 179–189 (1988).

    Article  CAS  PubMed  Google Scholar 

  47. Berenbaum, F. Diabetes-induced osteoarthritis: from a new paradigm to a new phenotype. Ann. Rheum. Dis. 70, 1354–1356 (2011).

    Article  PubMed  Google Scholar 

  48. McNulty, A. L., Stabler, T. V., Vail, T. P., McDaniel, G. E. & Kraus, V. B. Dehydroascorbate transport in human chondrocytes is regulated by hypoxia and is a physiologically relevant source of ascorbic acid in the joint. Arthritis Rheum. 52, 2676–2685 (2005).

    Article  CAS  PubMed  Google Scholar 

  49. Henrotin, Y. E., Bruckner, P. & Pujol, J. P. The role of reactive oxygen species in homeostasis and degradation of cartilage. Osteoarthritis Cartilage 11, 747–755 (2003).

    Article  CAS  PubMed  Google Scholar 

  50. Hiraiwa, H. et al. Inflammatory effect of advanced glycation end products on human meniscal cells from osteoarthritic knees. Inflamm. Res. 60, 1039–1048 (2011).

    Article  CAS  PubMed  Google Scholar 

  51. Nah, S. S. et al. Advanced glycation end products increases matrix metalloproteinase-1, -3, and -13, and TNF-α in human osteoarthritic chondrocytes. FEBS Lett. 581, 1928–1932 (2007).

    Article  CAS  PubMed  Google Scholar 

  52. Nah, S. S. et al. Effects of advanced glycation end products on the expression of COX-2, PGE2 and NO in human osteoarthritic chondrocytes. Rheumatology (Oxford) 47, 425–431 (2008).

    Article  CAS  Google Scholar 

  53. Rasheed, Z., Akhtar, N. & Haqqi, T. M. Advanced glycation end products induce the expression of interleukin-6 and interleukin-8 by receptor for advanced glycation end product-mediated activation of mitogen-activated protein kinases and nuclear factor-κB in human osteoarthritis chondrocytes. Rheumatology (Oxford) 50, 838–851 (2011).

    Article  CAS  Google Scholar 

  54. Yammani, R. R., Carlson, C. S., Bresnick, A. R. & Loeser, R. F. Increase in production of matrix metalloproteinase 13 by human articular chondrocytes due to stimulation with S100A4: Role of the receptor for advanced glycation end products. Arthritis Rheum. 54, 2901–2911 (2006).

    Article  CAS  PubMed  Google Scholar 

  55. Steenvoorden, M. M. et al. Activation of receptor for advanced glycation end products in osteoarthritis leads to increased stimulation of chondrocytes and synoviocytes. Arthritis Rheum. 54, 253–263 (2006).

    Article  CAS  PubMed  Google Scholar 

  56. Cecil, D. L. et al. Inflammation-induced chondrocyte hypertrophy is driven by receptor for advanced glycation end products. J. Immunol. 175, 8296–8302 (2005).

    Article  CAS  PubMed  Google Scholar 

  57. Loeser, R. F. et al. Articular chondrocytes express the receptor for advanced glycation end products: Potential role in osteoarthritis. Arthritis Rheum. 52, 2376–2385 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Stannus, O. et al. Circulating levels of IL-6 and TNF-α are associated with knee radiographic osteoarthritis and knee cartilage loss in older adults. Osteoarthritis Cartilage 18, 1441–1447 (2010).

    Article  CAS  PubMed  Google Scholar 

  59. Hurley, M. V. The role of muscle weakness in the pathogenesis of osteoarthritis. Rheum. Dis. Clin. North Am. 25, 283–298, vi (1999).

    Article  CAS  PubMed  Google Scholar 

  60. Slemenda, C. et al. Quadriceps weakness and osteoarthritis of the knee. Ann. Intern. Med. 127, 97–104 (1997).

    Article  CAS  PubMed  Google Scholar 

  61. Shakoor, N., Lee, K. J., Fogg, L. F. & Block, J. A. Generalized vibratory deficits in osteoarthritis of the hip. Arthritis Rheum. 59, 1237–1240 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Felson, D. T., Anderson, J. J., Naimark, A., Walker, A. M. & Meenan, R. F. Obesity and knee osteoarthritis. The Framingham Study. Ann. Intern. Med. 109, 18–24 (1988).

    Article  CAS  PubMed  Google Scholar 

  63. Pottie, P. et al. Obesity and osteoarthritis: more complex than predicted! Ann. Rheum. Dis. 65, 1403–1405 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Gabay, O., Hall, D. J., Berenbaum, F., Henrotin, Y. & Sanchez, C. Osteoarthritis and obesity: experimental models. Joint Bone Spine 75, 675–679 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  65. Chowdhury, T. T. et al. Dynamic compression counteracts IL-1β induced inducible nitric oxide synthase and cyclo-oxygenase-2 expression in chondrocyte/agarose constructs. Arthritis Res. Ther. 10, R35 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Gosset, M. et al. Prostaglandin E2 synthesis in cartilage explants under compression: mPGES-1 is a mechanosensitive gene. Arthritis Res. Ther. 8, R135 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Gabay, O. et al. Stress-induced signaling pathways in hyalin chondrocytes: inhibition by Avocado-Soybean Unsaponifiables (ASU). Osteoarthritis Cartilage 16, 373–384 (2008).

    Article  CAS  PubMed  Google Scholar 

  68. Fitzgerald, J. B. et al. Shear- and compression-induced chondrocyte transcription requires MAPK activation in cartilage explants. J. Biol. Chem. 283, 6735–6743 (2008).

    Article  CAS  PubMed  Google Scholar 

  69. Shimazaki, A., Wright, M. O., Elliot, K., Salter, D. M. & Millward-Sadler, S. J. Calcium/calmodulin-dependent protein kinase II in human articular chondrocytes. Biorheology 43, 223–233 (2006).

    CAS  PubMed  Google Scholar 

  70. Lajeunesse, D. Altered subchondral osteoblast cellular metabolism in osteoarthritis: cytokines, eicosanoids, and growth factors. J. Musculoskelet. Neuronal Interact. 2, 504–506 (2002).

    CAS  PubMed  Google Scholar 

  71. Sanchez, C. et al. Regulation of subchondral bone osteoblast metabolism by cyclic compression. Arthritis Rheum. 64, 1193–1203 (2012).

    Article  CAS  PubMed  Google Scholar 

  72. Liu, J. et al. Early responses of osteoblast-like cells to different mechanical signals through various signaling pathways. Biochem. Biophys. Res. Commun. 348, 1167–1173 (2006).

    Article  CAS  PubMed  Google Scholar 

  73. 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. Arthritis Rheum. 60, 2935–2944 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Inoue, D., Kido, S. & Matsumoto, T. Transcriptional induction of FosB/DeltaFosB gene by mechanical stress in osteoblasts. J. Biol. Chem. 279, 49795–49803 (2004).

    Article  CAS  PubMed  Google Scholar 

  75. Chen, N. X., Geist, D. J., Genetos, D. C., Pavalko, F. M. & Duncan, R. L. Fluid shear-induced NFκB translocation in osteoblasts is mediated by intracellular calcium release. Bone 33, 399–410 (2003).

    Article  CAS  PubMed  Google Scholar 

  76. Aspden, R. M. Obesity punches above its weight in osteoarthritis. Nat. Rev. Rheumatol. 7, 65–68 (2011).

    Article  PubMed  Google Scholar 

  77. Sowers, M. R. & Karvonen-Gutierrez, C. A. The evolving role of obesity in knee osteoarthritis. Curr. Opin. Rheumatol. 22, 533–537 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  78. Gomez, R., Lago, F., Gomez-Reino, J., Dieguez, C. & Gualillo, O. Adipokines in the skeleton: influence on cartilage function and joint degenerative diseases. J. Mol. Endocrinol. 43, 11–18 (2009).

    Article  CAS  PubMed  Google Scholar 

  79. Zhang, Y. et al. Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432 (1994).

    Article  CAS  PubMed  Google Scholar 

  80. Dumond, H. et al. Evidence for a key role of leptin in osteoarthritis. Arthritis Rheum. 48, 3118–3129 (2003).

    Article  CAS  PubMed  Google Scholar 

  81. Otero, M., Gomez Reino, J. J. & Gualillo, O. Synergistic induction of nitric oxide synthase type II: in vitro effect of leptin and interferon-γ in human chondrocytes and ATDC5 chondrogenic cells. Arthritis Rheum. 48, 404–409 (2003).

    Article  CAS  PubMed  Google Scholar 

  82. Iliopoulos, D., Malizos, K. N. & Tsezou, A. Epigenetic regulation of leptin affects MMP-13 expression in osteoarthritic chondrocytes: possible molecular target for osteoarthritis therapeutic intervention. Ann. Rheum. Dis. 66, 1616–1621 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Sanna, V. et al. Leptin surge precedes onset of autoimmune encephalomyelitis and correlates with development of pathogenic T cell responses. J. Clin. Invest. 111, 241–250 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Faggioni, R., Feingold, K. R. & Grunfeld, C. Leptin regulation of the immune response and the immunodeficiency of malnutrition. FASEB J. 15, 2565–2571 (2001).

    Article  CAS  PubMed  Google Scholar 

  85. Gomez, R. et al. What's new in our understanding of the role of adipokines in rheumatic diseases? Nat. Rev. Rheumatol. 7, 528–536 (2011).

    Article  CAS  PubMed  Google Scholar 

  86. Mutabaruka, M. S., 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 Res. Ther. 12, R20 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Motyl, K. J. & Rosen, C. J. Understanding leptin-dependent regulation of skeletal homeostasis. Biochimie http://dx.doi.org/10.1016/j.biochi.2012.04.015.

  88. Chen, T. H. et al. Evidence for a protective role for adiponectin in osteoarthritis. Biochim. Biophys. Acta 1762, 711–718 (2006).

    Article  CAS  PubMed  Google Scholar 

  89. Laurberg, T. B. et al. Plasma adiponectin in patients with active, early, and chronic rheumatoid arthritis who are steroid- and disease-modifying antirheumatic drug-naive compared with patients with osteoarthritis and controls. J. Rheumatol. 36, 1885–1891 (2009).

    Article  CAS  PubMed  Google Scholar 

  90. Filkov, M. et al. Increased serum adiponectin levels in female patients with erosive compared with non-erosive osteoarthritis. Ann. Rheum. Dis. 68, 295–296 (2009).

    Article  Google Scholar 

  91. Honsawek, S. & Chayanupatkul, M. Correlation of plasma and synovial fluid adiponectin with knee osteoarthritis severity. Arch. Med. Res. 41, 593–598 (2010).

    Article  CAS  PubMed  Google Scholar 

  92. Hao, D. et al. Synovial fluid level of adiponectin correlated with levels of aggrecan degradation markers in osteoarthritis. Rheumatol. Int. 31, 1433–1437 (2011).

    Article  CAS  PubMed  Google Scholar 

  93. Ehling, A. et al. The potential of adiponectin in driving arthritis. J. Immunol. 176, 4468–4478 (2006).

    Article  CAS  PubMed  Google Scholar 

  94. Lago, R. et al. A new player in cartilage homeostasis: adiponectin induces nitric oxide synthase type II and pro-inflammatory cytokines in chondrocytes. Osteoarthritis Cartilage 16, 1101–1109 (2008).

    Article  CAS  PubMed  Google Scholar 

  95. Lee, S. W., Kim, J. H., Park, M. C., Park, Y. B. & Lee, S. K. Adiponectin mitigates the severity of arthritis in mice with collagen-induced arthritis. Scand. J. Rheumatol. 37, 260–268 (2008).

    Article  CAS  PubMed  Google Scholar 

  96. Empana, J. P. Adiponectin isoforms and cardiovascular disease: the epidemiological evidence has just begun. Eur. Heart J. 29, 1221–1223 (2008).

    Article  CAS  PubMed  Google Scholar 

  97. Frommer, K. W. et al. Adiponectin isoforms: a potential therapeutic target in rheumatoid arthritis? Ann. Rheum. Dis. http://dx.doi.org/10.1136/annrheumdis-2011-200924.

  98. Nakano, Y. et al. A novel enzyme-linked immunosorbent assay specific for high-molecular-weight adiponectin. J. Lipid Res. 47, 1572–1582 (2006).

    Article  CAS  PubMed  Google Scholar 

  99. Bokarewa, M., Nagaev, I., Dahlberg, L., Smith, U. & Tarkowski, A. Resistin, an adipokine with potent proinflammatory properties. J. Immunol. 174, 5789–5795 (2005).

    Article  CAS  PubMed  Google Scholar 

  100. Åenolt, L. et al. Resistin in rheumatoid arthritis synovial tissue, synovial fluid and serum. Ann. Rheum. Dis. 66, 458–463 (2007).

    Google Scholar 

  101. Gonzalez-Gay, M. A. et al. Anti-TNF-α therapy modulates resistin in patients with rheumatoid arthritis. Clin. Exp. Rheumatol. 26, 311–316 (2008).

    CAS  PubMed  Google Scholar 

  102. Gupta, K., Shukla, M., Cowland, J. B., Malemud, C. J. & Haqqi, T. M. Neutrophil gelatinase-associated lipocalin is expressed in osteoarthritis and forms a complex with matrix metalloproteinase 9. Arthritis Rheum. 56, 3326–3335 (2007).

    Article  CAS  PubMed  Google Scholar 

  103. Vallon, R. et al. Serum amyloid A (apoSAA) expression is up-regulated in rheumatoid arthritis and induces transcription of matrix metalloproteinases. J. Immunol. 166, 2801–2807 (2001).

    Article  CAS  PubMed  Google Scholar 

  104. Sowers, M. et al. Knee osteoarthritis in obese women with cardiometabolic clustering. Arthritis Rheum. 61, 1328–1336 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  105. Yoshimura, N. et al. Association of knee osteoarthritis with the accumulation of metabolic risk factors such as overweight, hypertension, dyslipidemia, and impaired glucose tolerance in Japanese men and women: the ROAD study. J. Rheumatol. 38, 921–930 (2011).

    Article  PubMed  Google Scholar 

  106. Korochina, I. E. & Bagirova, G. G. Metabolic syndrome and a course of osteoarthrosis [Russian]. Ter. Arkh. 79, 13–20 (2007).

    CAS  PubMed  Google Scholar 

  107. Velasquez, M. T. & Katz, J. D. Osteoarthritis: another component of metabolic syndrome? Metab. Syndr. Relat. Disord. 8, 295–305 (2010).

    Article  PubMed  Google Scholar 

  108. Mendel, O. I. et al. Osteoarthritis and cardiovascular diseases in elderly patients: clinical and pathogenetic interrelationship [Russian]. Adv. Gerontol. 23, 304–313 (2010).

    CAS  PubMed  Google Scholar 

  109. Philbin, E. F. et al. Osteoarthritis as a determinant of an adverse coronary heart disease risk profile. J. Cardiovasc. Risk 3, 529–533 (1996).

    Article  CAS  PubMed  Google Scholar 

  110. Huffman, K. M. & Kraus, W. E. Osteoarthritis and the metabolic syndrome: more evidence that the etiology of OA is different in men and women. Osteoarthritis Cartilage 20, 603–604 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Devaraj, S. Goyal, R. & Jialal, I. Inflammation, oxidative stress, and the metabolic syndrome. US Endocrinology 4, 32–37 (2008).

    Article  Google Scholar 

  112. Patel, S. B., Reams, G. P., Spear, R. M., Freeman, R. H. & Villarreal, D. Leptin: linking obesity, the metabolic syndrome, and cardiovascular disease. Curr. Hypertens. Rep. 10, 131–137 (2008).

    Article  CAS  PubMed  Google Scholar 

  113. Ceriello, A. & Motz, E. Is oxidative stress the pathogenic mechanism underlying insulin resistance, diabetes, and cardiovascular disease? The common soil hypothesis revisited. Arterioscler. Thromb. Vasc. Biol. 24, 816–823 (2004).

    Article  CAS  PubMed  Google Scholar 

  114. Urakawa, H. et al. Oxidative stress is associated with adiposity and insulin resistance in men. J. Clin. Endocrinol. Metab. 88, 4673–4676 (2003).

    Article  CAS  PubMed  Google Scholar 

  115. Ford, E. S., Mokdad, A. H., Giles, W. H. & Brown, D. W. The metabolic syndrome and antioxidant concentrations. Diabetes 52, 2346–2352 (2003).

    Article  CAS  PubMed  Google Scholar 

  116. Gomes, V. A., Casella-Filho, A., Chagas, A. C. & Tanus-Santos, J. E. Enhanced concentrations of relevant markers of nitric oxide formation after exercise training in patients with metabolic syndrome. Nitric Oxide 19, 345–350 (2008).

    Article  CAS  PubMed  Google Scholar 

  117. Fortuno, A. et al. Phagocytic NADPH oxidase overactivity underlies oxidative stress in metabolic syndrome. Diabetes 55, 209–215 (2006).

    Article  CAS  PubMed  Google Scholar 

  118. Bedard, K. & Krause, K. H. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol. Rev. 87, 245–313 (2007).

    Article  CAS  PubMed  Google Scholar 

  119. Cardona, F. et al. Fat overload aggravates oxidative stress in patients with the metabolic syndrome. Eur. J. Clin. Invest. 38, 510–515 (2008).

    Article  CAS  PubMed  Google Scholar 

  120. Ziskoven, C. et al. Oxidative stress in secondary osteoarthritis: from cartilage destruction to clinical presentation? Orthop. Rev. (Pavia) 2, e23 (2010).

    Article  Google Scholar 

  121. Marok, R. et al. Activation of the transcription factor nuclear factor-κB in human inflamed synovial tissue. Arthritis Rheum. 39, 583–591 (1996).

    Article  CAS  PubMed  Google Scholar 

  122. Boileau, C. et al. Protective effects of total fraction of avocado/soybean unsaponifiables on the structural changes in experimental dog osteoarthritis: inhibition of nitric oxide synthase and matrix metalloproteinase-13. Arthritis Res. Ther. 11, R41 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Anagnostis, P., Athyros, V. G., Adamidou, F., Florentin, M. & Karagiannis, A. Vitamin D and cardiovascular disease: a novel agent for reducing cardiovascular risk? Curr. Vasc. Pharmacol. 8, 720–730 (2010).

    Article  CAS  PubMed  Google Scholar 

  124. Kim, M. K. et al. The association of serum vitamin D level with presence of metabolic syndrome and hypertension in middle-aged Korean subjects. Clin. Endocrinol. (Oxf.) 73, 330–338 (2010).

    Article  CAS  Google Scholar 

  125. Chaganti, R. K. et al. Association of 25-hydroxyvitamin D with prevalent osteoarthritis of the hip in elderly men: the osteoporotic fractures in men study. Arthritis Rheum. 62, 511–514 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Bergink, A. P. et al. Vitamin D status, bone mineral density, and the development of radiographic osteoarthritis of the knee: The Rotterdam Study. J. Clin. Rheumatol. 15, 230–237 (2009).

    Article  PubMed  Google Scholar 

  127. Parker, J. et al. Levels of vitamin D and cardiometabolic disorders: systematic review and meta-analysis. Maturitas 65, 225–236 (2010).

    Article  CAS  PubMed  Google Scholar 

  128. Anitua, E. et al. Relationship between investigative biomarkers and radiographic grading in patients with knee osteoarthritis. Int. J. Rheumatol. 2009, 747432 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Wu, Q. et al. Induction of an osteoarthritis-like phenotype and degradation of phosphorylated Smad3 by Smurf2 in transgenic mice. Arthritis Rheum. 58, 3132–3144 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Horie, T. et al. TG-interacting factor is required for the differentiation of preadipocytes. J. Lipid Res. 49, 1224–1234 (2008).

    Article  CAS  PubMed  Google Scholar 

  131. Ibrahim, M. M. Subcutaneous and visceral adipose tissue: structural and functional differences. Obes. Rev. 11, 11–18.

  132. 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. Osteoarthritis Cartilage 20, 614–621 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Sowers, M. R. et al. Estradiol and its metabolites and their association with knee osteoarthritis. Arthritis Rheum. 54, 2481–2487 (2006).

    Article  CAS  PubMed  Google Scholar 

  134. Maleki-Fischbach, M. & Jordan, J. M. New developments in osteoarthritis. Sex differences in magnetic resonance imaging-based biomarkers and in those of joint metabolism. Arthritis Res. Ther. 12, 212.

  135. Gimbrone, M. A., Jr, Topper, J. N., Nagel, T., Anderson, K. R. & Garcia-Cardena, G. Endothelial dysfunction, hemodynamic forces, and atherogenesis. Ann. NY Acad. Sci. 902, 230–239; discussion 239–240 (2000).

    Article  CAS  PubMed  Google Scholar 

  136. Huang, P. L. Unraveling the links between diabetes, obesity, and cardiovascular disease. Circ. Res. 96, 1129–1131 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Kim, J. A., Montagnani, M., Koh, K. K. & Quon, M. J. Reciprocal relationships between insulin resistance and endothelial dysfunction: molecular and pathophysiological mechanisms. Circulation 113, 1888–1904 (2006).

    Article  PubMed  Google Scholar 

  138. Jonsson, H. et al. Hand osteoarthritis in older women is associated with carotid and coronary atherosclerosis: the AGES Reykjavik study. Ann. Rheum. Dis. 68, 1696–1700 (2009).

    Article  CAS  PubMed  Google Scholar 

  139. Hoeven, T. A. et al. Association of atherosclerosis with presence and progression of osteoarthritis: the Rotterdam Study. Ann. Rheum. Dis. http://dx.doi.org/10.1136/annrheumdis-2011-201178.

  140. Jonsson, H. et al. The presence of total knee or hip replacements due to osteoarthritis enhances the positive association between hand osteoarthritis and atherosclerosis in women: the AGES-Reykjavik study. Ann. Rheum. Dis. 70, 1087–1090 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  141. Miller, D. et al. Endothelial dysfunction and decreased vascular responsiveness in the anterior cruciate ligament-deficient model of osteoarthritis. J. Appl. Physiol. 102, 1161–1169 (2007).

    Article  CAS  PubMed  Google Scholar 

  142. Dimmeler, S. et al. Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature 399, 601–605 (1999).

    Article  CAS  PubMed  Google Scholar 

  143. Fulton, D. et al. Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature 399, 597–601 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Fahmi, H., Martel-Pelletier, J., Pelletier, J. P. & Kapoor, M. Peroxisome proliferator-activated receptor gamma in osteoarthritis. Mod. Rheumatol. 21, 1–9 (2011).

    Article  CAS  PubMed  Google Scholar 

  145. Jouzeau, J. Y. et al. Pathophysiological relevance of peroxisome proliferators activated receptors (PPAR) to joint diseases - the pro and con of agonists [French]. J. Soc. Biol. 202, 289–312 (2008).

    Article  CAS  PubMed  Google Scholar 

  146. Yudoh, K. & Karasawa, R. Statin prevents chondrocyte aging and degeneration of articular cartilage in osteoarthritis (OA). Aging (Albany NY) 2, 990–998 (2010).

    Article  CAS  Google Scholar 

  147. Baker, J. F., Walsh, P. & Mulhall, K. J. Statins: apotential role in the management of osteoarthritis? Joint Bone Spine 78, 31–34 (2011).

    Article  CAS  PubMed  Google Scholar 

  148. Clockaerts, S. et al. Statin use is associated with reduced incidence and progression of knee osteoarthritis in the Rotterdam study. Ann. Rheum. Dis. 71(5), 642–647 (2011).

    Article  CAS  PubMed  Google Scholar 

  149. Beattie, M. S., Lane, N. E., Hung, Y.-Y. & Nevitt, M. C. Association of statin use and development and progression of hip osteoarthritis in elderly women. J. Rheumatol. 32, 106–110 (2005).

    PubMed  Google Scholar 

  150. Liu, F. C. et al. A Benzamide-Linked Small Molecule HS-Cf Inhibits TNF-α-induced interferon regulatory factor-1 in porcine chondrocytes: a potential disease-modifying drug for osteoarthritis therapeutics. J. Clin. Immunol. 31, 1131–1142 (2011).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors wish to thank Dr Wei Chai and Dr Guoqiang Zhang for helpful discussions during the revision of this manuscript.

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Q. Zhuo, W. Yang and Y. Wang contributed equally to researching data for the article, discussions of content, writing the article and review/editing of the manuscript before submission. J. Chen made substantial contributions to researching data for the article, discussions of content and review/editing of the manuscript before submission.

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Correspondence to Yan Wang.

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Zhuo, Q., Yang, W., Chen, J. et al. Metabolic syndrome meets osteoarthritis. Nat Rev Rheumatol 8, 729–737 (2012). https://doi.org/10.1038/nrrheum.2012.135

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