Metabolic syndrome meets osteoarthritis

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).

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

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

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).

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).

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).

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).

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

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).

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).

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).

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

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

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

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).

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).

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

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

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

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

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).

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

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).

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

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

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

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

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

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).

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

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).

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

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

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).

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

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).

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).

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).

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).

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).

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

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).

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

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).

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).

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).

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

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).

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).

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

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).

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).

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).

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).

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).

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

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).

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).

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

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

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).

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).

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

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

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).

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

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

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

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).

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

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

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).

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).

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

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).

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

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

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).

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

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

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).

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).

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).

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

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).

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).

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 .

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

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).

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).

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

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

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

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).

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).

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

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 .

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

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

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

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

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).

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).

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

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).

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

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

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

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

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).

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

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).

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).

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

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

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).

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

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

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

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

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

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).

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).

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).

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).

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).

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

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

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).

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

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

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).

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

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.

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).

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

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).

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).

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 .

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).

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).

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

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

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

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).

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

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

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).

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).

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).