Perspective | Published:


Modern-day environmental factors in the pathogenesis of osteoarthritis


The prevalence of osteoarthritis (OA) is rising for reasons that are not fully understood. In this Opinion article, we review the possibility that OA is an evolutionary mismatch disease, which is a disease more common today than in the past because genes inherited from previous generations are inadequately or imperfectly adapted to modern environmental conditions. We focus on four major environmental factors in OA pathogenesis that have become ubiquitous within the past half-century: obesity, metabolic syndrome, dietary changes and physical inactivity. Because a cure for OA does not yet exist, prevention strategies that target these modifiable environmental factors are needed to curb further increases in OA prevalence.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


  1. 1.

    Felson, D. T. et al. Osteoarthritis: new insights. Part 1: the disease and its risk factors. Ann. Intern. Med. 133, 635–646 (2000).

  2. 2.

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

  3. 3.

    Wallace, I. J. et al. Knee osteoarthritis has doubled in prevalence since the mid-20th century. Proc. Natl Acad. Sci. USA 114, 9332–9336 (2017).

  4. 4.

    Nguyen, U. S. et al. Increasing prevalence of knee pain and symptomatic knee osteoarthritis: survey and cohort data. Ann. Intern. Med. 155, 725–732 (2011).

  5. 5.

    GBD 2013 DALYs and HALE Collaborators. Global, regional, and national disability-adjusted life years (DALYs) for 306 diseases and injuries and healthy life expectancy (HALE) for 188 countries, 1990-2013: quantifying the epidemiological transition. Lancet 386, 2145–2191 (2015).

  6. 6.

    Kiadaliri, A. A., Lohmander, L. S., Moradi-Lakeh, M., Petersson, I. F. & Englund, M. High and rising burden of hip and knee osteoarthritis in the Nordic region, 1990–2015. Acta Orthop. 89, 177–183 (2017).

  7. 7.

    Sandell, L. J. Etiology of osteoarthritis: genetics and synovial joint development. Nat. Rev. Rheumatol. 8, 77–89 (2012).

  8. 8.

    Gluckman, P. D. & Hanson, M. A. Mismatch: The Lifestyle Diseases Timebomb (Oxford Univ. Press, 2013).

  9. 9.

    Lieberman, D. E. The Story of the Human Body: Evolution, Health and Disease (Pantheon Books, 2013).

  10. 10.

    Rose, M. R. & Lauder, G. V. Adaptation (Academic Press, 1996).

  11. 11.

    Menke, A., Casagrande, S., Geiss, L. & Cowie, C. C. Prevalence of and trends in diabetes among adults in the United States, 1988–2012. JAMA 314, 1021–1029 (2015).

  12. 12.

    Zuk, M. Paleofantasy: What Evolution Really Tells Us About Sex, Diet, and How We Live (W. H. Norton, 2014).

  13. 13.

    Pontzer, H. et al. Locomotor anatomy and biomechanics of the Dmanisi hominins. J. Hum. Evol. 58, 492–504 (2010).

  14. 14.

    Larsen, C. S. et al. Bioarchaeology of Neolithic Çatalhöyük: lives and lifestyles of an early farming society in transition. J. World Prehistory 28, 27–68 (2015).

  15. 15.

    Rogers, J. & Dieppe, P. Is tibiofemoral osteoarthritis in the knee joint a new disease? Ann. Rheum. Dis. 53, 612–613 (1994).

  16. 16.

    Inoue, K. et al. Prevalence of large-joint osteoarthritis in Asian and Caucasian skeletal populations. Rheumatology 40, 70–73 (2001).

  17. 17.

    Lieberman, D. E. Is exercise really medicine? An evolutionary perspective. Curr. Sports Med. Rep. 14, 313–319 (2015).

  18. 18.

    Reyes, C. et al. Association between overweight and obesity and risk of clinically diagnosed knee, hip, and hand osteoarthritis: a population-based cohort study. Arthritis Rheum. 68, 1869–1875 (2016).

  19. 19.

    Felson, D. T. Epidemiology of hip and knee osteoarthritis. Epidemiol. Rev. 10, 1–28 (1988).

  20. 20.

    Ng, M. et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 384, 766–781 (2014).

  21. 21.

    Wluka, A. E., Lombard, C. B. & Cicuttini, F. M. Tackling obesity in knee osteoarthritis. Nat. Rev. Rheumatol. 9, 225–235 (2013).

  22. 22.

    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).

  23. 23.

    Gelber, A. C. et al. Body mass index in young men and the risk of subsequent knee and hip osteoarthritis. Am. J. Med. 107, 542–548 (1999).

  24. 24.

    Richette, P. et al. Benefits of massive weight loss on symptoms, systemic inflammation and cartilage turnover in obese patients with knee osteoarthritis. Ann. Rheum. Dis. 70, 139–144 (2011).

  25. 25.

    King, W. C. et al. Change in pain and physical function following bariatric surgery for severe obesity. JAMA 315, 1362–1371 (2016).

  26. 26.

    Gersing, A. S. et al. Is weight loss associated with less progression of changes in knee articular cartilage among obese and overweight patients as assessed with MR imaging over 48 months? Data from the Osteoarthritis Initiative. Radiology 284, 508–520 (2017).

  27. 27.

    Stefanik, J. J. et al. Changes in pain sensitization after bariatric surgery. Arthritis Care Res. (2018).

  28. 28.

    Wearing, S. C., Hennig, E. M., Byrne, N. M., Steele, J. R. & Hills, A. P. Musculoskeletal disorders associated with obesity: a biomechanical perspective. Obes. Rev. 7, 239–250 (2006).

  29. 29.

    Griffin, T. M. & Guilak, F. The role of mechanical loading in the onset and progression of osteoarthritis. Exerc. Sport Sci. Rev. 33, 195–200 (2005).

  30. 30.

    Giorgi, M., Carriero, A., Shefelbine, S. J. & Nowlan, N. C. Effects of normal and abnormal loading conditions on morphogenesis of the prenatal hip joint: application to hip dysplasia. J. Biomechan. 48, 3390–3397 (2015).

  31. 31.

    Felson, D. T. Osteoarthritis as a disease of mechanics. Osteoarthritis Cartilage 21, 10–15 (2013).

  32. 32.

    Felson, D. T., Goggins, J., Niu, J., Zhang, Y. & Hunter, D. J. The effect of body weight on progression of knee osteoarthritis is dependent on alignment. Arthritis Rheum. 50, 3904–3909 (2004).

  33. 33.

    Slemenda, C. et al. Reduced quadriceps strength relative to body weight: a risk factor for knee osteoarthritis in women? Arthritis Rheum. 41, 1951–1959 (1998).

  34. 34.

    Buckwalter, J. A. & Mankin, H. J. Articular cartilage: tissue design and chondrocyte-matrix interactions. Instr. Course Lect. 47, 477–486 (1998).

  35. 35.

    Sanchez-Adams, J., Leddy, H. A., McNulty, A. L., O’Conor, C. J. & Guilak, F. The mechanobiology of articular cartilage: bearing the burden of osteoarthritis. Curr. Rheumatol. Rep. 16, 451–451 (2014).

  36. 36.

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

  37. 37.

    Houard, X., Goldring, M. B. & Berenbaum, F. Homeostatic mechanisms in articular cartilage and role of inflammation in osteoarthritis. Curr. Rheumatol. Rep. 15, 375–375 (2013).

  38. 38.

    Millward-Sadler, S. J. & Salter, D. M. Integrin-dependent signal cascades in chondrocyte mechanotransduction. Ann. Biomed. Engineer. 32, 435–446 (2004).

  39. 39.

    Loeser, R. F., Goldring, S. R., Scanzello, C. R. & Goldring, M. B. Osteoarthritis: a disease of the joint as an organ. Arthritis Rheum. 64, 1697–1707 (2012).

  40. 40.

    Yusuf, E. et al. Association between weight or body mass index and hand osteoarthritis: a systematic review. Ann. Rheum. Dis. 69, 761–765 (2010).

  41. 41.

    Visser, A. W. et al. The relative contribution of mechanical stress and systemic processes in different types of osteoarthritis: the NEO study. Ann. Rheum. Dis. 74, 1842–1847 (2015).

  42. 42.

    Hotamisligil, G. S. Inflammation, metaflammation and immunometabolic disorders. Nature 542, 177–185 (2017).

  43. 43.

    Berenbaum, F., Eymard, F. & Houard, X. Osteoarthritis, inflammation and obesity. Curr. Opin. Rheumatol. 25, 114–118 (2013).

  44. 44.

    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).

  45. 45.

    Berenbaum, F. Osteoarthritis as an inflammatory disease (osteoarthritis is not osteoarthrosis!). Osteoarthritis Cartilage 21, 16–21 (2013).

  46. 46.

    Francisco, V. et al. Biomechanics, obesity, and osteoarthritis. The role of adipokines: when the levee breaks. J. Orthop. Res. 36, 594–604 (2018).

  47. 47.

    Eckel, R. H., Grundy, S. M. & Zimmet, P. Z. The metabolic syndrome. Lancet 365, 1415–1428 (2005).

  48. 48.

    Kaplan, H. et al. Coronary atherosclerosis in indigenous South American Tsimane: a cross-sectional cohort study. Lancet 389, 1730–1739 (2017).

  49. 49.

    Kaminer, B. & Lutz, W. P. Blood pressure in Bushmen of the Kalahari Desert. Circulation 22, 289–295 (1960).

  50. 50.

    Raichlen, D. A. et al. Physical activity patterns and biomarkers of cardiovascular disease risk in hunter-gatherers. Am. J. Hum. Biol. 29, e22919 (2017).

  51. 51.

    Moore, J. X., Chaudhary, N. & Akinyemiju, T. Metabolic syndrome prevalence by race/ethnicity and sex in the United States, National Health and Nutrition Examination Survey, 1988–2012. Prev. Chron. Dis. 14, E24 (2017).

  52. 52.

    Lee, Y. S., Wollam, J. & Olefsky, J. M. An integrated view of immunometabolism. Cell 172, 22–40 (2018).

  53. 53.

    Berenbaum, F., Griffin, T. M. & Liu-Bryan, R. Metabolic regulation of inflammation in osteoarthritis. Arthritis Rheumatol. 69, 9–21 (2017).

  54. 54.

    Zhuo, Q., Yang, W., Chen, J. & Wang, Y. Metabolic syndrome meets osteoarthritis. Nat. Rev. Rheumatol. 8, 729 (2012).

  55. 55.

    Rosa, S. C. et al. Impaired glucose transporter-1 degradation and increased glucose transport and oxidative stress in response to high glucose in chondrocytes from osteoarthritic versus normal human cartilage. Arthritis Res. Ther. 11, R80 (2009).

  56. 56.

    Rosa, S. C. et al. Role of glucose as a modulator of anabolic and catabolic gene expression in normal and osteoarthritic human chondrocytes. J. Cell. Biochem. 112, 2813–2824 (2011).

  57. 57.

    Vaamonde-Garcia, C. et al. The nuclear factor-erythroid 2-related factor/heme oxygenase-1 axis is critical for the inflammatory features of type 2 diabetes-associated osteoarthritis. J. Biol. Chem. 292, 14505–14515 (2017).

  58. 58.

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

  59. 59.

    Shane Anderson, A. & Loeser, R. F. Why is osteoarthritis an age-related disease? Best practice and research. Clin. Rheumatol. 24, 15–26 (2010).

  60. 60.

    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).

  61. 61.

    de Munter, W., van der Kraan, P. M., van den Berg, W. B. & van Lent, P. L. High systemic levels of low-density lipoprotein cholesterol: fuel to the flames in inflammatory osteoarthritis? Rheumatology 55, 16–24 (2016).

  62. 62.

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

  63. 63.

    Niu, J., Clancy, M., Aliabadi, P., Vasan, R. & Felson, D. T. Metabolic syndrome, its components, and knee osteoarthritis: The Framingham Osteoarthritis Study. Arthritis Rheumatol. 69, 1194–1203 (2017).

  64. 64.

    Louati, K., Vidal, C., Berenbaum, F. & Sellam, J. Association between diabetes mellitus and osteoarthritis: systematic literature review and meta-analysis. RMD Open 1, e000077 (2015).

  65. 65.

    Neumann, J. et al. Type 2 diabetes patients have accelerated cartilage matrix degeneration compared to diabetes free controls: data from the Osteoarthritis Initiative. Osteoarthritis Cartilage 26, 751–761 (2018).

  66. 66.

    Ruiz-Nunez, B., Pruimboom, L., Dijck-Brouwer, D. A. & Muskiet, F. A. Lifestyle and nutritional imbalances associated with Western diseases: causes and consequences of chronic systemic low-grade inflammation in an evolutionary context. J. Nutr. Biochem. 24, 1183–1201 (2013).

  67. 67.

    Lepetsos, P. & Papavassiliou, A. G. ROS/oxidative stress signaling in osteoarthritis. Biochim. Biophys. Acta 1862, 576–591 (2016).

  68. 68.

    Simopoulos, A. P. An increase in the omega-6/omega-3 fatty acid ratio increases the risk for obesity. Nutrients 8, 128 (2016).

  69. 69.

    Wu, C. L. et al. Dietary fatty acid content regulates wound repair and the pathogenesis of osteoarthritis following joint injury. Ann. Rheum. Dis. 74, 2076–2083 (2015).

  70. 70.

    Cai, A. et al. Metabolic enrichment of omega-3 polyunsaturated fatty acids does not reduce the onset of idiopathic knee osteoarthritis in mice. Osteoarthritis Cartilage 22, 1301–1309 (2014).

  71. 71.

    Senftleber, N. et al. Marine oil supplements for arthritis pain: a systematic review and meta-analysis of randomized trials. Nutrients 9, 42 (2017).

  72. 72.

    Hill, C. L. et al. Fish oil in knee osteoarthritis: a randomised clinical trial of low dose versus high dose. Ann. Rheum. Dis. 75, 23–29 (2016).

  73. 73.

    Davidson, R. K. et al. Sulforaphane represses matrix-degrading proteases and protects cartilage from destruction in vitro and in vivo. Arthritis Rheum. 65, 3130–3140 (2013).

  74. 74.

    Berenbaum, F. Does broccoli protect from osteoarthritis? Joint Bone Spine 81, 284–286 (2014).

  75. 75.

    Davidson, R. et al. Isothiocyanates are detected in human synovial fluid following broccoli consumption and can affect the tissues of the knee joint. Sci. Rep. 7, 3398 (2017).

  76. 76.

    McAlindon, T. E. et al. Do antioxidant micronutrients protect against the development and progression of knee osteoarthritis? Arthritis Rheum. 39, 648–656 (1996).

  77. 77.

    Sanghi, D. et al. Elucidation of dietary risk factors in osteoarthritis knee — a case-control study. J. Am. College Nutr. 34, 15–20 (2015).

  78. 78.

    Peregoy, J. & Wilder, F. V. The effects of vitamin C supplementation on incident and progressive knee osteoarthritis: a longitudinal study. Publ. Health Nutr. 14, 709–715 (2011).

  79. 79.

    Chaganti, R. K. et al. High plasma levels of vitamin C and E are associated with incident radiographic knee osteoarthritis. Osteoarthritis Cartilage 22, 190–196 (2014).

  80. 80.

    Kraus, V. B. et al. Ascorbic acid increases the severity of spontaneous knee osteoarthritis in a guinea pig model. Arthritis Rheum. 50, 1822–1831 (2004).

  81. 81.

    Misra, D. et al. Vitamin K deficiency is associated with incident knee osteoarthritis. Am. J. Med. 126, 243–248 (2013).

  82. 82.

    Neogi, T. et al. Low vitamin K status is associated with osteoarthritis in the hand and knee. Arthritis Rheum. 54, 1255–1261 (2006).

  83. 83.

    Shea, M. K. et al. The association between vitamin K status and knee osteoarthritis features in older adults: the Health, Aging and Body Composition Study. Osteoarthritis Cartilage 23, 370–378 (2015).

  84. 84.

    Datta, P. et al. High-fat diet-induced acceleration of osteoarthritis is associated with a distinct and sustained plasma metabolite signature. Sci. Rep. 7, 8205 (2017).

  85. 85.

    Mooney, R. A., Sampson, E. R., Lerea, J., Rosier, R. N. & Zuscik, M. J. High-fat diet accelerates progression of osteoarthritis after meniscal/ligamentous injury. Arthritis Res. Ther. 13, R198 (2011).

  86. 86.

    Le Chatelier, E. et al. Richness of human gut microbiome correlates with metabolic markers. Nature 500, 541–546 (2013).

  87. 87.

    Biagi, E. et al. Through ageing, and beyond: gut microbiota and inflammatory status in seniors and centenarians. PLOS ONE 5, e10667 (2010).

  88. 88.

    Conlon, M. A. & Bird, A. R. The impact of diet and lifestyle on gut microbiota and human health. Nutrients 7, 17–44 (2015).

  89. 89.

    Brahe, L. K., Astrup, A. & Larsen, L. H. Is butyrate the link between diet, intestinal microbiota and obesity-related metabolic diseases? Obes. Rev. 14, 950–959 (2013).

  90. 90.

    Russell, W. R., Hoyles, L., Flint, H. J. & Dumas, M. E. Colonic bacterial metabolites and human health. Curr. Opin. Microbiol. 16, 246–254 (2013).

  91. 91.

    Boulange, C. L., Neves, A. L., Chilloux, J., Nicholson, J. K. & Dumas, M. E. Impact of the gut microbiota on inflammation, obesity, and metabolic disease. Genome Med. 8, 42 (2016).

  92. 92.

    Huang, Z. & Kraus, V. B. Does lipopolysaccharide-mediated inflammation have a role in OA? Nat. Rev. Rheumatol. 12, 123–129 (2016).

  93. 93.

    Collins, K. H. et al. Relationship between inflammation, the gut microbiota, and metabolic osteoarthritis development: studies in a rat model. Osteoarthritis Cartilage 23, 1989–1998 (2015).

  94. 94.

    Dai, Z., Lu, N., Niu, J., Felson, D. T. & Zhang, Y. Dietary fiber intake in relation to knee pain trajectory. Arthritis Care Res. 69, 1331–1339 (2017).

  95. 95.

    Dai, Z., Niu, J., Zhang, Y., Jacques, P. & Felson, D. T. Dietary intake of fibre and risk of knee osteoarthritis in two US prospective cohorts. Ann. Rheum. Dis. 76, 1411–1419 (2017).

  96. 96.

    Schott, E. M. et al. Targeting the gut microbiome to treat the osteoarthritis of obesity. JCI Insight (2018).

  97. 97.

    Palmieri-Smith, R. M. et al. The role of athletic trainers in preventing and managing posttraumatic osteoarthritis in physically active populations: a consensus statement of the Athletic Trainers’ Osteoarthritis Consortium. J. Athlet. Train. 52, 610–623 (2017).

  98. 98.

    Shaw, C. N. & Stock, J. T. Extreme mobility in the Late Pleistocene? Comparing limb biomechanics among fossil Homo, varsity athletes and Holocene foragers. J. Hum. Evol. 64, 242–249 (2013).

  99. 99.

    Berger, T. D. & Trinkaus, E. Patterns of trauma among the Neandertals. J. Archaeol. Sci. 22, 841–852 (1995).

  100. 100.

    Hallal, P. C. et al. Global physical activity levels: surveillance progress, pitfalls and prospects. Lancet 380, 247–257 (2012).

  101. 101.

    Jacka, F. N. et al. Lower levels of physical activity in childhood associated with adult depression. J. Sci. Med. Sport 14, 222–226 (2011).

  102. 102.

    Arsenis, N. C., You, T., Ogawa, E. F., Tinsley, G. M. & Zuo, L. Physical activity and telomere length: impact of aging and potential mechanisms of action. Oncotarget 8, 45008–45019 (2017).

  103. 103.

    Weibel, E. R., Taylor, C. R. & Hoppeler, H. The concept of symmorphosis: a testable hypothesis of structure-function relationship. Proc. Natl Acad. Sci. USA 88, 10357–10361 (1991).

  104. 104.

    Roos, E. M. & Arden, N. K. Strategies for the prevention of knee osteoarthritis. Nat. Rev. Rheumatol. 12, 92–101 (2016).

  105. 105.

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

  106. 106.

    Vanwanseele, B., Eckstein, F., Knecht, H., Spaepen, A. & Stussi, E. Longitudinal analysis of cartilage atrophy in the knees of patients with spinal cord injury. Arthritis Rheum. 48, 3377–3381 (2003).

  107. 107.

    Vanwanseele, B., Eckstein, F., Knecht, H., Stüssi, E. & Spaepen, A. Knee cartilage of spinal cord-injured patients displays progressive thinning in the absence of normal joint loading and movement. Arthritis Rheum. 46, 2073–2078 (2002).

  108. 108.

    Urquhart, D. M. et al. What is the effect of physical activity on the knee joint? A systematic review. Med. Sci. Sports Exerc. 43, 432–442 (2011).

  109. 109.

    Jones, G. et al. Knee articular cartilage development in children: a longitudinal study of the effect of sex, growth, body composition, and physical activity. Pediatr. Res. 54, 230–236 (2003).

  110. 110.

    Racunica, T. L. et al. Effect of physical activity on articular knee joint structures in community-based adults. Arthritis Rheum. 57, 1261–1268 (2007).

  111. 111.

    Leong, D. J. et al. Matrix metalloproteinase-3 in articular cartilage is upregulated by joint immobilization and suppressed by passive joint motion. Matrix Biol. 29, 420–426 (2010).

  112. 112.

    Nomura, M. et al. Thinning of articular cartilage after joint unloading or immobilization. An experimental investigation of the pathogenesis in mice. Osteoarthritis Cartilage 25, 727–736 (2017).

  113. 113.

    Paukkonen, K., Jurvelin, J. & Helminen, H. J. Effects of immobilization on the articular cartilage in young rabbits. A quantitative light microscopic stereological study. Clin. Orthop. Relat. research, 270–280 (1986).

  114. 114.

    Campbell, T. M., Reilly, K., Laneuville, O., Uhthoff, H. & Trudel, G. Bone replaces articular cartilage in the rat knee joint after prolonged immobilization. Bone 106, 42–51 (2018).

  115. 115.

    Bricca, A., Juhl, C. B., Grodzinsky, A. J. & Roos, E. M. Impact of a daily exercise dose on knee joint cartilage — a systematic review and meta-analysis of randomized controlled trials in healthy animals. Osteoarthritis Cartilage 25, 1223–1237 (2017).

  116. 116.

    Teichtahl, A. J. et al. The interaction between physical activity and amount of baseline knee cartilage. Rheumatology 55, 1277–1284 (2016).

  117. 117.

    Arokoski, J. P., Jurvelin, J. S., Vaatainen, U. & Helminen, H. J. Normal and pathological adaptations of articular cartilage to joint loading. Scand. J. Med. Sci. Sports 10, 186–198 (2000).

Download references


The work of the authors is financially supported by grants from the French Society of Rheumatology, Fondation Arthritis (ROAD network) (to F.B.), the Hintze Family Charitable Foundation, the American School of Prehistoric Research (Harvard University) (to D.E.L.) and a grant from the US National Institutes of Health (AR47785 to D.T.F.).

Author information

All authors researched data for the article, wrote the article, made substantial contribution to discussions of the content and reviewed and/or edited the manuscript before submission.

Competing interests

The authors declare no competing interests.

Correspondence to Francis Berenbaum.



A phenotypic trait favoured by natural selection because it improves an organism’s ability to survive and reproduce.

Developed nations

Wealthy countries with post-industrial economies and advanced technological infrastructure.


People who subsist on foraged wild plants and hunted wild animals, in contrast to agriculturalists who subsist mainly on domesticated plants and animals.

Knee adduction moments

Dynamic rotational forces (torques) that act on the knee in the coronal plane, applying a compressive force to the medial side of the knee.

Kellgren−Lawrence score

A common method of classifying the severity of knee osteoarthritis using radiography.


Focal inflammation owing to a local mechanical insult.


Chronic, low-grade, metabolic and systemic inflammation.

Varus malalignment

A deformity of the knee in which the distal leg is angled medially in relation to the axis of the thigh, resulting in a bowlegged appearance.

Rights and permissions

To obtain permission to re-use content from this article visit RightsLink.

About this article

Publication history

  • Published

  • Issue Date


Fig. 1: Model of osteoarthritis as a mismatch disease.
Fig. 2: Mechaflammation versus metaflammation.
Fig. 3: Diet as a mismatch factor.
Fig. 4: Physical inactivity as a mismatch factor.