The role of metabolism in the pathogenesis of osteoarthritis

Journal name:
Nature Reviews Rheumatology
Year published:
Published online


Metabolism is important for cartilage and synovial joint function. Under adverse microenvironmental conditions, mammalian cells undergo a switch in cell metabolism from a resting regulatory state to a highly metabolically activate state to maintain energy homeostasis. This phenomenon also leads to an increase in metabolic intermediates for the biosynthesis of inflammatory and degradative proteins, which in turn activate key transcription factors and inflammatory signalling pathways involved in catabolic processes, and the persistent perpetuation of drivers of pathogenesis. In the past few years, several studies have demonstrated that metabolism has a key role in inflammatory joint diseases. In particular, metabolism is drastically altered in osteoarthritis (OA) and aberrant immunometabolism may be a key feature of many phenotypes of OA. This Review focuses on aberrant metabolism in the pathogenesis of OA, summarizing the current state of knowledge on the role of impaired metabolism in the cells of the osteoarthritic joint. We also highlight areas for future research, such as the potential to target metabolic pathways and mediators therapeutically.

At a glance


  1. Factors underlying metabolic alterations in osteoarthritis.
    Figure 1: Factors underlying metabolic alterations in osteoarthritis.

    Poor diet and lifestyle choices can contribute to weight gain and lead to obesity. Ageing, obesity and other co-morbidities associated with osteoarthritis (OA) contribute to metabolic reprogramming in a variety of cells and tissues, leading to inflammaging and cellular senescence, which in turn cause further changes in cellular metabolism in OA.

  2. Phenotypes of osteoarthritis.
    Figure 2: Phenotypes of osteoarthritis.

    Evidence suggests that patients with osteoarthritis (OA) fall into multiple phenotypic subgroups defined on the basis of the main driver of disease, one of which is a distinct metabolic phenotype, although all OA phenotypes probably involve metabolic alterations. Cartilage, bone and synovium are all affected by external and internal drivers of disease such as inflammation, injury or biomechanical alterations, metabolic reprogramming and immunomodulation, but different synovial joint tissues dominate the disease in different patients with OA.

  3. Metabolism in homeostatic chondrocytes.
    Figure 3: Metabolism in homeostatic chondrocytes.

    In healthy joints, chondrocytes utilize glucose as well as other metabolic fuels and sources of energy. Glucose utilization via glycolysis and oxidative phosphorylation helps to maintain an optimal level of mitochondrial function and biogenesis. The metabolism of healthy chondrocytes is therefore optimized to maintain normal energy homeostasis via signalling through the AMPK–SIRT1–PGC1α pathway. AMPK, AMP-activated protein kinase; ETC, electron transport chain; GLUT1, glucose transporter type 1; PGC1α, peroxisome proliferator-activated receptor γ co-activator 1α; ROS, reactive oxygen species; SIRT1, NAD-dependent protein deacetylase sirtuin-1; TCA, tricarboxylic acid.

  4. Altered metabolism in chondrocytes in osteoarthritis.
    Figure 4: Altered metabolism in chondrocytes in osteoarthritis.

    Chondrocytes in osteoarthritis (OA) switch from oxidative phosphorylation to glycolysis as their main source of energy metabolism. In osteoarthritic joints, chondrocytes are exposed to proinflammatory cytokines and microenvironmental alterations, including hypoxia and nutrient stress. Mitochondrial metabolism is impaired and reactive oxygen species (ROS) accumulate, causing damage to mitochondria which inhibits AMPK signalling and activity, downregulate SIRT1 and decrease levels of PGC1α, the master regulator of mitochondrial biogenesis. AMPK, AMP-activated protein kinase; ETC, electron transport chain; GLUT1, glucose transporter type 1; PGC1α, peroxisome proliferator-activated receptor γ co-activator 1α; SIRT1, NAD-dependent protein deacetylase sirtuin-1; TCA, tricarboxylic acid.


  1. Mathis, D. & Shoelson, S. E. Immunometabolism: an emerging frontier. Nat. Rev. Immunol. 11, 81 (2011).
  2. Ferrante, A. W. Macrophages, fat, and the emergence of immunometabolism. J. Clin. Invest. 123, 49924993 (2013).
  3. O'Neill, L. A. J., Kishton, R. J. & Rathmell, J. A guide to immunometabolism for immunologists. Nat. Rev. Immunol. 16, 553565 (2016).
  4. Osborn, O. & Olefsky, J. M. The cellular and signaling networks linking the immune system and metabolism in disease. Nat. Med. 18, 363374 (2012).
  5. van der Kraan, P., Matta, C. & Mobasheri, A. Age-related alterations in signaling pathways in articular chondrocytes: implications for the pathogenesis and progression of osteoarthritis — a mini-review. Gerontology 63, 2935 (2016).
  6. Mobasheri, A., Matta, C., Zákány, R. & Musumeci, G. Chondrosenescence: definition, hallmarks and potential role in the pathogenesis of osteoarthritis. Maturitas 80, 237244 (2015).
  7. Early, J. O. & Curtis, A. M. Immunometabolism: is it under the eye of the clock? Semin. Immunol. 28, 478490 (2016).
  8. Loftus, R. M. & Finlay, D. K. Immunometabolism: cellular metabolism turns immune regulator. J. Biol. Chem. 291, 110 (2016).
  9. Michalek, R. D. & Rathmell, J. C. The metabolic life and times of a T-cell. Immunol. Rev. 236, 190202 (2010).
  10. 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, 1118 (2009).
  11. Sellam, J. & Berenbaum, F. Is osteoarthritis a metabolic disease? Joint Bone Spine 80, 568573 (2013).
  12. Kluzek, S., Newton, J. L. & Arden, N. K. Is osteoarthritis a metabolic disorder? Br. Med. Bull. 115, 111121 (2015).
  13. June, R. K., Liu-Bryan, R., Long, F. & Griffin, T. M. Emerging role of metabolic signaling in synovial joint remodeling and osteoarthritis. J. Orthop. Res. 24, 20482058 (2016).
  14. Loeser, R. F. Aging and osteoarthritis. Curr. Opin. Rheumatol. 23, 492496 (2011).
  15. Berenbaum, F. Osteoarthritis as an inflammatory disease (osteoarthritis is not osteoarthrosis!). Osteoarthritis Cartilage 21, 1621 (2013).
  16. Glyn-Jones, S. et al. Osteoarthritis. Lancet 386, 376387 (2015).
  17. Bhattaram, P. & Chandrasekharan, U. The joint synovium: a critical determinant of articular cartilage fate in inflammatory joint diseases. Semin. Cell Dev. Biol. 62, 8693 (2017).
  18. Braun, H. J. & Gold, G. E. Diagnosis of osteoarthritis: imaging. Bone 51, 278288 (2012).
  19. Hasegawa, A. et al. Anterior cruciate ligament changes in the human knee joint in aging and osteoarthritis. Arthritis Rheum. 64, 696704 (2012).
  20. Conde, J. et al. Differential expression of adipokines in infrapatellar fat pad (IPFP) and synovium of osteoarthritis patients and healthy individuals. Ann. Rheum. Dis. 73, 631633 (2014).
  21. Goldring, S. R. Alterations in periarticular bone and cross talk between subchondral bone and articular cartilage in osteoarthritis. Ther. Adv. Musculoskelet. Dis. 4, 249258 (2012).
  22. Goldring, S. R. & Goldring, M. B. Changes in the osteochondral unit during osteoarthritis: structure, function and cartilage–bone crosstalk. Nat. Rev. Rheumatol. 12, 632644 (2016).
  23. Guilak, F. Biomechanical factors in osteoarthritis. Best Pract. Res. Clin. Rheumatol. 25, 815823 (2011).
  24. Scanzello, C. R. Role of low-grade inflammation in osteoarthritis. Curr. Opin. Rheumatol. 29, 7985 (2017).
  25. Wang, Q. et al. Identification of a central role for complement in osteoarthritis. Nat. Med. 17, 16741679 (2011).
  26. Hunter, D. J. Osteoarthritis. Best Pract. Res. Clin. Rheumatol. 25, 801814 (2011).
  27. Thijssen, E., van Caam, A. & van der Kraan, P. M. Obesity and osteoarthritis, more than just wear and tear: pivotal roles for inflamed adipose tissue and dyslipidaemia in obesity-induced osteoarthritis. Rheumatology (Oxford) 54, 588600 (2015).
  28. Malemud, C. J. Biologic basis of osteoarthritis: state of the evidence. Curr. Opin. Rheumatol. 27, 289294 (2015).
  29. Wluka, A. E., Lombard, C. B. & Cicuttini, F. M. Tackling obesity in knee osteoarthritis. Nat. Rev. Rheumatol. 9, 225235 (2013).
  30. Zhuo, Q., Yang, W., Chen, J. & Wang, Y. Metabolic syndrome meets osteoarthritis. Nat. Rev. Rheumatol. 8, 729737 (2012).
  31. Gierman, L. M. et al. Metabolic stress-induced inflammation plays a major role in the development of osteoarthritis in mice. Arthritis Rheum. 64, 11721181 (2012).
  32. 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, 1824 (1988).
  33. Andriacchi, T. P. & Mündermann, A. The role of ambulatory mechanics in the initiation and progression of knee osteoarthritis. Curr. Opin. Rheumatol. 18, 514518 (2006).
  34. Grotle, M., Hagen, K. B., Natvig, B., Dahl, F. A. & Kvien, T. K. Obesity and osteoarthritis in knee, hip and/or hand: an epidemiological study in the general population with 10 years follow-up. BMC Musculoskelet. Disord. 9, 132 (2008).
  35. Abella, V. et al. Leptin in the interplay of inflammation, metabolism and immune system disorders. Nat. Rev. Rheumatol. 13, 100109 (2017).
  36. Wang, X., Hunter, D., Xu, J. & Ding, C. Metabolic triggered inflammation in osteoarthritis. Osteoarthritis Cartilage 23, 2230 (2015).
  37. Scotece, M. et al. Adipokines as drug targets in joint and bone disease. Drug Discov. Today 19, 241258 (2014).
  38. Lago, F., Dieguez, C., Gómez-Reino, J. & Gualillo, O. Adipokines as emerging mediators of immune response and inflammation. Nat. Clin. Pract. Rheumatol. 3, 716724 (2007).
  39. Scotece, M. et al. Adipokines induce pro-inflammatory factors in activated CD4+ T cells from osteoarthritis patients. J. Orthop. Res. (2016).
  40. Bora, F. W. & Miller, G. Joint physiology, cartilage metabolism, and the etiology of osteoarthritis. Hand Clin. 3, 325336 (1987).
  41. Mobasheri, A. et al. Facilitative glucose transporters in articular chondrocytes. Expression, distribution and functional regulation of GLUT isoforms by hypoxia, hypoxia mimetics, growth factors and pro-inflammatory cytokines. Adv. Anat. Embryol. Cell Biol. 200, 184 (2008).
  42. Masuda, K., Sah, R. L., Hejna, M. J. & Thonar, E. J.-M. A. A novel two-step method for the formation of tissue-engineered cartilage by mature bovine chondrocytes: the alginate-recovered-chondrocyte (ARC) method. J. Orthop. Res. 21, 139148 (2003).
  43. Verzijl, N. et al. Effect of collagen turnover on the accumulation of advanced glycation end products. J. Biol. Chem. 275, 3902739031 (2000).
  44. Eyre, D. R., Weis, M. A. & Wu, J. J. Articular cartilage collagen: an irreplaceable framework? Eur. Cell. Mater. 12, 5763 (2006).
  45. Martin, J. A. & Buckwalter, J. A. Aging, articular cartilage chondrocyte senescence and osteoarthritis. Biogerontology 3, 257264 (2002).
  46. Mobasheri, A. Glucose: an energy currency and structural precursor in articular cartilage and bone with emerging roles as an extracellular signaling molecule and metabolic regulator. Front. Endocrinol. (Lausanne) 3, 153 (2012).
  47. Mobasheri, A. et al. Glucose transport and metabolism in chondrocytes: a key to understanding chondrogenesis, skeletal development and cartilage degradation in osteoarthritis. Histol. Histopathol. 17, 12391267 (2002).
  48. Shikhman, A. R., Brinson, D. C., Valbracht, J. & Lotz, M. K. Cytokine regulation of facilitated glucose transport in human articular chondrocytes. J. Immunol. 167, 70017008 (2001).
  49. Lane, R. S. et al. Mitochondrial respiration and redox coupling in articular chondrocytes. Arthritis Res. Ther. 17, 54 (2015).
  50. Lotz, M. & Loeser, R. F. Effects of ageing on articular cartilage homeostasis. Bone 51, 241248 (2012).
  51. Zhang, L., Hu, J. & Athanasiou, K. A. The role of tissue engineering in articular cartilage repair and regeneration. Crit. Rev. Biomed. Eng. 37, 157 (2009).
  52. Vander Heiden, M. G., Cantley, L. C. & Thompson, C. B. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 10291033 (2009).
  53. Salinas, D. et al. Combining targeted metabolomic data with a model of glucose metabolism: toward progress in chondrocyte mechanotransduction. PLoS ONE 12, e0168326 (2017).
  54. Richardson, S. et al. Molecular characterization and partial cDNA cloning of facilitative glucose transporters expressed in human articular chondrocytes; stimulation of 2-deoxyglucose uptake by IGF-I and elevated MMP-2 secretion by glucose deprivation. Osteoarthritis Cartilage 11, 92101 (2003).
  55. Peansukmanee, S. et al. Effects of hypoxia on glucose transport in primary equine chondrocytes in vitro and evidence of reduced GLUT1 gene expression in pathologic cartilage in vivo. J. Orthop. Res. 27, 529535 (2009).
  56. Ramakrishnan, P. et al. Oxidant conditioning protects cartilage from mechanically induced damage. J. Orthop. Res. 28, 914920 (2010).
  57. Maneiro, E. et al. Mitochondrial respiratory activity is altered in osteoarthritic human articular chondrocytes. Arthritis Rheum. 48, 700708 (2003).
  58. Richardson, S. M. et al. Mesenchymal stem cells in regenerative medicine: opportunities and challenges for articular cartilage and intervertebral disc tissue engineering. J. Cell. Physiol. 222, 2332 (2010).
  59. Liu-Bryan, R. Synovium and the innate inflammatory network in osteoarthritis progression. Curr. Rheumatol. Rep. 15, 323 (2013).
  60. Misra, D. et al. CT imaging for evaluation of calcium crystal deposition in the knee: initial experience from the Multicenter Osteoarthritis (MOST) study. Osteoarthritis Cartilage 23, 244248 (2015).
  61. Shutt, T. E. & Shadel, G. S. A compendium of human mitochondrial gene expression machinery with links to disease. Environ. Mol. Mutagen. 51, 360379 (2010).
  62. Monlun, M., Hyernard, C., Blanco, P., Lartigue, L. & Faustin, B. Mitochondria as molecular platforms integrating multiple innate immune signaling. J. Mol. Biol. 429, 113 (2017).
  63. Loeser, R. F., Collins, J. A. & Diekman, B. O. Ageing and the pathogenesis of osteoarthritis. Nat. Rev. Rheumatol. 12, 412420 (2016).
  64. Grishko, V. I., Ho, R., Wilson, G. L. & Pearsall, A. W. Diminished mitochondrial DNA integrity and repair capacity in OA chondrocytes. Osteoarthritis Cartilage 17, 107113 (2009).
  65. Blanco, F. J., López-Armada, M. J. & Maneiro, E. Mitochondrial dysfunction in osteoarthritis. Mitochondrion 4, 715728 (2004).
  66. Mobasheri, A., Richardson, S., Mobasheri, R., Shakibaei, M. & Hoyland, J. A. Hypoxia inducible factor-1 and facilitative glucose transporters GLUT1 and GLUT3: putative molecular components of the oxygen and glucose sensing apparatus in articular chondrocytes. Histol. Histopathol. 20, 13271338 (2005).
  67. Martin, J. A. et al. Mitochondrial electron transport and glycolysis are coupled in articular cartilage. Osteoarthritis Cartilage 20, 323329 (2012).
  68. Vaillancourt, F. et al. 4-Hydroxynonenal induces apoptosis in human osteoarthritic chondrocytes: the protective role of glutathione-S-transferase. Arthritis Res. Ther. 10, R107 (2008).
  69. Johnson, K. et al. Mitochondrial oxidative phosphorylation is a downstream regulator of nitric oxide effects on chondrocyte matrix synthesis and mineralization. Arthritis Rheum. 43, 15601570 (2000).
  70. Cillero-Pastor, B., Rego-Pérez, I., Oreiro, N., Fernandez-Lopez, C. & Blanco, F. J. Mitochondrial respiratory chain dysfunction modulates metalloproteases -1, -3 and -13 in human normal chondrocytes in culture. BMC Musculoskelet. Disord. 14, 235 (2013).
  71. Grange, L. et al. NAD(P)H oxidase activity of Nox4 in chondrocytes is both inducible and involved in collagenase expression. Antioxid. Redox Signal. 8, 14851496 (2006).
  72. Henrotin, Y., Kurz, B. & Aigner, T. Oxygen and reactive oxygen species in cartilage degradation: friends or foes? Osteoarthritis Cartilage 13, 643654 (2005).
  73. Musumeci, G., Szychlinska, M. A. & Mobasheri, A. Age-related degeneration of articular cartilage in the pathogenesis of osteoarthritis: molecular markers of senescent chondrocytes. Histol. Histopathol. 30, 112 (2015).
  74. Loeser, R. F., Carlson, C. S., Del Carlo, M. & Cole, A. Detection of nitrotyrosine in aging and osteoarthritic cartilage: correlation of oxidative damage with the presence of interleukin-1beta and with chondrocyte resistance to insulin-like growth factor 1. Arthritis Rheum. 46, 23492357 (2002).
  75. Hashimoto, S., Takahashi, K., Amiel, D., Coutts, R. D. & Lotz, M. Chondrocyte apoptosis and nitric oxide production during experimentally induced osteoarthritis. Arthritis Rheum. 41, 12661274 (1998).
  76. Pelletier, J. P. et al. Selective inhibition of inducible nitric oxide synthase in experimental osteoarthritis is associated with reduction in tissue levels of catabolic factors. J. Rheumatol. 26, 20022014 (1999).
  77. Studer, R., Jaffurs, D., Stefanovic-Racic, M., Robbins, P. D. & Evans, C. H. Nitric oxide in osteoarthritis. Osteoarthritis Cartilage 7, 377379 (1999).
  78. Kim, J. et al. Mitochondrial DNA damage is involved in apoptosis caused by pro-inflammatory cytokines in human OA chondrocytes. Osteoarthritis Cartilage 18, 424432 (2010).
  79. Liu, J. T. et al. Mitochondrial function is altered in articular chondrocytes of an endemic osteoarthritis, Kashin–Beck disease. Osteoarthritis Cartilage 18, 12181226 (2010).
  80. Wang, W. et al. Oxidative stress and status of antioxidant enzymes in children with Kashin–Beck disease. Osteoarthritis Cartilage 21, 17811789 (2013).
  81. Yudoh, K. et al. Potential involvement of oxidative stress in cartilage senescence and development of osteoarthritis: oxidative stress induces chondrocyte telomere instability and downregulation of chondrocyte function. Arthritis Res. Ther. 7, R380R391 (2005).
  82. Henrotin, Y. E., Bruckner, P. & Pujol, J. P. L. The role of reactive oxygen species in homeostasis and degradation of cartilage. Osteoarthritis Cartilage 11, 747755 (2003).
  83. Jovanovic, D. V. et al. Nitric oxide induced cell death in human osteoarthritic synoviocytes is mediated by tyrosine kinase activation and hydrogen peroxide and/or superoxide formation. J. Rheumatol. 29, 21652175 (2002).
  84. Johnson, K. et al. Up-regulated expression of the phosphodiesterase nucleotide pyrophosphatase family member PC-1 is a marker and pathogenic factor for knee meniscal cartilage matrix calcification. Arthritis Rheum. 44, 10711081 (2001).
  85. Reed, K. N., Wilson, G., Pearsall, A. & Grishko, V. I. The role of mitochondrial reactive oxygen species in cartilage matrix destruction. Mol. Cell. Biochem. 397, 195201 (2014).
  86. Blanco, F. J., Rego, I. & Ruiz-Romero, C. The role of mitochondria in osteoarthritis. Nat. Rev. Rheumatol. 7, 161169 (2011).
  87. Vaamonde-García, C. et al. Mitochondrial dysfunction increases inflammatory responsiveness to cytokines in normal human chondrocytes. Arthritis Rheum. 64, 29272936 (2012).
  88. Nakagawa, S. et al. N-acetylcysteine prevents nitric oxide-induced chondrocyte apoptosis and cartilage degeneration in an experimental model of osteoarthritis. J. Orthop. Res. 28, 156163 (2010).
  89. Liu, X. et al. Rescue of proinflammatory cytokine-inhibited chondrogenesis by the antiarthritic effect of melatonin in synovium mesenchymal stem cells via suppression of reactive oxygen species and matrix metalloproteinases. Free Radic. Biol. Med. 68, 234246 (2014).
  90. Liu-Bryan, R. & Terkeltaub, R. Emerging regulators of the inflammatory process in osteoarthritis. Nat. Rev. Rheumatol. 11, 3544 (2015).
  91. Wang, Y., Zhao, X., Lotz, M., Terkeltaub, R. & Liu-Bryan, R. Mitochondrial biogenesis is impaired in osteoarthritis chondrocytes but reversible via peroxisome proliferator-activated receptor γ coactivator 1α. Arthritis Rheumatol. 67, 21412153 (2015).
  92. Zhao, X. et al. Peroxisome proliferator-activated receptor γ coactivator 1α and FoxO3A mediate chondroprotection by AMP-activated protein kinase. Arthritis Rheumatol. 66, 30733082 (2014).
  93. Moon, M. H. et al. SIRT1, a class III histone deacetylase, regulates TNF-α-induced inflammation in human chondrocytes. Osteoarthritis Cartilage 21, 470480 (2013).
  94. Matsushita, T. et al. The overexpression of SIRT1 inhibited osteoarthritic gene expression changes induced by interleukin-1β in human chondrocytes. J. Orthop. Res. 31, 531537 (2013).
  95. Salminen, A. & Kaarniranta, K. AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network. Ageing Res. Rev. 11, 230241 (2012).
  96. Zhang, Y. et al. Cartilage-specific deletion of mTOR upregulates autophagy and protects mice from osteoarthritis. Ann. Rheum. Dis. 74, 14321440 (2015).
  97. Vasheghani, F. et al. PPARγ deficiency results in severe, accelerated osteoarthritis associated with aberrant mTOR signalling in the articular cartilage. Ann. Rheum. Dis. 74, 569578 (2015).
  98. Cui, X. et al. Overexpression of microRNA-634 suppresses survival and matrix synthesis of human osteoarthritis chondrocytes by targeting PIK3R1. Sci. Rep. 6, 23117 (2016).
  99. Alman, B. A. The role of hedgehog signalling in skeletal health and disease. Nat. Rev. Rheumatol. 11, 552560 (2015).
  100. van den Bosch, M. H. et al. Wnts talking with the TGF-β superfamily: WISPers about modulation of osteoarthritis. Rheumatology (Oxford) 55, 15361547 (2016).
  101. Lories, R. J., Corr, M. & Lane, N. E. To Wnt or not to Wnt: the bone and joint health dilemma. Nat. Rev. Rheumatol. 9, 328339 (2013).
  102. Salminen, A., Kaarniranta, K. & Kauppinen, A. Inflammaging: disturbed interplay between autophagy and inflammasomes. Aging 4, 166175 (2012).
  103. Gavriilidis, C., Miwa, S., von Zglinicki, T., Taylor, R. W. & Young, D. A. Mitochondrial dysfunction in osteoarthritis is associated with down-regulation of superoxide dismutase 2. Arthritis Rheum. 65, 378387 (2013).
  104. Siebuhr, A. S. et al. Inflammation (or synovitis)-driven osteoarthritis: an opportunity for personalizing prognosis and treatment? Scand. J. Rheumatol. 45, 8798 (2016).
  105. Rahmati, M., Mobasheri, A. & Mozafari, M. Inflammatory mediators in osteoarthritis: a critical review of the state-of-the-art, current prospects, and future challenges. Bone 85, 8190 (2016).
  106. Mahjoub, M., Berenbaum, F. & Houard, X. Why subchondral bone in osteoarthritis? The importance of the cartilage bone interface in osteoarthritis. Osteoporos Int. 23 (Suppl 8), S841S846 (2012).
  107. Goldring, M. B. & Goldring, S. R. Osteoarthritis. J. Cell. Physiol. 213, 626634 (2007).
  108. Scanzello, C. R. & Goldring, S. R. The role of synovitis in osteoarthritis pathogenesis. Bone 51, 249257 (2012).
  109. Wenham, C. Y. & Conaghan, P. G. The role of synovitis in osteoarthritis. Ther. Adv. Musculoskelet. Dis. 2, 349359 (2010).
  110. Sutton, S. et al. The contribution of the synovium, synovial derived inflammatory cytokines and neuropeptides to the pathogenesis of osteoarthritis. Vet. J. 179, 1024 (2009).
  111. de Lange-Brokaar, B. J. E. et al. Synovial inflammation, immune cells and their cytokines in osteoarthritis: a review. Osteoarthritis Cartilage 20, 14841499 (2012).
  112. Sellam, J. & Berenbaum, F. The role of synovitis in pathophysiology and clinical symptoms of osteoarthritis. Nat. Rev. Rheumatol. 6, 625635 (2010).
  113. Poulet, B. & Beier, F. Targeting oxidative stress to reduce osteoarthritis. Arthritis Res. Ther. 18, 32 (2016).
  114. Adams, S. B. Jr et al. Global metabolic profiling of human osteoarthritic synovium. Osteoarthritis Cartilage 20, 6467 (2012).
  115. Biniecka, M. et al. Dysregulated bioenergetics: a key regulator of joint inflammation. Ann. Rheum. Dis. 75, 21922200 (2016).
  116. Garcia-Carbonell, R. et al. Critical role of glucose metabolism in rheumatoid arthritis fibroblast-like synoviocytes. Arthritis Rheumatol. 68, 16141626 (2016).
  117. Zong, M. et al. Glucose-6-phosphate isomerase promotes the proliferation and inhibits the apoptosis in fibroblast-like synoviocytes in rheumatoid arthritis. Arthritis Res. Ther. 17, 100 (2015).
  118. Funasaka, T., Haga, A., Raz, A. & Nagase, H. Tumor autocrine motility factor is an angiogenic factor that stimulates endothelial cell motility. Biochem. Biophys. Res. Commun. 284, 11161125 (2001).
  119. Mapp, P. I. & Walsh, D. A. Mechanisms and targets of angiogenesis and nerve growth in osteoarthritis. Nat. Rev. Rheumatol. 8, 390398 (2012).
  120. Tsai, C.-H. et al. High glucose induces vascular endothelial growth factor production in human synovial fibroblasts through reactive oxygen species generation. Biochim. Biophys. Acta 1830, 26492658 (2013).
  121. Muz, B., Larsen, H., Madden, L., Kiriakidis, S. & Paleolog, E. M. Prolyl hydroxylase domain enzyme 2 is the major player in regulating hypoxic responses in rheumatoid arthritis. Arthritis Rheum. 64, 28562867 (2012).
  122. Liu, S.-C. et al. Berberine attenuates CCN2-induced IL-1β expression and prevents cartilage degradation in a rat model of osteoarthritis. Toxicol. Appl. Pharmacol. 289, 2029 (2015).
  123. Onodera, Y., Teramura, T., Takehara, T., Shigi, K. & Fukuda, K. Reactive oxygen species induce Cox-2 expression via TAK1 activation in synovial fibroblast cells. FEBS Open Bio 5, 492501 (2015).
  124. Takayama, K. et al. Local intra-articular injection of rapamycin delays articular cartilage degeneration in a murine model of osteoarthritis. Arthritis Res. Ther. 16, 482 (2014).
  125. Caramés, B. et al. Autophagy activation by rapamycin reduces severity of experimental osteoarthritis. Ann. Rheum. Dis. 71, 575581 (2012).
  126. Husa, M., Petursson, F., Lotz, M., Terkeltaub, R. & Liu-Bryan, R. C/EBP homologous protein drives pro-catabolic responses in chondrocytes. Arthritis Res. Ther. 15, R218 (2013).
  127. O'Neill, L. A. J. & Hardie, D. G. Metabolism of inflammation limited by AMPK and pseudo-starvation. Nature 493, 346355 (2013).
  128. Qu, J. et al. PFKFB3 modulates glycolytic metabolism and alleviates endoplasmic reticulum stress in human osteoarthritis cartilage. Clin. Exp. Pharmacol. Physiol. 43, 312318 (2016).
  129. Mobasheri, A. The future of osteoarthritis therapeutics: emerging biological therapy. Curr. Rheumatol. Rep. 15, 385 (2013).
  130. Rhoads, J. P., Major, A. S. & Rathmell, J. C. Fine tuning of immunometabolism for the treatment of rheumatic diseases. Nat. Rev. Rheumatol. (2017).
  131. Lotz, M. et al. Value of biomarkers in osteoarthritis: current status and perspectives. Ann. Rheum. Dis. 72, 17561763 (2013).
  132. Blanco, F. J. & Ruiz-Romero, C. Osteoarthritis: metabolomic characterization of metabolic phenotypes in OA. Nat. Rev. Rheumatol. 8, 130132 (2012).
  133. Zhang, W. et al. Classification of osteoarthritis phenotypes by metabolomics analysis. BMJ Open 4, e006286 (2014).
  134. Mickiewicz, B. et al. Metabolic profiling of synovial fluid in a unilateral ovine model of anterior cruciate ligament reconstruction of the knee suggests biomarkers for early osteoarthritis. J. Orthop. Res. 33, 7177 (2015).

Download references

Author information


  1. Department of Veterinary Preclinical Sciences, School of Veterinary Medicine, Faculty of Health and Medical Sciences University of Surrey, Guildford GU2 7AL, UK.

    • Ali Mobasheri
  2. Arthritis Research UK Centre for Sport, Exercise and Osteoarthritis and MRC Arthritis Research UK Centre for Musculoskeletal Ageing Research, Queen's Medical Centre, Nottingham NG7 2UH, UK.

    • Ali Mobasheri
  3. Department of Nutritional Sciences, School of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7XH, UK.

    • Margaret P. Rayman
  4. SERGAS (Servizo Galego de Saude) and IDIS (Instituto de Investigación Sanitaria de Santiago), The NEIRID Group (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Santiago University Clinical Hospital, Building C, Travesia da Choupana S/N, Santiago de Compostela 15706, Spain.

    • Oreste Gualillo
  5. Department of Rheumatology, Inflammation–Immunopathology–Biotherapy Department (DHU i2B), Saint-Antoine Hospital, Assistance Publique-Hôpitaux de Paris (APHP), 184 Rue de Faubourg Saint-Antoine, 75012 Paris, France.

    • Jérémie Sellam
  6. Inflammation–Immunopathology–Biotherapy Department (DHU i2B), INSERM, UMR S938, Sorbonne University, University of Paris 6, 75005 Paris, France.

    • Jérémie Sellam
  7. Department of Rheumatology, Experimental Rheumatology, Radboud University Medical Center, Geert Grooteplein 26–28, 6500 HB Nijmegen, Netherlands.

    • Peter van der Kraan
  8. Department of Molecular Rheumatology, Trinity College Dublin, University of Dublin, College Green, Dublin 2, Ireland.

    • Ursula Fearon


All authors researched the data for the article, provided a substantial contribution to discussions of the content, contributed to writing the article and reviewed and/or edited the manuscript before submission.

Competing interests statement

A.M. declares that he has served as a Scientific Advisory Board Member for AbbVie and has received honoraria from AbbVie and Bioiberica. J.S. declares that he has served as a Scientific Advisory Board Member for AbbVie, BMS, MSD and Roche. The other authors declare no competing interests.

Corresponding author

Correspondence to:

Author details

  • Ali Mobasheri

    Ali Mobasheri is Professor of Musculoskeletal Physiology at the University of Surrey, Guildford, UK. He gained his BSc (Hons) in Biochemistry from Imperial College, London, UK, his MSc in Physiology and Biochemistry from the University of Toronto, Canada and his PhD in Molecular and Cellular Physiology from the University of Oxford, UK. He served as Associate Dean for Research and Enterprise at the University of Surrey from August 2015 to January 2017. He coordinates the European Union 7th Framework Programme funded D-BOARD consortium, is a participating member of the APPROACH Innovative Medicines Initiative consortium and is a member of the Osteoarthritis Research Society International (OARSI) Board of Directors. He will assume the position of OARSI President-Elect in April 2017.

  • Margaret P. Rayman

    Margaret P. Rayman is Professor of Nutritional Medicine at the University of Surrey, Guildford, UK and Visiting Professor and Honorary Director of the Clinical Research Centre at the First Affiliated Hospital, Xi'an Jiaotong University School of Medicine, Xi'an, China. She gained her first-class honours degree in Chemistry from Queen's University, Belfast, UK and her PhD in Inorganic Biochemistry from the University of Oxford, UK. She went on to complete postdoctoral fellowships at the Institute of Cancer Research and Imperial College, both in London, UK. She is now a Thomson-Reuters Highly Cited Researcher and her research focuses on the effects of specific micronutrient deficiencies in human health.

  • Oreste Gualillo

    Oreste Gualillo obtained his PharmD and PhD in Pharmacology at the University of Naples Federico II, Italy. He completed his training in Molecular Endocrinology at the Necker School of Medicine, Paris, France, and in the Department of Physiology and Medicine, University of Santiago de Compostela, Spain, where he was a Marie Curie Researcher funded by the European Commission. He is currently a staff researcher in the Spanish National Health System at Servizo Galego de Saude (SERGAS) and Head of the Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases (NEIRID) in Instituto de Investigación Sanitaria de Santiago (IDIS) at Santiago University Clinical Hospital, Spain.

  • Jérémie Sellam

    Jérémie Sellam is Professor of Rheumatology at Pierre et Marie Curie Paris 6 University and Saint-Antoine Hospital, Paris, France, a role he has held since 2014. He is also a researcher at the Institut National de la Santé et de la Recherche Médicale (INSERM), focusing on osteoarthritis and rheumatoid arthritis. One of his fields of interest is the role of obesity, type 2 diabetes mellitus and metabolism in rheumatoid arthritis and osteoarthritis pathophysiology and outcomes.

  • Peter van der Kraan

    Peter M. van der Kraan is Head of Experimental Rheumatology at Radboud University Medical Centre, Nijmegen, Netherlands. He has a special interest in the role of growth factors (for example, transforming growth factor-β, bone morphogenic proteins and Wnts) in rheumatic diseases such as osteoarthritis and systemic sclerosis. His research is focused on elucidation of the mechanisms of tissue destruction and application of this knowledge in the prevention of tissue damage and the stimulation of repair. He is a member of the Osteoarthritis Research Society International (OARSI) Board of Directors.

  • Ursula Fearon

    Ursula Fearon is Professor of Molecular Rheumatology at Trinity College Dublin, Republic of Ireland. She has established an international reputation for her research in the areas of synovial pathology, hypoxia, angiogenesis, metabolism and synovial fibroblast invasion, and has published extensively in this field. She is the Arthritis Ireland Head of Molecular Rheumatology at Trinity College Dublin and is part of the EULAR Centre for Rheumatology Excellence in Dublin.

Additional data