Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The role of metabolism in the pathogenesis of osteoarthritis

Key Points

  • Metabolism has a key role in the physiological turnover of synovial joint tissues, including articular cartilage

  • In osteoarthritis (OA), chondrocytes and cells in joint tissues other than cartilage undergo metabolic alterations and shift from a resting regulatory state to a highly metabolically active state

  • Inflammatory mediators, metabolic intermediates and immune cells influence cellular responses in the pathophysiology of OA

  • Key metabolic pathways and mediators might be targets of future therapies for OA

Abstract

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Factors underlying metabolic alterations in osteoarthritis.
Figure 2: Phenotypes of osteoarthritis.
Figure 3: Metabolism in homeostatic chondrocytes.
Figure 4: Altered metabolism in chondrocytes in osteoarthritis.

Similar content being viewed by others

References

  1. Mathis, D. & Shoelson, S. E. Immunometabolism: an emerging frontier. Nat. Rev. Immunol. 11, 81 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Ferrante, A. W. Macrophages, fat, and the emergence of immunometabolism. J. Clin. Invest. 123, 4992–4993 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. O'Neill, L. A. J., Kishton, R. J. & Rathmell, J. A guide to immunometabolism for immunologists. Nat. Rev. Immunol. 16, 553–565 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Osborn, O. & Olefsky, J. M. The cellular and signaling networks linking the immune system and metabolism in disease. Nat. Med. 18, 363–374 (2012).

    Article  CAS  PubMed  Google Scholar 

  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, 29–35 (2016).

    Article  PubMed  Google Scholar 

  6. Mobasheri, A., Matta, C., Zákány, R. & Musumeci, G. Chondrosenescence: definition, hallmarks and potential role in the pathogenesis of osteoarthritis. Maturitas 80, 237–244 (2015).

    Article  CAS  PubMed  Google Scholar 

  7. Early, J. O. & Curtis, A. M. Immunometabolism: is it under the eye of the clock? Semin. Immunol. 28, 478–490 (2016).

    Article  CAS  PubMed  Google Scholar 

  8. Loftus, R. M. & Finlay, D. K. Immunometabolism: cellular metabolism turns immune regulator. J. Biol. Chem. 291, 1–10 (2016).

    Article  CAS  PubMed  Google Scholar 

  9. Michalek, R. D. & Rathmell, J. C. The metabolic life and times of a T-cell. Immunol. Rev. 236, 190–202 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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, 11–18 (2009).

    Article  CAS  PubMed  Google Scholar 

  11. Sellam, J. & Berenbaum, F. Is osteoarthritis a metabolic disease? Joint Bone Spine 80, 568–573 (2013).

    Article  CAS  PubMed  Google Scholar 

  12. Kluzek, S., Newton, J. L. & Arden, N. K. Is osteoarthritis a metabolic disorder? Br. Med. Bull. 115, 111–121 (2015).

    Article  CAS  PubMed  Google Scholar 

  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, 2048–2058 (2016).

    Article  Google Scholar 

  14. Loeser, R. F. Aging and osteoarthritis. Curr. Opin. Rheumatol. 23, 492–496 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  16. Glyn-Jones, S. et al. Osteoarthritis. Lancet 386, 376–387 (2015).

    Article  CAS  PubMed  Google Scholar 

  17. Bhattaram, P. & Chandrasekharan, U. The joint synovium: a critical determinant of articular cartilage fate in inflammatory joint diseases. Semin. Cell Dev. Biol. 62, 86–93 (2017).

    Article  CAS  PubMed  Google Scholar 

  18. Braun, H. J. & Gold, G. E. Diagnosis of osteoarthritis: imaging. Bone 51, 278–288 (2012).

    Article  PubMed  Google Scholar 

  19. Hasegawa, A. et al. Anterior cruciate ligament changes in the human knee joint in aging and osteoarthritis. Arthritis Rheum. 64, 696–704 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  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, 631–633 (2014).

    Article  CAS  PubMed  Google Scholar 

  21. Goldring, S. R. Alterations in periarticular bone and cross talk between subchondral bone and articular cartilage in osteoarthritis. Ther. Adv. Musculoskelet. Dis. 4, 249–258 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Goldring, S. R. & Goldring, M. B. Changes in the osteochondral unit during osteoarthritis: structure, function and cartilage–bone crosstalk. Nat. Rev. Rheumatol. 12, 632–644 (2016).

    Article  PubMed  Google Scholar 

  23. Guilak, F. Biomechanical factors in osteoarthritis. Best Pract. Res. Clin. Rheumatol. 25, 815–823 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Scanzello, C. R. Role of low-grade inflammation in osteoarthritis. Curr. Opin. Rheumatol. 29, 79–85 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wang, Q. et al. Identification of a central role for complement in osteoarthritis. Nat. Med. 17, 1674–1679 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hunter, D. J. Osteoarthritis. Best Pract. Res. Clin. Rheumatol. 25, 801–814 (2011).

    Article  PubMed  Google Scholar 

  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, 588–600 (2015).

    Article  CAS  Google Scholar 

  28. Malemud, C. J. Biologic basis of osteoarthritis: state of the evidence. Curr. Opin. Rheumatol. 27, 289–294 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

  30. Zhuo, Q., Yang, W., Chen, J. & Wang, Y. Metabolic syndrome meets osteoarthritis. Nat. Rev. Rheumatol. 8, 729–737 (2012).

    Article  CAS  PubMed  Google Scholar 

  31. Gierman, L. M. et al. Metabolic stress-induced inflammation plays a major role in the development of osteoarthritis in mice. Arthritis Rheum. 64, 1172–1181 (2012).

    Article  CAS  PubMed  Google Scholar 

  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, 18–24 (1988).

    Article  CAS  PubMed  Google Scholar 

  33. Andriacchi, T. P. & Mündermann, A. The role of ambulatory mechanics in the initiation and progression of knee osteoarthritis. Curr. Opin. Rheumatol. 18, 514–518 (2006).

    Article  PubMed  Google Scholar 

  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).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Abella, V. et al. Leptin in the interplay of inflammation, metabolism and immune system disorders. Nat. Rev. Rheumatol. 13, 100–109 (2017).

    Article  CAS  PubMed  Google Scholar 

  36. Wang, X., Hunter, D., Xu, J. & Ding, C. Metabolic triggered inflammation in osteoarthritis. Osteoarthritis Cartilage 23, 22–30 (2015).

    Article  CAS  PubMed  Google Scholar 

  37. Scotece, M. et al. Adipokines as drug targets in joint and bone disease. Drug Discov. Today 19, 241–258 (2014).

    Article  CAS  PubMed  Google Scholar 

  38. Lago, F., Dieguez, C., Gómez-Reino, J. & Gualillo, O. Adipokines as emerging mediators of immune response and inflammation. Nat. Clin. Pract. Rheumatol. 3, 716–724 (2007).

    Article  CAS  PubMed  Google Scholar 

  39. Scotece, M. et al. Adipokines induce pro-inflammatory factors in activated CD4+ T cells from osteoarthritis patients. J. Orthop. Res. http://dx.doi.org/10.1002/jor.23377 (2016).

  40. Bora, F. W. & Miller, G. Joint physiology, cartilage metabolism, and the etiology of osteoarthritis. Hand Clin. 3, 325–336 (1987).

    PubMed  Google Scholar 

  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, 1–84 (2008).

    Article  PubMed  Google Scholar 

  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, 139–148 (2003).

    Article  CAS  PubMed  Google Scholar 

  43. Verzijl, N. et al. Effect of collagen turnover on the accumulation of advanced glycation end products. J. Biol. Chem. 275, 39027–39031 (2000).

    Article  CAS  PubMed  Google Scholar 

  44. Eyre, D. R., Weis, M. A. & Wu, J. J. Articular cartilage collagen: an irreplaceable framework? Eur. Cell. Mater. 12, 57–63 (2006).

    Article  CAS  PubMed  Google Scholar 

  45. Martin, J. A. & Buckwalter, J. A. Aging, articular cartilage chondrocyte senescence and osteoarthritis. Biogerontology 3, 257–264 (2002).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  Google Scholar 

  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, 1239–1267 (2002).

    CAS  PubMed  Google Scholar 

  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, 7001–7008 (2001).

    Article  CAS  PubMed  Google Scholar 

  49. Lane, R. S. et al. Mitochondrial respiration and redox coupling in articular chondrocytes. Arthritis Res. Ther. 17, 54 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Lotz, M. & Loeser, R. F. Effects of ageing on articular cartilage homeostasis. Bone 51, 241–248 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Zhang, L., Hu, J. & Athanasiou, K. A. The role of tissue engineering in articular cartilage repair and regeneration. Crit. Rev. Biomed. Eng. 37, 1–57 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Vander Heiden, M. G., Cantley, L. C. & Thompson, C. B. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029–1033 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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, 92–101 (2003).

    Article  CAS  PubMed  Google Scholar 

  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, 529–535 (2009).

    Article  CAS  PubMed  Google Scholar 

  56. Ramakrishnan, P. et al. Oxidant conditioning protects cartilage from mechanically induced damage. J. Orthop. Res. 28, 914–920 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Maneiro, E. et al. Mitochondrial respiratory activity is altered in osteoarthritic human articular chondrocytes. Arthritis Rheum. 48, 700–708 (2003).

    Article  CAS  PubMed  Google Scholar 

  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, 23–32 (2010).

    Article  CAS  PubMed  Google Scholar 

  59. Liu-Bryan, R. Synovium and the innate inflammatory network in osteoarthritis progression. Curr. Rheumatol. Rep. 15, 323 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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, 244–248 (2015).

    Article  CAS  PubMed  Google Scholar 

  61. Shutt, T. E. & Shadel, G. S. A compendium of human mitochondrial gene expression machinery with links to disease. Environ. Mol. Mutagen. 51, 360–379 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Monlun, M., Hyernard, C., Blanco, P., Lartigue, L. & Faustin, B. Mitochondria as molecular platforms integrating multiple innate immune signaling. J. Mol. Biol. 429, 1–13 (2017).

    Article  CAS  PubMed  Google Scholar 

  63. Loeser, R. F., Collins, J. A. & Diekman, B. O. Ageing and the pathogenesis of osteoarthritis. Nat. Rev. Rheumatol. 12, 412–420 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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, 107–113 (2009).

    Article  CAS  PubMed  Google Scholar 

  65. Blanco, F. J., López-Armada, M. J. & Maneiro, E. Mitochondrial dysfunction in osteoarthritis. Mitochondrion 4, 715–728 (2004).

    Article  CAS  PubMed  Google Scholar 

  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, 1327–1338 (2005).

    CAS  PubMed  Google Scholar 

  67. Martin, J. A. et al. Mitochondrial electron transport and glycolysis are coupled in articular cartilage. Osteoarthritis Cartilage 20, 323–329 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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, 1560–1570 (2000).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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, 1485–1496 (2006).

    Article  CAS  PubMed  Google Scholar 

  72. Henrotin, Y., Kurz, B. & Aigner, T. Oxygen and reactive oxygen species in cartilage degradation: friends or foes? Osteoarthritis Cartilage 13, 643–654 (2005).

    Article  CAS  PubMed  Google Scholar 

  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, 1–12 (2015).

    CAS  PubMed  Google Scholar 

  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, 2349–2357 (2002).

    Article  CAS  PubMed  Google Scholar 

  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, 1266–1274 (1998).

    Article  CAS  PubMed  Google Scholar 

  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, 2002–2014 (1999).

    CAS  PubMed  Google Scholar 

  77. Studer, R., Jaffurs, D., Stefanovic-Racic, M., Robbins, P. D. & Evans, C. H. Nitric oxide in osteoarthritis. Osteoarthritis Cartilage 7, 377–379 (1999).

    Article  CAS  PubMed  Google Scholar 

  78. Kim, J. et al. Mitochondrial DNA damage is involved in apoptosis caused by pro-inflammatory cytokines in human OA chondrocytes. Osteoarthritis Cartilage 18, 424–432 (2010).

    Article  CAS  PubMed  Google Scholar 

  79. Liu, J. T. et al. Mitochondrial function is altered in articular chondrocytes of an endemic osteoarthritis, Kashin–Beck disease. Osteoarthritis Cartilage 18, 1218–1226 (2010).

    Article  CAS  PubMed  Google Scholar 

  80. Wang, W. et al. Oxidative stress and status of antioxidant enzymes in children with Kashin–Beck disease. Osteoarthritis Cartilage 21, 1781–1789 (2013).

    Article  CAS  PubMed  Google Scholar 

  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, R380–R391 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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, 747–755 (2003).

    Article  CAS  PubMed  Google Scholar 

  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, 2165–2175 (2002).

    CAS  PubMed  Google Scholar 

  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, 1071–1081 (2001).

    Article  CAS  PubMed  Google Scholar 

  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, 195–201 (2014).

    Article  CAS  PubMed  Google Scholar 

  86. Blanco, F. J., Rego, I. & Ruiz-Romero, C. The role of mitochondria in osteoarthritis. Nat. Rev. Rheumatol. 7, 161–169 (2011).

    Article  CAS  PubMed  Google Scholar 

  87. Vaamonde-García, C. et al. Mitochondrial dysfunction increases inflammatory responsiveness to cytokines in normal human chondrocytes. Arthritis Rheum. 64, 2927–2936 (2012).

    Article  CAS  PubMed  Google Scholar 

  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, 156–163 (2010).

    CAS  PubMed  Google Scholar 

  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, 234–246 (2014).

    Article  CAS  PubMed  Google Scholar 

  90. Liu-Bryan, R. & Terkeltaub, R. Emerging regulators of the inflammatory process in osteoarthritis. Nat. Rev. Rheumatol. 11, 35–44 (2015).

    Article  CAS  PubMed  Google Scholar 

  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, 2141–2153 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Zhao, X. et al. Peroxisome proliferator-activated receptor γ coactivator 1α and FoxO3A mediate chondroprotection by AMP-activated protein kinase. Arthritis Rheumatol. 66, 3073–3082 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Moon, M. H. et al. SIRT1, a class III histone deacetylase, regulates TNF-α-induced inflammation in human chondrocytes. Osteoarthritis Cartilage 21, 470–480 (2013).

    Article  PubMed  Google Scholar 

  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, 531–537 (2013).

    Article  CAS  PubMed  Google Scholar 

  95. Salminen, A. & Kaarniranta, K. AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network. Ageing Res. Rev. 11, 230–241 (2012).

    Article  CAS  PubMed  Google Scholar 

  96. Zhang, Y. et al. Cartilage-specific deletion of mTOR upregulates autophagy and protects mice from osteoarthritis. Ann. Rheum. Dis. 74, 1432–1440 (2015).

    Article  CAS  PubMed  Google Scholar 

  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, 569–578 (2015).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Alman, B. A. The role of hedgehog signalling in skeletal health and disease. Nat. Rev. Rheumatol. 11, 552–560 (2015).

    Article  CAS  PubMed  Google Scholar 

  100. van den Bosch, M. H. et al. Wnts talking with the TGF-β superfamily: WISPers about modulation of osteoarthritis. Rheumatology (Oxford) 55, 1536–1547 (2016).

    Article  CAS  Google Scholar 

  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, 328–339 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Salminen, A., Kaarniranta, K. & Kauppinen, A. Inflammaging: disturbed interplay between autophagy and inflammasomes. Aging 4, 166–175 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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, 378–387 (2013).

    Article  CAS  PubMed  Google Scholar 

  104. Siebuhr, A. S. et al. Inflammation (or synovitis)-driven osteoarthritis: an opportunity for personalizing prognosis and treatment? Scand. J. Rheumatol. 45, 87–98 (2016).

    Article  CAS  PubMed  Google Scholar 

  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, 81–90 (2016).

    Article  CAS  PubMed  Google Scholar 

  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), S841–S846 (2012).

    Article  PubMed  Google Scholar 

  107. Goldring, M. B. & Goldring, S. R. Osteoarthritis. J. Cell. Physiol. 213, 626–634 (2007).

    Article  CAS  PubMed  Google Scholar 

  108. Scanzello, C. R. & Goldring, S. R. The role of synovitis in osteoarthritis pathogenesis. Bone 51, 249–257 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Wenham, C. Y. & Conaghan, P. G. The role of synovitis in osteoarthritis. Ther. Adv. Musculoskelet. Dis. 2, 349–359 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Sutton, S. et al. The contribution of the synovium, synovial derived inflammatory cytokines and neuropeptides to the pathogenesis of osteoarthritis. Vet. J. 179, 10–24 (2009).

    Article  CAS  PubMed  Google Scholar 

  111. de Lange-Brokaar, B. J. E. et al. Synovial inflammation, immune cells and their cytokines in osteoarthritis: a review. Osteoarthritis Cartilage 20, 1484–1499 (2012).

    Article  CAS  PubMed  Google Scholar 

  112. Sellam, J. & Berenbaum, F. The role of synovitis in pathophysiology and clinical symptoms of osteoarthritis. Nat. Rev. Rheumatol. 6, 625–635 (2010).

    Article  CAS  PubMed  Google Scholar 

  113. Poulet, B. & Beier, F. Targeting oxidative stress to reduce osteoarthritis. Arthritis Res. Ther. 18, 32 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Adams, S. B. Jr et al. Global metabolic profiling of human osteoarthritic synovium. Osteoarthritis Cartilage 20, 64–67 (2012).

    Article  PubMed  Google Scholar 

  115. Biniecka, M. et al. Dysregulated bioenergetics: a key regulator of joint inflammation. Ann. Rheum. Dis. 75, 2192–2200 (2016).

    Article  CAS  PubMed  Google Scholar 

  116. Garcia-Carbonell, R. et al. Critical role of glucose metabolism in rheumatoid arthritis fibroblast-like synoviocytes. Arthritis Rheumatol. 68, 1614–1626 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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, 1116–1125 (2001).

    Article  CAS  PubMed  Google Scholar 

  119. Mapp, P. I. & Walsh, D. A. Mechanisms and targets of angiogenesis and nerve growth in osteoarthritis. Nat. Rev. Rheumatol. 8, 390–398 (2012).

    Article  CAS  PubMed  Google Scholar 

  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, 2649–2658 (2013).

    Article  CAS  PubMed  Google Scholar 

  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, 2856–2867 (2012).

    Article  CAS  PubMed  Google Scholar 

  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, 20–29 (2015).

    Article  CAS  PubMed  Google Scholar 

  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, 492–501 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Caramés, B. et al. Autophagy activation by rapamycin reduces severity of experimental osteoarthritis. Ann. Rheum. Dis. 71, 575–581 (2012).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. O'Neill, L. A. J. & Hardie, D. G. Metabolism of inflammation limited by AMPK and pseudo-starvation. Nature 493, 346–355 (2013).

    Article  CAS  PubMed  Google Scholar 

  128. Qu, J. et al. PFKFB3 modulates glycolytic metabolism and alleviates endoplasmic reticulum stress in human osteoarthritis cartilage. Clin. Exp. Pharmacol. Physiol. 43, 312–318 (2016).

    Article  CAS  PubMed  Google Scholar 

  129. Mobasheri, A. The future of osteoarthritis therapeutics: emerging biological therapy. Curr. Rheumatol. Rep. 15, 385 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Rhoads, J. P., Major, A. S. & Rathmell, J. C. Fine tuning of immunometabolism for the treatment of rheumatic diseases. Nat. Rev. Rheumatol. http://dx.doi.org/10.1038/nrrheum.2017.54 (2017).

  131. Lotz, M. et al. Value of biomarkers in osteoarthritis: current status and perspectives. Ann. Rheum. Dis. 72, 1756–1763 (2013).

    Article  CAS  PubMed  Google Scholar 

  132. Blanco, F. J. & Ruiz-Romero, C. Osteoarthritis: metabolomic characterization of metabolic phenotypes in OA. Nat. Rev. Rheumatol. 8, 130–132 (2012).

    Article  CAS  PubMed  Google Scholar 

  133. Zhang, W. et al. Classification of osteoarthritis phenotypes by metabolomics analysis. BMJ Open 4, e006286 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  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, 71–77 (2015).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to acknowledge current and previous members of their laboratories and their internal and external collaborators for their contributions. We apologize to those authors whose work could not be included in this focused Review due to space and word count limitations. The work of the authors is supported by grants from the European Union 7th Framework Programme (FP7) projects FP7- HEALTH.2012.2.4.5-2 Novel Diagnostics and Biomarkers for Early Identification of Chronic Inflammatory Joint Diseases 305815 (A.M.) and Marie Skłodowska-Curie scheme FP7-PEOPLE-2013-IEF CHONDRION 625746 (A.M.); Arthritis Research UK 20194 (A.M.); the Innovative Medicine Initiative, Applied Public-Private Research Enabling Osteoarthritis Clinical Headway (APPROACH) consortium 115770 (A.M. and J.S.); the European Union MSCA-RISE 734899 (O.G.); and Instituto de Salud Carlos III and Fondo Europeo de Desarrollo Regional (FEDER) PIE 13/00024, PI14/00016 and RIER RD16/0012/0014 (O.G.).

Author information

Authors and Affiliations

Authors

Contributions

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.

Corresponding author

Correspondence to Ali Mobasheri.

Ethics declarations

Competing interests

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.

PowerPoint slides

Glossary

Glycolysis

An oxygen-independent metabolic pathway that generates two molecules of pyruvate, ATP and NADH from every one molecule of glucose, supporting the tricarboxylic acid cycle and providing intermediates for the pentose phosphate pathway, glycosylation reactions and the synthesis of biomolecules (including serine, glycine, alanine and acetyl-CoA).

Tricarboxylic acid (TCA) cycle

(Also known as the Krebs cycle) A set of connected pathways in the mitochondrial matrix, which metabolize acetyl-CoA derived from glycolysis or fatty acid oxidation, producing NADH and FADH2 for the electron transport chain and precursors for amino acid and fatty acid synthesis.

Pentose phosphate pathway

(PPP). An anabolic metabolic pathway parallel to glycolysis that branches out from glycolysis with the conversion of glucose-6-phosphate to ribose 5-phosphate and generates the reducing equivalents NADPH, ribose-5-phosphate (used in the synthesis of nucleotides and nucleic acids) and erythrose-4-phosphosphate (used in the synthesis of amino acids).

Fatty acid oxidation

A metabolic process that produces ATP from the oxidation of acetyl-CoA derived from the mobilization of fatty acids.

Inflammaging

The low-grade proinflammatory phenotype that accompanies ageing.

Warburg effect

The high utilization of glycolysis by rapidly proliferating cells and the subsequent release of lactate into the extracellular milieu; a phenomenon first described by Otto Warburg.

Metabolic syndrome

The collective term used to describe the combination of type 2 diabetes mellitus, high blood pressure, dyslipidemia and obesity.

Electron transport chain

A series of proteins in the inner mitochondrial membrane that transfer electrons from one to the other in a series of redox reactions, resulting in the movement of protons out of the mitochondrial matrix and in the synthesis of ATP.

Oxidative phosphorylation

A metabolic pathway that produces ATP from the oxidation of acetyl-CoA and the transfer of electrons to the electron transport chain via NADH and FADH2.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mobasheri, A., Rayman, M., Gualillo, O. et al. The role of metabolism in the pathogenesis of osteoarthritis. Nat Rev Rheumatol 13, 302–311 (2017). https://doi.org/10.1038/nrrheum.2017.50

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrrheum.2017.50

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing