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
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
Open Access articles citing this article.
Pyruvate Dehydrogenase Kinase 1 inhibition mediated oxidative phosphorylation enhancement in cartilage promotes osteoarthritis progression
BMC Musculoskeletal Disorders Open Access 20 July 2023
Journal of Orthopaedic Surgery and Research Open Access 17 June 2023
Label-free, multi-parametric assessments of cell metabolism and matrix remodeling within human and early-stage murine osteoarthritic articular cartilage
Communications Biology Open Access 13 April 2023
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
Prices may be subject to local taxes which are calculated during checkout
Mathis, D. & Shoelson, S. E. Immunometabolism: an emerging frontier. Nat. Rev. Immunol. 11, 81 (2011).
Ferrante, A. W. Macrophages, fat, and the emergence of immunometabolism. J. Clin. Invest. 123, 4992–4993 (2013).
O'Neill, L. A. J., Kishton, R. J. & Rathmell, J. A guide to immunometabolism for immunologists. Nat. Rev. Immunol. 16, 553–565 (2016).
Osborn, O. & Olefsky, J. M. The cellular and signaling networks linking the immune system and metabolism in disease. Nat. Med. 18, 363–374 (2012).
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).
Mobasheri, A., Matta, C., Zákány, R. & Musumeci, G. Chondrosenescence: definition, hallmarks and potential role in the pathogenesis of osteoarthritis. Maturitas 80, 237–244 (2015).
Early, J. O. & Curtis, A. M. Immunometabolism: is it under the eye of the clock? Semin. Immunol. 28, 478–490 (2016).
Loftus, R. M. & Finlay, D. K. Immunometabolism: cellular metabolism turns immune regulator. J. Biol. Chem. 291, 1–10 (2016).
Michalek, R. D. & Rathmell, J. C. The metabolic life and times of a T-cell. Immunol. Rev. 236, 190–202 (2010).
Gomez, R., Lago, F., Gomez-Reino, J., Dieguez, C. & Gualillo, O. Adipokines in the skeleton: influence on cartilage function and joint degenerative diseases. J. Mol. Endocrinol. 43, 11–18 (2009).
Sellam, J. & Berenbaum, F. Is osteoarthritis a metabolic disease? Joint Bone Spine 80, 568–573 (2013).
Kluzek, S., Newton, J. L. & Arden, N. K. Is osteoarthritis a metabolic disorder? Br. Med. Bull. 115, 111–121 (2015).
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).
Loeser, R. F. Aging and osteoarthritis. Curr. Opin. Rheumatol. 23, 492–496 (2011).
Berenbaum, F. Osteoarthritis as an inflammatory disease (osteoarthritis is not osteoarthrosis!). Osteoarthritis Cartilage 21, 16–21 (2013).
Glyn-Jones, S. et al. Osteoarthritis. Lancet 386, 376–387 (2015).
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).
Braun, H. J. & Gold, G. E. Diagnosis of osteoarthritis: imaging. Bone 51, 278–288 (2012).
Hasegawa, A. et al. Anterior cruciate ligament changes in the human knee joint in aging and osteoarthritis. Arthritis Rheum. 64, 696–704 (2012).
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).
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).
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).
Guilak, F. Biomechanical factors in osteoarthritis. Best Pract. Res. Clin. Rheumatol. 25, 815–823 (2011).
Scanzello, C. R. Role of low-grade inflammation in osteoarthritis. Curr. Opin. Rheumatol. 29, 79–85 (2017).
Wang, Q. et al. Identification of a central role for complement in osteoarthritis. Nat. Med. 17, 1674–1679 (2011).
Hunter, D. J. Osteoarthritis. Best Pract. Res. Clin. Rheumatol. 25, 801–814 (2011).
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).
Malemud, C. J. Biologic basis of osteoarthritis: state of the evidence. Curr. Opin. Rheumatol. 27, 289–294 (2015).
Wluka, A. E., Lombard, C. B. & Cicuttini, F. M. Tackling obesity in knee osteoarthritis. Nat. Rev. Rheumatol. 9, 225–235 (2013).
Zhuo, Q., Yang, W., Chen, J. & Wang, Y. Metabolic syndrome meets osteoarthritis. Nat. Rev. Rheumatol. 8, 729–737 (2012).
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).
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).
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).
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).
Abella, V. et al. Leptin in the interplay of inflammation, metabolism and immune system disorders. Nat. Rev. Rheumatol. 13, 100–109 (2017).
Wang, X., Hunter, D., Xu, J. & Ding, C. Metabolic triggered inflammation in osteoarthritis. Osteoarthritis Cartilage 23, 22–30 (2015).
Scotece, M. et al. Adipokines as drug targets in joint and bone disease. Drug Discov. Today 19, 241–258 (2014).
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).
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).
Bora, F. W. & Miller, G. Joint physiology, cartilage metabolism, and the etiology of osteoarthritis. Hand Clin. 3, 325–336 (1987).
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).
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).
Verzijl, N. et al. Effect of collagen turnover on the accumulation of advanced glycation end products. J. Biol. Chem. 275, 39027–39031 (2000).
Eyre, D. R., Weis, M. A. & Wu, J. J. Articular cartilage collagen: an irreplaceable framework? Eur. Cell. Mater. 12, 57–63 (2006).
Martin, J. A. & Buckwalter, J. A. Aging, articular cartilage chondrocyte senescence and osteoarthritis. Biogerontology 3, 257–264 (2002).
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).
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).
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).
Lane, R. S. et al. Mitochondrial respiration and redox coupling in articular chondrocytes. Arthritis Res. Ther. 17, 54 (2015).
Lotz, M. & Loeser, R. F. Effects of ageing on articular cartilage homeostasis. Bone 51, 241–248 (2012).
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).
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).
Salinas, D. et al. Combining targeted metabolomic data with a model of glucose metabolism: toward progress in chondrocyte mechanotransduction. PLoS ONE 12, e0168326 (2017).
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).
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).
Ramakrishnan, P. et al. Oxidant conditioning protects cartilage from mechanically induced damage. J. Orthop. Res. 28, 914–920 (2010).
Maneiro, E. et al. Mitochondrial respiratory activity is altered in osteoarthritic human articular chondrocytes. Arthritis Rheum. 48, 700–708 (2003).
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).
Liu-Bryan, R. Synovium and the innate inflammatory network in osteoarthritis progression. Curr. Rheumatol. Rep. 15, 323 (2013).
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).
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).
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).
Loeser, R. F., Collins, J. A. & Diekman, B. O. Ageing and the pathogenesis of osteoarthritis. Nat. Rev. Rheumatol. 12, 412–420 (2016).
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).
Blanco, F. J., López-Armada, M. J. & Maneiro, E. Mitochondrial dysfunction in osteoarthritis. Mitochondrion 4, 715–728 (2004).
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).
Martin, J. A. et al. Mitochondrial electron transport and glycolysis are coupled in articular cartilage. Osteoarthritis Cartilage 20, 323–329 (2012).
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).
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).
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).
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).
Henrotin, Y., Kurz, B. & Aigner, T. Oxygen and reactive oxygen species in cartilage degradation: friends or foes? Osteoarthritis Cartilage 13, 643–654 (2005).
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).
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).
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).
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).
Studer, R., Jaffurs, D., Stefanovic-Racic, M., Robbins, P. D. & Evans, C. H. Nitric oxide in osteoarthritis. Osteoarthritis Cartilage 7, 377–379 (1999).
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).
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).
Wang, W. et al. Oxidative stress and status of antioxidant enzymes in children with Kashin–Beck disease. Osteoarthritis Cartilage 21, 1781–1789 (2013).
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).
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).
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).
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).
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).
Blanco, F. J., Rego, I. & Ruiz-Romero, C. The role of mitochondria in osteoarthritis. Nat. Rev. Rheumatol. 7, 161–169 (2011).
Vaamonde-García, C. et al. Mitochondrial dysfunction increases inflammatory responsiveness to cytokines in normal human chondrocytes. Arthritis Rheum. 64, 2927–2936 (2012).
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).
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).
Liu-Bryan, R. & Terkeltaub, R. Emerging regulators of the inflammatory process in osteoarthritis. Nat. Rev. Rheumatol. 11, 35–44 (2015).
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).
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).
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).
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).
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).
Zhang, Y. et al. Cartilage-specific deletion of mTOR upregulates autophagy and protects mice from osteoarthritis. Ann. Rheum. Dis. 74, 1432–1440 (2015).
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).
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).
Alman, B. A. The role of hedgehog signalling in skeletal health and disease. Nat. Rev. Rheumatol. 11, 552–560 (2015).
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).
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).
Salminen, A., Kaarniranta, K. & Kauppinen, A. Inflammaging: disturbed interplay between autophagy and inflammasomes. Aging 4, 166–175 (2012).
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).
Siebuhr, A. S. et al. Inflammation (or synovitis)-driven osteoarthritis: an opportunity for personalizing prognosis and treatment? Scand. J. Rheumatol. 45, 87–98 (2016).
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).
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).
Goldring, M. B. & Goldring, S. R. Osteoarthritis. J. Cell. Physiol. 213, 626–634 (2007).
Scanzello, C. R. & Goldring, S. R. The role of synovitis in osteoarthritis pathogenesis. Bone 51, 249–257 (2012).
Wenham, C. Y. & Conaghan, P. G. The role of synovitis in osteoarthritis. Ther. Adv. Musculoskelet. Dis. 2, 349–359 (2010).
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).
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).
Sellam, J. & Berenbaum, F. The role of synovitis in pathophysiology and clinical symptoms of osteoarthritis. Nat. Rev. Rheumatol. 6, 625–635 (2010).
Poulet, B. & Beier, F. Targeting oxidative stress to reduce osteoarthritis. Arthritis Res. Ther. 18, 32 (2016).
Adams, S. B. Jr et al. Global metabolic profiling of human osteoarthritic synovium. Osteoarthritis Cartilage 20, 64–67 (2012).
Biniecka, M. et al. Dysregulated bioenergetics: a key regulator of joint inflammation. Ann. Rheum. Dis. 75, 2192–2200 (2016).
Garcia-Carbonell, R. et al. Critical role of glucose metabolism in rheumatoid arthritis fibroblast-like synoviocytes. Arthritis Rheumatol. 68, 1614–1626 (2016).
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).
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).
Mapp, P. I. & Walsh, D. A. Mechanisms and targets of angiogenesis and nerve growth in osteoarthritis. Nat. Rev. Rheumatol. 8, 390–398 (2012).
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).
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).
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).
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).
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).
Caramés, B. et al. Autophagy activation by rapamycin reduces severity of experimental osteoarthritis. Ann. Rheum. Dis. 71, 575–581 (2012).
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).
O'Neill, L. A. J. & Hardie, D. G. Metabolism of inflammation limited by AMPK and pseudo-starvation. Nature 493, 346–355 (2013).
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).
Mobasheri, A. The future of osteoarthritis therapeutics: emerging biological therapy. Curr. Rheumatol. Rep. 15, 385 (2013).
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).
Lotz, M. et al. Value of biomarkers in osteoarthritis: current status and perspectives. Ann. Rheum. Dis. 72, 1756–1763 (2013).
Blanco, F. J. & Ruiz-Romero, C. Osteoarthritis: metabolomic characterization of metabolic phenotypes in OA. Nat. Rev. Rheumatol. 8, 130–132 (2012).
Zhang, W. et al. Classification of osteoarthritis phenotypes by metabolomics analysis. BMJ Open 4, e006286 (2014).
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).
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.).
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.
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.
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.
About this article
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
This article is cited by
Military Medical Research (2023)
Progress in biomechanical stimuli on the cell-encapsulated hydrogels for cartilage tissue regeneration
Biomaterials Research (2023)
Journal of Orthopaedic Surgery and Research (2023)
Pyruvate Dehydrogenase Kinase 1 inhibition mediated oxidative phosphorylation enhancement in cartilage promotes osteoarthritis progression
BMC Musculoskeletal Disorders (2023)
Signal Transduction and Targeted Therapy (2023)