The role of metabolism in the pathogenesis of osteoarthritis

Nature Reviews Rheumatology

Volumn 13, Issue 5, 2017, Pages 302-311

  Mobasheri, Ali ^a,b   Rayman, Margaret P ^a   Gualillo, Oreste ^c   Sellam, Jérémie ^d,e   Van Der Kraan, Peter ^f   Fearon, Ursula ^g  

^a UNIVERSITY OF SURREY   (United Kingdom)

^b QUEEN S MEDICAL CENTRE   (United Kingdom)

^c Santiago University Clinical Hospital   (Spain)

^d ASSISTANCE PUBLIQUE HÔPITAUX DE PARIS   (France)

^e SORBONNE UNIVERSITÉ   (France)

^f RADBOUD UNIVERSITY MEDICAL CENTER   (Netherlands)

^g TRINITY COLLEGE DUBLIN   (Ireland)

Author keywords

[No Author keywords available]

Indexed keywords

ADAMTS PROTEIN; AGGRECAN; CASPASE 3; INTERLEUKIN 1BETA; METFORMIN; METHOTREXATE; PENTOSE PHOSPHATE; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA COACTIVATOR 1ALPHA; SALICYLATE SODIUM;

AMINO ACID METABOLISM; BIOGENESIS; CELL METABOLISM; CELL VIABILITY; CITRIC ACID CYCLE; ENERGY METABOLISM; ENZYME ACTIVITY; EXTRACELLULAR MATRIX; FATTY ACID OXIDATION; FATTY ACID SYNTHESIS; GLUCOSE METABOLISM; GLYCOLYSIS; HUMAN; IMMUNOMODULATION; IMMUNOPHENOTYPING; IMMUNOREGULATION; KASHIN BECK DISEASE; LIFESPAN; LIFESTYLE; LIPID PEROXIDATION; METABOLOMICS; MICROENVIRONMENT; MITOCHONDRIAL MEMBRANE POTENTIAL; MITOCHONDRIAL RESPIRATION; NONHUMAN; OSTEOARTHRITIS; OXIDATIVE PHOSPHORYLATION; OXIDATIVE STRESS; PATHOGENESIS; PHENOTYPE; PRIORITY JOURNAL; REVIEW; SYNOVIUM; ANIMAL; METABOLISM; PATHOLOGY; SIGNAL TRANSDUCTION;

ANIMALS; ENERGY METABOLISM; HUMANS; METABOLIC NETWORKS AND PATHWAYS; OSTEOARTHRITIS; SIGNAL TRANSDUCTION;

EID: 85017164368     PISSN: 17594790     EISSN: 17594804     Source Type: Journal    
DOI: 10.1038/nrrheum.2017.50     Document Type: Review

References (134)

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, 4992-4993 (2013).
3. O'Neill, L. A. J., Kishton, R. J. & Rathmell, J. A guide to immunometabolism for immunologists. Nat. Rev. Immunol. 16, 553-565 (2016).
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).
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).
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).
7. Early, J. O. & Curtis, A. M. Immunometabolism: is it under the eye of the clock? Semin. Immunol. 28, 478-490 (2016).
8. Loftus, R. M. & Finlay, D. K. Immunometabolism: cellular metabolism turns immune regulator. J. Biol. Chem. 291, 1-10 (2016).
9. Michalek, R. D. & Rathmell, J. C. The metabolic life and times of a T-cell. Immunol. Rev. 236, 190-202 (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, 11-18 (2009).
11. Sellam, J. & Berenbaum, F. Is osteoarthritis a metabolic disease? Joint Bone Spine 80, 568-573 (2013).
12. Kluzek, S., Newton, J. L. & Arden, N. K. Is osteoarthritis a metabolic disorder? Br. Med. Bull. 115, 111-121 (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, 2048-2058 (2016).
14. Loeser, R. F. Aging and osteoarthritis. Curr. Opin. Rheumatol. 23, 492-496 (2011).
15. Berenbaum, F. Osteoarthritis as an inflammatory disease (osteoarthritis is not osteoarthrosis!). Osteoarthritis Cartilage 21, 16-21 (2013).
16. Glyn-Jones, S. et al. Osteoarthritis. Lancet 386, 376-387 (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, 86-93 (2017).
18. Braun, H. J. & Gold, G. E. Diagnosis of osteoarthritis: imaging. Bone 51, 278-288 (2012).
19. Hasegawa, A. et al. Anterior cruciate ligament changes in the human knee joint in aging and osteoarthritis. Arthritis Rheum. 64, 696-704 (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, 631-633 (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, 249-258 (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, 632-644 (2016).
23. Guilak, F. Biomechanical factors in osteoarthritis. Best Pract. Res. Clin. Rheumatol. 25, 815-823 (2011).
24. Scanzello, C. R. Role of low-grade inflammation in osteoarthritis. Curr. Opin. Rheumatol. 29, 79-85 (2017).
25. Wang, Q. et al. Identification of a central role for complement in osteoarthritis. Nat. Med. 17, 1674-1679 (2011).
26. Hunter, D. J. Osteoarthritis. Best Pract. Res. Clin. Rheumatol. 25, 801-814 (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, 588-600 (2015).
28. Malemud, C. J. Biologic basis of osteoarthritis: state of the evidence. Curr. Opin. Rheumatol. 27, 289-294 (2015).
29. Wluka, A. E., Lombard, C. B. & Cicuttini, F. M. Tackling obesity in knee osteoarthritis. Nat. Rev. Rheumatol. 9, 225-235 (2013).
30. Zhuo, Q., Yang, W., Chen, J. & Wang, Y. Metabolic syndrome meets osteoarthritis. Nat. Rev. Rheumatol. 8, 729-737 (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, 1172-1181 (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, 18-24 (1988).
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).
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, 100-109 (2017).
36. Wang, X., Hunter, D., Xu, J. & Ding, C. Metabolic triggered inflammation in osteoarthritis. Osteoarthritis Cartilage 23, 22-30 (2015).
37. Scotece, M. et al. Adipokines as drug targets in joint and bone disease. Drug Discov. Today 19, 241-258 (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, 716-724 (2007).
39. + 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).
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).
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).
43. Verzijl, N. et al. Effect of collagen turnover on the accumulation of advanced glycation end products. J. Biol. Chem. 275, 39027-39031 (2000).
44. Eyre, D. R., Weis, M. A. & Wu, J. J. Articular cartilage collagen: an irreplaceable framework? Eur. Cell. Mater. 12, 57-63 (2006).
45. Martin, J. A. & Buckwalter, J. A. Aging, articular cartilage chondrocyte senescence and osteoarthritis. Biogerontology 3, 257-264 (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, 1239-1267 (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, 7001-7008 (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, 241-248 (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, 1-57 (2009).
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).
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, 92-101 (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, 529-535 (2009).
56. Ramakrishnan, P. et al. Oxidant conditioning protects cartilage from mechanically induced damage. J. Orthop. Res. 28, 914-920 (2010).
57. Maneiro, E. et al. Mitochondrial respiratory activity is altered in osteoarthritic human articular chondrocytes. Arthritis Rheum. 48, 700-708 (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, 23-32 (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, 244-248 (2015).
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).
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).
63. Loeser, R. F., Collins, J. A. & Diekman, B. O. Ageing and the pathogenesis of osteoarthritis. Nat. Rev. Rheumatol. 12, 412-420 (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, 107-113 (2009).
65. Blanco, F. J., López-Armada, M. J. & Maneiro, E. Mitochondrial dysfunction in osteoarthritis. Mitochondrion 4, 715-728 (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, 1327-1338 (2005).
67. Martin, J. A. et al. Mitochondrial electron transport and glycolysis are coupled in articular cartilage. Osteoarthritis Cartilage 20, 323-329 (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, 1560-1570 (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, 1485-1496 (2006).
72. Henrotin, Y., Kurz, B. & Aigner, T. Oxygen and reactive oxygen species in cartilage degradation: friends or foes? Osteoarthritis Cartilage 13, 643-654 (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, 1-12 (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, 2349-2357 (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, 1266-1274 (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, 2002-2014 (1999).
77. Studer, R., Jaffurs, D., Stefanovic-Racic, M., Robbins, P. D. & Evans, C. H. Nitric oxide in osteoarthritis. Osteoarthritis Cartilage 7, 377-379 (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, 424-432 (2010).
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).
80. Wang, W. et al. Oxidative stress and status of antioxidant enzymes in children with Kashin-Beck disease. Osteoarthritis Cartilage 21, 1781-1789 (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, R380-R391 (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, 747-755 (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, 2165-2175 (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, 1071-1081 (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, 195-201 (2014).
86. Blanco, F. J., Rego, I. & Ruiz-Romero, C. The role of mitochondria in osteoarthritis. Nat. Rev. Rheumatol. 7, 161-169 (2011).
87. Vaamonde-García, C. et al. Mitochondrial dysfunction increases inflammatory responsiveness to cytokines in normal human chondrocytes. Arthritis Rheum. 64, 2927-2936 (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, 156-163 (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, 234-246 (2014).
90. Liu-Bryan, R. & Terkeltaub, R. Emerging regulators of the inflammatory process in osteoarthritis. Nat. Rev. Rheumatol. 11, 35-44 (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, 2141-2153 (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, 3073-3082 (2014).
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).
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).
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).
96. Zhang, Y. et al. Cartilage-specific deletion of mTOR upregulates autophagy and protects mice from osteoarthritis. Ann. Rheum. Dis. 74, 1432-1440 (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, 569-578 (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, 552-560 (2015).
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).
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).
102. Salminen, A., Kaarniranta, K. & Kauppinen, A. Inflammaging: disturbed interplay between autophagy and inflammasomes. Aging 4, 166-175 (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, 378-387 (2013).
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).
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).
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).
107. Goldring, M. B. & Goldring, S. R. Osteoarthritis. J. Cell. Physiol. 213, 626-634 (2007).
108. Scanzello, C. R. & Goldring, S. R. The role of synovitis in osteoarthritis pathogenesis. Bone 51, 249-257 (2012).
109. Wenham, C. Y. & Conaghan, P. G. The role of synovitis in osteoarthritis. Ther. Adv. Musculoskelet. Dis. 2, 349-359 (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, 10-24 (2009).
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).
112. Sellam, J. & Berenbaum, F. The role of synovitis in pathophysiology and clinical symptoms of osteoarthritis. Nat. Rev. Rheumatol. 6, 625-635 (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, 64-67 (2012).
115. Biniecka, M. et al. Dysregulated bioenergetics: a key regulator of joint inflammation. Ann. Rheum. Dis. 75, 2192-2200 (2016).
116. Garcia-Carbonell, R. et al. Critical role of glucose metabolism in rheumatoid arthritis fibroblast-like synoviocytes. Arthritis Rheumatol. 68, 1614-1626 (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, 1116-1125 (2001).
119. Mapp, P. I. & Walsh, D. A. Mechanisms and targets of angiogenesis and nerve growth in osteoarthritis. Nat. Rev. Rheumatol. 8, 390-398 (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, 2649-2658 (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, 2856-2867 (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, 20-29 (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, 492-501 (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. Caramis, B. et al. Autophagy activation by rapamycin reduces severity of experimental osteoarthritis. Ann. Rheum. Dis. 71, 575-581 (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, 346-355 (2013).
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).
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. 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).
132. Blanco, F. J. & Ruiz-Romero, C. Osteoarthritis: metabolomic characterization of metabolic phenotypes in OA. Nat. Rev. Rheumatol. 8, 130-132 (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, 71-77 (2015).