rspНаучно-практическая ревматологияRheumatology Science and Practice1995-44841995-4492IMA-PRESS, LLC10.14412/1995-4484-2016-590-597rsp-2307Research ArticleОБЗОРЫФУНКЦИИ СИГНАЛЬНОГО ПУ ТИ MТОR В ЗДОРОВЫХ ХОНДРОЦИТАХ СУСТАВНОГО ХРЯЩА И ПРИ ОСТЕОАРТРОЗЕFUNCTIONS OF THE mTOR SIGNALING PATHWAY IN NORMAL ARTICULAR CARTILAGE CHONDROCYTES AND IN OSTEOARTHRITISЧетинаЕ. В.ChetinaE. V.

Елена Васильевна Четина.

115522 Москва, Каширское шоссе, 34А

Elena Chetina.

34A, Kashirskoe Shosse, Moscow 115522

etchetina@mail.ruКашевароваН. Г.KashevarovaN. G.

115522 Москва, Каширское шоссе, 34А

34A, Kashirskoe Shosse, Moscow 115522

ШараповаЕ. П.SharapovaE. P.

115522 Москва, Каширское шоссе, 34А

34A, Kashirskoe Shosse, Moscow 115522

Научноисследовательский институт ревматологии имени В.А. НасоновойРоссияV.A. Nasonova Research Institute of RheumatologyRussian Federation201609122016545590597Copyright © Четина Е.В., Кашеварова Н.Г., Шарапова Е.П., 20162016Четина Е.В., Кашеварова Н.Г., Шарапова Е.П.Chetina E.V., Kashevarova N.G., Sharapova E.P.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://rsp.mediar-press.net/rsp/article/view/2307

Остеоартроз  (ОА) – это хроническое заболевание, которое связано с болью, скованностью, ограничением подвижности и воспалением сустава, а также с деструкцией  суставного хряща. Недавние  исследования показали значение  дифференцировки (гипертрофии) хондроцитов  как одного из механизмов  деградации хряща при ОА. Это указывает на глубокие изменения метаболизма  хондроцитов  в ходе резорбции хряща, которые обусловливаются нарушением регуляции функционирования клеток. Одним из основных  клеточных метаболических  регуляторов является  белок mTOR (mechanistictargetofrapamycin),  который  контролирует клеточные процессы  роста, пролиферации, биосинтеза  белка, а также интегрирует внеклеточные сигналы от факторов  роста и гормонов с доступностью аминокислот и внутриклеточным энергетическим статусом. Значение активности mTOR для разрушения суставного хряща при ОА подтверждается  значительными изменениями  в работе регуляторной  сети mTOR, включающей  многочисленные внутриклеточные (факторы  роста, аденозинтрифосфат, доступность кислорода  и аутофагию) и внеклеточные (глюкозу, аминокислоты, липиды и гексозамин) сигналы. Более того, измененная экспрессия гена mTOR в крови больных ОА связана либо

Osteoarthritis  (OA) is a chronic disease associated with pain, stiffness, limited mobility and joint inflammation, as well as articular cartilage destruction.  Recent studies have shown the importance  of chondrocyte  differentiation (hypertrophy) as one of the mechanisms  of cartilage degradation in OA. This suggests that chondrocyte  metabolism undergoes the profound changes during cartilage resorption,  which are due to dysregulation of cell function. One of the major cellular metabolic regulators is the protein mTOR (mechanistic target of rapamycin) that controls cell growth, proliferation, protein biosynthesis and integrates extracellular signals from growth factors and hormones with amino acid availability and intracellular energy status. The importance  of mTOR activity for articular cartilage destruction  in OA

mTORостеоартрозсуставной хрящпериферическая кровьрегуляция путей метаболизмаmTORosteoarthritisarticular cartilageperipheral bloodregulation of metabolic pathwaysReferencesPoole AR, Guilak F, Abramson SB. Etiopathogenesis of osteoarthritis. In: Moskowitz RW, Altman RD, Hochberg MC, et al., editors. Osteoarthritis: Diagnosis and Medical/Surgical Management. 4th ed. Lippincott, PA: Williams &Wilkins; 2007. P. 27-9.Poole AR, Guilak F, Abramson SB. Etiopathogenesis of osteoarthritis. In: Moskowitz RW, Altman RD, Hochberg MC, et al., editors. Osteoarthritis: Diagnosis and Medical/Surgical Management. 4th ed. Lippincott, PA: Williams &Wilkins; 2007. P. 27-9.Tchetina EV. Developmental mechanisms in articular cartilage degradation in osteoarthritis. Arthritis. 2011;2011:683970. doi: 10.1155/2011/683970. Epub 2010 Dec 29.Tchetina EV. Developmental mechanisms in articular cartilage degradation in osteoarthritis. Arthritis. 2011;2011:683970. doi: 10.1155/2011/683970. Epub 2010 Dec 29.Tchetina EV, Webb G, Poole AR. Increased type II collagen degradation and very early focal cartilage degeneration is associated with upregulation of chondrocyte differentiation related genes in early human articular cartilage lesions. J Rheumatol. 2005 May;32(5):876-86.Tchetina EV, Webb G, Poole AR. Increased type II collagen degradation and very early focal cartilage degeneration is associated with upregulation of chondrocyte differentiation related genes in early human articular cartilage lesions. J Rheumatol. 2005 May;32(5):876-86.Tchetina EV, Kobayashi M, Yasuda T, et al. Chondrocyte hypertrophy can be induced by a cryptic sequence of type II collagen and is accompanied by the induction of MMP-13 and collagenase activity: implications for development and arthritis. Matrix Biology. 2007 May;26(4):247-58. doi: 10.1016/j.mat-bio.2007.01.006. Epub 2007 Jan 19.Tchetina EV, Kobayashi M, Yasuda T, et al. Chondrocyte hypertrophy can be induced by a cryptic sequence of type II collagen and is accompanied by the induction of MMP-13 and collagenase activity: implications for development and arthritis. Matrix Biology. 2007 May;26(4):247-58. doi: 10.1016/j.mat-bio.2007.01.006. Epub 2007 Jan 19.Tchetina EV, Antoniou J, Tanzer M, et al. Transforming growth factor-beta2 suppresses collagen cleavage in cultured human osteoarthritic cartilage, reduces expression of genes associated with chondrocyte hypertrophy and degradation, and increases prostaglandin E(2) production. Am J Pathol. 2006 Jan;168(1):131-40. doi: 10.2353/ajpath.2006.050369Tchetina EV, Antoniou J, Tanzer M, et al. Transforming growth factor-beta2 suppresses collagen cleavage in cultured human osteoarthritic cartilage, reduces expression of genes associated with chondrocyte hypertrophy and degradation, and increases prostaglandin E(2) production. Am J Pathol. 2006 Jan;168(1):131-40. doi: 10.2353/ajpath.2006.050369Glasson SS. In vivo osteoarthritis target validation utilizing genetically-modified mice. Curr Drug Targets. 2007 Feb;8(2):367-76. doi: 10.2174/138945007779940061Glasson SS. In vivo osteoarthritis target validation utilizing genetically-modified mice. Curr Drug Targets. 2007 Feb;8(2):367-76. doi: 10.2174/138945007779940061Little CB, Fosang AJ. Is cartilage matrix breakdown an appropriate therapeutic target in osteoarthritis — insights from studies of aggrecan and collagen proteolysis? Curr Drug Targets. 2010 May;11(5):561-75. doi: 10.2174/138945010791011956Little CB, Fosang AJ. Is cartilage matrix breakdown an appropriate therapeutic target in osteoarthritis — insights from studies of aggrecan and collagen proteolysis? Curr Drug Targets. 2010 May;11(5):561-75. doi: 10.2174/138945010791011956Botter SM, Glasson SS, Hopkins B, et al. ADAMTS5-/micehave less subchondral bone changes after induction of osteoarthri-tis through surgical instability: implications for a link between cartilage and subchondral bone changes. Osteoarthr Cartilage. 2009 May;17(5):636-45. doi: 10.1016/j.joca.2008.09.018. Epub 2008 Oct 17.Botter SM, Glasson SS, Hopkins B, et al. ADAMTS5-/micehave less subchondral bone changes after induction of osteoarthri-tis through surgical instability: implications for a link between cartilage and subchondral bone changes. Osteoarthr Cartilage. 2009 May;17(5):636-45. doi: 10.1016/j.joca.2008.09.018. Epub 2008 Oct 17.Bondeson J. Are we moving in the right direction with osteoarthritis drug discovery? Expert Opin Ther Targets. 2011 Dec;15(12):1355-68. doi: 10.1517/14728222.2011.636740. Epub 2011 Nov 16.Bondeson J. Are we moving in the right direction with osteoarthritis drug discovery? Expert Opin Ther Targets. 2011 Dec;15(12):1355-68. doi: 10.1517/14728222.2011.636740. Epub 2011 Nov 16.Chevalier X, Mugnier B, Bouvenot G. Targeted anti-cytokine therapies for osteoarthritis. Bull Acad Natl Med. 2006 Oct;190(7):1411-20.Chevalier X, Mugnier B, Bouvenot G. Targeted anti-cytokine therapies for osteoarthritis. Bull Acad Natl Med. 2006 Oct;190(7):1411-20.Gonzalo-Gil E, Criado G, Santiago B, et al. Transforming growth factor (TGF)-β signalling is increased in rheumatoid synovium but TGF-β blockade does not modify experimental arthritis. Clin Exp Immunol. 2013 Nov;174(2):245-55. doi: 10.1111/cei.12179Gonzalo-Gil E, Criado G, Santiago B, et al. Transforming growth factor (TGF)-β signalling is increased in rheumatoid synovium but TGF-β blockade does not modify experimental arthritis. Clin Exp Immunol. 2013 Nov;174(2):245-55. doi: 10.1111/cei.12179Schroeppel JP, Crist JD, Anderson HC, Wang J. Molecular regulation of articular chondrocyte function and its significance in osteoarthritis. Histol Histopathol. 2011 Mar;26(3):377-94.Schroeppel JP, Crist JD, Anderson HC, Wang J. Molecular regulation of articular chondrocyte function and its significance in osteoarthritis. Histol Histopathol. 2011 Mar;26(3):377-94.Rousseau JC, Delmas PD. Biological markers in osteoarthritis. Nat Clin Pract Rheumatol. 2007 Jun;3(6):346-56. doi: 10.1038/ncprheum0508Rousseau JC, Delmas PD. Biological markers in osteoarthritis. Nat Clin Pract Rheumatol. 2007 Jun;3(6):346-56. doi: 10.1038/ncprheum0508Wu L, Huang X, Li L, et al. Insights on biology and pathology of HIF-1α/-2α, TGFβ/BMP, Wnt/β-catenin, and NF-κB pathways in osteoarthritis. Curr Pharm Design. 2012;18(22):3293-312. doi: 10.2174/1381612811209023293Wu L, Huang X, Li L, et al. Insights on biology and pathology of HIF-1α/-2α, TGFβ/BMP, Wnt/β-catenin, and NF-κB pathways in osteoarthritis. Curr Pharm Design. 2012;18(22):3293-312. doi: 10.2174/1381612811209023293Scanzello CR, Plaas A, Crow MK. Innate immune system activation in osteoarthritis: is osteoarthritis a chronic wound? Curr Opin Rheumatol. 2008 Sept;20(5):565-72. doi: 10.1097/BOR.0b013e32830aba34Scanzello CR, Plaas A, Crow MK. Innate immune system activation in osteoarthritis: is osteoarthritis a chronic wound? Curr Opin Rheumatol. 2008 Sept;20(5):565-72. doi: 10.1097/BOR.0b013e32830aba34Marcu KB, Otero M, Olivotto E, et al. NF-kappaB signaling: multiple angles to target OA. Curr Drug Targets. 2010 May;11(5):599-613. doi: 10.2174/138945010791011938Marcu KB, Otero M, Olivotto E, et al. NF-kappaB signaling: multiple angles to target OA. Curr Drug Targets. 2010 May;11(5):599-613. doi: 10.2174/138945010791011938Valdes AM, Spector TD. The clinical relevance of genetic susceptibility to osteoarthritis. Best Pract Res Clin Rheumatol. 2010 Feb;24(1):3-14. doi: 10.1016/j.berh.2009.08.005Valdes AM, Spector TD. The clinical relevance of genetic susceptibility to osteoarthritis. Best Pract Res Clin Rheumatol. 2010 Feb;24(1):3-14. doi: 10.1016/j.berh.2009.08.005Dreier R. Hypertrophic differentiation of chondrocytes in osteoarthritis: the developmental aspect of degenerative joint disorders. Arthritis Res Ther. 2010;12(5):216. doi: 10.1186/ar3117. Epub 2010 Sep 16.Dreier R. Hypertrophic differentiation of chondrocytes in osteoarthritis: the developmental aspect of degenerative joint disorders. Arthritis Res Ther. 2010;12(5):216. doi: 10.1186/ar3117. Epub 2010 Sep 16.Prasadam I, van Gennip S, Friis T, et al. ERK-1/2 and p38 in the regulation of hypertrophic changes of normal articular cartilage chondrocytes induced by osteoarthritic subchondral osteoblasts. Arthritis Rheum. 2010 May;62(5):1349-60. doi: 10.1002/art.27397Prasadam I, van Gennip S, Friis T, et al. ERK-1/2 and p38 in the regulation of hypertrophic changes of normal articular cartilage chondrocytes induced by osteoarthritic subchondral osteoblasts. Arthritis Rheum. 2010 May;62(5):1349-60. doi: 10.1002/art.27397Li TF, Gao L, Sheu TJ, et al. Aberrant hypertrophy in Smad3deficient murine chondrocytes is rescued by restoring transforming growth factor beta-activated kinase 1/activating transcription factor 2 signaling: a potential clinical implication for osteoarthritis. Arthritis Rheum. 2010 Aug;62(8):2359-69. doi: 10.1002/art.27537Li TF, Gao L, Sheu TJ, et al. Aberrant hypertrophy in Smad3deficient murine chondrocytes is rescued by restoring transforming growth factor beta-activated kinase 1/activating transcription factor 2 signaling: a potential clinical implication for osteoarthritis. Arthritis Rheum. 2010 Aug;62(8):2359-69. doi: 10.1002/art.27537Berenbaum F. Signaling transduction: target in osteoarthritis. Curr Opin Rheumatol. 2004 Sep;16(5):616-22. doi: 10.1097/01.bor.0000133663.37352.4aBerenbaum F. Signaling transduction: target in osteoarthritis. Curr Opin Rheumatol. 2004 Sep;16(5):616-22. doi: 10.1097/01.bor.0000133663.37352.4aBlom AB, van Lent PL, van der Kraan PM, van den Berg WB. To seek shelter from the WNT in osteoarthritis? WNT-signaling as a target for osteoarthritis therapy. Curr Drug Targets. 2010 May;11(5):620-9. doi: 10.2174/138945010791011901Blom AB, van Lent PL, van der Kraan PM, van den Berg WB. To seek shelter from the WNT in osteoarthritis? WNT-signaling as a target for osteoarthritis therapy. Curr Drug Targets. 2010 May;11(5):620-9. doi: 10.2174/138945010791011901Walker WA, Blackburn G. Symposium introduction: nutrition and gene regulation. J Nutr. 2004 Sep;134(9):2434S-6S.Walker WA, Blackburn G. Symposium introduction: nutrition and gene regulation. J Nutr. 2004 Sep;134(9):2434S-6S.Marshall S. Role of insulin, adipocyte hormones, and nutrientsensing pathways in regulating fuel metabolism and energy homeostasis: a nutritional perspective of diabetes, obesity, and cancer. Sci STKE. 2006 Aug 1;2006(346):re7. doi: 10.1126/stke.3462006re7Marshall S. Role of insulin, adipocyte hormones, and nutrientsensing pathways in regulating fuel metabolism and energy homeostasis: a nutritional perspective of diabetes, obesity, and cancer. Sci STKE. 2006 Aug 1;2006(346):re7. doi: 10.1126/stke.3462006re7Kimball SR, Jefferson LS. Molecular mechanisms through which amino acids mediate signaling through the mammalian target of rapamycin. Curr Opin Clin Nutr Metab Care. 2004 Jan;7(1):39-44. doi: 10.1097/00075197-200401000-00008Kimball SR, Jefferson LS. Molecular mechanisms through which amino acids mediate signaling through the mammalian target of rapamycin. Curr Opin Clin Nutr Metab Care. 2004 Jan;7(1):39-44. doi: 10.1097/00075197-200401000-00008Maloney CA, Rees WD. Gene-nutrient interactions during fetal development. Reproduction. 2005 Oct;130(4):401-10. doi: 10.1530/rep.1.00523Maloney CA, Rees WD. Gene-nutrient interactions during fetal development. Reproduction. 2005 Oct;130(4):401-10. doi: 10.1530/rep.1.00523Laplante M, Sabatini DM. mTOR signaling at a glance. J Cell Sci. 2009 Oct 15;122(Pt 20):3589-94. doi: 10.1242/jcs.051011Laplante M, Sabatini DM. mTOR signaling at a glance. J Cell Sci. 2009 Oct 15;122(Pt 20):3589-94. doi: 10.1242/jcs.051011Altomare DA, Khaled AR. Homeostasis and the importance for a balance between AKT/mTOR activity and intracellular signaling. Curr Med Chem. 2012;19(22):3748-62. doi: 10.2174/092986712801661130Altomare DA, Khaled AR. Homeostasis and the importance for a balance between AKT/mTOR activity and intracellular signaling. Curr Med Chem. 2012;19(22):3748-62. doi: 10.2174/092986712801661130Martin TD, Chen X-W, Kaplan REW, et al. Ral and Rheb GTPase activating proteins integrate mTOR and GTPase signaling in aging, autophagy, and tumor cell invasion. Mol Cell. 2014 Jan 22;53(2):209-20. doi: 10.1016/j.molcel.2013.12.004. Epub 2014 Jan 2.Martin TD, Chen X-W, Kaplan REW, et al. Ral and Rheb GTPase activating proteins integrate mTOR and GTPase signaling in aging, autophagy, and tumor cell invasion. Mol Cell. 2014 Jan 22;53(2):209-20. doi: 10.1016/j.molcel.2013.12.004. Epub 2014 Jan 2.Zoncu R, Efeyan A, Sabatini DM. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol. 2011 Jan;12(1):21-35. doi: 10.1038/nrm3025. Epub 2010 Dec 15.Zoncu R, Efeyan A, Sabatini DM. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol. 2011 Jan;12(1):21-35. doi: 10.1038/nrm3025. Epub 2010 Dec 15.Wang RH, Kim HS, Xiao C, et al. Hepatic Sirt1 deficiency in mice impairs mTorc2/Akt signaling and results in hyperglycemia, oxidative damage, and insulin resistance. J Clin Invest. 2011 Nov;121(11):4477-90. doi: 10.1172/JCI46243. Epub 2011 Oct 3.Wang RH, Kim HS, Xiao C, et al. Hepatic Sirt1 deficiency in mice impairs mTorc2/Akt signaling and results in hyperglycemia, oxidative damage, and insulin resistance. J Clin Invest. 2011 Nov;121(11):4477-90. doi: 10.1172/JCI46243. Epub 2011 Oct 3.Bohensky J, Leshinsky S, Srinivas V, Shapiro IM. Chondrocyte autophagy is stimulated by HIF-1 dependent AMPK activation and mTOR suppression. Pediatr Nephrol. 2010 Apr;25(4):633-42. doi: 10.1007/s00467-009-1310-y. Epub 2009 Oct 15.Bohensky J, Leshinsky S, Srinivas V, Shapiro IM. Chondrocyte autophagy is stimulated by HIF-1 dependent AMPK activation and mTOR suppression. Pediatr Nephrol. 2010 Apr;25(4):633-42. doi: 10.1007/s00467-009-1310-y. Epub 2009 Oct 15.Kim MS, Wu KY, Auyeung V, et al. Leucine restriction inhibits chondrocyte proliferation and differentiation through mechanisms both dependent and independent of mTOR signaling. Am J Physiol Endocrinol Metab. 2009 Jun; 296(6):E1374-82. doi: 10.1152/ajpendo.91018.2008. Epub 2009 Apr 28.Kim MS, Wu KY, Auyeung V, et al. Leucine restriction inhibits chondrocyte proliferation and differentiation through mechanisms both dependent and independent of mTOR signaling. Am J Physiol Endocrinol Metab. 2009 Jun; 296(6):E1374-82. doi: 10.1152/ajpendo.91018.2008. Epub 2009 Apr 28.Sanchez CP, He Y-Z. Bone growth during rapamycin therapy in young rats. BMC Pediatrics. 2009 Jan 13;9:3. doi: 10.1186/1471-2431-9-3Sanchez CP, He Y-Z. Bone growth during rapamycin therapy in young rats. BMC Pediatrics. 2009 Jan 13;9:3. doi: 10.1186/1471-2431-9-3Rokutanda S, Fujita T, Kanatani N, et al. Akt regulates skeletal development through GSK3, mTOR, and FoxOs. Dev Biol. 2009 Apr 1;328(1):78-93. doi: 10.1016/j.ydbio.2009.01.009. Epub 2009 Jan 14.Rokutanda S, Fujita T, Kanatani N, et al. Akt regulates skeletal development through GSK3, mTOR, and FoxOs. Dev Biol. 2009 Apr 1;328(1):78-93. doi: 10.1016/j.ydbio.2009.01.009. Epub 2009 Jan 14.Lai LP, Lilley BN, Sanes JR, McMahon AP. Lkb1/Stk11 regulation of mTOR signaling controls the transition of chondrocyte fates and suppresses skeletal tumor formation. Proc Natl Acad Sci USA. 2013 Nov 26;110(48):19450-5. doi: 10.1073/pnas.1309001110. Epub 2013 Nov 11.Lai LP, Lilley BN, Sanes JR, McMahon AP. Lkb1/Stk11 regulation of mTOR signaling controls the transition of chondrocyte fates and suppresses skeletal tumor formation. Proc Natl Acad Sci USA. 2013 Nov 26;110(48):19450-5. doi: 10.1073/pnas.1309001110. Epub 2013 Nov 11.Wei Y, Sinha S, Levine B. Dual role of JNK1-mediated phosphorylation of Bcl-2 in autophagy and apoptosis regulation. Autophagy. 2008 Oct;4(7):949-51. doi: 10.4161/auto.6788. Epub 2008 Oct 14.Wei Y, Sinha S, Levine B. Dual role of JNK1-mediated phosphorylation of Bcl-2 in autophagy and apoptosis regulation. Autophagy. 2008 Oct;4(7):949-51. doi: 10.4161/auto.6788. Epub 2008 Oct 14.Cejka D, Hayer S, Niederreiter B, et al. Mammalian target of rapamycin signaling is crucial for joint destruction in experimental arthritis and is activated in osteoclasts from patients with rheumatoid arthritis. Arthritis Rheum. 2010 Aug;62(8):2294-302. doi: 10.1002/art.27504Cejka D, Hayer S, Niederreiter B, et al. Mammalian target of rapamycin signaling is crucial for joint destruction in experimental arthritis and is activated in osteoclasts from patients with rheumatoid arthritis. Arthritis Rheum. 2010 Aug;62(8):2294-302. doi: 10.1002/art.27504Tchetina EV, Poole AR, Zaitseva EM, et al. Differences in Mammalian target of rapamycin gene expression in the peripheral blood and articular cartilages of osteoarthritic patients and disease activity. Arthritis. 2013;2013:461486. doi: 10.1155/2013/461486. Epub 2013 Jun 25.Tchetina EV, Poole AR, Zaitseva EM, et al. Differences in Mammalian target of rapamycin gene expression in the peripheral blood and articular cartilages of osteoarthritic patients and disease activity. Arthritis. 2013;2013:461486. doi: 10.1155/2013/461486. Epub 2013 Jun 25.Lotz MK, Carames B. Autophagy and cartilage homeostasis mechanisms in joint health, aging and OA. Nat Rev Rheumatol. 2011 Aug2;7(10):579-87. doi: 10.1038/nrrheum.2011.109Lotz MK, Carames B. Autophagy and cartilage homeostasis mechanisms in joint health, aging and OA. Nat Rev Rheumatol. 2011 Aug2;7(10):579-87. doi: 10.1038/nrrheum.2011.109Srinivas V, Bohensky J, Zahm AM, Shapiro IM. Autophagy in mineralizing tissues: microenvironmental perspectives. Cell Cycle. 2009 Feb 1;8(3):391-3. doi: 10.4161/cc.8.3.7545Srinivas V, Bohensky J, Zahm AM, Shapiro IM. Autophagy in mineralizing tissues: microenvironmental perspectives. Cell Cycle. 2009 Feb 1;8(3):391-3. doi: 10.4161/cc.8.3.7545Srinivas V, Bohensky J, Shapiro IM. Autophagy: a new phase in the maturation of growth plate chondrocytes is regulated by HIF, mTOR and AMP kinase. Cells Tissues Organs. 2009;189(1-4):88- 92. doi: 10.1159/000151428. Epub 2009 Feb 4.Srinivas V, Bohensky J, Shapiro IM. Autophagy: a new phase in the maturation of growth plate chondrocytes is regulated by HIF, mTOR and AMP kinase. Cells Tissues Organs. 2009;189(1-4):88- 92. doi: 10.1159/000151428. Epub 2009 Feb 4.Sasaki H, Takayama K, Matsushita T, et al. Autophagy modulates osteoarthritis-related gene expression in human chondrocytes. Arthritis Rheum. 2012 Jun;64(6):1920-8. doi: 10.1002/art.34323. Epub 2011 Dec 6.Sasaki H, Takayama K, Matsushita T, et al. Autophagy modulates osteoarthritis-related gene expression in human chondrocytes. Arthritis Rheum. 2012 Jun;64(6):1920-8. doi: 10.1002/art.34323. Epub 2011 Dec 6.Raught B, Gingras AC, Sonenberg N. The target of rapamycin (TOR) proteins. Proc Natl Acad Sci USA. 2001 Jun 19;98(13):7037-44Raught B, Gingras AC, Sonenberg N. The target of rapamycin (TOR) proteins. Proc Natl Acad Sci USA. 2001 Jun 19;98(13):7037-44Zhang M, Zhang J, Lu L, et al. Enhancement of chondrocyte autophagy is an early response in the degenerative cartilage of the temporomandibular joint to biomechanical dental stimulation. Apoptosis. 2013 Apr;18(4):423-34. doi: 10.1007/s10495-013-0811-0Zhang M, Zhang J, Lu L, et al. Enhancement of chondrocyte autophagy is an early response in the degenerative cartilage of the temporomandibular joint to biomechanical dental stimulation. Apoptosis. 2013 Apr;18(4):423-34. doi: 10.1007/s10495-013-0811-0Shapiro IM, Adams CS, Freeman T, Srinivas V. Fate of the hypertrophic chondrocyte: microenvironmental perspectives on apoptosis and survival in the epiphyseal growth plate. Birth Defects Res C Embryo Today. 2005 Dec;75(4):330-9. doi: 10.1002/bdrc.20057Shapiro IM, Adams CS, Freeman T, Srinivas V. Fate of the hypertrophic chondrocyte: microenvironmental perspectives on apoptosis and survival in the epiphyseal growth plate. Birth Defects Res C Embryo Today. 2005 Dec;75(4):330-9. doi: 10.1002/bdrc.20057Srinivas V, Shapiro IM. Chondrocytes embedded in the epiphyseal growth plates of long bones undergo autophagy prior to the induction of osteogenesis. Autophagy. 2006 Jul-Sep;2(3):215-6. doi: 10.4161/auto.2649. Epub 2006 Jul 6.Srinivas V, Shapiro IM. Chondrocytes embedded in the epiphyseal growth plates of long bones undergo autophagy prior to the induction of osteogenesis. Autophagy. 2006 Jul-Sep;2(3):215-6. doi: 10.4161/auto.2649. Epub 2006 Jul 6.Almonte-Becerril M, Navarro-Garcia F, Gonzalez-Robles A, et al. Cell death of chondrocytes is a combination between apoptosis and autophagy during the pathogenesis of osteoarthritis within an experimental model. Apoptosis. 2010 May;15(5):631-8. doi: 10.1007/s10495-010-0458-zAlmonte-Becerril M, Navarro-Garcia F, Gonzalez-Robles A, et al. Cell death of chondrocytes is a combination between apoptosis and autophagy during the pathogenesis of osteoarthritis within an experimental model. Apoptosis. 2010 May;15(5):631-8. doi: 10.1007/s10495-010-0458-zCarames B, Taniguchi N, Otsuki S, et al. Autophagy is a protective mechanism in normal cartilage, and its aging-related loss is linked with cell death and osteoarthritis. Arthritis Rheum. 2010 Mar;62(3):791-801. doi: 10.1002/art.27305Carames B, Taniguchi N, Otsuki S, et al. Autophagy is a protective mechanism in normal cartilage, and its aging-related loss is linked with cell death and osteoarthritis. Arthritis Rheum. 2010 Mar;62(3):791-801. doi: 10.1002/art.27305Carames B, Hasegawa A, Taniguchi N, et al. Autophagy activation by rapamycin reduces severity of experimental osteoarthritis. Ann Rheum Dis. 2012 Apr;71(4):575-81. doi: 10.1136/annrheumdis-2011-200557. Epub 2011 Nov 14.Carames B, Hasegawa A, Taniguchi N, et al. Autophagy activation by rapamycin reduces severity of experimental osteoarthritis. Ann Rheum Dis. 2012 Apr;71(4):575-81. doi: 10.1136/annrheumdis-2011-200557. Epub 2011 Nov 14.Phornphutkul C, Wu KY, Auyeung V, et al. mTOR signaling contributes to chondrocyte differentiation. Dev Dyn. 2008 Mar;237(3):702-12. doi: 10.1002/dvdy.21464Phornphutkul C, Wu KY, Auyeung V, et al. mTOR signaling contributes to chondrocyte differentiation. Dev Dyn. 2008 Mar;237(3):702-12. doi: 10.1002/dvdy.21464Proud CG. Amino acids and mTOR signalling in anabolic function. Biochem Soc Trans. 2007 Nov;35(Pt 5):1187-90. doi: 10.1042/BST0351187Proud CG. Amino acids and mTOR signalling in anabolic function. Biochem Soc Trans. 2007 Nov;35(Pt 5):1187-90. doi: 10.1042/BST0351187Akhtar N, Miller MJ, Haqqi TM. Effect of a Herbal-Leucine mix on the IL-1β-induced cartilage degradation and inflammatory gene expression in human chondrocytes. BMC Complement Altern Med. 2011 Aug 19;11:66. doi: 10.1186/1472-6882-11-66Akhtar N, Miller MJ, Haqqi TM. Effect of a Herbal-Leucine mix on the IL-1β-induced cartilage degradation and inflammatory gene expression in human chondrocytes. BMC Complement Altern Med. 2011 Aug 19;11:66. doi: 10.1186/1472-6882-11-66Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell. 2003 Nov 26;115(5):577-90. doi: 10.1016/S0092-8674(03)00929-2Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell. 2003 Nov 26;115(5):577-90. doi: 10.1016/S0092-8674(03)00929-2Lee MN, Ha SH, Kim J, et al. Glycolytic flux signals to mTOR through glyceraldehyde-3-phosphate dehydrogenase-mediated regulation of Rheb. Mol Cell Biol. 2009 Jul;29(4):3991-4001. doi: 10.1128/MCB.00165-09. Epub 2009 May 18.Lee MN, Ha SH, Kim J, et al. Glycolytic flux signals to mTOR through glyceraldehyde-3-phosphate dehydrogenase-mediated regulation of Rheb. Mol Cell Biol. 2009 Jul;29(4):3991-4001. doi: 10.1128/MCB.00165-09. Epub 2009 May 18.Shikhman AR, Brinson DC, Lotz MK. Distinct pathways regulate facilitated glucose transport in human articular chondrocytes during anabolic and catabolic responses. Am J Physiol Endocrinol Metab. 2004 Jun;286(6):E980-5. doi: 10.1152/ajpendo.00243.2003. Epub 2004 Jan 28.Shikhman AR, Brinson DC, Lotz MK. Distinct pathways regulate facilitated glucose transport in human articular chondrocytes during anabolic and catabolic responses. Am J Physiol Endocrinol Metab. 2004 Jun;286(6):E980-5. doi: 10.1152/ajpendo.00243.2003. Epub 2004 Jan 28.Johnson K, Jung A, Murphy A, et al. Mitochondrial oxidative phosphorylation is a downstream regulator of nitric oxide effects on chondrocyte matrix synthesis and mineralization. Arthritis Rheum. 2000 Jul;43(7):1560-70. doi: 10.1002/1529-0131(200007)43:7<1560::AID-ANR21>3.0.CO;2-SJohnson K, Jung A, Murphy A, et al. Mitochondrial oxidative phosphorylation is a downstream regulator of nitric oxide effects on chondrocyte matrix synthesis and mineralization. Arthritis Rheum. 2000 Jul;43(7):1560-70. doi: 10.1002/1529-0131(200007)43:7<1560::AID-ANR21>3.0.CO;2-SMartin JA, Martini A, Molinari A, et al. Mitochondrial electron transport and glycolysis are coupled in articular cartilage. Osteoarthr Cartilage. 2012 Apr;20(4):323-9. doi: 10.1016/j.joca.2012.01.003. Epub 2012 Jan 16.Martin JA, Martini A, Molinari A, et al. Mitochondrial electron transport and glycolysis are coupled in articular cartilage. Osteoarthr Cartilage. 2012 Apr;20(4):323-9. doi: 10.1016/j.joca.2012.01.003. Epub 2012 Jan 16.Baker MS, Bolis S, Lowther DA. Oxidation of articular cartilage glyceraldehyde-3-phosphate dehydrogenase (G3PDH) occurs in vivo during carrageenin-induced arthritis. Agents Actions. 1991 Mar;32(3-4):299-304. doi: 10.1007/BF01980890Baker MS, Bolis S, Lowther DA. Oxidation of articular cartilage glyceraldehyde-3-phosphate dehydrogenase (G3PDH) occurs in vivo during carrageenin-induced arthritis. Agents Actions. 1991 Mar;32(3-4):299-304. doi: 10.1007/BF01980890Nishida T, Kubota S, Aoyama E, Takigawa M. Impaired glycolytic metabolism causes chondrocyte hypertrophy-like changes via promotion of phospho-Smad1/5/8 translocation into nucleus. Osteoarthr Cartilage. 2013 May;21(5):700-9. doi: 10.1016/j.joca.2013.01.013. Epub 2013 Feb 4.Nishida T, Kubota S, Aoyama E, Takigawa M. Impaired glycolytic metabolism causes chondrocyte hypertrophy-like changes via promotion of phospho-Smad1/5/8 translocation into nucleus. Osteoarthr Cartilage. 2013 May;21(5):700-9. doi: 10.1016/j.joca.2013.01.013. Epub 2013 Feb 4.Ruiz-Romero C, Carreira V, Rego I, et al. Proteomic analysis of human osteoarthritic chondrocytes reveals protein changes in stress and glycolysis. Proteomics. 2008 Feb;8(3):495-507. doi: 10.1002/pmic.200700249Ruiz-Romero C, Carreira V, Rego I, et al. Proteomic analysis of human osteoarthritic chondrocytes reveals protein changes in stress and glycolysis. Proteomics. 2008 Feb;8(3):495-507. doi: 10.1002/pmic.200700249Jiang L, Li L, Geng C, et al. Monosodium iodoacetate induces apoptosis via the mitochondrial pathway involving ROS production and caspase activation in rat chondrocytes in vitro. J Orthop Res. 2013 Mar;31(3):364-9. doi: 10.1002/jor.22250. Epub 2012 Nov 1.Jiang L, Li L, Geng C, et al. Monosodium iodoacetate induces apoptosis via the mitochondrial pathway involving ROS production and caspase activation in rat chondrocytes in vitro. J Orthop Res. 2013 Mar;31(3):364-9. doi: 10.1002/jor.22250. Epub 2012 Nov 1.Peansukmanee S, Vaughan-Thomas A, Carter SD, 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. 2009 Apr;27(4):529-35. doi: 10.1002/jor.20772Peansukmanee S, Vaughan-Thomas A, Carter SD, 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. 2009 Apr;27(4):529-35. doi: 10.1002/jor.20772Starkman BG, Cravero JD, Delcarlo M, Loeser RF. IGF-I stimulation of proteoglycan synthesis by chondrocytes requires activation of the PI 3-kinase pathway but not ERK MAPK. Biochem J. 2005 Aug 1;389(Pt 3):723-9. doi: 10.1042/BJ20041636Starkman BG, Cravero JD, Delcarlo M, Loeser RF. IGF-I stimulation of proteoglycan synthesis by chondrocytes requires activation of the PI 3-kinase pathway but not ERK MAPK. Biochem J. 2005 Aug 1;389(Pt 3):723-9. doi: 10.1042/BJ20041636Qureshi HY, Ahmad R, Sylvester J, Zafarullah M. Requirement of phosphatidylinositol 3-kinase/Akt signaling pathway for regulation of tissue inhibitor of metalloproteinases-3 gene expression by TGF-beta in human chondrocytes. Cell Signal. 2007 Aug;19(8):1643-51. doi: 10.1016/j.cellsig.2007.02.007. Epub 2007 Feb 22.Qureshi HY, Ahmad R, Sylvester J, Zafarullah M. Requirement of phosphatidylinositol 3-kinase/Akt signaling pathway for regulation of tissue inhibitor of metalloproteinases-3 gene expression by TGF-beta in human chondrocytes. Cell Signal. 2007 Aug;19(8):1643-51. doi: 10.1016/j.cellsig.2007.02.007. Epub 2007 Feb 22.Kahn BB, Alquier T, Carling D, Hardie DG. AMP-activated protein kinase: Ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab. 2005 Jan;1(1):15-25. doi: 10.1016/j.cmet.2004.12.003Kahn BB, Alquier T, Carling D, Hardie DG. AMP-activated protein kinase: Ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab. 2005 Jan;1(1):15-25. doi: 10.1016/j.cmet.2004.12.003Gwinn DM, Shackelford DB, Egan DF, et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell. 2008 Apr 25;30(2):214-26. doi: 10.1016/j.molcel.2008.03.003Gwinn DM, Shackelford DB, Egan DF, et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell. 2008 Apr 25;30(2):214-26. doi: 10.1016/j.molcel.2008.03.003Terkeltaub R, Yang B, Lotz M, Liu-Bryan R. Chondrocyte AMPactivated protein kinase activity suppresses matrix degradation responses to proinflammatory cytokines interleukin-1β and tumor necrosis factor α. Arthritis Rheum. 2011 Jul;63(7):1928-37. doi: 10.1002/art.30333Terkeltaub R, Yang B, Lotz M, Liu-Bryan R. Chondrocyte AMPactivated protein kinase activity suppresses matrix degradation responses to proinflammatory cytokines interleukin-1β and tumor necrosis factor α. Arthritis Rheum. 2011 Jul;63(7):1928-37. doi: 10.1002/art.30333Petursson F, Husa M, June R, et al. Linked decreases in liver kinase B1 and AMP-activated protein kinase activity modulate matrix catabolic responses to biomechanical injury in chondrocytes. Arthritis Res Ther. 2013 Jul 25;15(4):R77. doi: 10.1186/ar4254Petursson F, Husa M, June R, et al. Linked decreases in liver kinase B1 and AMP-activated protein kinase activity modulate matrix catabolic responses to biomechanical injury in chondrocytes. Arthritis Res Ther. 2013 Jul 25;15(4):R77. doi: 10.1186/ar4254Husa M, Petursson F, Lotz M, et al. C/EBP homologous protein drives pro-catabolic responses in chondrocytes. Arthritis Res Ther. 2013 Dec 19;15(6):R218. doi: 10.1186/ar4415Husa M, Petursson F, Lotz M, et al. C/EBP homologous protein drives pro-catabolic responses in chondrocytes. Arthritis Res Ther. 2013 Dec 19;15(6):R218. doi: 10.1186/ar4415Sofer A, Lei K, Johannessen CM, Ellisen LW. Regulation of mTOR and cell growth in response to energy stress by REDD1. Mol Cell Biol. 2005 Jul;25(14):5834-45. doi: 10.1128/MCB.25.14.5834-5845.2005Sofer A, Lei K, Johannessen CM, Ellisen LW. Regulation of mTOR and cell growth in response to energy stress by REDD1. Mol Cell Biol. 2005 Jul;25(14):5834-45. doi: 10.1128/MCB.25.14.5834-5845.2005Seol JW, Lee HB, Lee YJ, et al. Hypoxic resistance to articular chondrocyte apoptosis – a possible mechanism of maintaining homeostasis of normal articular cartilage. FEBS J. 2009 Dec;276(24):7375-85. doi: 10.1111/j.1742-4658.2009.07451.xSeol JW, Lee HB, Lee YJ, et al. Hypoxic resistance to articular chondrocyte apoptosis – a possible mechanism of maintaining homeostasis of normal articular cartilage. FEBS J. 2009 Dec;276(24):7375-85. doi: 10.1111/j.1742-4658.2009.07451.xFermor B, Christensen SE, Youn I, et al. Oxygen, nitric oxide and articular cartilage. Eur Cell Mater. 2007 Apr 11;13:56-65.Fermor B, Christensen SE, Youn I, et al. Oxygen, nitric oxide and articular cartilage. Eur Cell Mater. 2007 Apr 11;13:56-65.Fermor B, Gurumurthy A, Diekman BO. Hypoxia, RONS and energy metabolism in articular cartilage. Osteoarthr Cartilage. 2010 Sep;18(9):1167-73. doi: 10.1016/j.joca.2010.06.004. Epub 2010 Jul 13.Fermor B, Gurumurthy A, Diekman BO. Hypoxia, RONS and energy metabolism in articular cartilage. Osteoarthr Cartilage. 2010 Sep;18(9):1167-73. doi: 10.1016/j.joca.2010.06.004. Epub 2010 Jul 13.Mobasheri A, Platt N, Thorpe C, Shakibaei M. Regulation of 2-deoxy-D-glucose transport, lactate metabolism, and MMP-2 secretion by the hypoxia mimetic cobalt chloride in articular chondrocytes. Ann N Y Acad Sci. 2006 Dec;1091:83-93. doi: 10.1196/annals.1378.057Mobasheri A, Platt N, Thorpe C, Shakibaei M. Regulation of 2-deoxy-D-glucose transport, lactate metabolism, and MMP-2 secretion by the hypoxia mimetic cobalt chloride in articular chondrocytes. Ann N Y Acad Sci. 2006 Dec;1091:83-93. doi: 10.1196/annals.1378.057Semenza GL. Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. Annu Rev Cell Dev Biol. 1999;15:551-Semenza GL. Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. Annu Rev Cell Dev Biol. 1999;15:551-doi: 10.1146/annurev.cellbio.15.1.551doi: 10.1146/annurev.cellbio.15.1.551Pfander D, Gelse K. Hypoxia and osteoarthritis: how chondrocytes survive hypoxic environments. Curr Opin Rheumatol. 2007 Sep;19(5):457-62. doi: 10.1097/BOR.0b013e3282ba5693Pfander D, Gelse K. Hypoxia and osteoarthritis: how chondrocytes survive hypoxic environments. Curr Opin Rheumatol. 2007 Sep;19(5):457-62. doi: 10.1097/BOR.0b013e3282ba5693Pfander D, Cramer T, Swoboda B. Hypoxia and HIF-1alpha in osteoarthritis. Int Orthop. 2005 Feb;29(1):6-9. doi: 10.1007/s00264-004-0618-2. Epub 2004 Dec 21.Pfander D, Cramer T, Swoboda B. Hypoxia and HIF-1alpha in osteoarthritis. Int Orthop. 2005 Feb;29(1):6-9. doi: 10.1007/s00264-004-0618-2. Epub 2004 Dec 21.Gelse K, Mü hle C, Knaup K, et al. Chondrogenic differentiation of growth factor-stimulated precursor cells in cartilage repair tissue is associated with increased HIF-1alpha activity. Osteoarthr Cartilage. 2008 Dec;16(12):1457-65. doi: 10.1016/j.joca.2008.04.006. Epub 2008 Jun 3.Gelse K, Mü hle C, Knaup K, et al. Chondrogenic differentiation of growth factor-stimulated precursor cells in cartilage repair tissue is associated with increased HIF-1alpha activity. Osteoarthr Cartilage. 2008 Dec;16(12):1457-65. doi: 10.1016/j.joca.2008.04.006. Epub 2008 Jun 3.Windhaber RA, Wilkins RJ, Meredith D. Functional characterisation of glucose transport in bovine articular chondrocytes. Pflugers Arch. 2003 Aug;446(5):572-7. doi: 10.1007/s00424-003-1080-5. Epub 2003 May 15.Windhaber RA, Wilkins RJ, Meredith D. Functional characterisation of glucose transport in bovine articular chondrocytes. Pflugers Arch. 2003 Aug;446(5):572-7. doi: 10.1007/s00424-003-1080-5. Epub 2003 May 15.Carames B, Kiosses WB, Akasaki Y, et al. Glucosamine activates autophagy in vitro and in vivo. Arthritis Rheum. 2013 Jul;65(7):1843-52. doi: 10.1002/art.37977Carames B, Kiosses WB, Akasaki Y, et al. Glucosamine activates autophagy in vitro and in vivo. Arthritis Rheum. 2013 Jul;65(7):1843-52. doi: 10.1002/art.37977Mobasheri A, Vannucci SJ, Bondy CA, et al. Glucose transport and metabolism in chondrocytes: a key to understanding chondrogenesis, skeletal development and cartilage degradation in osteoarthritis. Histol Histopathol. 2002 Oct;17(4):1239-67.Mobasheri A, Vannucci SJ, Bondy CA, et al. Glucose transport and metabolism in chondrocytes: a key to understanding chondrogenesis, skeletal development and cartilage degradation in osteoarthritis. Histol Histopathol. 2002 Oct;17(4):1239-67.Nakatani S, Mano H, Im R, et al. Glucosamine regulates differentiation of a chondrogenic cell line, ATDC5. Biol Pharm Bull. 2007 Mar;30(3):433-8. doi: 10.1248/bpb.30.433Nakatani S, Mano H, Im R, et al. Glucosamine regulates differentiation of a chondrogenic cell line, ATDC5. Biol Pharm Bull. 2007 Mar;30(3):433-8. doi: 10.1248/bpb.30.433Terry DE, Rees-Milton K, Pruss C, et al. Modulation of articular chondrocyte proliferation and anionic glycoconjugate synthesis by glucosamine (GlcN), N-acetyl GlcN (GlcNAc) GlcN sulfate salt (GlcN.S) and covalent glucosamine sulfates (GlcN-SO4). Osteoarthr Cartilage. 2007 Aug;15(8):946-56. doi: 10.1016/j.joca.2007.02.010. Epub 2007 Apr 2.Terry DE, Rees-Milton K, Pruss C, et al. Modulation of articular chondrocyte proliferation and anionic glycoconjugate synthesis by glucosamine (GlcN), N-acetyl GlcN (GlcNAc) GlcN sulfate salt (GlcN.S) and covalent glucosamine sulfates (GlcN-SO4). Osteoarthr Cartilage. 2007 Aug;15(8):946-56. doi: 10.1016/j.joca.2007.02.010. Epub 2007 Apr 2.Piperno M, Reboul P, Hellio Le Graverand MP, et al. Glucosamine sulfate modulates dysregulated activities of human osteoarthritic chondrocytes in vitro. Osteoarthr Cartilage. 2000 May;8(3):207-12. doi: 10.1053/joca.1999.0291Piperno M, Reboul P, Hellio Le Graverand MP, et al. Glucosamine sulfate modulates dysregulated activities of human osteoarthritic chondrocytes in vitro. Osteoarthr Cartilage. 2000 May;8(3):207-12. doi: 10.1053/joca.1999.0291Gouze JN, Gouze E, Popp MP, et al. Exogenous glucosamine globally protects chondrocytes from the arthritogenic effects of IL-1beta. Arthritis Res Ther. 2006;8:R173. doi: 10.1186/ar2082Gouze JN, Gouze E, Popp MP, et al. Exogenous glucosamine globally protects chondrocytes from the arthritogenic effects of IL-1beta. Arthritis Res Ther. 2006;8:R173. doi: 10.1186/ar2082Igarashi M, Kaga I, Takamori Y, et al. Effects of glucosamine derivatives and uronic acids on the production of glycosaminoglycans by human synovial cells and chondrocytes. Int J Mol Med. 2011 Jun;27(6):821-7. doi: 10.3892/ijmm.2011.662. Epub 2011 Mar 31.Igarashi M, Kaga I, Takamori Y, et al. Effects of glucosamine derivatives and uronic acids on the production of glycosaminoglycans by human synovial cells and chondrocytes. Int J Mol Med. 2011 Jun;27(6):821-7. doi: 10.3892/ijmm.2011.662. Epub 2011 Mar 31.Pavelka K, Gatterova J, Olejarova M, et al. Glucosamine sulfate use and delay of progression of knee osteoarthritis: a 3-year, randomized, placebo-controlled, double-blind study. Arch Intern Med. 2002 Oct 14;162(18):2113-23. doi: 10.1001/archinte.162.18.2113Pavelka K, Gatterova J, Olejarova M, et al. Glucosamine sulfate use and delay of progression of knee osteoarthritis: a 3-year, randomized, placebo-controlled, double-blind study. Arch Intern Med. 2002 Oct 14;162(18):2113-23. doi: 10.1001/archinte.162.18.2113Petersen SG, Saxne T, Heinegard D, et al. Glucosamine but not ibuprofen alters cartilage turnover in osteoarthritis patients in response to physical training. Osteoarthr Cartilage. 2010 Jan;18(1):34-40. doi: 10.1016/j.joca.2009.07.004. Epub 2009 Jul 15.Petersen SG, Saxne T, Heinegard D, et al. Glucosamine but not ibuprofen alters cartilage turnover in osteoarthritis patients in response to physical training. Osteoarthr Cartilage. 2010 Jan;18(1):34-40. doi: 10.1016/j.joca.2009.07.004. Epub 2009 Jul 15.Ali AA, Lewis SM, Badgley HL, et al. Oral glucosamine increases expression of transforming growth factor β1 (TGFβ1) and connective tissue growth factor (CTGF) mRNA in rat cartilage and kidney: implications for human efficacy and toxicity. Arch Biochem Biophys. 2011 Jun 1;510(1):11-8. doi: 10.1016/j.abb.2011.03.014. Epub 2011 Apr 3.Ali AA, Lewis SM, Badgley HL, et al. Oral glucosamine increases expression of transforming growth factor β1 (TGFβ1) and connective tissue growth factor (CTGF) mRNA in rat cartilage and kidney: implications for human efficacy and toxicity. Arch Biochem Biophys. 2011 Jun 1;510(1):11-8. doi: 10.1016/j.abb.2011.03.014. Epub 2011 Apr 3.Durmus D, Alayli G, Aliyazicioglu Y, et al. Effects of glucosamine sulfate and exercise therapy on serum leptin levels in patients with knee osteoarthritis: preliminary results of randomized controlled clinical trial. Rheumatol Int. 2013 Mar;33(3):593-9. doi: 10.1007/s00296-012-2401-9. Epub 2012 Apr 3.Durmus D, Alayli G, Aliyazicioglu Y, et al. Effects of glucosamine sulfate and exercise therapy on serum leptin levels in patients with knee osteoarthritis: preliminary results of randomized controlled clinical trial. Rheumatol Int. 2013 Mar;33(3):593-9. doi: 10.1007/s00296-012-2401-9. Epub 2012 Apr 3.Henrotin Y, Mobasheri A, Marty M. Is there any scientific evidence for the use of glucosamine in the management of human osteoarthritis? Arthritis Res Ther. 2012 Jan 30;14(1):201. doi: 10.1186/ar3657Henrotin Y, Mobasheri A, Marty M. Is there any scientific evidence for the use of glucosamine in the management of human osteoarthritis? Arthritis Res Ther. 2012 Jan 30;14(1):201. doi: 10.1186/ar3657Sherman AL, Ojeda-Correal G, Mena J. Use of glucosamine and chondroitin in persons with osteoarthritis. PM R. 2012 May;4(5 Suppl):S110-6. doi: 10.1016/j.pmrj.2012.02.021Sherman AL, Ojeda-Correal G, Mena J. Use of glucosamine and chondroitin in persons with osteoarthritis. PM R. 2012 May;4(5 Suppl):S110-6. doi: 10.1016/j.pmrj.2012.02.021Iannone F, Lapadula G. Obesity and inflammation – targets for OA therapy. Curr Drug Targets. 2010 May;11(5):586-98. doi: 10.2174/138945010791011857Iannone F, Lapadula G. Obesity and inflammation – targets for OA therapy. Curr Drug Targets. 2010 May;11(5):586-98. doi: 10.2174/138945010791011857Villavilla A, Gomez R, Largo R, Herrero-Beaumont G. Lipid transport and metabolism in healthy and osteoarthritic cartilage. Int J Mol Sci. 2013 Oct 16;14(10):20793-808. doi: 10.3390/ijms141020793Villavilla A, Gomez R, Largo R, Herrero-Beaumont G. Lipid transport and metabolism in healthy and osteoarthritic cartilage. Int J Mol Sci. 2013 Oct 16;14(10):20793-808. doi: 10.3390/ijms141020793Tong KM, Chen CP, Huang KC, et al. Adiponectin increases MMP-3 expression in human chondrocytes through AdipoR1 signaling pathway. J Cell Biochem. 2011 May;112(5):1431-40. doi: 10.1002/jcb.23059Tong KM, Chen CP, Huang KC, et al. Adiponectin increases MMP-3 expression in human chondrocytes through AdipoR1 signaling pathway. J Cell Biochem. 2011 May;112(5):1431-40. doi: 10.1002/jcb.23059Kang EH, Lee YJ, Kim TK, et al. Adiponectin is a potential catabolic mediator in osteoarthritis cartilage. Arthritis Res Ther. 2010;12(6):R231. doi: 10.1186/ar3218. Epub 2010 Dec 31.Kang EH, Lee YJ, Kim TK, et al. Adiponectin is a potential catabolic mediator in osteoarthritis cartilage. Arthritis Res Ther. 2010;12(6):R231. doi: 10.1186/ar3218. Epub 2010 Dec 31.Tang CH, Chiu YC, Tan TW, et al. Adiponectin enhances IL-6 production in human synovial fibroblast via an AdipoR1 receptor, AMPK, p38, and NF-kappa B pathway. J Immunol. 2007 Oct 15;179(8):5483-92. doi: 10.4049/jimmunol.179.8.5483Tang CH, Chiu YC, Tan TW, et al. Adiponectin enhances IL-6 production in human synovial fibroblast via an AdipoR1 receptor, AMPK, p38, and NF-kappa B pathway. J Immunol. 2007 Oct 15;179(8):5483-92. doi: 10.4049/jimmunol.179.8.5483Gkretsi V, Simopoulou T, Tsezou A. Lipid metabolism and osteoarthritis: Lessons from atherosclerosis. Prog. Lipid Res. 2011 Apr;50(2):133-40. doi: 10.1016/j.plipres.2010.11.001. Epub 2010 Nov 27.Gkretsi V, Simopoulou T, Tsezou A. Lipid metabolism and osteoarthritis: Lessons from atherosclerosis. Prog. Lipid Res. 2011 Apr;50(2):133-40. doi: 10.1016/j.plipres.2010.11.001. Epub 2010 Nov 27.Kosinska MK, Liebisch G, Lochnit G, et al. A lipidomic study of phospholipid classes and species in human synovial fluid. Arthritis Rheum. 2013 Sep;65(9):2323-33. doi: 10.1002/art.38053Kosinska MK, Liebisch G, Lochnit G, et al. A lipidomic study of phospholipid classes and species in human synovial fluid. Arthritis Rheum. 2013 Sep;65(9):2323-33. doi: 10.1002/art.38053Tsezou A, Iliopoulos D, Malizos KN, Simopoulou T. Impaired expression of genes regulating cholesterol efflux in human osteoarthritic chondrocytes. J Orthop Res. 2010 Aug;28(8):1033-9. doi: 10.1002/jor.21084Tsezou A, Iliopoulos D, Malizos KN, Simopoulou T. Impaired expression of genes regulating cholesterol efflux in human osteoarthritic chondrocytes. J Orthop Res. 2010 Aug;28(8):1033-9. doi: 10.1002/jor.21084Bernstein P, Sticht C, Jacobi A, et al. Expression pattern differences between osteoarthritic chondrocytes and mesenchymal stem cells during chondrogenic differentiation. Osteoarthr Cartilage. 2010 Dec;18(12):1596-607. doi: 10.1016/j.joca.2010.09.007. Epub 2010 Sep 29.Bernstein P, Sticht C, Jacobi A, et al. Expression pattern differences between osteoarthritic chondrocytes and mesenchymal stem cells during chondrogenic differentiation. Osteoarthr Cartilage. 2010 Dec;18(12):1596-607. doi: 10.1016/j.joca.2010.09.007. Epub 2010 Sep 29.Gabay O, Sanchez, Salvat C, et al. A phytosterol with potential anti-osteoarthritic properties. Osteoarthr Cartilage. 2010 Jan;18(1):106-16. doi: 10.1016/j.joca.2009.08.019. Epub 2009 Sep 15.Gabay O, Sanchez, Salvat C, et al. A phytosterol with potential anti-osteoarthritic properties. Osteoarthr Cartilage. 2010 Jan;18(1):106-16. doi: 10.1016/j.joca.2009.08.019. Epub 2009 Sep 15.Huang MJ, Wang L, Jin DD, et al. Enhancement of the synthesis of n-3 PUFAs in fat-1 transgenic mice inhibits mTORC1 signalling and delays surgically induced osteoarthritis in comparison with wild-type mice. Ann Rheum Dis. 2014 Sep;73(9):1719-27. doi: 10.1136/annrheumdis-2013-203231. Epub 2013 Jul 12.Huang MJ, Wang L, Jin DD, et al. Enhancement of the synthesis of n-3 PUFAs in fat-1 transgenic mice inhibits mTORC1 signalling and delays surgically induced osteoarthritis in comparison with wild-type mice. Ann Rheum Dis. 2014 Sep;73(9):1719-27. doi: 10.1136/annrheumdis-2013-203231. Epub 2013 Jul 12.Loeser RF. Aging and osteoarthritis. Curr Opin Rheumatol. 2011 Sep;23(5):492-6. doi: 10.1097/BOR.0b013e3283494005Loeser RF. Aging and osteoarthritis. Curr Opin Rheumatol. 2011 Sep;23(5):492-6. doi: 10.1097/BOR.0b013e3283494005Grcevic D, Jajic Z, Kovacic N, et al. Peripheral blood expression profiles of bone morphogenetic proteins, tumor necrosis factorsuperfamily molecules, and transcription factor Runx2 could be used as markers of the form of arthritis, disease activity, and therapeutic responsiveness. J Rheumatol. 2010 Feb;37(2):246-56. doi: 10.3899/jrheum.090167. Epub 2009 Dec 15.Grcevic D, Jajic Z, Kovacic N, et al. Peripheral blood expression profiles of bone morphogenetic proteins, tumor necrosis factorsuperfamily molecules, and transcription factor Runx2 could be used as markers of the form of arthritis, disease activity, and therapeutic responsiveness. J Rheumatol. 2010 Feb;37(2):246-56. doi: 10.3899/jrheum.090167. Epub 2009 Dec 15.Mahr S, Burmester GR, Hilke D, et al. Cis and Trans-acting gene regulation is associated with osteoarthritis. Am J Hum Genet. 2006 May;78(5):793-803. doi: 10.1086/503849. Epub 2006 Mar 22.Mahr S, Burmester GR, Hilke D, et al. Cis and Trans-acting gene regulation is associated with osteoarthritis. Am J Hum Genet. 2006 May;78(5):793-803. doi: 10.1086/503849. Epub 2006 Mar 22.Marshal KW, Zhang H, Yager TD, et al. Blood-based biomarkers for detecting mild osteoarthritis in the human knee. Osteoarthritis Cartilage. 2005 Oct13;(10):861-71. doi: 10.1016/j.joca.2005.06.002Marshal KW, Zhang H, Yager TD, et al. Blood-based biomarkers for detecting mild osteoarthritis in the human knee. Osteoarthritis Cartilage. 2005 Oct13;(10):861-71. doi: 10.1016/j.joca.2005.06.002Attur M, Belitskaya-Levy I, Oh C, et al. Increased interleukin-1β gene expression in peripheral blood leukocytes is associated with increased pain and predicts risk for progression of symptomatic knee osteoarthritis. Arthritis Rheum. 2011 Jul;63(7):1908-17. doi: 10.1002/art.30360Attur M, Belitskaya-Levy I, Oh C, et al. Increased interleukin-1β gene expression in peripheral blood leukocytes is associated with increased pain and predicts risk for progression of symptomatic knee osteoarthritis. Arthritis Rheum. 2011 Jul;63(7):1908-17. doi: 10.1002/art.30360Melemedjian OK, Khoutorsky A, Sorge RE, et al. mTORC1 inhibition induces pain via IRS-1-dependent feedback activation of ERK. Pain. 2013 Jul;154(7):1080-91. doi: 10.1016/j.pain.2013.03.021. Epub 2013 Mar 15.Melemedjian OK, Khoutorsky A, Sorge RE, et al. mTORC1 inhibition induces pain via IRS-1-dependent feedback activation of ERK. Pain. 2013 Jul;154(7):1080-91. doi: 10.1016/j.pain.2013.03.021. Epub 2013 Mar 15.Laragione T, Gulko PS. MTOR regulates the invasive properties of synovial fibroblasts in rheumatoid arthritis. Mol Med. 2010 Sept-Oct;16(9-10):352-8. doi: 10.2119/molmed.2010.00049. Epub 2010 May 27.Laragione T, Gulko PS. MTOR regulates the invasive properties of synovial fibroblasts in rheumatoid arthritis. Mol Med. 2010 Sept-Oct;16(9-10):352-8. doi: 10.2119/molmed.2010.00049. Epub 2010 May 27.

The authors declare that there are no conflicts of interest present.