Ageing and Osteoarthritis

  • Pradeep Kumar Sacitharan
Part of the Subcellular Biochemistry book series (SCBI, volume 91)


The increase in global lifespan has in turn increased the prevalence of osteoarthritis which is now the most common type of arthritis. Cartilage tissue located on articular joints erodes during osteoarthritis which causes pain and may lead to a crippling loss of function in patients. The pathophysiology of osteoarthritis has been understudied and currently no disease modifying treatments exist. The only current end-point treatment remains joint replacement surgery. The primary risk factor for osteoarthritis is age. Clinical and basic research is now focused on understanding the ageing process of cartilage and its role in osteoarthritis. This chapter will outline the physiology of cartilage tissue, the clinical presentation and treatment options for the disease and the cellular ageing processes which are involved in the pathophysiology of the disease.


Osteoarthritis Aging Cartilage Chondrocytes 



Work by this author was supported by a U.S.-U.K. All Disciplines Fulbright Research Scholar Award.


  1. Aigner T, Fundel K, Saas J et al (2006) Large-scale gene expression profiling reveals major pathogenetic pathways of cartilage degeneration in osteoarthritis. Arthritis Rheum 54:3533–3544. CrossRefPubMedGoogle Scholar
  2. Ailixiding M, Aibibula Z, Iwata M et al (2015) Pivotal role of Sirt6 in the crosstalk among ageing, metabolic syndrome and osteoarthritis. Biochem Biophys Res Commun 466:319–326. CrossRefPubMedGoogle Scholar
  3. Akasaki Y, Alvarez-Garcia O, Saito M, et al (2014a) FOXO transcription factors support oxidative stress resistance in human chondrocytes. Arthritis Rheumatol (Hoboken, NJ).
  4. Akasaki Y, Hasegawa A, Saito M et al (2014b) Dysregulated FOXO transcription factors in articular cartilage in aging and osteoarthritis. Osteoarthr Cartil 22:162–170. CrossRefPubMedGoogle Scholar
  5. Alvarez J, Balbin M, Fernandez M, Lopez JM (2001) Collagen metabolism is markedly altered in the hypertrophic cartilage of growth plates from rats with growth impairment secondary to chronic renal failure. J Bone Miner Res 16:511–524CrossRefGoogle Scholar
  6. Amin AR (1999) Regulation of tumor necrosis factor-alpha and tumor necrosis factor converting enzyme in human osteoarthritis. Osteoarthr Cartil 7:392–394CrossRefGoogle Scholar
  7. Amin AR, Abramson SB (1998) The role of nitric oxide in articular cartilage breakdown in osteoarthritis. Curr Opin Rheumatol 10:263–268. CrossRefPubMedGoogle Scholar
  8. Archer CW, Francis-West P (2003) The chondrocyte. Int J Biochem Cell Biol 35:401–404CrossRefGoogle Scholar
  9. Arden NK, Lane NE, Parimi N et al (2009) Defining incident radiographic hip osteoarthritis for epidemiologic studies in women. Arthritis Rheum 60:1052–1059. CrossRefPubMedPubMedCentralGoogle Scholar
  10. Baker MS, Feigan JLD (1988) Chondrocyte antioxidant defences: the roles of catalase and glutathione peroxidase in protection against H2O2 dependent inhibition of proteoglycan biosynthesis. J Rheumatol 15:670–677PubMedGoogle Scholar
  11. Bell DM, Leung KK, Wheatley SC et al (1997) SOX9 directly regulates the type-II collagen gene. Nat Genet 16:174–178. CrossRefPubMedGoogle Scholar
  12. Bijlsma JWJ, Berenbaum F, Lafeber FPJG (2011) Osteoarthritis: an update with relevance for clinical practice. Lancet 377:2115–2126. CrossRefPubMedGoogle Scholar
  13. Blaney Davidson EN, Vitters EL, van Beuningen HM et al (2007) Resemblance of osteophytes in experimental osteoarthritis to transforming growth factor beta-induced osteophytes: limited role of bone morphogenetic protein in early osteoarthritic osteophyte formation. Arthritis Rheum 56:4065–4073. CrossRefPubMedGoogle Scholar
  14. Blom AB, van Lent PLEM, Holthuysen AEM et al (2004) Synovial lining macrophages mediate osteophyte formation during experimental osteoarthritis. Osteoarthr Cartil 12:627–635. CrossRefPubMedGoogle Scholar
  15. Boileau C, Martel-pelletier J, Fahmi H, Boily M (2007) The peroxisome proliferator – activated receptor gamma agonist pioglitazone reduces the development of cartilage lesions in an experimental dog model of osteoarthritis: in vivo protective effects mediated through the inhibition of key signaling and catabolic pathways. Arthritis Rheum 56:2288–2298. CrossRefPubMedGoogle Scholar
  16. Bouderlique T, Vuppalapati KK, Newton PT, et al (2015) Targeted deletion of Atg5 in chondrocytes promotes age-related osteoarthritis. Ann Rheum Dis annrheumdis-2015-207742.
  17. Boya P, Reggiori F, Codogno P (2013) Emerging regulation and functions of autophagy. Nat Cell Biol 15:1017–1017. CrossRefGoogle Scholar
  18. Brandt KD, Dieppe P, Radin E (2009) Etiopathogenesis of osteoarthritis. Med Clin North Am 93:1–24CrossRefGoogle Scholar
  19. Brook MS, Wilkinson DJ, Phillips BE et al (2015) Skeletal muscle homeostasis and plasticity in youth and ageing: impact of nutrition and exercise. Acta Physiol n/a-n/a.
  20. Buckingham JC (2006) Glucocorticoids: exemplars of multi-tasking. Br J Pharmacol 147(Suppl):S258–S268. CrossRefPubMedPubMedCentralGoogle Scholar
  21. Buckwalter JA, Mankin HJ (1998) Articular cartilage: tissue design and chondrocyte-matrix interactions. Instr Course Lect 47:477–486PubMedGoogle Scholar
  22. Burleigh A, Chanalaris A, Gardiner MD et al (2012) Joint immobilization prevents murine osteoarthritis and reveals the highly mechanosensitive nature of protease expression in vivo. Arthritis Rheum 64:2278–2288. CrossRefPubMedGoogle Scholar
  23. Calich ALG, Domiciano DS, Fuller R (2010) Osteoarthritis: can anti-cytokine therapy play a role in treatment? Clin Rheumatol 29:451–455. CrossRefPubMedGoogle Scholar
  24. Caramés B, Taniguchi N, Otsuki S et al (2010) Autophagy is a protective mechanism in normal cartilage, and its aging-related loss is linked with cell death and osteoarthritis. Arthritis Rheum 62:791–801. CrossRefPubMedPubMedCentralGoogle Scholar
  25. Carames B, Hasegawa A, Taniguchi N et al (2012) Autophagy activation by rapamycin reduces severity of experimental osteoarthritis. Ann Rheum Dis 71:575–581. CrossRefPubMedGoogle Scholar
  26. Caramés B, Olmer M, Kiosses WB, Lotz MK (2015) The relationship of autophagy defects to cartilage damage during joint aging in a mouse model. Arthritis Rheumatol 67:1568–1576. CrossRefPubMedPubMedCentralGoogle Scholar
  27. Carlo MD, Loeser RF (2003) Increased oxidative stress with aging reduces chondrocyte survival: correlation with intracellular glutathione levels. Arthritis Rheum 48:3419–3430. CrossRefPubMedGoogle Scholar
  28. Carlsén S, Hansson AS, Olsson H et al (1998) Cartilage oligomeric matrix protein (COMP)-induced arthritis in rats. Clin Exp Immunol 114:477–484. CrossRefPubMedPubMedCentralGoogle Scholar
  29. Chakravarti S (2002) Functions of lumican and fibromodulin: lessons from knockout mice. Glycoconj J 19:287–293CrossRefGoogle Scholar
  30. Cheng DS, Visco CJ (2012) Pharmaceutical therapy for osteoarthritis. PM R 4:S82–S88. CrossRefPubMedGoogle Scholar
  31. Chevalier X, Eymard F, Richette P (2013) Biologic agents in osteoarthritis: hopes and disappointments. Nat Rev Rheumatol 9:400–410. CrossRefPubMedGoogle Scholar
  32. Christensen R, Bartels EM, Astrup A, Bliddal H (2007) Effect of weight reduction in obese patients diagnosed with knee osteoarthritis: a systematic review and meta-analysis. Ann Rheum Dis 66:433–439. CrossRefPubMedPubMedCentralGoogle Scholar
  33. Cicuttini FM, Wluka AE (2014) Osteoarthritis: is OA a mechanical or systemic disease? Nat Rev Rheumatol 10:1–2. CrossRefGoogle Scholar
  34. Cirillo DJ, Wallace RB, Wu L, Yood RA (2006) Effect of hormone therapy on risk of hip and knee joint replacement in the women’s health initiative. Arthritis Rheum 54:3194–3204. CrossRefPubMedGoogle Scholar
  35. Clockaerts S, Bastiaansen-jenniskens YM, Feijt C et al (2011) Peroxisome proliferator activated receptor alpha activation decreases inflammatory and destructive responses in osteoarthritic cartilage. Osteoarthr Cartil 19:895–902. CrossRefPubMedGoogle Scholar
  36. Daans M, Luyten FP, Lories RJU (2011) GDF5 deficiency in mice is associated with instability-driven joint damage, gait and subchondral bone changes. Ann Rheum Dis 70:208–213. CrossRefPubMedGoogle Scholar
  37. Dagenais S, Garbedian S, Wai EK (2009) Systematic review of the prevalence of radiographic primary hip osteoarthritis. Clin Orthop Relat Res 467(3):623–637CrossRefGoogle Scholar
  38. De Crombrugghe B, Lefebvre V, Behringer RR et al (2000) Transcriptional mechanisms of chondrocyte differentiation. Matrix Biol 19:389–394CrossRefGoogle Scholar
  39. DeLise AM, Fischer L, Tuan RS (2000) Cellular interactions and signaling in cartilage development. Osteoarthr Cartil 8:309–334. CrossRefPubMedGoogle Scholar
  40. Drissi H, Zuscik M, Rosier R, O’Keefe R (2005) Transcriptional regulation of chondrocyte maturation: potential involvement of transcription factors in OA pathogenesis. Mol Aspects Med 26:169–179CrossRefGoogle Scholar
  41. Dvir-Ginzberg M, Gagarina V, Lee E-J, Hall DJ (2008) Regulation of cartilage-specific gene expression in human chondrocytes by SirT1 and nicotinamide phosphoribosyltransferase. J Biol Chem 283:36300–36310. CrossRefPubMedPubMedCentralGoogle Scholar
  42. Eijkelenboom A, Burgering BMT (2013) FOXOs: signalling integrators for homeostasis maintenance. Nat Rev Mol Cell Biol 14:83–97. CrossRefPubMedGoogle Scholar
  43. Ekenstedt KJ, Sonntag WE, Loeser RF et al (2006) Effects of chronic growth hormone and insulin-like growth factor 1 deficiency on osteoarthritis severity in rat knee joints. Arthritis Rheum 54:3850–3858. CrossRefPubMedGoogle Scholar
  44. Englund M, Guermazi A, Gale D et al (2008) Incidental meniscal findings on knee MRI in middle-aged and elderly persons. N Engl J Med 359:1108–1115. CrossRefPubMedPubMedCentralGoogle Scholar
  45. Fang W, Wu P, Hu R, Huang Z (2003) Environmental Se-Mo-B deficiency and its possible effects on crops and Keshan-beck disease (KBD) in the Chousang area, Yao County, Shaanxi Province. China Environ Geochem Health 25:267–280. CrossRefPubMedGoogle Scholar
  46. Feldmann M, Maini RN (2001) Anti-TNF alpha therapy of rheumatoid arthritis: what have we learned? Annu Rev Immunol 19:163–196. doi: 19/1/163[pii]\r10.1146/annurev.immunol.19.1.163Google Scholar
  47. Felson DT, Naimark A, Anderson J et al (1987) The prevalence of knee osteoarthritis in the elderly. The Framingham Osteoarthritis Study. Arthritis Rheum 30:914–918. CrossRefPubMedGoogle Scholar
  48. Felson DT, Zhang Y, Anthony JM et al (1992) Weight loss reduces the risk for symptomatic knee osteoarthritis in women: the Framingham Study. Ann Intern Med 116:535–539. CrossRefPubMedGoogle Scholar
  49. Ferguson MA, Kinoshita T, Hart GW (2009) Essentials of glycobiology, 2nd edn. Cold Spring Harbor Laboratory Press, New YorkGoogle Scholar
  50. Fortier LA, Mohammed HO, Lust G, Nixon a J (2002) Cell-based repair of articular cartilage. J Bone Jt Surg Br 84:276–288CrossRefGoogle Scholar
  51. Francois M, Richette P, Tsagris L et al (2006) Activation of the peroxisome proliferator-activated receptor alpha pathway potentiates interleukin-1 receptor antagonist production in cytokine-treated chondrocytes. Arthritis Rheum 54:1233–1245. CrossRefPubMedGoogle Scholar
  52. Fujita N, Matsushita T, Ishida K et al (2011) Potential involvement of SIRT1 in the pathogenesis of osteoarthritis through the modulation of chondrocyte gene expressions. J Orthop Res 29:511–515. CrossRefPubMedGoogle Scholar
  53. Fukumoto T, Sperling JW, Sanyal A et al (2003) Combined effects of insulin-like growth factor-1 and transforming growth factor-beta1 on periosteal mesenchymal cells during chondrogenesis in vitro. Osteoarthr Cartil 11:55–64. CrossRefPubMedGoogle Scholar
  54. Gabay O, Oppenhiemer H, Meir H, et al (2012) NIH Public Access. 71:613–616.
  55. Gabay O, Sanchez C, Dvir-Ginzberg M et al (2013) Sirtuin 1 enzymatic activity is required for cartilage homeostasis in vivo in a mouse model. Arthritis Rheum 65:159–166. CrossRefPubMedPubMedCentralGoogle Scholar
  56. Gendron C, Kashiwagi M, Hughes C et al (2003) TIMP-3 inhibits aggrecanase-mediated glycosaminoglycan release from cartilage explants stimulated by catabolic factors. FEBS Lett 555:431–436. CrossRefPubMedGoogle Scholar
  57. Giblin W, Skinner ME, Lombard DB (2014) Sirtuins: guardians of mammalian healthspan. Trends Genet 30:271–286. CrossRefPubMedPubMedCentralGoogle Scholar
  58. Glasson SS, Askew R, Sheppard B et al (2004) Characterization of and osteoarthritis susceptibility in ADAMTS-4-knockout mice. Arthritis Rheum 50:2547–2558. CrossRefPubMedGoogle Scholar
  59. Glyn-Jones S, Palmer AJR, Agricola R et al (2015) Osteoarthritis. Lancet 386:376–387. CrossRefPubMedGoogle Scholar
  60. Goldring MB (2012) Chondrogenesis, chondrocyte differentiation, and articular cartilage metabolism in health and osteoarthritis. Ther Adv Musculoskelet Dis 4:269–285. CrossRefPubMedPubMedCentralGoogle Scholar
  61. Goldring MB, Berenbaum F (2015) Emerging targets in osteoarthritis therapy. Curr Opin Pharmacol 22:51–63.
  62. Goldring MB, Marcu KB (2012) Epigenomic and microRNA-mediated regulation in cartilage development, homeostasis, and osteoarthritis. Trends Mol Med 18:109–118. CrossRefPubMedGoogle Scholar
  63. Goldring MB, Otero M (2011) Inflammation in osteoarthritis. Curr Opin Rheumatol 23:471–478. CrossRefPubMedPubMedCentralGoogle Scholar
  64. Goodrich LR, Hidaka C, Robbins PD et al (2007) Genetic modification of chondrocytes with insulin-like growth factor-1 enhances cartilage healing in an equine model. J Bone Jt Surg Br 89–B:672–685. CrossRefGoogle Scholar
  65. Gorrini C, Harris IS, Mak TW (2013) Modulation of oxidative stress as an anticancer strategy. Nat Rev Drug Discov 12:931–947. CrossRefPubMedGoogle Scholar
  66. Gudbergsen H, Lohmander LS, Jones G et al (2013) Correlations between radiographic assessments and MRI features of knee osteoarthritis – a cross-sectional study. Osteoarthr Cartil 21:535–543. CrossRefPubMedGoogle Scholar
  67. Hall BK, Miyake T (1992) The membranous skeleton: the role of cell condensations in vertebrate skeletogenesis. Anat Embryol (Berl) 186:107–124CrossRefGoogle Scholar
  68. Heinegård D, Saxne T (2011) The role of the cartilage matrix in osteoarthritis. Nat Rev Rheumatol 7:50–56. CrossRefPubMedGoogle Scholar
  69. Heinegard D, Inerot S, Olsson SE, Saxne T (1987) Cartilage proteoglycans in degenerative joint disease. J Rheumatol 14:110–112PubMedGoogle Scholar
  70. Hetz C (2012) The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Publ Gr 13:89–102. CrossRefGoogle Scholar
  71. Hiligsmann M, Cooper C, Guillemin F et al (2014) A reference case for economic evaluations in osteoarthritis: an expert consensus article from the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO). Semin Arthritis Rheum 44:271–282CrossRefGoogle Scholar
  72. Hiramatsu K, Iwai T, Yoshikawa H, Tsumaki N (2011) Expression of dominant negative TGF-β receptors inhibits cartilage formation in conditional transgenic mice. J Bone Miner Metab 29:493–500. CrossRefPubMedGoogle Scholar
  73. Hochberg MC, Altman RD, April KT et al (2012) American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res 64:465–474. CrossRefGoogle Scholar
  74. Hofmann C, Gropp R, von der Mark K (1992) Expression of anchorin CII, a collagen-binding protein of the annexin family, in the developing chick embryo. Dev Biol 151:391–400. CrossRefPubMedGoogle Scholar
  75. Hunter DJ (2011) Pharmacologic therapy for osteoarthritis – the era of disease modification. Nat Rev Rheumatol 7:13–22. CrossRefPubMedGoogle Scholar
  76. Hunter DJ, Demissie S, Cupples LA et al (2004) A genome scan for joint-specific hand osteoarthritis susceptibility: the Framingham Study. Arthritis Rheum 50:2489–2496. CrossRefPubMedGoogle Scholar
  77. Husa M, Petursson F, Lotz M et al (2013) C/EBP homologous protein drives pro-catabolic responses in chondrocytes. Arthritis Res Ther 15:R218. CrossRefPubMedPubMedCentralGoogle Scholar
  78. Jallali N, Ridha H, Thrasivoulou C et al (2005) Vulnerability to ROS-induced cell death in ageing articular cartilage: the role of antioxidant enzyme activity. Osteoarthr Cartil 13:614–622. CrossRefPubMedGoogle Scholar
  79. Jallali N, Ridha H, Thrasivoulou C et al (2007) Modulation of intracellular reactive oxygen species level in chondrocytes by IGF-1, FGF, and TGF-beta1. Connect Tissue Res 48:149–158. CrossRefPubMedGoogle Scholar
  80. Järvinen TA, Jozsa L, Kannus P et al (1999) Mechanical loading regulates tenascin-C expression in the osteotendinous junction. J Cell Sci 112(Pt 18):3157–3166PubMedGoogle Scholar
  81. Jensen LK, Eenberg W (1996) Occupation as a risk factor for knee disorders. Scand J Work Environ Heal 22:165–175CrossRefGoogle Scholar
  82. Jordan JM, Helmick CG, Renner JB et al (2009) Prevalence of hip symptoms and radiographic and symptomatic hip osteoarthritis in African Americans and Caucasians: the Johnston County osteoarthritis project. J Rheumatol 36:809–815. CrossRefPubMedPubMedCentralGoogle Scholar
  83. Kapoor M, Martel-Pelletier J, Lajeunesse D et al (2011) Role of proinflammatory cytokines in the pathophysiology of osteoarthritis. Nat Rev Rheumatol 7:33–42. CrossRefPubMedGoogle Scholar
  84. Karlson EW, Mandl LA, Aweh GN et al (2003) Total hip replacement due to osteoarthritis: the importance of age, obesity, and other modifiable risk factors. Am J Med 114:93–98. CrossRefPubMedGoogle Scholar
  85. Kashiwagi M, Tortorella M, Nagase H, Brew K (2001) TIMP-3 is a potent inhibitor of aggrecanase 1 (ADAM-TS4) and aggrecanase 2 (ADAM-TS5). J Biol Chem 276:12501–12504. CrossRefPubMedGoogle Scholar
  86. Keene DR, Jordan CD, Reinhardt DP et al (1997) Fibrillin-1 in human cartilage: developmental expression and formation of special banded fibers. J Histochem Cytochem 45:1069–1082. CrossRefPubMedGoogle Scholar
  87. Kellgren J, Lawrence J (1957) Radiological assessment of osteoarthritis. Ann Rheum Dis 16:494CrossRefGoogle Scholar
  88. King LK, March L, Anandacoomarasamy A (2013) Obesity & osteoarthritis. Indian J Med Res 138:185–193PubMedPubMedCentralGoogle Scholar
  89. Knudson CB, Knudson W (2001) Cartilage proteoglycans. Semin Cell Dev Biol 12:69–78. CrossRefPubMedGoogle Scholar
  90. Knudson W, Aguiar DJ, Hua Q, Knudson CB (1996) CD44-anchored hyaluronan-rich pericellular matrices: an ultrastructural and biochemical analysis. Exp Cell Res 228:216–228. CrossRefPubMedGoogle Scholar
  91. Lane NE, Gore LR, Cummings SR et al (1999) Serum vitamin D levels and incident changes of radiographic hip osteoarthritis: a longitudinal study. Study of Osteoporotic Fractures Research Group. Arthritis Rheum 42:854–860.<854::AID-ANR3>3.0.CO;2-I CrossRefPubMedGoogle Scholar
  92. Leyland KM, Hart DJ, Javaid MK et al (2012) The natural history of radiographic knee osteoarthritis: a fourteen-year population-based cohort study. Arthritis Rheum 64:2243–2251. CrossRefPubMedGoogle Scholar
  93. Little CB, Barai A, Burkhardt D et al (2009) Matrix metalloproteinase 13-deficient mice are resistant to osteoarthritic cartilage erosion but not chondrocyte hypertrophy or osteophyte development. Arthritis Rheum 60:3723–3733. CrossRefPubMedPubMedCentralGoogle Scholar
  94. Liu Y, Zhou J, Zhao W et al (2012) XBP1S associates with RUNX2 and regulates chondrocyte hypertrophy. J Biol Chem 287:34500–34513. CrossRefPubMedPubMedCentralGoogle Scholar
  95. Liu-Bryan R, Terkeltaub R (2015) Emerging regulators of the inflammatory process in osteoarthritis. Nat Rev Rheumatol 11:35–44. CrossRefPubMedGoogle Scholar
  96. Lo YY, Cruz TF (1995) Involvement of reactive oxygen species in cytokine and growth factor induction of c-fos expression in chondrocytes. J Biol Chem 270:11727–11730CrossRefGoogle Scholar
  97. Loeser RF (2012a) NIH Public Access. 23:492–496.
  98. Loeser RF (2012b) Aging processes and the development of osteoarthritis. Curr Opin Rheumatol 25(1).
  99. Loeser RF, Shanker G, Carlson CS et al (2000) Reduction in the chondrocyte response to insulin-like growth factor 1 in aging and osteoarthritis: studies in a non-human primate model of naturally occurring disease. Arthritis Rheum 43:2110–2120.<2110::AID-ANR23>3.0.CO;2-U CrossRefPubMedGoogle Scholar
  100. Loeser RF, Carlson CS, Del Carlo M, Cole A (2002) 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. CrossRefPubMedGoogle Scholar
  101. Lotz MK, Caramés B (2011) Autophagy and cartilage homeostasis mechanisms in joint health, aging and OA. Nat Rev Rheumatol 7:579–587. CrossRefPubMedPubMedCentralGoogle Scholar
  102. Lotz M, Loeser RF (2012) Effects of aging on articular cartilage homeostasis. Bone 51:241–248. CrossRefPubMedPubMedCentralGoogle Scholar
  103. Loughlin J (2001) Genetic epidemiology of primary osteoarthritis. Curr Opin Rheumatol 13:111–116. CrossRefPubMedGoogle Scholar
  104. Loughlin J (2005) The genetic epidemiology of human primary osteoarthritis: current status. Expert Rev Mol Med 7:1–12. CrossRefPubMedGoogle Scholar
  105. Luo G, D’Souza R, Hogue D, Karsenty G (1995) The matrix Gla protein gene is a marker of the chondrogenesis cell lineage during mouse development. J Bone Miner Res 10:325–334. CrossRefPubMedGoogle Scholar
  106. Maroudas A, Bullough P (1968) Permeability of articular cartilage. Nature 219:1260–1261. CrossRefPubMedGoogle Scholar
  107. Massagué J (2012) TGFβ signalling in context. Nat Rev Mol Cell Biol 13:616–630. CrossRefPubMedPubMedCentralGoogle Scholar
  108. Matsiko A, Levingstone TJ, O’Brien FJ (2013) Advanced strategies for articular cartilage defect repair. Materials (Basel) 6:637–668. CrossRefGoogle Scholar
  109. Matsuzaki T, Matsushita T, Takayama K et al (2013) Disruption of Sirt1 in chondrocytes causes accelerated progression of osteoarthritis under mechanical stress and during ageing in mice. Ann Rheum Dis.
  110. McAlindon TE, Felson DT, Zhang Y et al (1996a) Relation of dietary intake and serum levels of vitamin D to progression of osteoarthritis of the knee among participants in the Framingham Study. Ann Intern Med 125:353–359. CrossRefPubMedGoogle Scholar
  111. McAlindon TE, Jacques P, Zhang Y et al (1996b) Do antioxidant micronutrients protect against the development and progression of knee osteoarthritis? Arthritis Rheum 39:648–656. CrossRefPubMedGoogle Scholar
  112. McInnes IB, Schett G (2007) Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol 7:429–442. CrossRefPubMedGoogle Scholar
  113. McMillan G, Nichols L (2005) Osteoarthritis and meniscus disorders of the knee as occupational diseases of miners. Occup Environ Med 62:567–575. CrossRefPubMedPubMedCentralGoogle Scholar
  114. Melchiorri C, Meliconi R, Frizziero L et al (1998) Enhanced and coordinated in vivo expression of inflammatory cytokines and nitric oxide synthase by chondrocytes from patients with osteoarthritis. Arthritis Rheum 41:2165–2174.<2165::AID-ART11>3.0.CO;2-O CrossRefPubMedGoogle Scholar
  115. Messier SP, Loeser RF, Miller GD et al (2004) Exercise and dietary weight loss in overweight and obese older adults with knee osteoarthritis: the arthritis, diet, and activity promotion trial. Arthritis Rheum 50:1501–1510. CrossRefPubMedGoogle Scholar
  116. Milner JM, Rowan AD, Cawston TE, D a Y (2006) Metalloproteinase and inhibitor expression profiling of resorbing cartilage reveals pro-collagenase activation as a critical step for collagenolysis. Arthritis Res Ther 8:R142. CrossRefPubMedPubMedCentralGoogle Scholar
  117. Mintz G, Fraga A (1973) Severe osteoarthritis of the elbow in foundry workers. Arch Environ Heal An Int J 27:78–80. CrossRefGoogle Scholar
  118. Miyamoto Y, Mabuchi A, Shi DQ et al (2007) A functional polymorphism in the 5′ UTR of GDF5 is associated with susceptibility to osteoarthritis. Nat Genet 39:529–533. CrossRefPubMedGoogle Scholar
  119. Moos V, Fickert S, Müller B et al (1999) Immunohistological analysis of cytokine expression in human osteoarthritic and healthy cartilage. J Rheumatol 26:870–879PubMedGoogle Scholar
  120. Morales TI (2008) The quantitative and functional relation between insulin-like growth factor-I (IGF) and IGF-binding proteins during human osteoarthritis. J Orthop Res 26:465–474. CrossRefPubMedPubMedCentralGoogle Scholar
  121. Moreno-Reyes R, Mathieu F, Boelaert M et al (2003) Selenium and iodine supplementation of rural Tibetan children affected by Kashin-Beck osteoarthropathy. Am J Clin Nutr 78:137–144CrossRefGoogle Scholar
  122. Morris BJ (2013) Seven sirtuins for seven deadly diseases of aging. Free Radic Biol Med 56:133–171. CrossRefPubMedGoogle Scholar
  123. Murphy K, Travers P, Walport M et al (2008) Janeway’s immunobiology. New York: Garland Science Janeway’s immunobiology, 7th edn. Shock 29:770Google Scholar
  124. Nagase H, Kashiwagi M (2003) Aggrecanases and cartilage matrix degradation. Arthritis Res Ther 5:94–103. CrossRefPubMedPubMedCentralGoogle Scholar
  125. Nagase H, Visse R, Murphy G (2006) Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res 69:562–573. CrossRefPubMedGoogle Scholar
  126. Nakagawa T, Guarente L (2011) Sirtuins at a glance. J Cell Sci 124:833–838. CrossRefPubMedPubMedCentralGoogle Scholar
  127. Nathan C, Cunningham-Bussel A (2013) Beyond oxidative stress: an immunologist’s guide to reactive oxygen species. Nat Rev Immunol 13:349–361. CrossRefPubMedPubMedCentralGoogle Scholar
  128. Nelson F, Billinghurst RC, Pidoux RT et al (2006) Early post-traumatic osteoarthritis-like changes in human articular cartilage following rupture of the anterior cruciate ligament. Osteoarthr Cartil 14:114–119. CrossRefPubMedGoogle Scholar
  129. Neogi T, Zhang Y (2013) Epidemiology of osteoarthritis. Rheum Dis Clin North Am 39:1–19CrossRefGoogle Scholar
  130. Neogi T, Felson DT, Sarno R, Booth SL (2008) Vitamin K in hand osteoarthritis: results from a randomised clinical trial. Ann Rheum Dis 67:1570–1573. CrossRefPubMedPubMedCentralGoogle Scholar
  131. Neuhold LA, Killar L, Zhao W et al (2001) Postnatal expression in hyaline cartilage of constitutively active human collagenase-3 (MMP-13) induces osteoarthritis in mice. J Clin Invest 107:35–44. CrossRefPubMedPubMedCentralGoogle Scholar
  132. Nevitt MC, Felson DT, Williams EN, Grady D (2001) The effect of estrogen plus progestin on knee symptoms and related disability in postmenopausal women: The Heart and Estrogen/Progestin Replacement Study, a randomized, double-blind, placebo-controlled trial. Arthritis Rheum 44(4):811–818
  133. Øiestad BE, Engebretsen L, Storheim K, Risberg MA (2009) Knee osteoarthritis after anterior cruciate ligament injury: a systematic review. Am J Sports Med 37:1434–1443. CrossRefPubMedGoogle Scholar
  134. Okamura Y, Watari M, Jerud ES et al (2001) The extra domain A of fibronectin activates Toll-like receptor 4. J Biol Chem 276:10229–10233.
  135. Oldberg A, Antonsson P, Lindblom K, Heinegård D (1992) COMP (cartilage oligomeric matrix protein) is structurally related to the thrombospondins. J Biol Chem 267:22346–22350PubMedGoogle Scholar
  136. Olin AI, Mörgelin M, Sasaki T et al (2001) The proteoglycans aggrecan and versican form networks with fibulin-2 through their lectin domain binding. J Biol Chem 276:1253–1261. CrossRefPubMedPubMedCentralGoogle Scholar
  137. Oliveria SA, Felson DT, Reed JI et al (1995) Incidence of symptomatic hand, hip, and knee osteoarthritis among patients in a health maintenance organization. Arthritis Rheum 38:1134–1141. CrossRefPubMedGoogle Scholar
  138. Orlowsky EW, Kraus VB (2015) The role of innate immunity in osteoarthritis: When our first line of defense goes on the offensive. J Rheumatol 42(3):363–371.
  139. Page-McCaw A, Ewald AJ, Werb Z (2007) Matrix metalloproteinases and the regulation of tissue remodelling. Nat Rev Mol Cell Biol 8:221–233. CrossRefPubMedPubMedCentralGoogle Scholar
  140. Peach CA, Carr AJ, Loughlin J (2005) Recent advances in the genetic investigation of osteoarthritis. Trends Mol Med 11:186–191CrossRefGoogle Scholar
  141. Pearle AD, Warren RF, S a R (2005) Basic science of articular cartilage and osteoarthritis. Clin Sports Med 24:1–12. CrossRefPubMedGoogle Scholar
  142. Pelletier JP, Caron JP, Evans C et al (1997) In vivo suppression of early experimental osteoarthritis by interleukin-1 receptor antagonist using gene therapy. Arthritis Rheum 40:1012–1019.<1012::AID-ART3>3.0.CO;2-#
  143. Peters JM, Shah YM, Gonzalez FJ (2012) The role of peroxisome proliferator-activated receptors in carcinogenesis and chemoprevention. Nat Publ Gr 12:181–195. CrossRefGoogle Scholar
  144. Pettipher ER, Higgs G a, Henderson B (1986) Interleukin 1 induces leukocyte infiltration and cartilage proteoglycan degradation in the synovial joint. Proc Natl Acad Sci U S A 83:8749–8753. CrossRefPubMedPubMedCentralGoogle Scholar
  145. Petursson F, Husa M, June R et al (2013) Linked decreases in liver kinase B1 and AMP-activated protein kinase activity modulate matrix catabolic responses to biomechanical injury in chondrocytes. Arthritis Res Ther 15:R77. CrossRefPubMedPubMedCentralGoogle Scholar
  146. Pfander D, Heinz N, Rothe P et al (2004) Tenascin and aggrecan expression by articular chondrocytes is influenced by interleukin 1beta: a possible explanation for the changes in matrix synthesis during osteoarthritis. Ann Rheum Dis 63:240–244. CrossRefPubMedPubMedCentralGoogle Scholar
  147. Ratneswaran A, LeBlanc EAA, Walser E et al (2015) Peroxisome proliferator-activated receptor δ promotes the progression of posttraumatic osteoarthritis in a mouse model. Arthritis Rheumatol (Hoboken, NJ) 67:454–464. CrossRefGoogle Scholar
  148. Rees J a, Ali SY, Brown R a (1987) Ultrastructural localisation of fibronectin in human osteoarthritic articular cartilage. Ann Rheum Dis 46:816–822. CrossRefPubMedPubMedCentralGoogle Scholar
  149. Reynard LN, Loughlin J (2012) Genetics and epigenetics of osteoarthritis. Maturitas 71:200–204. CrossRefPubMedGoogle Scholar
  150. Reynard LN, Bui C, Canty-laird EG et al (2011) Expression of the osteoarthritis-associated gene GDF5 is modulated epigenetically by DNA methylation. Hum Mol Genet 20:3450–3460. CrossRefPubMedGoogle Scholar
  151. Rock MJ, Cain SA, Freeman LJ et al (2004) Molecular basis of elastic fiber formation: critical interactions and a tropoelastin-fibrillin-1 cross-link. J Biol Chem 279:23748–23758. CrossRefPubMedGoogle Scholar
  152. Ron D, Walter P (2007) Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 8:519–529. doi: nrm2199 [pii]\n10.1038/nrm2199Google Scholar
  153. Rosenberg K, Olsson H, Mörgelin M, Heinegård D (1998) Cartilage oligomeric matrix protein shows high affinity zinc-dependent interaction with triple helical collagen. J Biol Chem 273:20397–20403. CrossRefPubMedGoogle Scholar
  154. Rubinsztein DC, Mariño G, Kroemer G (2011) Autophagy and aging. Cell 146:682–695. CrossRefPubMedGoogle Scholar
  155. Ruiz-Romero C, López-Armada MJ, Blanco FJ (2006) Mitochondrial proteomic characterization of human normal articular chondrocytes. Osteoarthr Cartil 14:507–518. CrossRefPubMedGoogle Scholar
  156. Ruiz-Romero C, Calamia V, Mateos J et al (2009) Mitochondrial dysregulation of osteoarthritic human articular chondrocytes analyzed by proteomics: a decrease in mitochondrial superoxide dismutase points to a redox imbalance. Mol Cell Proteomics 8:172–189. CrossRefPubMedPubMedCentralGoogle Scholar
  157. Ryan MC, Sandell LJ (1990) Differential expression of a cysteine-rich domain in the amino-terminal propeptide of type II (cartilage) procollagen by alternative splicing of mRNA. J Biol Chem 265:10334–10339PubMedGoogle Scholar
  158. Sacitharan PK, Snelling SJB, Edwards JR (2012) Aging mechanisms in arthritic disease. Discov Med 14:345–352PubMedGoogle Scholar
  159. Sah R, Chen AC, Grodzinsky AJ, Trippel S (1994) Differential effect of bFGF and IGF-I on matrix metabolism in calf and adult bovine cartilage explants. Arch Biochem Biophys 308:137–147CrossRefGoogle Scholar
  160. Saklatvala J (1981) Characterization of catabolin, the major product of pig synovial tissue that induces resorption of cartilage proteoglycan in vitro. Biochem J 199:705–714CrossRefGoogle Scholar
  161. Saklatvala J (1986) Tumour necrosis factor alpha stimulates resorption and inhibits synthesis of proteoglycan in cartilage. Nature 322:547–549. CrossRefPubMedGoogle Scholar
  162. Salminen A, Kaarniranta K (2012) AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network. Ageing Res Rev 11:230–241. CrossRefPubMedGoogle Scholar
  163. Salmon WD, Daughaday WH (1957) A hormonally controlled serum factor which stimulates sulfate incorporation by cartilage in vitro. J Lab Clin Med 49:825–836. CrossRefPubMedGoogle Scholar
  164. Sandell LJ, Morris N, Robbins JR, Goldring MB (1991) Alternatively spliced type II procollagen mRNAs define distinct populations of cells during vertebral development: differential expression of the amino-propeptide. J Cell Biol 114:1307–1319. CrossRefPubMedGoogle Scholar
  165. Scanzello CR, Goldring SR (2012) The role of synovitis in osteoarthritis pathogenesis. Bone 51:249–257. CrossRefPubMedPubMedCentralGoogle Scholar
  166. Serra R, Johnson M, Filvaroff EH et al (1997) Expression of a truncated, kinase-defective TGF-β type II receptor in mouse skeletal tissue promotes terminal chondrocyte differentiation and osteoarthritis. J Cell Biol 139:541–552. CrossRefPubMedPubMedCentralGoogle Scholar
  167. Shane Anderson A, Loeser RF (2010) Why is osteoarthritis an age-related disease? Best Pract Res Clin Rheumatol 24:15–26CrossRefGoogle Scholar
  168. Shen J, Li J, Wang B et al (2013) Deletion of the transforming growth factor β receptor type II gene in articular chondrocytes leads to a progressive osteoarthritis-like phenotype in mice. Arthritis Rheum 65:3107–3119. CrossRefPubMedPubMedCentralGoogle Scholar
  169. Shen J, Li S, Chen D (2014) TGF-β signaling and the development of osteoarthritis. Bone Res 2:14002. CrossRefPubMedPubMedCentralGoogle Scholar
  170. Shoulders MD, Raines RT (2010) Collagen structure and stability. Annu Rev Biochem 78:929–958. CrossRefGoogle Scholar
  171. Singh D, Srivastava SK, Chaudhuri TK, Upadhyay G (2015) Multifaceted role of matrix metalloproteinases (MMPs). Front Mol Biosci 2:19. CrossRefPubMedPubMedCentralGoogle Scholar
  172. Smith MD, Triantafillou S, Parker a, et al (1997) Synovial membrane inflammation and cytokine production in patients with early osteoarthritis. J Rheumatol 24:365–371Google Scholar
  173. Sock E, Pagon RA, Keymolen K et al (2003) Loss of DNA-dependent dimerization of the transcription factor SOX9 as a cause for campomelic dysplasia. Hum Mol Genet 12:1439–1447. CrossRefPubMedGoogle Scholar
  174. Sophia Fox AJ, Bedi A, Rodeo SA (2009) The basic science of articular cartilage: structure, composition, and function. Sports Health 1:461–468. CrossRefPubMedPubMedCentralGoogle Scholar
  175. Spector TD, Cicuttini F, Baker J et al (1996) Genetic influences on osteoarthritis in women: a twin study. BMJ 312:940–943. CrossRefPubMedPubMedCentralGoogle Scholar
  176. Srikanth VK, Fryer JL, Zhai G et al (2005) A meta-analysis of sex differences prevalence, incidence and severity of osteoarthritis. Osteoarthr Cartil 13:769–781. CrossRefPubMedGoogle Scholar
  177. Stanton H, Melrose J, Little CB, Fosang AJ (2011) Proteoglycan degradation by the ADAMTS family of proteinases. Biochim Biophys Acta Mol Basis Dis 1812:1616–1629CrossRefGoogle Scholar
  178. Stefan L, Martin P, Stefan Lohmander OL et al (2007) The long-term consequence of ACL and meniscus injuries. Am J Sport Med 35:1756–1769. CrossRefGoogle Scholar
  179. Stockwell RA (1978) Chondrocytes. J Clin Pathol (Royal Coll Pathol) 12:7–13CrossRefGoogle Scholar
  180. Stockwell R a (1991) Cartilage failure in osteoarthritis: relevance of normal structure and function. A review. Clin Anat 4:161–191. CrossRefGoogle Scholar
  181. Styrkarsdottir U, Thorleifsson G, Helgadottir HT et al (2014) Severe osteoarthritis of the hand associates with common variants within the ALDH1A2 gene and with rare variants at 1p31. Nat Genet 46:498–502. CrossRefPubMedGoogle Scholar
  182. Takada K, Hirose J, Senba K et al (2011) Enhanced apoptotic and reduced protective response in chondrocytes following endoplasmic reticulum stress in osteoarthritic cartilage. Int J Exp Pathol 92:232–242. CrossRefPubMedPubMedCentralGoogle Scholar
  183. Takayama K, Ishida K, Matsushita T et al (2009) SIRT1 regulation of apoptosis of human chondrocytes. Arthritis Rheum 60:2731–2740. CrossRefPubMedGoogle Scholar
  184. Tepper S, Hochberg MC (1993) Factors associated with hip osteoarthritis: data from the First National Health and Nutrition Examination Survey (NHANES-I). Am J Epidemiol 137:1081–1088CrossRefGoogle Scholar
  185. Terkeltaub R, Yang B, Lotz M, Liu-Bryan R (2011) Chondrocyte AMP-activated protein kinase activity suppresses matrix degradation responses to proinflammatory cytokines interleukin-1β and tumor necrosis factor α. Arthritis Rheum 63:1928–1937. CrossRefPubMedPubMedCentralGoogle Scholar
  186. Thirunavukkarasu K, Pei Y, Wei T (2007) Characterization of the human ADAMTS-5 (aggrecanase-2) gene promoter. Mol Biol Rep 34:225–231. CrossRefPubMedGoogle Scholar
  187. Thomas JT, Ayad S, Grant ME (1994) Cartilage collagens: strategies for the study of their organisation and expression in the extracellular matrix. Ann Rheum Dis 53:488–496. CrossRefPubMedPubMedCentralGoogle Scholar
  188. Tortorella MD, Burn TC, Pratta MA et al (1999) Purification and cloning of aggrecanase-1: a member of the ADAMTS family of proteins. Science 284:1664–1666. CrossRefPubMedGoogle Scholar
  189. Tsukazaki T, Matsumoto T, Enomoto H, Usa T, Ohtsuru A, Namba H, Iwasaki KYS (1994) Growth hormone directly and indirectly stimulates articular chondrocyte cell growth. Osteoarthr Cartil 2:259–267CrossRefGoogle Scholar
  190. Uehara Y, Hirose J, Yamabe S et al (2014) Endoplasmic reticulum stress-induced apoptosis contributes to articular cartilage degeneration via C/EBP homologous protein. Osteoarthr Cartil 22:1007–1017. CrossRefPubMedGoogle Scholar
  191. Uthman OA, van der Windt DA, Jordan JL et al (2013) Exercise for lower limb osteoarthritis: systematic review incorporating trial sequential analysis and network meta-analysis. BMJ 347:f5555. CrossRefPubMedPubMedCentralGoogle Scholar
  192. Valdes AM, Spector TD (2009) The contribution of genes to osteoarthritis. Med Clin North Am 93:45–66CrossRefGoogle Scholar
  193. Valdes AM, Spector TD (2014) Genetics of osteoarthritis. Rheumatology: sixth edition. Elsevier Academic Press Inc, Massachusetts, pp 1477–1482Google Scholar
  194. van Saase JL, van Romunde LK, Cats a, et al (1989) Epidemiology of osteoarthritis: zoetermeer survey. Comparison of radiological osteoarthritis in a Dutch population with that in 10 other populations. Ann Rheum Dis 48:271–280. doi:
  195. Vasheghani F, Monemdjou R, Fahmi H et al (2013) SHORT COMMUNICATION Adult cartilage-specific peroxisome proliferator-activated receptor gamma knockout mice exhibit the spontaneous osteoarthritis phenotype. Am J Pathol 182:1099–1106. CrossRefPubMedGoogle Scholar
  196. Vasheghani F, Zhang Y, Li Y et al (2015) PPAR γ deficiency results in severe, accelerated osteoarthritis associated with aberrant mTOR signalling in the articular cartilage. Ann Rheum Dis:569–578.
  197. Verdin E (2014) The many faces of sirtuins: coupling of NAD metabolism, sirtuins and lifespan. Nat Med 20:25–27. CrossRefPubMedGoogle Scholar
  198. Verma RP, Hansch C (2007) Matrix metalloproteinases (MMPs): chemical-biological functions and (Q)SARs. Bioorganic Med Chem 15:2223–2268CrossRefGoogle Scholar
  199. Vincent TL, Watt FE (2014) Osteoarthritis. Medicine (Baltimore) 42:213–219. CrossRefGoogle Scholar
  200. Westling J, Fosang AJ, Last K et al (2002) ADAMTS4 cleaves at the aggrecanase site (Glu373-Ala374) and secondarily at the matrix metalloproteinase site (Asn341-Phe342) in the aggrecan interglobular domain. J Biol Chem 277:16059–16066. CrossRefPubMedGoogle Scholar
  201. Wieland HA, Michaelis M, Kirschbaum BJ, Rudolphi KA (2005) Osteoarthritis – an untreatable disease? Nat Rev Drug Discov 4:331–344. CrossRefPubMedGoogle Scholar
  202. Wluka AE, Cicuttini FM, Spector TD (2000) Menopause, oestrogens and arthritis. Maturitas 35:183–199CrossRefGoogle Scholar
  203. Woolf AD, Pfleger B (2003) Burden of major musculoskeletal conditions. Bull World Health Organ 81:646–656. doi: S0042-96862003000900007 [pii]PubMedPubMedCentralGoogle Scholar
  204. Wu Q, Huang JH, Sampson ER et al (2009) Smurf2 induces degradation of GSK-3beta and upregulates beta-catenin in chondrocytes: a potential mechanism for Smurf2-induced degeneration of articular cartilage. Exp Cell Res 315:2386–2398. CrossRefPubMedPubMedCentralGoogle Scholar
  205. Wu Y, Chen L, Wang Y et al (2015) Overexpression of Sirtuin 6 suppresses cellular senescence and NF-κB mediated inflammatory responses in osteoarthritis development. Sci Rep 5:17602. CrossRefPubMedPubMedCentralGoogle Scholar
  206. Yang X, Chen L, Xu X et al (2001) TGF-beta/Smad3 signals repress chondrocyte hypertrophic differentiation and are required for maintaining articular cartilage. J Cell Biol 153:35–46. CrossRefPubMedPubMedCentralGoogle Scholar
  207. Zhang Y, Niu J, Kelly-Hayes M et al (2002) Prevalence of symptomatic hand osteoarthritis and its impact on functional status among the elderly: the Framingham Study. Am J Epidemiol 156:1021–1027. CrossRefPubMedGoogle Scholar
  208. Zhang Y, Vasheghani F, Li Y-H et al (2014) Cartilage-specific deletion of mTOR upregulates autophagy and protects mice from osteoarthritis. Ann Rheum Dis 1(9).
  209. Zhen G, Wen C, Jia X et al (2013) Inhibition of TGF-β signaling in mesenchymal stem cells of subchondral bone attenuates osteoarthritis. Nat Med 19:704–712. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Pradeep Kumar Sacitharan
    • 1
  1. 1.Institute of Ageing and Chronic DiseaseUniversity of LiverpoolLiverpoolUK

Personalised recommendations