Cellular senescence in osteoarthritis pathology

Aging Cell

Volumn 16, Issue 2, 2017, Pages 210-218

  McCulloch, Kendal ^a   Litherland, Gary J ^a   Rai, Taranjit Singh ^a  

^a UNIVERSITY OF THE WEST OF SCOTLAND   (United Kingdom)

Author keywords

cellular senescence; epigenetics; osteoarthritis

Indexed keywords

AUTOPHAGY; BONE; CARTILAGE; CELL AGING; CHONDROCYTE; EPIGENETICS; GENETIC ASSOCIATION; HUMAN; MICROENVIRONMENT; MOLECULAR PATHOLOGY; NONHUMAN; OSTEOARTHRITIS; PRIORITY JOURNAL; REVIEW; SENESCENCE; ANIMAL; BIOLOGICAL MODEL; GENETIC EPIGENESIS; GENETICS; PATHOLOGY;

ANIMALS; CELL AGING; EPIGENESIS, GENETIC; HUMANS; MODELS, BIOLOGICAL; OSTEOARTHRITIS;

EID: 85014393758     PISSN: 14749718     EISSN: 14749726     Source Type: Journal    
DOI: 10.1111/acel.12562     Document Type: Review

References (108)

1. Acosta JC, O'Loghlen A, Banito A, Guijarro MV, Augert A, Raguz S, Fumagalli M, Da Costa M, Brown C, Popov N, Takatsu Y, Melamed J, d'Adda di Fagagna F, Bernard D, Hernando E, Gil J (2008) Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell 133, 1006–1018.
2. Acosta JC, Banito A, Wuestefeld T, Georgilis A, Janich P, Morton JP, Athineos D, Kang TW, Lasitschka F, Andrulis M, Pascual G, Morris KJ, Khan S, Jin H, Dharmalingam G, Snijders AP, Carroll T, Capper D, Pritchard C, Inman GJ, Longerich T, Sansom OJ, Benitah SA, Zender L, Gil J (2013) A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat. Cell Biol. 15, 978–990.
3. d'Adda di Fagagna F (2008) Living on a break: cellular senescence as a DNA-damage response. Nat. Rev. Cancer 8, 512–522.
4. d'Adda di Fagagna F, Reaper PM, Clay-Farrace L, Fiegler H, Carr P, Von Zglinicki T, Saretzki G, Carter NP, Jackson SP (2003) A DNA damage checkpoint response in telomere-initiated senescence. Nature 426, 194–198.
5. Aigner T, Hemmel M, Neureiter D, Gebhard PM, Zeiler G, Kirchner T, McKenna L (2001) Apoptotic cell death is not a widespread phenomenon in normal aging and osteoarthritis human articular knee cartilage: a study of proliferation, programmed cell death (apoptosis), and viability of chondrocytes in normal and osteoarthritic human knee cartilage. Arthritis Rheum. 44, 1304–1312.
6. Ashraf S, Ahn J, Cha BH, Kim JS, Han I, Park H, Lee SH (2016) RHEB: a potential regulator of chondrocyte phenotype for cartilage tissue regeneration. J. Tissue Eng. Regen. Med. DOI: 10.1002/term.2148.
7. Baker DJ, Perez-Terzic C, Jin F, Pitel K, Niederlander NJ, Jeganathan K, Yamada S, Reyes S, Rowe L, Hiddinga HJ, Eberhardt NL, Terzic A, van Deursen JM (2008) Opposing roles for p16Ink4a and p19Arf in senescence and ageing caused by BubR1 insufficiency. Nat. Cell Biol. 10, 825–836.
8. Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG, van de Sluis B, Kirkland JL, van Deursen JM (2011) Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479, 232–236.
9. Baker DJ, Weaver RL, van Deursen JM (2013) p21 both attenuates and drives senescence and aging in BubR1 progeroid mice. Cell Rep. 3, 1164–1174.
10. Baker DJ, Childs BG, Durik M, Wijers ME, Sieben CJ, Zhong J, Saltness RA, Jeganathan KB, Verzosa GC, Pezeshki A, Khazaie K, Miller JD, van Deursen JM (2016) Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature 530, 184–189.
11. Benito MJ, Veale DJ, FitzGerald O, van den Berg WB, Bresnihan B (2005) Synovial tissue inflammation in early and late osteoarthritis. Ann. Rheum. Dis. 64, 1263–1267.
12. Billinghurst RC, Dahlberg L, Ionescu M, Reiner A, Bourne R, Rorabeck C, Mitchell P, Hambor J, Diekmann O, Tschesche H, Chen J, Van Wart H, Poole AR (1997) Enhanced cleavage of type II collagen by collagenases in osteoarthritic articular cartilage. J. Clin. Invest. 99, 1534–1545.
13. Bouderlique T, Vuppalapati KK, Newton PT, Li L, Barenius B, Chagin AS (2016) Targeted deletion of Atg5 in chondrocytes promotes age-related osteoarthritis. Ann. Rheum. Dis. 75, 627–631.
14. Bucala R, Ritchlin C, Winchester R, Cerami A (1991) Constitutive production of inflammatory and mitogenic cytokines by rheumatoid synovial fibroblasts. J. Exp. Med. 173, 569–574.
15. Bui C, Barter MJ, Scott JL, Xu Y, Galler M, Reynard LN, Rowan AD, Young DA (2012) cAMP response element-binding (CREB) recruitment following a specific CpG demethylation leads to the elevated expression of the matrix metalloproteinase 13 in human articular chondrocytes and osteoarthritis. FASEB J. 26, 3000–3011.
16. Burd CE, Sorrentino JA, Clark KS, Darr DB, Krishnamurthy J, Deal AM, Bardeesy N, Castrillon DH, Beach DH, Sharpless NE (2013) Monitoring tumorigenesis and senescence in vivo with a p16(INK4a)-luciferase model. Cell 152, 340–351.
17. Burton DG, Sheerin AN, Ostler EL, Smith K, Giles PJ, Lowe J, Rhys-Williams W, Kipling DG, Faragher RG (2007) Cyclin D1 overexpression permits the reproducible detection of senescent human vascular smooth muscle cells. Ann. N. Y. Acad. Sci. 1119, 20–31.
18. Campisi J (2005) Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell 120, 513–522.
19. Carames B, Taniguchi N, Otsuki S, Blanco FJ, Lotz M (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.
20. Carames 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.
21. Chang J, Wang Y, Shao L, Laberge R-M, Demaria M, Campisi J, Janakiraman K, Sharpless NE, Ding S, Feng W, Luo Y, Wang X, Aykin-Burns N, Krager K, Ponnappan U, Hauer-Jensen M, Meng A, Zhou D (2016) Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat. Med. 22, 78–83.
22. Cheung JOP, Hillarby MC, Ayad S, Hoyland JA, Jones CJP, Denton J, Thomas JT, Wallis GA, Grant ME (2001) A novel cell culture model of chondrocyte differentiation during mammalian endochondral ossification. J. Bone Miner. Res. 16, 309–318.
23. Cheung JO, Grant ME, Jones CJ, Hoyland JA, Freemont AJ, Hillarby MC (2003) Apoptosis of terminal hypertrophic chondrocytes in an in vitro model of endochondral ossification. J. Pathol. 201, 496–503.
24. Childs BG, Baker DJ, Wijshake T, Conover CA, Campisi J, van Deursen JM (2016) Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science 354, 472–477.
25. Cross M, Smith E, Hoy D, Nolte S, Ackerman I, Fransen M, Bridgett L, Williams S, Guillemin F, Hill CL, Laslett LL, Jones G, Cicuttini F, Osborne R, Vos T, Buchbinder R, Woolf A, March L (2014) The global burden of hip and knee osteoarthritis: estimates from the global burden of disease 2010 study. Ann. Rheum. Dis. 73, 1323–1330.
26. Cruickshanks HA, McBryan T, Nelson DM, Vanderkraats ND, Shah PP, van Tuyn J, Singh Rai T, Brock C, Donahue G, Dunican DS, Drotar ME, Meehan RR, Edwards JR, Berger SL, Adams PD (2013) Senescent cells harbour features of the cancer epigenome. Nat. Cell Biol. 15, 1495–1506.
27. Culley KL, Hui W, Barter MJ, Davidson RK, Swingler TE, Destrument APM, Scott JL, Donell ST, Fenwick S, Rowan AD, Young DA, Clark IM (2013) Class I histone deacetylase inhibition modulates metalloproteinase expression and blocks cytokine-induced cartilage degradation. Arthritis Rheum. 65, 1822–1830.
28. D'Angelo M, Yan Z, Nooreyazdan M, Pacifici M, Sarment DS, Billings PC, Leboy PS (2000) MMP-13 is induced during chondrocyte hypertrophy. J. Cell. Biochem. 77, 678–693.
29. Delmore Jake E, Issa Ghayas C, Lemieux Madeleine E, Rahl Peter B, Shi J, Jacobs Hannah M, Kastritis E, Gilpatrick T, Paranal Ronald M, Qi J, Chesi M, Schinzel Anna C, McKeown Michael R, Heffernan Timothy P, Vakoc Christopher R, Bergsagel PL, Ghobrial Irene M, Richardson Paul G, Young Richard A, Hahn William C, Anderson Kenneth C, Kung Andrew L, Bradner JE, Mitsiades CS (2011) BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 146, 904–917.
30. Demidenko ZN, Blagosklonny MV (2008) Growth stimulation leads to cellular senescence when the cell cycle is blocked. Cell Cycle 7, 3355–3361.
31. Dhomen N, Reis-Filho JS, da Rocha Dias S, Hayward R, Savage K, Delmas V, Larue L, Pritchard C, Marais R (2009) Oncogenic Braf induces melanocyte senescence and melanoma in mice. Cancer Cell 15, 294–303.
32. Di Leonardo A, Linke SP, Clarkin K, Wahl GM (1994) DNA damage triggers a prolonged p53-dependent G1 arrest and long-term induction of Cip1 in normal human fibroblasts. Genes Dev. 8, 2540–2551.
33. Di Micco R, Fumagalli M, Cicalese A, Piccinin S, Gasparini P, Luise C, Schurra C, Garre M, Giovanni Nuciforo P, Bensimon A, Maestro R, Giuseppe Pelicci P, d'Adda di Fagagna F (2006) Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature 444, 638–642.
34. Di Micco R, Sulli G, Dobreva M, Liontos M, Botrugno OA, Gargiulo G, dal Zuffo R, Matti V, d'Ario G, Montani E, Mercurio C, Hahn WC, Gorgoulis V, Minucci S, d'Adda di Fagagna F (2011) Interplay between oncogene-induced DNA damage response and heterochromatin in senescence and cancer. Nat. Cell Biol. 13, 292–302.
35. Dimri GP, Hara E, Campisi J (1994) Regulation of two E2F-related genes in presenescent and senescent human fibroblasts. J. Biol. Chem. 269, 16180–16186.
36. Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, Medrano EE, Linskens M, Rubelj I, Pereira-Smith O, Peacocke M, Campisi J (1995) A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc. Natl Acad. Sci. USA 92, 9363–9367.
37. Dimri GP, Testori A, Acosta M, Campisi J (1996) Replicative senescence, aging and growth-regulatory transcription factors. Biol. Signals 5, 154–162.
38. Enomoto H, Enomoto-Iwamoto M, Iwamoto M, Nomura S, Himeno M, Kitamura Y, Kishimoto T, Komori T (2000) Cbfa1 is a positive regulatory factor in chondrocyte maturation. J. Biol. Chem. 275, 8695–8702.
39. Enomoto H, Inoki I, Komiya K, Shiomi T, Ikeda E, Obata K-I, Matsumoto H, Toyama Y, Okada Y (2003) Vascular endothelial growth factor isoforms and their receptors are expressed in human osteoarthritic cartilage. Am. J. Pathol. 162, 171–181.
40. Erusalimsky JD, Kurz DJ (2005) Cellular senescence in vivo: its relevance in ageing and cardiovascular disease. Exp. Gerontol. 40, 634–642.
41. Ezura Y, Sekiya I, Koga H, Muneta T, Noda M (2009) Methylation status of CpG islands in the promoter regions of signature genes during chondrogenesis of human synovium–derived mesenchymal stem cells. Arthritis Rheum. 60, 1416–1426.
42. Farr JN, Fraser DG, Wang H, Jaehn K, Ogrodnik MB, Weivoda MM, Drake MT, Tchkonia T, LeBrasseur NK, Kirkland JL, Bonewald LF, Pignolo RJ, Monroe DG, Khosla S (2016) Identification of senescent cells in the bone microenvironment. J. Bone Miner. Res. 31, 1920–1929.
43. Feinberg AP, Vogelstein B (1983) Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature 301, 89–92.
44. Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, Nakajima Y, Nakayama O, Makishima M, Matsuda M, Shimomura I (2004) Increased oxidative stress in obesity and its impact on metabolic syndrome. J. Clin. Invest. 114, 1752–1761.
45. Gao S-G, Zeng C, Li L-J, Luo W, Zhang F-J, Tian J, Cheng C, Tu M, Xiong Y-L, Jiang W, Xu M, Lei G-H (2016) Correlation between senescence-associated beta-galactosidase expression in articular cartilage and disease severity of patients with knee osteoarthritis. Int. J. Rheum. Dis. 19, 226–232.
46. García-Prat L, Martínez-Vicente M, Perdiguero E, Ortet L, Rodríguez-Ubreva J, Rebollo E, Ruiz-Bonilla V, Gutarra S, Ballestar E, Serrano AL, Sandri M, Muñoz-Cánoves P (2016) Autophagy maintains stemness by preventing senescence. Nature 529, 37–42.
47. Gelber AC, Hochberg MC, Mead LA, Wang N, Wigley FM, Klag MJ (2000) Joint injury in young adults and risk for subsequent knee and hip osteoarthritis. Ann. Intern. Med. 133, 321–328.
48. Giatromanolaki A, Sivridis E, Maltezos E, Athanassou N, Papazoglou D, Gatter KC, Harris AL, Koukourakis MI (2003) Upregulated hypoxia inducible factor-1alpha and -2alpha pathway in rheumatoid arthritis and osteoarthritis. Arthritis. Res. Ther. 5, R193–R201.
49. Goel VK, Ibrahim N, Jiang G, Singhal M, Fee S, Flotte T, Westmoreland S, Haluska FS, Hinds PW, Haluska FG (2009) Melanocytic nevus-like hyperplasia and melanoma in transgenic BRAFV600E mice. Oncogene 28, 2289–2298.
50. Grounds MD (2014) Therapies for sarcopenia and regeneration of old skeletal muscles: more a case of old tissue architecture than old stem cells. Bioarchitecture 4, 81–87.
51. Harbo M, Bendix L, Bay-Jensen A-C, Graakjaer J, Søe K, Andersen TL, Kjaersgaard-Andersen P, Koelvraa S, Delaisse J-M (2012) The distribution pattern of critically short telomeres in human osteoarthritic knees. Arthritis. Res. Ther. 14, R12–R12.
52. Harbo M, Delaisse JM, Kjaersgaard-Andersen P, Soerensen FB, Koelvraa S, Bendix L (2013) The relationship between ultra-short telomeres, aging of articular cartilage and the development of human hip osteoarthritis. Mech. Ageing Dev. 134, 367–372.
53. Hashimoto S, Creighton-Achermann L, Takahashi K, Amiel D, Coutts RD, Lotz M (2002) Development and regulation of osteophyte formation during experimental osteoarthritis. Osteoarthritis Cartilage 10, 180–187.
54. Hashimoto K, Oreffo ROC, Gibson MB, Goldring MB, Roach HI (2009) DNA De-methylation at specific CpG sites in the IL1B promoter in response to inflammatory cytokines in human articular chondrocytes. Arthritis Rheum. 60, 3303–3313.
55. Hayami T, Pickarski M, Wesolowski GA, McLane J, Bone A, Destefano J, Rodan GA, Duong LT (2004) The role of subchondral bone remodeling in osteoarthritis: reduction of cartilage degeneration and prevention of osteophyte formation by alendronate in the rat anterior cruciate ligament transection model. Arthritis Rheum. 50, 1193–1206.
56. Hayflick L, Moorhead PS (1961) The serial cultivation of human diploid cell strains. Exp. Cell Res. 25, 585–621.
57. Herbig U, Jobling WA, Chen BP, Chen DJ, Sedivy JM (2004) Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21(CIP1), but not p16(INK4a). Mol. Cell 14, 501–513.
58. Jeyapalan JC, Ferreira M, Sedivy JM, Herbig U (2007) Accumulation of senescent cells in mitotic tissue of aging primates. Mech. Ageing Dev. 128, 36–44.
59. Kamekura S, Kawasaki Y, Hoshi K, Shimoaka T, Chikuda H, Maruyama Z, Komori T, Sato S, Takeda S, Karsenty G, Nakamura K, Chung UI, Kawaguchi H (2006) Contribution of runt-related transcription factor 2 to the pathogenesis of osteoarthritis in mice after induction of knee joint instability. Arthritis Rheum. 54, 2462–2470.
60. Keaney JF, Larson MG, Vasan RS, Wilson PWF, Lipinska I, Corey D, Massaro JM, Sutherland P, Vita JA, Benjamin EJ (2003) Obesity and systemic oxidative stress. Arterioscler. Thromb. Vasc. Biol. 23, 434.
61. Koobatian MT, Liang MS, Swartz DD, Andreadis ST (2015) Differential effects of culture senescence and mechanical stimulation on the proliferation and leiomyogenic differentiation of MSC from different sources: implications for engineering vascular grafts. Tissue Eng. Part A 21, 1364–1375.
62. Krishnamurthy J, Torrice C, Ramsey MR, Kovalev GI, Al-Regaiey K, Su L, Sharpless NE (2004) Ink4a/Arf expression is a biomarker of aging. J. Clin. Invest. 114, 1299–1307.
63. Krizhanovsky V, Yon M, Dickins RA, Hearn S, Simon J, Miething C, Yee H, Zender L, Lowe SW (2008) Senescence of activated stellate cells limits liver fibrosis. Cell 134, 657–667.
64. Kuilman T, Peeper DS (2009) Senescence-messaging secretome: SMS-ing cellular stress. Nat. Rev. Cancer 9, 81–94.
65. Kuilman T, Michaloglou C, Vredeveld LC, Douma S, van Doorn R, Desmet CJ, Aarden LA, Mooi WJ, Peeper DS (2008) Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 133, 1019–1031.
66. Lefebvre V, Huang W, Harley VR, Goodfellow PN, de Crombrugghe B (1997) SOX9 is a potent activator of the chondrocyte-specific enhancer of the pro alpha1(II) collagen gene. Mol. Cell. Biol. 17, 2336–2346.
67. Lefevre S, Knedla A, Tennie C, Kampmann A, Wunrau C, Dinser R, Korb A, Schnaker EM, Tarner IH, Robbins PD, Evans CH, Sturz H, Steinmeyer J, Gay S, Scholmerich J, Pap T, Muller-Ladner U, Neumann E (2009) Synovial fibroblasts spread rheumatoid arthritis to unaffected joints. Nat. Med. 15, 1414–1420.
68. Little CB, Barai A, Burkhardt D, Smith SM, Fosang AJ, Werb Z, Shah M, Thompson EW (2009) Matrix metalloproteinase 13-deficient mice are resistant to osteoarthritic cartilage erosion but not chondrocyte hypertrophy or osteophyte development. Arthritis Rheum. 60, 3723–3733.
69. Mao Z, Ke Z, Gorbunova V, Seluanov A (2012) Replicatively senescent cells are arrested in G1 and G2 phases. Aging 4, 431–435.
70. von der Mark K, Kirsch T, Nerlich A, Kuss A, Weseloh G, Gluckert K, Stoss H (1992) Type X collagen synthesis in human osteoarthritic cartilage. Indication of chondrocyte hypertrophy. Arthritis Rheum. 35, 806–811.
71. Martin JA, Buckwalter JA (2001) Telomere erosion and senescence in human articular cartilage chondrocytes. J. Gerontol. A Biol. Sci. Med. Sci. 56, B172–B179.
72. Martin JA, Brown T, Heiner A, Buckwalter JA (2004a) Post-traumatic osteoarthritis: the role of accelerated chondrocyte senescence. Biorheology 41, 479–491.
73. Martin JA, Klingelhutz AJ, Moussavi-Harami F, Buckwalter JA (2004b) Effects of oxidative damage and telomerase activity on human articular cartilage chondrocyte senescence. J. Gerontol. A Biol. Sci. Med. Sci. 59, 324–337.
74. Matsuo K, Tang SH, Zeki K, Gutman RA, Fagin JA (1993) Aberrant deoxyribonucleic acid methylation in human thyroid tumors. J. Clin. Endocrinol. Metab. 77, 991–995.
75. Michaloglou C, Vredeveld LC, Soengas MS, Denoyelle C, Kuilman T, van der Horst CM, Majoor DM, Shay JW, Mooi WJ, Peeper DS (2005) BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 436, 720–724.
76. Minamino T, Miyauchi H, Yoshida T, Ishida Y, Yoshida H, Komuro I (2002) Endothelial cell senescence in human atherosclerosis: role of telomere in endothelial dysfunction. Circulation 105, 1541–1544.
77. Narita M, Lowe SW (2005) Senescence comes of age. Nat. Med. 11, 920–922.
78. Narita M, Young AR, Arakawa S, Samarajiwa SA, Nakashima T, Yoshida S, Hong S, Berry LS, Reichelt S, Ferreira M, Tavare S, Inoki K, Shimizu S (2011) Spatial coupling of mTOR and autophagy augments secretory phenotypes. Science 332, 966–970.
79. Neuhold LA, Killar L, Zhao W, Sung ML, Warner L, Kulik J, Turner J, Wu W, Billinghurst C, Meijers T, Poole AR, Babij P, DeGennaro LJ (2001) Postnatal expression in hyaline cartilage of constitutively active human collagenase-3 (MMP-13) induces osteoarthritis in mice. J. Clin. Invest. 107, 35–44.
80. Ng CT, Biniecka M, Kennedy A, McCormick J, Fitzgerald O, Bresnihan B, Buggy D, Taylor CT, O'Sullivan J, Fearon U, Veale DJ (2010) Synovial tissue hypoxia and inflammation in vivo. Ann. Rheum. Dis. 69, 1389–1395.
81. Ogryzko VV, Hirai TH, Russanova VR, Barbie DA, Howard BH (1996) Human fibroblast commitment to a senescence-like state in response to histone deacetylase inhibitors is cell cycle dependent. Mol. Cell. Biol. 16, 5210–5218.
82. Pap T, Nawrath M, Heinrich J, Bosse M, Baier A, Hummel KM, Petrow P, Kuchen S, Michel BA, Gay RE, Muller-Ladner U, Moelling K, Gay S (2004) Cooperation of Ras- and c-Myc-dependent pathways in regulating the growth and invasiveness of synovial fibroblasts in rheumatoid arthritis. Arthritis Rheum. 50, 2794–2802.
83. Pfander D, Kortje D, Zimmermann R, Weseloh G, Kirsch T, Gesslein M, Cramer T, Swoboda B (2001) Vascular endothelial growth factor in articular cartilage of healthy and osteoarthritic human knee joints. Ann. Rheum. Dis. 60, 1070–1073.
84. Philipot D, Guerit D, Platano D, Chuchana P, Olivotto E, Espinoza F, Dorandeu A, Pers YM, Piette J, Borzi RM, Jorgensen C, Noel D, Brondello JM (2014) p16INK4a and its regulator miR-24 link senescence and chondrocyte terminal differentiation-associated matrix remodeling in osteoarthritis. Arthritis. Res. Ther. 16, R58.
85. Price JS, Waters JG, Darrah C, Pennington C, Edwards DR, Donell ST, Clark IM (2002) The role of chondrocyte senescence in osteoarthritis. Aging Cell 1, 57–65.
86. Roach HI, Yamada N, Cheung KSC, Tilley S, Clarke NMP, Oreffo ROC, Kokubun S, Bronner F (2005) Association between the abnormal expression of matrix-degrading enzymes by human osteoarthritic chondrocytes and demethylation of specific CpG sites in the promoter regions. Arthritis Rheum. 52, 3110–3124.
87. Rodier F, Coppe JP, Patil CK, Hoeijmakers WA, Munoz DP, Raza SR, Freund A, Campeau E, Davalos AR, Campisi J (2009) Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat. Cell Biol. 11, 973–979.
88. Schafer MJ, White TA, Evans G, Tonne JM, Verzosa GC, Stout MB, Mazula DL, Palmer AK, Baker DJ, Jensen MD, Torbenson MS, Miller JD, Ikeda Y, Tchkonia T, van Deursen JM, Kirkland JL, LeBrasseur NK (2016) Exercise prevents diet-induced cellular senescence in adipose tissue. Diabetes 65, 1606–1615.
89. Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW (1997) Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88, 593–602.
90. Sherr CJ, DePinho RA (2000) Cellular senescence. Cell 102, 407–410.
91. Shlopov BV, Lie W-R, Mainardi CL, Cole AA, Chubinskaya S, Hasty KA (1997) Osteoarthritic lesions. Involvement of three different collagenases. Arthritis Rheum. 40, 2065–2074.
92. Srikanth VK, Fryer JL, Zhai G, Winzenberg TM, Hosmer D, Jones G (2005) A meta-analysis of sex differences prevalence, incidence and severity of osteoarthritis. Osteoarthritis Cartilage 13, 769–781.
93. Tchkonia T, Morbeck DE, von Zglinicki T, van Deursen J, Lustgarten J, Scrable H, Khosla S, Jensen MD, Kirkland JL (2010) Fat tissue, aging, and cellular senescence. Aging Cell 9, 667–684.
94. Terman A, Dalen H, Eaton JW, Neuzil J, Brunk UT (2003) Mitochondrial recycling and aging of cardiac myocytes: the role of autophagocytosis. Exp. Gerontol. 38, 863–876.
95. Toshima T, Shirabe K, Fukuhara T, Ikegami T, Yoshizumi T, Soejima Y, Ikeda T, Okano S, Maehara Y (2014) Suppression of autophagy during liver regeneration impairs energy charge and hepatocyte senescence in mice. Hepatology 60, 290–300.
96. Waaijer ME, Parish WE, Strongitharm BH, van Heemst D, Slagboom PE, de Craen AJ, Sedivy JM, Westendorp RG, Gunn DA, Maier AB (2012) The number of p16INK4a positive cells in human skin reflects biological age. Aging Cell 11, 722–725.
97. de Wind N, Dekker M, Berns A, Radman M, te Riele H (1995) Inactivation of the mouse Msh2 gene results in mismatch repair deficiency, methylation tolerance, hyperrecombination, and predisposition to cancer. Cell 82, 321–330.
98. Wu JJ, Quijano C, Chen E, Liu H, Cao L, Fergusson MM, Rovira II, Gutkind S, Daniels MP, Komatsu M, Finkel T (2009) Mitochondrial dysfunction and oxidative stress mediate the physiological impairment induced by the disruption of autophagy. Aging 1, 425–437.
99. Xiao Y, Liang L, Huang M, Qiu Q, Zeng S, Shi M, Zou Y, Ye Y, Yang X, Xu H (2016) Bromodomain and extra-terminal domain bromodomain inhibition prevents synovial inflammation via blocking IkappaB kinase-dependent NF-kappaB activation in rheumatoid fibroblast-like synoviocytes. Rheumatology 55, 173–184.
100. Xu M, Bradley EW, Weivoda MM, Hwang SM, Pirtskhalava T, Decklever T, Curran GL, Ogrodnik M, Jurk D, Johnson KO, Lowe V, Tchkonia T, Westendorf JJ, Kirkland JL (2016) Transplanted senescent cells induce an osteoarthritis-like condition in mice. J. Gerontol. A Biol. Sci. Med. Sci. DOI: 10.1093/gerona/glw154.
101. Yang X, Chen L, Xu X, Li C, Huang C, Deng CX (2001) TGF-beta/Smad3 signals repress chondrocyte hypertrophic differentiation and are required for maintaining articular cartilage. J. Cell Biol. 153, 35–46.
102. Young JI, Smith JR (2001) DNA methyltransferase inhibition in normal human fibroblasts induces a p21-dependent cell cycle withdrawal. J. Biol. Chem. 276, 19610–19616.
103. Yudoh K, Nguyen VT, Nakamura H, Hongo-Masuko K, Kato T, Nishioka K (2005) Potential involvement of oxidative stress in cartilage senescence and development of osteoarthritis: oxidative stress induces chondrocyte telomere instability and downregulation of chondrocyte function. Arthritis. Res. Ther. 7, R380–R391.
104. Zhang QG, Qian J, Zhu YC (2015) Targeting bromodomain-containing protein 4 (BRD4) benefits rheumatoid arthritis. Immunol. Lett. 166, 103–108.
105. Zheng Q, Zhou G, Morello R, Chen Y, Garcia-Rojas X, Lee B (2003) Type X collagen gene regulation by Runx2 contributes directly to its hypertrophic chondrocyte-specific expression in vivo. J. Cell Biol. 162, 833–842.
106. Zhou HW, Lou SQ, Zhang K (2004) Recovery of function in osteoarthritic chondrocytes induced by p16INK4a-specific siRNA in vitro. Rheumatology 43, 555–568.
107. Zhu Y, Tchkonia T, Fuhrmann-Stroissnigg H, Dai HM, Ling YY, Stout MB, Pirtskhalava T, Giorgadze N, Johnson KO, Giles CB, Wren JD, Niedernhofer LJ, Robbins PD, Kirkland JL (2015a) Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors. Aging Cell 15, 428–435.
108. Zhu Y, Tchkonia T, Pirtskhalava T, Gower AC, Ding H, Giorgadze N, Palmer AK, Ikeno Y, Hubbard GB, Lenburg M, O'Hara SP, LaRusso NF, Miller JD, Roos CM, Verzosa GC, LeBrasseur NK, Wren JD, Farr JN, Khosla S, Stout MB, McGowan SJ, Fuhrmann-Stroissnigg H, Gurkar AU, Zhao J, Colangelo D, Dorronsoro A, Ling YY, Barghouthy AS, Navarro DC, Sano T, Robbins PD, Niedernhofer LJ, Kirkland JL (2015b) The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 14, 644–658.