Epigenetics of osteoarticular diseases: recent developments

Rheumatology International

Volumn 35, Issue 8, 2015, Pages 1293-1305

  Roberts, S B ^a   Wootton, E ^b   De Ferrari, L ^a   Albagha, O M ^a   Salter, D M ^a  

^a UNIVERSITY OF EDINBURGH   (United Kingdom)

^b UNIVERSITY OF EDINBURGH   (United Kingdom)

Author keywords

Epigenetics; Methylation; Osteoarthritis; Osteoporosis; Rheumatoid arthritis; Sarcoma

Indexed keywords

AGGRECANASE 1; BIOLOGICAL MARKER; COLLAGENASE 3; GELATINASE B; GROWTH DIFFERENTIATION FACTOR 5; HISTONE; INDUCIBLE NITRIC OXIDE SYNTHASE; INTERLEUKIN 1BETA; MANGANESE SUPEROXIDE DISMUTASE; MICRORNA; STROMELYSIN; SUPPRESSOR OF CYTOKINE SIGNALING 2; TRANSCRIPTION FACTOR SOX9;

ANKYLOSING SPONDYLITIS; DISEASE PREDISPOSITION; DNA METHYLATION; DNA MODIFICATION; EPIGENETICS; GENE EXPRESSION; HERITABILITY; HISTONE ACETYLATION; HISTONE MODIFICATION; HUMAN; NUCLEOSOME; OSTEOARTHRITIS; OSTEOARTHROPATHY; OSTEOBLAST; OSTEOPOROSIS; PATHOGENESIS; PRIORITY JOURNAL; REVIEW; RHEUMATOID ARTHRITIS; SARCOMA; SYSTEMIC LUPUS ERYTHEMATOSUS; BONE TUMOR; CHONDROSARCOMA; EWING SARCOMA; GENETIC EPIGENESIS; GENETICS; OSTEOSARCOMA;

ARTHRITIS, RHEUMATOID; BONE NEOPLASMS; CHONDROSARCOMA; DNA METHYLATION; EPIGENESIS, GENETIC; HUMANS; MICRORNAS; OSTEOARTHRITIS; OSTEOPOROSIS; OSTEOSARCOMA; SARCOMA; SARCOMA, EWING; SPONDYLITIS, ANKYLOSING;

EID: 84931567319     PISSN: 01728172     EISSN: 1437160X     Source Type: Journal    
DOI: 10.1007/s00296-015-3260-y     Document Type: Review

References (102)

1. Waddington CH (1942) The epigenotype. Endeavour 1:18–20
2. Houseman EA, Accomando WP, Koestler DC, Christensen BC, Marsit CJ, Nelson HH et al (2012) DNA methylation arrays as surrogate measures of cell mixture distribution. BMC Bioinformatics 13:86,2105-13-86
3. Fabbri M, Garzon R, Cimmino A, Liu Z, Zanesi N, Callegari E et al (2007) MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B. Proc Natl Acad Sci USA 104:15805–15810
4. Kobayashi T, Lu J, Cobb BS, Rodda SJ, McMahon AP, Schipani E et al (2008) Dicer-dependent pathways regulate chondrocyte proliferation and differentiation. Proc Natl Acad Sci USA 105:1949–1954
5. Feil R, Fraga MF (2012) Epigenetics and the environment: emerging patterns and implications. Nat Rev Genet 13:97–109
6. Dominguez-Salas P, Moore SE, Baker MS, Bergen AW, Cox SE, Dyer RA et al (2014) Maternal nutrition at conception modulates DNA methylation of human metastable epialleles. Nat Commun 5:3746
7. Rakyan VK, Down TA, Maslau S, Andrew T, Yang TP, Beyan H et al (2010) Human aging-associated DNA hypermethylation occurs preferentially at bivalent chromatin domains. Genome Res 20:434–439
8. Bijlsma JW, Berenbaum F, Lafeber FP (2011) Osteoarthritis: an update with relevance for clinical practice. Lancet 377:2115–2126
9. arcOGEN Consortium, arcOGEN Collaborators, Zeggini E, Panoutsopoulou K, Southam L, Rayner NW, et al (2012) Identification of new susceptibility loci for osteoarthritis (arcOGEN): a genome-wide association study. Lancet 380:815–823
10. Sesselmann S, Soder S, Voigt R, Haag J, Grogan SP, Aigner T (2009) DNA methylation is not responsible for p21WAF1/CIP1 down-regulation in osteoarthritic chondrocytes. Osteoarthr Cartil 17:507–512
11. Delgado-Calle J, Fernandez AF, Sainz J, Zarrabeitia MT, Sanudo C, Garcia-Renedo R et al (2013) Genome-wide profiling of bone reveals differentially methylated regions in osteoporosis and osteoarthritis. Arthritis Rheum 65:197–205
12. Fernandez-Tajes J, Soto-Hermida A, Vazquez-Mosquera ME, Cortes-Pereira E, Mosquera A, Fernandez-Moreno M et al (2014) Genome-wide DNA methylation analysis of articular chondrocytes reveals a cluster of osteoarthritic patients. Ann Rheum Dis 73:668–677
13. Rushton MD, Reynard LN, Barter MJ, Refaie R, Rankin KS, Young DA, et al (2014) Characterization of the cartilage DNA methylome in knee and hip osteoarthritis. Arthritis Rheumatol 66:2450–2460
14. den Hollander W, Ramos YF, Bos SD, Bomer N, van der Breggen R, Lakenberg N et al (2014) Knee and hip articular cartilage have distinct epigenomic landscapes: implications for future cartilage regeneration approaches. Ann Rheum Dis 73:2208–2212
15. Fernandez MP, Young MF, Sobel ME (1985) Methylation of type II and type I collagen genes in differentiated and dedifferentiated chondrocytes. J Biol Chem 260:2374–2378
16. Hashimoto K, Otero M, Imagawa K, de Andres MC, Coico JM, Roach HI et al (2013) Regulated transcription of human matrix metalloproteinase 13 (MMP13) and interleukin-1beta (IL1B) genes in chondrocytes depends on methylation of specific proximal promoter CpG sites. J Biol Chem 288:10061–10072
17. de Andres MC, Imagawa K, Hashimoto K, Gonzalez A, Roach HI, Goldring MB et al (2013) Loss of methylation in CpG sites in the NF-kappaB enhancer elements of inducible nitric oxide synthase is responsible for gene induction in human articular chondrocytes. Arthritis Rheum 65:732–742
18. Kim KI, Park YS, Im GI (2013) Changes in the epigenetic status of the SOX-9 promoter in human osteoarthritic cartilage. J Bone Miner Res 28:1050–1060
19. Iliopoulos D, Malizos KN, Tsezou A (2007) Epigenetic regulation of leptin affects MMP-13 expression in osteoarthritic chondrocytes: possible molecular target for osteoarthritis therapeutic intervention. Ann Rheum Dis 66:1616–1621
20. Chapman K, Takahashi A, Meulenbelt I, Watson C, Rodriguez-Lopez J, Egli R et al (2008) A meta-analysis of European and Asian cohorts reveals a global role of a functional SNP in the 5′ UTR of GDF5 with osteoarthritis susceptibility. Hum Mol Genet 17:1497–1504
21. Reynard LN, Bui C, Canty-Laird EG, Young DA, Loughlin J (2011) Expression of the osteoarthritis-associated gene GDF5 is modulated epigenetically by DNA methylation. Hum Mol Genet 20:3450–3460
22. Reynard LN, Bui C, Syddall CM, Loughlin J (2014) CpG methylation regulates allelic expression of GDF5 by modulating binding of SP1 and SP3 repressor proteins to the osteoarthritis susceptibility SNP rs143383. Hum Genet 133:1059–1073
23. Bomer N, den Hollander W, Ramos YF, Bos SD, van der Breggen R, Lakenberg N, et al (2014)Underlying molecular mechanisms of DIO2 susceptibility in symptomatic osteoarthritis. Ann Rheum Dis. doi:10.1136/annrheumdis-2013-204739 [Epub ahead of print]
24. Zimmermann P, Boeuf S, Dickhut A, Boehmer S, Olek S, Richter W (2008) Correlation of COL10A1 induction during chondrogenesis of mesenchymal stem cells with demethylation of two CpG sites in the COL10A1 promoter. Arthritis Rheum 58:2743–2753
25. Poschl E, Fidler A, Schmidt B, Kallipolitou A, Schmid E, Aigner T (2005) DNA methylation is not likely to be responsible for aggrecan down regulation in aged or osteoarthritic cartilage. Ann Rheum Dis 64:477–480
26. Roach HI, Yamada N, Cheung KS, Tilley S, Clarke NM, Oreffo RO et al (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
27. Hashimoto K, Oreffo RO, Gibson MB, Goldring MB, Roach HI (2009) DNA demethylation at specific CpG sites in the IL1B promoter in response to inflammatory cytokines in human articular chondrocytes. Arthritis Rheum 60:3303–3313
28. de Andres MC, Imagawa K, Hashimoto K, Gonzalez A, Goldring MB, Roach HI et al (2011) Suppressors of cytokine signalling (SOCS) are reduced in osteoarthritis. Biochem Biophys Res Commun 407:54–59
29. Scott JL, Gabrielides C, Davidson RK, Swingler TE, Clark IM, Wallis GA et al (2010) Superoxide dismutase downregulation in osteoarthritis progression and end-stage disease. Ann Rheum Dis 69:1502–1510
30. Bos SD, Bovee JV, Duijnisveld BJ, Raine EV, van Dalen WJ, Ramos YF et al (2012) Increased type II deiodinase protein in OA-affected cartilage and allelic imbalance of OA risk polymorphism rs225014 at DIO2 in human OA joint tissues. Ann Rheum Dis 71:1254–1258
31. Iliopoulos D, Malizos KN, Oikonomou P, Tsezou A (2008) Integrative microRNA and proteomic approaches identify novel osteoarthritis genes and their collaborative metabolic and inflammatory networks. PLoS ONE 3:e3740
32. Jones SW, Watkins G, Le Good N, Roberts S, Murphy CL, Brockbank SM et al (2009) The identification of differentially expressed microRNA in osteoarthritic tissue that modulate the production of TNF-alpha and MMP13. Osteoarthr Cartil 17:464–472
33. Diaz-Prado S, Cicione C, Muinos-Lopez E, Hermida-Gomez T, Oreiro N, Fernandez-Lopez C, et al (2012) Characterization of microRNA expression profiles in normal and osteoarthritic human chondrocytes. BMC Musculoskelet Disord 13:144,2474-13-144
34. Miyaki S, Nakasa T, Otsuki S, Grogan SP, Higashiyama R, Inoue A et al (2009) MicroRNA-140 is expressed in differentiated human articular chondrocytes and modulates interleukin-1 responses. Arthritis Rheum 60:2723–2730
35. Swingler TE, Wheeler G, Carmont V, Elliott HR, Barter MJ, Abu-Elmagd M et al (2012) The expression and function of microRNAs in chondrogenesis and osteoarthritis. Arthritis Rheum 64:1909–1919
36. Higashiyama R, Miyaki S, Yamashita S, Yoshitaka T, Lindman G, Ito Y et al (2010) Correlation between MMP-13 and HDAC7 expression in human knee osteoarthritis. Mod Rheumatol 20:11–17
37. Saito T, Nishida K, Furumatsu T, Yoshida A, Ozawa M, Ozaki T (2013) Histone deacetylase inhibitors suppress mechanical stress-induced expression of RUNX-2 and ADAMTS-5 through the inhibition of the MAPK signaling pathway in cultured human chondrocytes. Osteoarthr Cartil 21:165–174
38. Culley KL, Hui W, Barter MJ, Davidson RK, Swingler TE, Destrument AP et al (2013) Class I histone deacetylase inhibition modulates metalloproteinase expression and blocks cytokine-induced cartilage degradation. Arthritis Rheum 65:1822–1830
39. Dvir-Ginzberg M, Steinmeyer J (2013) Towards elucidating the role of SirT1 in osteoarthritis. Front Biosci (Landmark Ed) 18:343–355
40. Gagarina V, Gabay O, Dvir-Ginzberg M, Lee EJ, Brady JK, Quon MJ et al (2010) SirT1 enhances survival of human osteoarthritic chondrocytes by repressing protein tyrosine phosphatase 1B and activating the insulin-like growth factor receptor pathway. Arthritis Rheum 62:1383–1392
41. Fujita N, Matsushita T, Ishida K, Kubo S, Matsumoto T, Takayama 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
42. Matsushita T, Sasaki H, Takayama K, Ishida K, Matsumoto T, Kubo S et al (2013) The overexpression of SIRT1 inhibited osteoarthritic gene expression changes induced by interleukin-1beta in human chondrocytes. J Orthop Res 31:531–537
43. Moon MH, Jeong JK, Lee YJ, Seol JW, Jackson CJ, Park SY (2013) SIRT1, a class III histone deacetylase, regulates TNF-alpha-induced inflammation in human chondrocytes. Osteoarthr Cartil 21:470–480
44. El Mansouri FE, Chabane N, Zayed N, Kapoor M, Benderdour M, Martel-Pelletier J et al (2011) Contribution of H3K4 methylation by SET-1A to interleukin-1-induced cyclooxygenase 2 and inducible nitric oxide synthase expression in human osteoarthritis chondrocytes. Arthritis Rheum 63:168–179
45. Rodova M, Lu Q, Li Y, Woodbury BG, Crist JD, Gardner BM et al (2011) Nfat1 regulates adult articular chondrocyte function through its age-dependent expression mediated by epigenetic histone methylation. J Bone Miner Res 26:1974–1986
46. Kevorkian L, Young DA, Darrah C, Donell ST, Shepstone L, Porter S et al (2004) Expression profiling of metalloproteinases and their inhibitors in cartilage. Arthritis Rheum 50:131–141
47. Murata K, Yoshitomi H, Tanida S, Ishikawa M, Nishitani K, Ito H et al (2010) Plasma and synovial fluid microRNAs as potential biomarkers of rheumatoid arthritis and osteoarthritis. Arthritis Res Ther 12:R86
48. Lokk K, Modhukur V, Rajashekar B, Martens K, Magi R, Kolde R et al (2014) DNA methylome profiling of human tissues identifies global and tissue-specific methylation patterns. Genome Biol 15:R54
49. Richardson B, Scheinbart L, Strahler J, Gross L, Hanash S, Johnson M (1990) Evidence for impaired T cell DNA methylation in systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum 33:1665–1673
50. Liu CC, Fang TJ, Ou TT, Wu CC, Li RN, Lin YC et al (2011) Global DNA methylation, DNMT1, and MBD2 in patients with rheumatoid arthritis. Immunol Lett 135:96–99
51. Nakano K, Whitaker JW, Boyle DL, Wang W, Firestein GS (2013) DNA methylome signature in rheumatoid arthritis. Ann Rheum Dis 72:110–117
52. Glossop JR, Emes RD, Nixon NB, Haworth KE, Packham JC, Dawes PT et al (2014) Genome-wide DNA methylation profiling in rheumatoid arthritis identifies disease-associated methylation changes that are distinct to individual T- and B-lymphocyte populations. Epigenetics 9:1228–1237
53. de la Rica L, Urquiza JM, Gomez-Cabrero D, Islam AB, Lopez-Bigas N, Tegner J et al (2013) Identification of novel markers in rheumatoid arthritis through integrated analysis of DNA methylation and microRNA expression. J Autoimmun 41:6–16
54. Bottini N, Firestein GS (2013) Epigenetics in rheumatoid arthritis: a primer for rheumatologists. Curr Rheumatol Rep 15:372,013-0372-9
55. Ammari M, Jorgensen C, Apparailly F (2013) Impact of microRNAs on the understanding and treatment of rheumatoid arthritis. Curr Opin Rheumatol 25:225–233
56. Miao CG, Yang YY, He X, Xu T, Huang C, Huang Y et al (2013) New advances of microRNAs in the pathogenesis of rheumatoid arthritis, with a focus on the crosstalk between DNA methylation and the microRNA machinery. Cell Signal 25:1118–1125
57. Smigielska-Czepiel K, van den Berg A, Jellema P, van der Lei RJ, Bijzet J, Kluiver J et al (2014) Comprehensive analysis of miRNA expression in T-cell subsets of rheumatoid arthritis patients reveals defined signatures of naive and memory Tregs. Genes Immun 15:115–125
58. Lu MC, Yu CL, Chen HC, Yu HC, Huang HB, Lai NS (2014) Increased miR-223 expression in T cells from patients with rheumatoid arthritis leads to decreased IGF-1 mediated IL-10 production. Clin Exp Immunol 177:641–651
59. Wada TT, Araki Y, Sato K, Aizaki Y, Yokota K, Kim YT et al (2014) Aberrant histone acetylation contributes to elevated interleukin-6 production in rheumatoid arthritis synovial fibroblasts. Biochem Biophys Res Commun 444:682–686
60. Gillespie J, Savic S, Wong C, Hempshall A, Inman M, Emery P et al (2012) Histone deacetylases are dysregulated in rheumatoid arthritis and a novel histone deacetylase 3-selective inhibitor reduces interleukin-6 production by peripheral blood mononuclear cells from rheumatoid arthritis patients. Arthritis Rheum 64:418–422
61. Trenkmann M, Brock M, Gay RE, Kolling C, Speich R, Michel BA et al (2011) Expression and function of EZH2 in synovial fibroblasts: epigenetic repression of the Wnt inhibitor SFRP1 in rheumatoid arthritis. Ann Rheum Dis 70:1482–1488
62. Maciejewska-Rodrigues H, Karouzakis E, Strietholt S, Hemmatazad H, Neidhart M, Ospelt C et al (2010) Epigenetics and rheumatoid arthritis: the role of SENP1 in the regulation of MMP-1 expression. J Autoimmun 35:15–22
63. Okada Y, Wu D, Trynka G, Raj T, Terao C, Ikari K et al (2014) Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature 506:376–381
64. Vrtacnik P, Marc J, Ostanek B (2014) Epigenetic mechanisms in bone. Clin Chem Lab Med 52:589–608
65. Harvey N, Dennison E, Cooper C (2014) Osteoporosis: a lifecourse approach. J Bone Miner Res 29:1917–1925
66. Yang N, Wang G, Hu C, Shi Y, Liao L, Shi S et al (2013) Tumor necrosis factor alpha suppresses the mesenchymal stem cell osteogenesis promoter miR-21 in estrogen deficiency-induced osteoporosis. J Bone Miner Res 28:559–573
67. Li H, Xie H, Liu W, Hu R, Huang B, Tan YF et al (2009) A novel microRNA targeting HDAC5 regulates osteoblast differentiation in mice and contributes to primary osteoporosis in humans. J Clin Invest 119:3666–3677
68. Wang X, Guo B, Li Q, Peng J, Yang Z, Wang A et al (2013) miR-214 targets ATF4 to inhibit bone formation. Nat Med 19:93–100
69. Lei SF, Papasian CJ, Deng HW (2011) Polymorphisms in predicted miRNA binding sites and osteoporosis. J Bone Miner Res 26:72–78
70. Wang Y, Li L, Moore BT, Peng XH, Fang X, Lappe JM et al (2012) MiR-133a in human circulating monocytes: a potential biomarker associated with postmenopausal osteoporosis. PLoS ONE 7:e34641
71. Cheng P, Chen C, He HB, Hu R, Zhou HD, Xie H et al (2013) miR-148a regulates osteoclastogenesis by targeting V-maf musculoaponeurotic fibrosarcoma oncogene homolog B. J Bone Miner Res 28:1180–1190
72. Cao Z, Moore BT, Wang Y, Peng XH, Lappe JM, Recker RR et al (2014) MiR-422a as a potential cellular MicroRNA biomarker for postmenopausal osteoporosis. PLoS ONE 9:e97098
73. Somers EC, Richardson BC (2014) Environmental exposures, epigenetic changes and the risk of lupus. Lupus 23:568–576
74. Coit P, Jeffries M, Altorok N, Dozmorov MG, Koelsch KA, Wren JD et al (2013) Genome-wide DNA methylation study suggests epigenetic accessibility and transcriptional poising of interferon-regulated genes in naive CD4+ T cells from lupus patients. J Autoimmun 43:78–84
75. Zhang Y, Zhao M, Sawalha AH, Richardson B, Lu Q (2013) Impaired DNA methylation and its mechanisms in CD4(+)T cells of systemic lupus erythematosus. J Autoimmun 41:92–99
76. Absher DM, Li X, Waite LL, Gibson A, Roberts K, Edberg J et al (2013) Genome-wide DNA methylation analysis of systemic lupus erythematosus reveals persistent hypomethylation of interferon genes and compositional changes to CD4+ T-cell populations. PLoS Genet 9:e1003678
77. Wu Z, Li X, Qin H, Zhu X, Xu J, Shi W (2013) Ultraviolet B enhances DNA hypomethylation of CD4+ T cells in systemic lupus erythematosus via inhibiting DNMT1 catalytic activity. J Dermatol Sci 71:167–173
78. Zhang Z, Song L, Maurer K, Petri MA, Sullivan KE (2010) Global H4 acetylation analysis by ChIP-chip in systemic lupus erythematosus monocytes. Genes Immun 11:124–133
79. Hu N, Qiu X, Luo Y, Yuan J, Li Y, Lei W et al (2008) Abnormal histone modification patterns in lupus CD4+ T cells. J Rheumatol 35:804–810
80. Zhou Y, Qiu X, Luo Y, Yuan J, Li Y, Zhong Q et al (2011) Histone modifications and methyl-CpG-binding domain protein levels at the TNFSF7 (CD70) promoter in SLE CD4+ T cells. Lupus 20:1365–1371
81. Liu D, Zhao H, Zhao S, Wang X (2014) MicroRNA expression profiles of peripheral blood mononuclear cells in patients with systemic lupus erythematosus. Acta Histochem 116:891–897
82. Dai Y, Sui W, Lan H, Yan Q, Huang H, Huang Y (2009) Comprehensive analysis of microRNA expression patterns in renal biopsies of lupus nephritis patients. Rheumatol Int 29:749–754
83. Tang Y, Luo X, Cui H, Ni X, Yuan M, Guo Y et al (2009) MicroRNA-146A contributes to abnormal activation of the type I interferon pathway in human lupus by targeting the key signaling proteins. Arthritis Rheum 60:1065–1075
84. Pan W, Zhu S, Yuan M, Cui H, Wang L, Luo X et al (2010) MicroRNA-21 and microRNA-148a contribute to DNA hypomethylation in lupus CD4+ T cells by directly and indirectly targeting DNA methyltransferase 1. J Immunol 184:6773–6781
85. Mishra N, Reilly CM, Brown DR, Ruiz P, Gilkeson GS (2003) Histone deacetylase inhibitors modulate renal disease in the MRL-lpr/lpr mouse. J. Clin. Invest. 111:539–552
86. Lai NS, Chou JL, Chen GC, Liu SQ, Lu MC, Chan MW (2014) Association between cytokines and methylation of SOCS-1 in serum of patients with ankylosing spondylitis. Mol Biol Rep 41:3773–3780
87. Toussirot E, Abbas W, Khan KA, Tissot M, Jeudy A, Baud L et al (2013) Imbalance between HAT and HDAC activities in the PBMCs of patients with ankylosing spondylitis or rheumatoid arthritis and influence of HDAC inhibitors on TNF alpha production. PLoS ONE 8:e70939
88. Lai NS, Yu HC, Chen HC, Yu CL, Huang HB, Lu MC (2013) Aberrant expression of microRNAs in T cells from patients with ankylosing spondylitis contributes to the immunopathogenesis. Clin Exp Immunol 173:47–57
89. Kresse SH, Rydbeck H, Skarn M, Namlos HM, Barragan-Polania AH, Cleton-Jansen AM et al (2012) Integrative analysis reveals relationships of genetic and epigenetic alterations in osteosarcoma. PLoS ONE 7:e48262
90. Alholle A, Brini AT, Gharanei S, Vaiyapuri S, Arrigoni E, Dallol A et al (2013) Functional epigenetic approach identifies frequently methylated genes in Ewing sarcoma. Epigenetics 8:1198–1204
91. Diao Y, Guo X, Jiang L, Wang G, Zhang C, Wan J et al (2014) miR-203, a tumor suppressor frequently down-regulated by promoter hypermethylation in rhabdomyosarcoma. J Biol Chem 289:529–539
92. Yoshitaka T, Kawai A, Miyaki S, Numoto K, Kikuta K, Ozaki T et al (2013) Analysis of microRNAs expressions in chondrosarcoma. J Orthop Res 31:1992–1998
93. Mahoney SE, Yao Z, Keyes CC, Tapscott SJ, Diede SJ (2012) Genome-wide DNA methylation studies suggest distinct DNA methylation patterns in pediatric embryonal and alveolar rhabdomyosarcomas. Epigenetics 7:400–408
94. Patel N, Black J, Chen X, Marcondes AM, Grady WM, Lawlor ER et al (2012) DNA methylation and gene expression profiling of ewing sarcoma primary tumors reveal genes that are potential targets of epigenetic inactivation. Sarcoma 2012:498472
95. Park HR, Jung WW, Kim HS, Park YK (2014) Microarray-based DNA methylation study of Ewing’s sarcoma of the bone. Oncol. Lett. 8:1613–1617
96. Sadikovic B, Yoshimoto M, Al-Romaih K, Maire G, Zielenska M, Squire JA (2008) In vitro analysis of integrated global high-resolution DNA methylation profiling with genomic imbalance and gene expression in osteosarcoma. PLoS ONE 3:e2834
97. de Bruijn DR, Allander SV, van Dijk AH, Willemse MP, Thijssen J, van Groningen JJ et al (2006) The synovial-sarcoma-associated SS18-SSX2 fusion protein induces epigenetic gene (de)regulation. Cancer Res 66:9474–9482
98. Vogt M, Munding J, Gruner M, Liffers ST, Verdoodt B, Hauk J et al (2011) Frequent concomitant inactivation of miR-34a and miR-34b/c by CpG methylation in colorectal, pancreatic, mammary, ovarian, urothelial, and renal cell carcinomas and soft tissue sarcomas. Virchows Arch 458:313–322
99. Mills J, Hricik T, Siddiqi S, Matushansky I (2011) Chromatin structure predicts epigenetic therapy responsiveness in sarcoma. Mol Cancer Ther 10:313–324
100. Pishas KI, Neuhaus SJ, Clayer MT, Schreiber AW, Lawrence DM, Perugini M et al (2014) Nutlin-3a efficacy in sarcoma predicted by transcriptomic and epigenetic profiling. Cancer Res 74:921–931
101. Gharanei S, Brini AT, Vaiyapuri S, Alholle A, Dallol A, Arrigoni E et al (2013) RASSF2 methylation is a strong prognostic marker in younger age patients with Ewing sarcoma. Epigenetics 8:893–898
102. Ouyang L, Liu P, Yang S, Ye S, Xu W, Liu X (2013) A three-plasma miRNA signature serves as novel biomarkers for osteosarcoma. Med Oncol 30:340,012-0340-7. Epub 2012 Dec 27