Current Osteoporosis Reports

, Volume 16, Issue 3, pp 246–255 | Cite as

Epigenetics of Skeletal Diseases

  • Alvaro del Real
  • Leyre Riancho-Zarrabeitia
  • Laura López-Delgado
  • José A. Riancho
Genetics (M Johnson and S Ralston, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Genetics


Purpose of Review

Epigenetic mechanisms modify gene activity in a stable manner without altering DNA sequence. They participate in the adaptation to the environment, as well as in the pathogenesis of common complex disorders. We provide an overview of the role of epigenetic mechanisms in bone biology and pathology.

Recent Findings

Extensive evidence supports the involvement of epigenetic mechanisms (DNA methylation, post-translational modifications of histone tails, and non-coding RNAs) in the differentiation of bone cells and mechanotransduction. A variety of epigenetic abnormalities have been described in patients with osteoporosis, osteoarthritis, and skeletal cancers, but their actual pathogenetic roles are still unclear. A few drugs targeting epigenetic marks have been approved for neoplastic disorders, and many more are being actively investigated.


Advances in the field of epigenetics underscore the complex interactions between genetic and environmental factors as determinants of osteoporosis and other common disorders. Likewise, they help to explain the mechanisms by which prenatal and post-natal external factors, from nutrition to psychological stress, impact our body and influence the risk of later disease.


Epigenetics DNA methylation Fractures Adaptation microRNA Histones 


Funding Information

This study was supported by a grant from the Instituto de Salud Carlos III (PI 16/0915), which can be co-funded by the European Union (FEDER Funds).

Compliance with Ethical Standards

Conflict of Interest

Leyre Riancho-Zarrabeitia reports travel grants from Amgen and Lilly outside the submitted work. José A. Riancho reports grants travel grants and speaker fees from Amgen and grants from the Intituto de Salud Carlos III. Laura López-Delgado reports travel grants from Amgen outside the submitted work and grants from the Intituto de Salud Carlos III. Alvaro del Real reports grants from the Intituto de Salud Carlos III.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance ••Of major importance

  1. 1.
    Herman JP, Mcklveen JM, Ghosal S, Kopp B, Wulsin A, Makinson R, et al. Regulation of the hypothalamic-pituitary-adrenocortical stress response. Compr Physiol. 2016;6:603–21.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Feil R, Fraga MF. Epigenetics and the environment: emerging patterns and implications. Nat Rev. 2011;13:97–109.Google Scholar
  3. 3.
    •• Pérez-Campo FM, Riancho JA. Epigenetic mechanisms regulating mesenchymal stem cell differentiation. Curr Genomics. 2015;16:368–83. Review of the role of epigenetic mechanisms in the differentiation of osteoblast precursors. CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Hassan MQ, Tye CE, Stein GS, Lian JB. Non-coding RNAs: epigenetic regulators of bone development and homeostasis. Bone. 2015;81:746–56.CrossRefPubMedGoogle Scholar
  5. 5.
    Husain A, Jeffries MA. Epigenetics and bone remodeling. Curr Osteoporos Rep. 2017;15:450–8.CrossRefPubMedGoogle Scholar
  6. 6.
    Yu F, Shen H, Deng HW. Systemic analysis of osteoblast-specific DNA methylation marks reveals novel epigenetic basis of osteoblast differentiation. Bone Reports. 2017;6:109–19.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    • del Real A, Pérez-Campo FM, Fernández AF, Sañudo C, Ibarbia CG, Pérez-Núñez MI, et al. Differential analysis of genome-wide methylation and gene expression in mesenchymal stem cells of patients with fractures and osteoarthritis. Epigenetics. 2017;12:113–22. A methylome and transcriptome analysis of human mesenchymal stem cells in osteoporosis. CrossRefPubMedGoogle Scholar
  8. 8.
    Sepulveda H, Villagra A, Montecino M. Tet-mediated DNA demethylation is required for SWI/SNF-dependent chromatin remodeling and histone modifying activities that trigger expression of the Sp7 osteoblast master gene during mesenchymal lineage commitment. Mol Cell Biol. 2017;37(20):e00177-17.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Dudakovic A, Camilleri ET, Xu F, Riester SM, McGee-Lawrence ME, Bradley EW, et al. Epigenetic control of skeletal development by the histone methyltransferase Ezh2. J Biol Chem. 2015;290:27604–17.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Yu Y, Deng P, Yu B, Szymanski JM, Aghaloo T, Hong C, et al. Inhibition of EZH2 promotes human embryonic stem cell differentiation into mesoderm by reducing H3K27me3. Stem Cell Reports. 2017;8:326–34.Google Scholar
  11. 11.
    Dudakovic A, van Wijnen AJ. Epigenetic control of osteoblast differentiation by enhancer of zeste homolog 2 (EZH2). Curr Mol Biol Reports. 2017;3:94–106.CrossRefGoogle Scholar
  12. 12.
    Wu H, Gordon JAR, Whitfield TW, Tai PWL, Van AJW, Stein JL, et al. Chromatin dynamics regulate mesenchymal stem cell lineage specification and differentiation to osteogenesis. Biochim Biophys Acta. 2017;1860:438–49.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Khani F, Thaler R, Paradise CR, Deyle DR, Kruijthof-de Julio M, Galindo M, et al. Histone H4 methyltransferase Suv420h2 maintains fidelity of osteoblast differentiation. J Cell Biochem. 2017;118:1262–72.Google Scholar
  14. 14.
    • Baud’huin M, Lamoureux F, Jacques C, Rodriguez Calleja L, Quillard T, Charrier C, et al. Inhibition of BET proteins and epigenetic signaling as a potential treatment for osteoporosis. Bone. 2017;94:10–21. Description of the role of BET family in bone. CrossRefPubMedGoogle Scholar
  15. 15.
    Hao L, Fu J, Tian Y, Wu J. Systematic analysis of lncRNAs, miRNAs and mRNAs for the identification of biomarkers for osteoporosis in the mandible of ovariectomized mice. Int J Mol Med. 2017;40:689–702.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Huang G, Kang Y, Huang Z, Zhang Z, Meng F, Chen W, et al. Identification and characterization of long non-coding RNAs in osteogenic differentiation of human adipose-derived stem cells. Cell Physiol Biochem. 2017;42(3):1037–50.Google Scholar
  17. 17.
    •• Gennari L, Bianciardi S, Merlotti D. MicroRNAs in bone diseases. Osteoporos Int. 2017;28(4):1191–213. Recent review of the role of miRNAs in bone homeostasis. CrossRefPubMedGoogle Scholar
  18. 18.
    Peschansky VJ, Wahlestedt C. Non-coding RNAs as direct and indirect modulators of epigenetic regulation. Epigenetics. 2014;9(1):3–12.CrossRefPubMedGoogle Scholar
  19. 19.
    Sati S, Cavalli G. Chromosome conformation capture technologies and their impact in understanding genome function. Chromosoma. 2017;126:33–44.CrossRefPubMedGoogle Scholar
  20. 20.
    Hao Z-C, Lu J, Wang S-Z, Wu H, Zhang Y-T, Xu S-G. Stem cell-derived exosomes: a promising strategy for fracture healing. Cell Prolif. 2017;50:312359.CrossRefGoogle Scholar
  21. 21.
    Ge M, Wu Y, Ke R, Cai T, Yang J, Mu X. Value of osteoblast-derived exosomes in bone diseases. J Craniofac Surg. 2017;28(4):866–70.CrossRefPubMedGoogle Scholar
  22. 22.
    Xie Y, Chen Y, Zhang L, Ge W, Tang P. The roles of bone-derived exosomes and exosomal microRNAs in regulating bone remodelling. J Cell Mol Med. 2017;21(5):1033–41.CrossRefPubMedGoogle Scholar
  23. 23.
    Li D, Liu J, Guo B, Liang C, Dang L, Lu C, et al. Osteoclast-derived exosomal miR-214-3p inhibits osteoblastic bone formation. Nat Commun. 2016;7:10872.Google Scholar
  24. 24.
    Huynh N, VonMoss L, Smith D, Rahman I, Felemban MF, Zuo J, et al. Characterization of regulatory extracellular vesicles from osteoclasts. J Dent Res. 2016;95(6):673–9.Google Scholar
  25. 25.
    Tang X, Lin J, Wang G, Lu J. MicroRNA-433-3p promotes osteoblast differentiation through targeting DKK1 expression. PLoS One. 2017;12(6):e0179860.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Cui Y, Luan J, Li H, Zhou X, Han J. Exosomes derived from mineralizing osteoblasts promote ST2 cell osteogenic differentiation by alteration of microRNA expression. FEBS Lett. 2016;590(1):185–92.CrossRefPubMedGoogle Scholar
  27. 27.
    • Qin Y, Peng Y, Zhao W, Pan J, Ksiezak-Reding H, Cardozo C, et al. Myostatin inhibits osteoblastic differentiation by suppressing osteocyte-derived exosomal microRNA-218: a novel mechanism in muscle-bone communication. J Biol Chem. 2017;292(26):11021–33. Exosome participation in cell-cell communication in the skeleton. Google Scholar
  28. 28.
    Zhang J, Liu X, Li H, Chen C, Hu B, Niu X, et al. Exosomes/tricalcium phosphate combination scaffolds can enhance bone regeneration by activating the PI3K/Akt signaling pathway. Stem Cell Res Ther. 2016;7(1):136.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Furuta T, Miyaki S, Ishitobi H, Ogura T, Kato Y, Kamei N, et al. Mesenchymal stem cell-derived exosomes promote fracture healing in a mouse model. Stem Cells Transl Med. 2016;5(12):1620–30.Google Scholar
  30. 30.
    Rubin J, Styner M, Uzer G. Physical signals may affect mesenchymal stem cell differentiation via epigenetic controls. Exerc Sport Sci Rev. 2018;46:42–7.CrossRefPubMedGoogle Scholar
  31. 31.
    Vlaikou AM, Kouroupis D, Sgourou A, Markopoulos GS, Bagli E, Markou M, et al. Mechanical stress affects methylation pattern of GNAS isoforms and osteogenic differentiation of hAT-MSCs. Biochim Biophys Acta Mol Cell Res. 2017;1864(8):1371–81.Google Scholar
  32. 32.
    • Wang C, Shan S, Wang C, Wang J, Li J, Hu G, et al. Mechanical stimulation promote the osteogenic differentiation of bone marrow stromal cells through epigenetic regulation of sonic hedgehog. Exp Cell Res. 2017;352(2):346–56. Involvement of epigenetic signals in mechanotransduction. CrossRefPubMedGoogle Scholar
  33. 33.
    Hum JM, Day RN, Bidwell JP, Wang Y, Pavalko FM. Mechanical loading in osteocytes induces formation of a Src/Pyk2/MBD2 complex that suppresses anabolic gene expression. PLoS One. 2014;9(5):e97942.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Mohan S, Wergedal JE, Das S, Kesavan C. Conditional disruption of miR17-92 cluster in collagen type I-producing osteoblasts results in reduced periosteal bone formation and bone anabolic response to exercise. Physiol Genomics. 2015;47(2):33–43.CrossRefPubMedGoogle Scholar
  35. 35.
    Sato T, Omeara MJ, Campbell N, Kronenberg JM, Gross TS, Wein MN. Histone deacetylases HDAC4 and HDAC5 participate in osteocyte mechanotransduction and are required for loading-induced bone formation. J Bone Miner Res. 2017;32(suppl):S353.Google Scholar
  36. 36.
    Guo B, Zhang Z-K, Liang C, Li J, Liu J, Lu A, et al. Molecular communication from skeletal muscle to bone: a review for muscle-derived myokines regulating bone metabolism. Calcif Tissue Int. 2017;100(2):184–92.Google Scholar
  37. 37.
    Kaji H. Effects of myokines on bone. Bonekey Rep. 2016;5:826.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Hou KL, Lin SK, Chao LH, Hsiang-Hua Lai E, Chang CC, Shun CT, et al. Sirtuin 6 suppresses hypoxia-induced inflammatory response in human osteoblasts via inhibition of reactive oxygen species production and glycolysis—a therapeutic implication in inflammatory bone resorption. Biofactors. 2017;43(2):170–80.Google Scholar
  39. 39.
    Zhou L, Il WS, Moon YJ, Kim KM, Lee KB, Park B-H, et al. Overexpression of SIRT1 prevents hypoxia-induced apoptosis in osteoblast cells. Mol Med Rep. 2017;16(3):2969–75.CrossRefPubMedGoogle Scholar
  40. 40.
    Barker DJP. The origins of the developmental origins theory. J Intern Med. 2007;261:412–7.CrossRefPubMedGoogle Scholar
  41. 41.
    Wood CL, Stenson C, Embleton N. The developmental origins of osteoporosis. Curr Genomics. 2015;16(6):411–8.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Mikkola TM, von Bonsdorff MB, Osmond C, Salonen MK, Kajantie E, Cooper C, et al. Childhood growth predicts higher bone mass and greater bone area in early old age: findings among a subgroup of women from the Helsinki Birth Cohort Study. Osteoporos Int. 2017;28(9):2717–22.Google Scholar
  43. 43.
    Mahon P, Harvey N, Crozier S, Inskip H, Robinson S, Arden N, et al. Low maternal vitamin D status and fetal bone development: cohort study. J Bone Miner Res. 2010;25:14–9.Google Scholar
  44. 44.
    Zhu K, Whitehouse AJ, Hart PH, Kusel M, Mountain J, Lye S, et al. Maternal vitamin D status during pregnancy and bone mass in offspring at 20 years of age: a prospective cohort study. J Bone Miner Res. 2014;29(5):1088–95.CrossRefPubMedGoogle Scholar
  45. 45.
    Mikkola TM, von Bonsdorff MB, Osmond C, Salonen MK, Kajantie E, Eriksson JG. Association of body size at birth and childhood growth with hip fractures in older age: an exploratory follow-up of the Helsinki Birth Cohort Study. J Bone Miner Res. 2017 Jun;32(6):1194–200.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Xue J, Schoenrock SA, Valdar W, Tarantino LM, Ideraabdullah FY. Maternal vitamin D depletion alters DNA methylation at imprinted loci in multiple generations. Clin Epigenetics. 2016;8:107.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Harvey NC, Sheppard A, Godfrey KM, McLean C, Garratt E, Ntani G, et al. Childhood bone mineral content is associated with methylation status of the RXRA promoter at birth. J Bone Miner Res. 2014;29(3):600–7.Google Scholar
  48. 48.
    Curtis EM, Murray R, Titcombe P, Cook E, Clarke-Harris R, Costello P, et al. Perinatal DNA methylation at CDKN2A is associated with offspring bone mass: findings from the Southampton Women’s Survey. J Bone Miner Res. 2017;32:2030–40.Google Scholar
  49. 49.
    Brennan-Olsen SL, Page RS, Berk M, Riancho JA, Leslie WD, Wilson SG, et al. DNA methylation and the social gradient of osteoporotic fracture: a conceptual model. Bone. 2016;84:204–12.Google Scholar
  50. 50.
    • Riancho JA, Brennan-Olsen SL. The epigenome at the crossroad between social factors, inflammation, and osteoporosis risk. Clin Rev Bone Miner Metab. 2017;15:59–68. Review of the influence of social factors and their epigenomic influences on the skeleton. CrossRefGoogle Scholar
  51. 51.
    Park-Min K-H, Lim E, Lee MJ, Park SH, Giannopoulou E, Yarilina A, et al. Inhibition of osteoclastogenesis and inflammatory bone resorption by targeting BET proteins and epigenetic regulation. Nat Commun. 2014;5:5418.Google Scholar
  52. 52.
    Guo D-W, Han Y-X, Cong L, Liang D, Tu G-J. Resveratrol prevents osteoporosis in ovariectomized rats by regulating microRNA-338-3p. Mol Med Rep. 2015;12(2):2098–106.CrossRefPubMedGoogle Scholar
  53. 53.
    Gjoksi B, Ghayor C, Siegenthaler B, Ruangsawasdi N, Zenobi-Wong M, Weber FE. The epigenetically active small chemical N-methyl pyrrolidone (NMP) prevents estrogen depletion induced osteoporosis. Bone. 2015;78:114–21.CrossRefPubMedGoogle Scholar
  54. 54.
    Dudakovic A, Camilleri ET, Riester SM, Paradise CR, Gluscevic M, O’Toole TM, et al. Enhancer of zeste homolog 2 inhibition stimulates bone formation and mitigates bone loss caused by ovariectomy in skeletally mature mice. J Biol Chem. 2016;291(47):24594–606.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Thaler R, Maurizi A, Roschger P, Sturmlechner I, Khani F, Spitzer S, et al. Anabolic and antiresorptive modulation of bone homeostasis by the epigenetic modulator sulforaphane, a naturally occurring isothiocyanate. J Biol Chem. 2016;291(13):6754–71.Google Scholar
  56. 56.
    Jintaridth P, Tungtrongchitr R, Preutthipan S, Mutirangura A. Hypomethylation of Alu elements in post-menopausal women with osteoporosis. PLoS One. 2013;8(8):e70386.Google Scholar
  57. 57.
    Riancho JA. Epigenetics of osteoporosis: critical analysis of epigenetic epidemiology studies. Curr Genomics. 2015;16(6):405–10.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Riancho J, del Real A, Riancho JA. How to interpret epigenetic association studies: a guide for clinicians. Bonekey Rep. 2016;5:797.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    • Morris JA, Tsai P-C, Joehanes R, Zheng J, Trajanoska K, Soerensen M, et al. Epigenome-wide association of DNA methylation in whole blood with bone mineral density. J Bone Miner Res. 2017;32:1644–50. Exploration of the association of DNA methylation in peripheral blood with bone mass. CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    • Delgado-Calle J, Fernández AF, Sainz J, Zarrabeitia MT, Sañudo C, Garcia-Renedo R, et al. Genome-wide profiling of bone reveals differentially methylated regions in osteoporosis and osteoarthritis. Arthritis Rheum. 2013;65(1):197–205. Comparison of DNA methylation in bone samples of patients with fractures and osteoarthritis. CrossRefPubMedGoogle Scholar
  61. 61.
    Garcia-Ibarbia C, Delgado-Calle J, Casafont I, Velasco J, Arozamena J, Perez-Nunez MI, et al. Contribution of genetic and epigenetic mechanisms to Wnt pathway activity in prevalent skeletal disorders. Gene. 2013;532(2):165–72.CrossRefPubMedGoogle Scholar
  62. 62.
    Reppe S, Lien TG, Hsu Y-H, Gautvik VT, Olstad OK, Yu R, et al. Distinct DNA methylation profiles in bone and blood of osteoporotic and healthy postmenopausal women. Epigenetics. 2017;12:674–87.Google Scholar
  63. 63.
    Toraño EG, Bayón GF, del Real Á, Sierra MI, García MG, Carella A, et al. Age-associated hydroxymethylation in human bone-marrow mesenchymal stem cells. J Transl Med. 2016;14(1):207.Google Scholar
  64. 64.
    • Roforth MM, Farr JN, Fujita K, McCready LK, Atkinson EJ, Therneau TM, et al. Global transcriptional profiling using RNA sequencing and DNA methylation patterns in highly enriched mesenchymal cells from young versus elderly women. Bone. 2015;76:49–57. Age-related changes in DNA methylation of mesenchymal stem cells. CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Seeliger C, Er B, van Griensven M. miRNAs related to skeletal diseases. Stem Cells Dev. 2016;25:1261–8.CrossRefPubMedGoogle Scholar
  66. 66.
    Hackl M, Heilmeier U, Weilner S, Grillari J. Circulating microRNAs as novel biomarkers for bone diseases—complex signatures for multifactorial diseases? Mol Cell Endocrinol. 2016;432:83–95.CrossRefPubMedGoogle Scholar
  67. 67.
    Garmilla-Ezquerra P, Sañudo C, Delgado-Calle J, Pérez-Nuñez MI, Sumillera M, JAl R. Analysis of the bone microRNome in osteoporotic fractures. Calcif Tissue Int. 2015;96(1):30–7.CrossRefPubMedGoogle Scholar
  68. 68.
    Seeliger C, Karpinski K, Haug AT, Vester H, Schmitt A, Bauer JS, et al. Five freely circulating miRNAs and bone tissue miRNAs are associated with osteoporotic fractures. J Bone Miner Res. 2014;29(8):1718–28.Google Scholar
  69. 69.
    Kocijan R, Muschitz C, Geiger E, Skalicky S, Baierl A, Dormann R, et al. Circulating microRNA signatures in patients with idiopathic and postmenopausal osteoporosis and fragility fractures. J Clin Endocrinol Metab. 2016;101(11):4125–34.Google Scholar
  70. 70.
    Yavropoulou MP, Anastasilakis AD, Makras P, Tsalikakis DG, Grammatiki M, Yovos JG. Expression of microRNAs that regulate bone turnover in the serum 1 of postmenopausal 2 women with low bone mass and vertebral fractures. Eur J Endocrinol. 2017;176(2):169–76.Google Scholar
  71. 71.
    Zhu D-L, Guo Y, Zhang Y, Dong S-S, Xu W, Hao R-H, et al. A functional SNP regulated by miR-196a-3p in the 3′UTR of FGF2 is associated with bone mineral density in the Chinese population. Hum Mutat. 2017;38(6):725–35.Google Scholar
  72. 72.
    Dole NS, Kapinas K, Kessler CB, Yee S-P, Adams DJ, Pereira RC, et al. A single nucleotide polymorphism in osteonectin 3′ untranslated region regulates bone volume and is targeted by miR-433. J Bone Miner Res. 2015;30(4):723–32.Google Scholar
  73. 73.
    Dole NS, Delany AM. MicroRNA variants as genetic determinants of bone mass. Bone. 2016;84:57–68.CrossRefPubMedGoogle Scholar
  74. 74.
    Ahn T-K, Kim J-O, Kumar H, Choi H, Jo M-J, Sohn S, et al. Polymorphisms of miR-146a, miR-149, miR-196a2, and miR-499 are associated with osteoporotic vertebral compression fractures in Korean postmenopausal women. J Orthop Res. In press Google Scholar
  75. 75.
    •• Ramos YFM, Meulenbelt I. The role of epigenetics in osteoarthritis. Curr Opin Rheumatol. 2017;29(1):119–29. Recent review of the epigenetics of osteoarthritis. CrossRefPubMedGoogle Scholar
  76. 76.
    Simon TC, Jeffries MA. The epigenomic landscape in osteoarthritis. Curr Rheumatol Re. 2017;19(6):30.CrossRefGoogle Scholar
  77. 77.
    van Meurs JBJ. Osteoarthritis year in review 2016: genetics, genomics and epigenetics. Osteoarthr Cartil. 2017;25(2):181–9.CrossRefPubMedGoogle Scholar
  78. 78.
    Jeffries MA, Donica M, Baker LW, Stevenson ME, Annan AC, Beth Humphrey M, et al. Genome-wide DNA methylation study identifies significant epigenomic changes in osteoarthritic subchondral bone and similarity to overlying cartilage. Arthritis Rheumatol. 2016;68(6):1403–14.Google Scholar
  79. 79.
    Beyer C, Zampetaki A, Lin N-Y, Kleyer A, Perricone C, Iagnocco A, et al. Signature of circulating microRNAs in osteoarthritis. Ann Rheum Dis. 2015;74(3):e18–e18.CrossRefGoogle Scholar
  80. 80.
    Monteagudo S, Cornelis FMF, Aznar-Lopez C, Yibmantasiri P, Guns L-A, Carmeliet P, et al. DOT1L safeguards cartilage homeostasis and protects against osteoarthritis. Nat Commun 2017 19. 8:15889.Google Scholar
  81. 81.
    Heuck CJ, Mehta J, Bhagat T, Gundabolu K, Yu Y, Khan S, et al. Myeloma is characterized by stage-specific alterations in DNA methylation that occur early during myelomagenesis. J Immunol. 2013;190:2966–75.Google Scholar
  82. 82.
    Landgren O, Kyle RA, Pfeiffer RM, Katzmann JA, Caporaso NE, Hayes RB, et al. Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study. Blood. 2009;113(22):5412–7.Google Scholar
  83. 83.
    Mithraprabhu S, Kalff A, Chow A, Khong T, Spencer A. Dysregulated Class I histone deacetylases are indicators of poor prognosis in multiple myeloma. Epigenetics. 2014;9(11):1511–20.CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Bueno MJ, Pérez de Castro I, Gómez de Cedrón M, Santos J, Calin GA, Cigudosa JC, et al. Genetic and epigenetic silencing of microRNA-203 enhances ABL1 and BCR-ABL1 oncogene expression. Cancer Cell. 2008;13(6):496–506.Google Scholar
  85. 85.
    Pichiorri F, Suh S-S, Rocci A, De Luca L, Taccioli C, Santhanam R, et al. Downregulation of p53-inducible microRNAs 192, 194, and 215 impairs the p53/MDM2 autoregulatory loop in multiple myeloma development. Cancer Cell. 2010;18(4):367–81.CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Soley L, Falank C, Reagan MR. MicroRNA transfer between bone marrow adipose and multiple myeloma cells. Curr Osteoporos Rep. 2017;15:162–70.CrossRefPubMedGoogle Scholar
  87. 87.
    Issa ME, Takhsha FS, Chirumamilla CS, Perez-Novo C, Vanden Berghe W, Cuendet M. Epigenetic strategies to reverse drug resistance in heterogeneous multiple myeloma. Clin Epigenetics. 2017;9:17.CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Wainwright EN, Scaffidi P. Epigenetics and cancer stem cells: unleashing, hijacking, and restricting cellular plasticity. Trends Cancer. 2017;3(5):372–86.CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Palmini G, Marini F, Brandi ML. What is new in the miRNA world regarding osteosarcoma and chondrosarcoma? Molecules. 2017;22:417.CrossRefGoogle Scholar
  90. 90.
    Chen L, Wang Q, Wang G, Wang H, Huang Y, Liu X, et al. miR-16 inhibits cell proliferation by targeting IGF1R and the Raf1-MEK1/2-ERK1/2 pathway in osteosarcoma. FEBS Lett. 2013;587(9):1366–72.Google Scholar
  91. 91.
    Pu Y, Zhao F, Cai W, Meng X, Li Y, Cai S. MiR-193a-3p and miR-193a-5p suppress the metastasis of human osteosarcoma cells by down-regulating Rab27B and SRR, respectively. Clin Exp Metastasis. 2016;33(4):359–72.CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Chen R, Wang G, Zheng Y, Hua Y, Cai Z. Long non-coding RNAs in osteosarcoma. Oncotarget. 2017;8(12):20462–75.PubMedPubMedCentralGoogle Scholar
  93. 93.
    Krum S, Miranda-Carboni G, Lillo-Osuna MA. Re-expression of estrogen receptor alpha in osteosarcomas leads to osteoblast differentiation. J Bone Miner Res. 2017;32:S16.Google Scholar
  94. 94.
    Hamm CA, Xie H, Costa FF, Vanin EF, Seftor EA, Sredni ST, et al. Global demethylation of rat chondrosarcoma cells after treatment with 5-aza-2′-deoxycytidine results in increased tumorigenicity. PLoS One. 2009;4(12):e8340.Google Scholar
  95. 95.
    Liu P, Shen JK, Xu J, Trahan CA, Hornicek FJ, Duan Z. Aberrant DNA methylations in chondrosarcoma. Epigenomics. 2016;8:1519–25.CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    • Prachayasittikul V, Prathipati P, Pratiwi R, Phanus-Umporn C, Malik AA, Schaduangrat N, et al. Exploring the epigenetic drug discovery landscape. Expert Opin Drug Discov. 2017;12(4):345–62. An update of the field of drugs targeting epigenetic mechanisms. CrossRefPubMedGoogle Scholar
  97. 97.
    • Cantley MD, Zannettino ACW, Bartold PM, Fairlie DP, Haynes DR. Histone deacetylases (HDAC) in physiological and pathological bone remodelling. Bone. 2017;95:162–74. Review of the role of these histone-modifying enzymes in bone. CrossRefPubMedGoogle Scholar
  98. 98.
    Artsi H, Cohen-Kfir E, Gurt I, Shahar R, Bajayo A, Kalish N, et al. The Sirtuin1 activator SRT3025 down-regulates sclerostin and rescues ovariectomy-induced bone loss and biomechanical deterioration in female mice. Endocrinology. 2014;155(9):3508–15.Google Scholar
  99. 99.
    Ackloo S, Brown PJ, Müller S. Chemical probes targeting epigenetic proteins: applications beyond oncology. Epigenetics. 2017;12(5):378–400.CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Nakasa T, Yoshizuka M, Andry Usman M, Elbadry Mahmoud E, Ochi M. MicroRNAs and bone regeneration. Curr Genomics. 2015;16:441–52.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Alvaro del Real
    • 1
  • Leyre Riancho-Zarrabeitia
    • 2
  • Laura López-Delgado
    • 1
  • José A. Riancho
    • 1
  1. 1.Department of Internal Medicine, Hospital U.M. Valdecilla IDIVALUniversity of CantabriaSantanderSpain
  2. 2.Service of RheumatologyHospital SierrallanaTorrelavegaSpain

Personalised recommendations