Bone is a complex connective tissue characterized by a calcified extracellular matrix. This mineralized matrix is constantly being formed and resorbed throughout life, allowing the bone to adapt to daily mechanical loads and maintain skeletal properties and composition. The imbalance between bone formation and bone resorption leads to changes in bone mass. This is the case of osteoporosis and osteoarthritis, two common skeletal disorders. While osteoporosis is characterized by a decreased bone mass and, consequently, higher susceptibly to fractures, bone mass tends to be higher in patients with osteoarthritis, especially in the subchondral bone region. It is known that these diseases are influenced by heritable factors. However, the DNA polymorphisms identified so far in GWAS explain less than 10% of the genetic risk, suggesting that other factors, and specifically epigenetic mechanisms, are involved in the pathogenesis of these disorders. This review summarizes current knowledge about the influence of epigenetic marks on bone homeostasis, paying special attention to the role of DNA methylation in the onset and progression of osteoporosis and osteoarthritis.
Jackson, L.; Jones, D.R.; Scotting, P.; Sottile, V. Adult mesenchymal stem cells: Differentiation potential and therapeutic applications. J. Postgrad. Med. 2007, 53, 121–127.
[3]
Vaananen, H.K.; Zhao, H.; Mulari, M.; Halleen, J.M. The cell biology of osteoclast function. J. Cell. Sci. 2000, 113, 377–381.
[4]
Dallas, S.L.; Bonewald, L.F. Dynamics of the transition from osteoblast to osteocyte. Ann. NY Acad. Sci. 2010, 1192, 437–443.
[5]
Boyce, B.F.; Xing, L. Functions of RANKL/RANK/OPG in bone modeling and remodeling. Arch. Biochem. Biophys. 2008, 473, 139–146, doi:10.1016/j.abb.2008.03.018.
[6]
Nakashima, T.; Hayashi, M.; Fukunaga, T.; Kurata, K.; Oh-Hora, M.; Feng, J.Q.; Bonewald, L.F.; Kodama, T.; Wutz, A.; et al. Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat. Med. 2011, 17, 1231–1234, doi:10.1038/nm.2452.
Bonewald, L.F. The amazing osteocyte. J. Bone Miner. Res. 2011, 26, 229–238, doi:10.1002/jbmr.320.
[9]
Zarrinkalam, M.R.; Mulaibrahimovic, A.; Atkins, G.J.; Moore, R.J. Changes in osteocyte density correspond with changes in osteoblast and osteoclast activity in an osteoporotic sheep model. Osteoporos. Int. 2012, 23, 1329–1336.
[10]
O’Brien, C.A.; Plotkin, L.I.; Galli, C.; Goellner, J.J.; Gortazar, A.R.; Allen, M.R.; Robling, A.G.; Bouxsein, M.; Schipani, E.; Turner, C.H.; et al. Control of bone mass and remodeling by PTH receptor signaling in osteocytes. PLoS One 2008, 3, e2942.
[11]
Winkler, D.G.; Sutherland, M.K.; Geoghegan, J.C.; Yu, C.; Hayes, T.; Skonier, J.E.; Shpektor, D.; Jonas, M.; Kovacevich, B.R.; Staehling-Hampton, K.; et al. Osteocyte control of bone formation via sclerostin, a novel BMP antagonist. EMBO J. 2003, 22, 6267–6276.
Boyce, B.F.; Xing, L. The RANKL/RANK/OPG pathway. Curr. Osteoporos. Rep. 2007, 5, 98–104, doi:10.1007/s11914-007-0024-y.
[14]
Kong, Y.Y.; Yoshida, H.; Sarosi, I.; Tan, H.L.; Timms, E.; Capparelli, C.; Morony, S.; Oliveira-dos-Santos, A.J.; van, G.; Itie, A.; et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 1999, 397, 315–323.
[15]
Hadjidakis, D.J.; Androulakis, I.I. Bone remodeling. Ann. NY Acad. Sci. 2006, 1092, 385–396, doi:10.1196/annals.1365.035.
[16]
Sims, N.A.; Gooi, J.H. Bone remodeling: Multiple cellular interactions required for coupling of bone formation and resorption. Semin. Cell Dev. Biol. 2008, 19, 444–451.
[17]
Raggatt, L.J.; Partridge, N.C. Cellular and molecular mechanisms of bone remodeling. J. Biol. Chem. 2010, 285, 25103–25108, doi:10.1074/jbc.R109.041087.
[18]
Dequeker, J.; Aerssens, J.; Luyten, F.P. Osteoarthritis and osteoporosis: Clinical and research evidence of inverse relationship. Aging Clin. Exp. Res. 2003, 15, 426–439.
[19]
Franz-Odendaal, T.A.; Hall, B.K.; Witten, P.E. Buried alive: how osteoblasts become osteocytes. Dev. Dyn. 2006, 235, 176–190, doi:10.1002/dvdy.20603.
[20]
Probst, A.V.; Dunleavy, E.; Almouzni, G. Epigenetic inheritance during the cell cycle. Nat. Rev. Mol. Cell. Biol. 2009, 10, 192–206.
[21]
Feinberg, A.P. Phenotypic plasticity and the epigenetics of human disease. Nature 2007, 447, 433–440, doi:10.1038/nature05919.
[22]
Esteller, M. Epigenetics in cancer. N. Engl. J. Med. 2008, 358, 1148–1159, doi:10.1056/NEJMra072067.
[23]
Feinberg, A.P.; Tycko, B. The history of cancer epigenetics. Nat. Rev. Cancer 2004, 4, 143–153, doi:10.1038/nrc1279.
[24]
Buiting, K.; Barnicoat, A.; Lich, C.; Pembrey, M.; Malcolm, S.; Horsthemke, B. Disruption of the bipartite imprinting center in a family with Angelman syndrome. Am. J. Hum. Genet. 2001, 68, 1290–1294.
[25]
Buiting, K.; Gross, S.; Lich, C.; Gillessen-Kaesbach, G.; El Maarri, O.; Horsthemke, B. Epimutations in Prader-Willi and Angelman syndromes: A molecular study of 136 patients with an imprinting defect. Am. J. Hum. Genet. 2003, 72, 571–577, doi:10.1086/367926.
[26]
Miranda, T.B.; Jones, P.A. DNA methylation: The nuts and bolts of repression. J. Cell. Physiol. 2007, 213, 384–390, doi:10.1002/jcp.21224.
[27]
Bird, A.P. DNA methylation and the frequency of CpG in animal DNA. Nucleic Acids Res. 1980, 8, 1499–1504.
Irizarry, R.A.; Ladd-Acosta, C.; Wen, B.; Wu, Z.; Montano, C.; Onyango, P.; Cui, H.; Gabo, K.; Rongione, M.; Webster, M.; et al. The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nat. Genet. 2009, 41, 178–186, doi:10.1038/ng.298.
[30]
Hermann, A.; Gowher, H.; Jeltsch, A. Biochemistry and biology of mammalian DNA methyltransferases. Cell. Mol. Life. Sci. 2004, 61, 2571–2587.
[31]
Leonhardt, H.; Page, A.W.; Weier, H.U.; Bestor, T.H. A targeting sequence directs DNA methyltransferase to sites of DNA replication in mammalian nuclei. Cell 1992, 71, 865–873, doi:10.1016/0092-8674(92)90561-P.
[32]
Okano, M.; Bell, D.W.; Haber, D.A.; Li, E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 1999, 99, 247–257, doi:10.1016/S0092-8674(00)81656-6.
[33]
Goll, M.G.; Kirpekar, F.; Maggert, K.A.; Yoder, J.A.; Hsieh, C.L.; Zhang, X.; Golic, K.G.; Jacobsen, S.E.; Bestor, T.H. Methylation of tRNAAsp by the DNA methyltransferase homolog Dnmt2. Science 2006, 311, 395–398.
[34]
Hashimshony, T.; Zhang, J.; Keshet, I.; Bustin, M.; Cedar, H. The role of DNA methylation in setting up chromatin structure during development. Nat. Genet. 2003, 34, 187–192.
[35]
Razin, A.; Cedar, H. Distribution of 5-methylcytosine in chromatin. Proc. Natl. Acad. Sci. USA 1977, 74, 2725–2728, doi:10.1073/pnas.74.7.2725.
[36]
Klose, R.J.; Bird, A.P. Genomic DNA methylation: The mark and its mediators. Trends Biochem. Sci. 2006, 31, 89–97, doi:10.1016/j.tibs.2005.12.008.
[37]
Frank, D.; Keshet, I.; Shani, M.; Levine, A.; Razin, A.; Cedar, H. Demethylation of CpG islands in embryonic cells. Nature 1991, 351, 239–241.
[38]
Straussman, R.; Nejman, D.; Roberts, D.; Steinfeld, I.; Blum, B.; Benvenisty, N.; Simon, I.; Yakhini, Z.; Cedar, H. Developmental programming of CpG island methylation profiles in the human genome. Nat. Struct. Mol. Biol. 2009, 16, 564–571, doi:10.1038/nsmb.1594.
[39]
Lienert, F.; Wirbelauer, C.; Som, I.; Dean, A.; Mohn, F.; Schubeler, D. Identification of genetic elements that autonomously determine DNA methylation states. Nat. Genet. 2011, 43, 1091–1097.
[40]
Epsztejn-Litman, S.; Feldman, N.; Abu-Remaileh, M.; Shufaro, Y.; Gerson, A.; Ueda, J.; Deplus, R.; Fuks, F.; Shinkai, Y.; Cedar, H.; et al. De novo DNA methylation promoted by G9a prevents reprogramming of embryonically silenced genes. Nat. Struct. Mol. Biol. 2008, 15, 1176–1183.
[41]
Feldman, N.; Gerson, A.; Fang, J.; Li, E.; Zhang, Y.; Shinkai, Y.; Cedar, H.; Bergman, Y. G9a-mediated irreversible epigenetic inactivation of Oct-3/4 during early embryogenesis. Nat. Cell. Biol. 2006, 8, 188–194, doi:10.1038/ncb1353.
[42]
Niehrs, C.; Schafer, A. Active DNA demethylation by Gadd45 and DNA repair. Trends Cell Biol. 2012, 22, 220–227, doi:10.1016/j.tcb.2012.01.002.
[43]
Tahiliani, M.; Koh, K.P.; Shen, Y.; Pastor, W.A.; Bandukwala, H.; Brudno, Y.; Agarwal, S.; Iyer, L.M.; Liu, D.R.; Aravind, L.; et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 2009, 324, 930–935, doi:10.1126/science.1170116.
[44]
Kerkel, K.; Spadola, A.; Yuan, E.; Kosek, J.; Jiang, L.; Hod, E.; Li, K.; Murty, V.V.; Schupf, N.; Vilain, E.; et al. Genomic surveys by methylation-sensitive SNP analysis identify sequence-dependent allele-specific DNA methylation. Nat. Genet. 2008, 40, 904–908, doi:10.1038/ng.174.
[45]
Tycko, B. Allele-specific DNA methylation: Beyond imprinting. Hum. Mol. Genet. 2010, 19, R210–R220, doi:10.1093/hmg/ddq376.
[46]
Bell, J.T.; Pai, A.A.; Pickrell, J.K.; Gaffney, D.J.; Pique-Regi, R.; Degner, J.F.; Gilad, Y.; Pritchard, J.K. DNA methylation patterns associate with genetic and gene expression variation in HapMap cell lines. Genome Biol. 2011, 12, R10.
[47]
Hellman, A.; Chess, A. Extensive sequence-influenced DNA methylation polymorphism in the human genome. Epigenetics Chromatin 2010, 3, 11, doi:10.1186/1756-8935-3-11.
[48]
Vire, E.; Brenner, C.; Deplus, R.; Blanchon, L.; Fraga, M.; Didelot, C.; Morey, L.; van Eynde, A.; Bernard, D.; Vanderwinden, J.M.; et al. The Polycomb group protein EZH2 directly controls DNA methylation. Nature 2006, 439, 871–874, doi:10.1038/nature04431.
[49]
Jiang, Y.; Mishima, H.; Sakai, S.; Liu, Y.K.; Ohyabu, Y.; Uemura, T. Gene expression analysis of major lineage-defining factors in human bone marrow cells: Effect of aging, gender, and age-related disorder. J. Orthop. Res. 2008, 26, 910–917, doi:10.1002/jor.20623.
[50]
Kang, M.I.; Kim, H.S.; Jung, Y.C.; Kim, Y.H.; Hong, S.J.; Kim, M.K.; Baek, K.H.; Kim, C.C.; Rhyu, M.G. Transitional CpG methylation between promoters and retroelements of tissue-specific genes during human mesenchymal cell differentiation. J. Cell. Biochem. 2007, 102, 224–239, doi:10.1002/jcb.21291.
[51]
Zhang, R.P.; Shao, J.Z.; Xiang, L.X. GADD45A protein plays an essential role in active DNA demethylation during terminal osteogenic differentiation of adipose-derived mesenchymal stem cells. J. Biol. Chem. 2011, 286, 41083–41094.
[52]
Locklin, R.M.; Oreffo, R.O.; Triffitt, J.T. Modulation of osteogenic differentiation in human skeletal cells in vitro by 5-azacytidine. Cell Biol. Int. 1998, 22, 207–215, doi:10.1006/cbir.1998.0240.
[53]
Delgado-Calle, J.; Sanudo, C.; Bolado, A.; Fernandez, A.F.; Arozamena, J.; Pascual-Carra, M.A.; Rodriguez-Rey, J.C.; Fraga, M.F.; Bonewald, L.F.; Riancho, J.A. DNA methylation contributes to the regulation of sclerostin expression in human osteocytes. J. Bone Miner. Res. 2012, 27, 926–937, doi:10.1002/jbmr.1491.
[54]
Delgado-Calle, J.; Sanudo, C.; Sanchez-Verde, L.; Garcia-Renedo, R.J.; Arozamena, J.; Riancho, J.A. Epigenetic regulation of alkaline phosphatase in human cells of the osteoblastic lineage. Bone 2011, 49, 830–838, doi:10.1016/j.bone.2011.06.006.
[55]
Arnsdorf, E.J.; Tummala, P.; Castillo, A.B.; Zhang, F.; Jacobs, C.R. The epigenetic mechanism of mechanically induced osteogenic differentiation. J. Biomech. 2010, 43, 2881–2886, doi:10.1016/j.jbiomech.2010.07.033.
[56]
Villagra, A.; Gutierrez, J.; Paredes, R.; Sierra, J.; Puchi, M.; Imschenetzky, M.; Wijnen, A.A.; Lian, J.; Stein, G.; Stein, J.; et al. Reduced CpG methylation is associated with transcriptional activation of the bone-specific rat osteocalcin gene in osteoblasts. J. Cell Biochem. 2002, 85, 112–122, doi:10.1002/jcb.10113.
[57]
Dansranjavin, T.; Krehl, S.; Mueller, T.; Mueller, L.P.; Schmoll, H.J.; Dammann, R.H. The role of promoter CpG methylation in the epigenetic control of stem cell related genes during differentiation. Cell Cycle 2009, 8, 916–924, doi:10.4161/cc.8.6.7934.
[58]
Loeser, R.F.; Im, H.J.; Richardson, B.; Lu, Q.; Chubinskaya, S. Methylation of the OP-1 promoter: Potential role in the age-related decline in OP-1 expression in cartilage. Osteoarthr. Cartil. 2009, 17, 513–517.
[59]
Lee, J.Y.; Lee, Y.M.; Kim, M.J.; Choi, J.Y.; Park, E.K.; Kim, S.Y.; Lee, S.P.; Yang, J.S.; Kim, D.S. Methylation of the mouse DIx5 and Osx gene promoters regulates cell type-specific gene expression. Mol. Cells 2006, 22, 182–188.
[60]
Penolazzi, L.; Lambertini, E.; Giordano, S.; Sollazzo, V.; Traina, G.; del Senno, L.; Piva, R. Methylation analysis of the promoter F of estrogen receptor alpha gene: Effects on the level of transcription on human osteoblastic cells. J. Steroid Biochem.Mol. Biol. 2004, 91, 1–9, doi:10.1016/j.jsbmb.2004.02.005.
[61]
Demura, M.; Bulun, S.E. CpG dinucleotide methylation of the CYP19 I.3/II promoter modulates cAMP-stimulated aromatase activity. Mol. Cell Endocrinol. 2008, 283, 127–132, doi:10.1016/j.mce.2007.12.003.
[62]
Thaler, R.; Agsten, M.; Spitzer, S.; Paschalis, E.P.; Karlic, H.; Klaushofer, K.; Varga, F. Homocysteine suppresses the expression of the collagen cross-linker lysyl oxidase involving IL-6, Fli1, and epigenetic DNA methylation. J. Biol. Chem. 2011, 286, 5578–5588.
Delgado-Calle, J.; Sanudo, C.; Fernandez, A.F.; Garcia-Renedo, R.; Fraga, M.F.; Riancho, J.A. Role of DNA methylation in the regulation of the RANKL-OPG system in human bone. Epigenetics 2012, 7, 83–91, doi:10.4161/epi.7.1.18753.
[66]
Kitazawa, R.; Kitazawa, S. Methylation status of a single CpG locus 3 bases upstream of TATA-box of receptor activator of nuclear factor-kappaB ligand RANKL. Gene promoter modulates cell- and tissue-specific RANKL expression and osteoclastogenesis. Mol. Endocrinol. 2007, 21, 148–158.
[67]
Yasui, T.; Hirose, J.; Aburatani, H.; Tanaka, S. Epigenetic regulation of osteoclast differentiation. Ann. NY Acad. Sci. 2011, 1240, 7–13.
[68]
Delgado-Calle, J.; Garmilla, P.; Riancho, J.A. Do epigenetic marks govern bone homeostasis? Curr. Genomics 2012, 13, 252–263.
[69]
Kato, S.; Inoue, K.; Youn, M.I. Emergence of the osteo-epigenome in bone biology. IBMS BoneKEy 2010, 7, 314–324, doi:10.1138/20100464.
[70]
Earl, S.C.; Harvey, N.; Cooper, C. The epigenetic regulation of bone mass. IBMS BoneKEy 2010, 7, 54–62, doi:10.1138/20100428.
[71]
Riggs, B.L.; Khosla, S.; Melton, L.J. Sex steroids and the construction and conservation of the adult skeleton. Endocr. Rev. 2002, 23, 279–302, doi:10.1210/er.23.3.279.
[72]
Manolagas, S.C. From estrogen-centric to aging and oxidative stress: A revised perspective of the pathogenesis of osteoporosis. Endocr. Rev. 2010, 31, 266–300, doi:10.1210/er.2009-0024.
[73]
Liu, L.; van Groen, T.; Kadish, I.; Li, Y.; Wang, D.; James, S.R.; Karpf, A.R.; Tollefsbol, T.O. Insufficient DNA methylation affects healthy aging and promotes age-related health problems. Clin. Epigenetics 2011, 2, 349–360, doi:10.1007/s13148-011-0042-6.
[74]
Rodriguez-Rodero, S.; Fernandez-Morera, J.L.; Fernandez, A.F.; Menendez-Torre, E.; Fraga, M.F. Epigenetic regulation of aging. Discov. Med. 2010, 10, 225–233.
[75]
Fraga, M.F.; Esteller, M. Epigenetics and aging: The targets and the marks. Trends Genet. 2007, 23, 413–418, doi:10.1016/j.tig.2007.05.008.
[76]
Fraga, M.F. Genetic and epigenetic regulation of aging. Curr. Opin. Immunol. 2009, 21, 446–453, doi:10.1016/j.coi.2009.04.003.
[77]
Calvanese, V.; Lara, E.; Kahn, A.; Fraga, M.F. The role of epigenetics in aging and age-related diseases. Ageing Res. Rev. 2009, 8, 268–276.
[78]
Huidobro, C.; Fernandez, A.F.; Fraga, M.F. Aging epigenetics: Causes and consequences. Mol. Asp. Med. 2012. in press.
[79]
Mahon, P.; Harvey, N.; Crozier, S.; Inskip, H.; Robinson, S.; Arden, N.; Swaminathan, R.; Cooper, C.; Godfrey, K. Low maternal vitamin D status and fetal bone development: Cohort study. J. Bone Miner. Res. 2010, 25, 14–19, doi:10.1359/jbmr.090701.
[80]
Oreffo, R.O.; Lashbrooke, B.; Roach, H.I.; Clarke, N.M.; Cooper, C. Maternal protein deficiency affects mesenchymal stem cell activity in the developing offspring. Bone 2003, 33, 100–107, doi:10.1016/S8756-3282(03)00166-2.
[81]
Lillycrop, K.A.; Phillips, E.S.; Torrens, C.; Hanson, M.A.; Jackson, A.A.; Burdge, G.C. Feeding pregnant rats a protein-restricted diet persistently alters the methylation of specific cytosines in the hepatic PPAR alpha promoter of the offspring. Br. J. Nutr. 2008, 100, 278–282.
[82]
Lillycrop, K.A.; Slater-Jefferies, J.L.; Hanson, M.A.; Godfrey, K.M.; Jackson, A.A.; Burdge, G.C. Induction of altered epigenetic regulation of the hepatic glucocorticoid receptor in the offspring of rats fed a protein-restricted diet during pregnancy suggests that reduced DNA methyltransferase-1 expression is involved in impaired DNA methylation and changes in histone modifications. Br. J. Nutr. 2007, 97, 1064–1073, doi:10.1017/S000711450769196X.
[83]
Lillycrop, K.A.; Phillips, E.S.; Jackson, A.A.; Hanson, M.A.; Burdge, G.C. Dietary protein restriction of pregnant rats induces and folic acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring. J. Nutr. 2005, 135, 1382–1386.
[84]
Brandt, K.D.; Dieppe, P.; Radin, E.L. Etiopathogenesis of osteoarthritis. Rheum. Dis. Clin. North Am. 2008, 34, 531–559.
[85]
Loeser, R.F.; Goldring, S.R.; Scanzello, C.R.; Goldring, M.B. Osteoarthritis: A disease of the joint as an organ. Arthritis Rheum. 2012, 64, 1697–1707.
[86]
Goldring, S.R. The role of bone in osteoarthritis pathogenesis. Rheum.Dis. Clin. North Am. 2008, 34, 561–571, doi:10.1016/j.rdc.2008.07.001.
[87]
Bellido, M.; Lugo, L.; Roman-Blas, J.A.; Castaneda, S.; Calvo, E.; Largo, R.; Herrero-Beaumont, G. Improving subchondral bone integrity reduces progression of cartilage damage in experimental osteoarthritis preceded by osteoporosis. Osteoarthr. Cartil. 2011, 19, 1228–1236, doi:10.1016/j.joca.2011.07.003.
[88]
Goldring, M.B.; Goldring, S.R. Articular cartilage and subchondral bone in the pathogenesis of osteoarthritis. Ann. NY Acad. Sci. 2010, 1192, 230–237, doi:10.1111/j.1749-6632.2009.05240.x.
[89]
Herrero-Beaumont, G.; Roman-Blas, J.A.; Largo, R.; Berenbaum, F.; Castaneda, S. Bone mineral density and joint cartilage: Four clinical settings of a complex relationship in osteoarthritis. Ann.Rheum. Dis. 2011, 70, 1523–1525, doi:10.1136/ard.2011.151233.
[90]
Suri, S.; Walsh, D.A. Osteochondral alterations in osteoarthritis. Bone 2012, 51, 204–211, doi:10.1016/j.bone.2011.10.010.
[91]
Roach, H.I.; Yamada, N.; Cheung, K.S.; Tilley, S.; Clarke, N.M.; Oreffo, R.O.; Kokubun, S.; Bronner, F. 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. 2005, 52, 3110–3124, doi:10.1002/art.21300.
[92]
Roach, H.I.; Aigner, T. DNA methylation in osteoarthritic chondrocytes: A new molecular target. Osteoarthr. Cartil. 2007, 15, 128–137, doi:10.1016/j.joca.2006.07.002.
[93]
Zimmermann, P.; Boeuf, S.; Dickhut, A.; Boehmer, S.; Olek, S.; Richter, W. Correlation of COL10A1 induction during chondrogenesis of mesenchymal stem cells with demethylation of two CpG sites in the COL10A1 promoter. Arthritis Rheum. 2008, 589, 2743–2753.
[94]
Barter, M.J.; Bui, C.; Young, D.A. Epigenetic mechanisms in cartilage and osteoarthritis: DNA methylation, histone modifications and microRNAs. Osteoarthr. Cartil. 2012, 20, 339–349.
[95]
Goldring, M.B.; Marcu, K.B. Epigenomic and microRNA-mediated regulation in cartilage development, homeostasis, and osteoarthritis. Trends Mol. Med. 2012, 18, 109–118, doi:10.1016/j.molmed.2011.11.005.
[96]
Bui, C.; Barter, M.J.; Scott, J.L.; Xu, Y.; Galler, M.; Reynard, L.N.; Rowan, A.D.; Young, D.A. 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. 2012, 26, 3000–3011.
[97]
Poschl, E.; Fidler, A.; Schmidt, B.; Kallipolitou, A.; Schmid, E.; Aigner, T. DNA methylation is not likely to be responsible for aggrecan down regulation in aged or osteoarthritic cartilage. Ann. Rheum. Dis. 2005, 64, 477–480.
[98]
Zuscik, M.J.; Baden, J.F.; Wu, Q.; Sheu, T.J.; Schwarz, E.M.; Drissi, H.; O’Keefe, R.J.; Puzas, J.E.; Rosier, R.N. 5-azacytidine alters TGF-beta and BMP signaling and induces maturation in articular chondrocytes. J. Cell Biochem. 2004, 922, 316–331.
[99]
Javaid, M.K.; Lane, N.E.; Mackey, D.C.; Lui, L.Y.; Arden, N.K.; Beck, T.J.; Hochberg, M.C.; Nevitt, M.C. Changes in proximal femoral mineral geometry precede the onset of radiographic hip osteoarthritis: The study of osteoporotic fractures. Arthritis Rheum. 2009, 60, 2028–2036, doi:10.1002/art.24639.
[100]
Baker-Lepain, J.C.; Lynch, J.A.; Parimi, N.; McCulloch, C.E.; Nevitt, M.C.; Corr, M.; Lane, N.E. Variant alleles of the WNT antagonist FRZB are determinants of hip shape and modify the relationship between hip shape and osteoarthritis. Arthritis Rheum. 2012, 64, 1457–1465, doi:10.1002/art.34526.
[101]
Schiffern, A.N.; Stevenson, D.A.; Carroll, K.L.; Pimentel, R.; Mineau, G.; Viskochil, D.H.; Roach, J.W. Total hip arthroplasty; hip osteoarthritis; total knee arthroplasty; and knee osteoarthritis in patients with developmental dysplasia of the hip and their family members: A kinship analysis report. J. Pediatr. Orthop. 2012, 32, 609–612.
[102]
Sandell, L.J. Etiology of osteoarthritis: genetics and synovial joint development. Nat. Rev. Rheumatol. 2012, 8, 77–89.
[103]
Bos, S.D.; Slagboom, P.E.; Meulenbelt, I. New insights into osteoarthritis: Early developmental features of an ageing-related disease. Curr. Opin. Rheumatol. 2008, 20, 553–559, doi:10.1097/BOR.0b013e32830aba48.
[104]
Aspden, R.M. Osteoarthritis: A problem of growth not decay? Rheumatology 2008, 47, 1452–1460, doi:10.1093/rheumatology/ken199.
[105]
Panoutsopoulou, K.; Southam, L.; Elliott, K.S.; Wrayner, N.; Zhai, G.; Beazley, C.; Thorleifsson, G.; Arden, N.K.; Carr, A.; Chapman, K.; et al. Insights into the genetic architecture of osteoarthritis from stage 1 of the arcOGEN study. Ann. Rheum. Dis. 2011, 70, 864–867, doi:10.1136/ard.2010.141473.
[106]
Arcogen Consortium. Identification of new susceptibility loci for osteoarthritis arcOGEN: A genome-wide association study. Lancet 2012, 380, 815–823, doi:10.1016/S0140-6736(12)60681-3.
[107]
Valdes, A.M.; Spector, T.D. Genetic epidemiology of hip and knee osteoarthritis. Nat. Rev. Rheumatol. 2011, 7, 23–32, doi:10.1038/nrrheum.2010.191.
[108]
Reynard, L.N.; Bui, C.; Canty-Laird, E.G.; Young, D.A.; Loughlin, J. Expression of the osteoarthritis-associated gene GDF5 is modulated epigenetically by DNA methylation. Hum. Mol. Genet. 2011, 20, 3450–3460, doi:10.1093/hmg/ddr253.
[109]
Delgado-Calle, J.; Fernandez, A.F.; Sainz, J.; Zarrabeitia, M.T.; Garcia-Renedo, R.J.; Perez-Nunez, M.I.; Garcia-Ibarbia, C.; Fraga, M.F.; Riancho, J.A. Genome-wide profiling of bone reveals differentially methylated regions in osteoporosis and osteoarthritis. Arthritis Rheum. 2012, doi:10.1002/art.37753.
[110]
Saha, B.; Kaur, P.; Tsao-Wei, D.; Naritoku, W.Y.; Groshen, S.; Datar, R.H.; Jones, L.W.; Imam, S.A. Unmethylated E-cadherin gene expression is significantly associated with metastatic human prostate cancer cells in bone. Prostate 2008, 68, 1681–1688.
[111]
Tost, J.; Hamzaoui, H.; Busato, F.; Neyret, A.; Mourah, S.; Dupont, JM.; Bouizar, Z. Methylation of specific CpG sites in the P2 promoter of parathyroid hormone-related protein determines the invasive potential of breast cancer cell lines. Epigenetics 2011, 6, 1035–1046, doi:10.4161/epi.6.8.16077.
