Annals of the Russian academy of medical sciencesAnnals of the Russian academy of medical sciencesВестник Российской академии медицинских наук0869-60472414-3545"Paediatrician" Publishers LLC54510.15690/vramn.v70.i5.1440ENDOCRINOLOGY: CURRENT ISSUESАКТУАЛЬНЫЕ ВОПРОСЫ ЭНДОКРИНОЛОГИИEpigenetic Aspects of OsteoporosisЭпигенетические аспекты остеопорозаGrebennikovaT. A.ГребенниковаТ. А.
Russian Federation

ординатор отделения нейроэндокринологии и остеопатий ФГБУ «Эндокринологический научный центр» Минздрава России Адрес: 117036, Москва, ул. Дмитрия Ульянова, д. 11

grebennikova@hotmail.comBelayaZh. E.БелаяЖ. Е.
Russian Federation

доктор медицинских наук, главный научный сотрудник, заведующая отделением нейроэндокринологии и остеопатий ФГБУ «Эндокринологический научный центр» Минздрава России Адрес: 117036, Москва, ул. Дмитрия Ульянова, д. 11, тел.: +7 (495) 668-20-79

jannabelaya@gmail.comRozhinskayaL. Ya.РожинскаяЛ. Я.
Russian Federation

доктор медицинских наук, главный научный сотрудник отделения нейроэндокринологии и остеопатий ФГБУ «Эндокринологический научный центр» Минздрава России Адрес: 117036, Москва, ул. Дмитрия Ульянова, д. 11, тел.: +7 (495) 668-20-79

rozhinskaya@rambler.ruMel'nichenkoG. A.МельниченкоГ. А.
Russian Federation

заместитель директора по научной работе, директор института клинической эндокринологии ФГБУ «Эндокринологический научный центр» Минздрава России, академик РАН Адрес: 117036, Москва, ул. Дмитрия Ульянова, д. 11, тел.: +7 (499) 124-43-00

teofrast2000@mail.ruDedovI. I.ДедовИ. И.
Russian Federation

директор ФГБУ «Эндокринологический научный центр» Минздрава России, академик РАН, Президент Российской ассоциации эндокринологов Адрес: 117036, Москва, ул. Дмитрия Ульянова, д. 11, тел.: +7 (499) 124-43-00

dedov@endocrincentr.ruNational Endocrine Research Centre, Moscow, Russian FederationЭндокринологический научный центр, Москва, Российская Федерация031220157055415480212201502122015Copyright ©; 2015, "Paediatrician" Publishers LLCCopyright ©; 2015, Издательство "Педиатръ"2015"Paediatrician" Publishers LLCИздательство "Педиатръ"https://vestnikramn.spr-journal.ru/jour/about/submissionshttps://vestnikramn.spr-journal.ru/jour/article/view/545

This review describes the epigenetic regulation of osteoblastogenesis and osteoclastogenesis and its future implementation in the diagnosis and treatment of osteoporosis. A considerable part of the review is dedicated to the microRNAs (miRNAs). miRNAs are small regulatory factors that regulate gene expression, by post-transcriptional regulation of genes playing an important role in numerous cellular processes, including cell differentiation and apoptosis. Recently, a number of studies have revealed that miRNAs participate in bone homeostasis and their role in the pathogenesis of osteoporosis is practically evident. In this review, we highlight the miRNAs involved in bone remodelling and their roles in osteoporosis. miRNAs are stable molecules which make them promising potential markers for bone remodeling and osteoporosis.

Обсуждаются перспективы использования эпигенетических механизмов регуляции остеобласто- и остеокластогенеза в ранней диагностике и лечении остеопороза. Особое внимание уделено классу малых некодирующих регуляторных РНК — микроРНК (мкРНК), которые контролируют экспрессию генов на посттранскрипционном уровне, участвуя практически во всех биологических процессах в клетке, включая клеточную дифференцировку и апоптоз. Изучение роли мкРНК в регуляции костного обмена начаты относительно недавно, однако все более очевидно их участие в патогенезе остеопороза. В статье приведен профиль микроРНК, наиболее значимо влияющих на костный метаболизм. Устойчивость мкРНК к разрушению в периферической крови дает возможность рассматривать некоторые специфичные для костной ткани мкРНК в качестве потенциальных диагностических маркеров костного ремоделированияи остеопороза.

osteoporosismiRNAbone epigeneticosteoblastogenesisостеопорозмикроРНКэпигенетика костиостеобластогенез1. Kanis J., McCloskey E., Johansson H., Cooper C., Rizzoli R., Reginster J. European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporosis Int. 2013; 24 (1): 23–57. DOI:10.1007/s00198-012-2074-y.2. ДDedov I.I., Mel'nichenko G.A., Belaya Zh.E., Rozhinskaya L.Ya. Osteoporosis - a symptom of a rare endocrine disease to the silent epidemic of XX-XXI centuries. Problemy endokrinologii = Problems of endocrinology. 2011;57(1):35–45. DOI: 10.14341/probl201157135-45.3. Lesnyak O.M., Benevolenskaya L.I. Osteoporosis in the Russian Federation: problems and prospects. Nauchno-prakticheskaya revmatologiya = Scientific-practical rheumatology. 2010;5:14. DOI: 10.14412/1995-4484-2010-725.4. Belaya Zh.E., Rozhinskaya L.Ya. Bisphosphonates: myths and reality. Effektivnaya farmakoterapiya v endokrinologii = Effective pharmacotherapy in endocrinology. 2010;38:52–58.5. Belaya Zh.E., Rozhinskaya L.Ya. Falls - an important social problem of the elderly. Basic mechanisms of development and ways of prevention. Russkii meditsinskii zhurnal = Russian medical journal. 2009;17(24):1614–1619.6. Vrtačnik P., Marc J., Ostanek B. Epigenetic mechanisms in bone. Clin. Chem. Lab. Med. 2014; 52 (5): 589–608. DOI: 10.1515/cclm-2013-0770.7. Belaya Zh.E., Rozhinskaya L.Ya. New trends in the treatment of osteoporosis - the use of monoclonal human bodies to RANKL (denosumab). Osteoporoz i osteopatii = Osteoporosis and osteopathy. 2011;2:23–26.8. Padhi D., Jang G., Stouch B., Fang L., Posvar E. Single dose, placebo controlled, randomized study of AMG 785, a sclerostin monoclonal antibody. J. Bone Miner Res. 2010; 26 (1): 19–26. DOI:10.1002/jbmr.173.9. Lewiecki E., Shah A., Shoback D. Sclerostin inhibition: a novel therapeutic approach in the treatment of osteoporosis. Int. J. Womens Health. 2015; 7: 565. DOI:10.2147/ijwh.s73244.10. Belaya Z.E., Rozhinskaya L.Y., Melnichenko G.A., Solodovnikov A.G., Dragunova N.V., Iljin A.V., Dzeranova L.K., Dedov I.I. Serum extracellular secreted antagonists of the canonical Wnt/β catenin signaling pathway in patients with Cushing’s syndrome. Osteoporos Int. 2013; 24 (8): 2191–2199. DOI:10.1007/s00198-013-2268-y.11. Schroeder T., Nair A., Staggs R., Lamblin A., Westendorf J. Gene profile analysis of osteoblast genes differentially regulated by histone deacetylase inhibitors. BMC Genomics. 2007; 8 (1): 362. DOI:10.1186/1471-2164-8-362.12. Schroeder T., Westendorf J. Histone deacetylase inhibitors promote osteoblast maturation. J. Bone Miner Res. 2005; 20 (12): 2254–2263. DOI:10.1359/jbmr.050813.13. Lee H., Suh J., Kim A., Lee Y., Park S., Kim J. Histone deacetylase-1 mediated histone modification regulates osteoblast differentiation. Mol. Endocrinol. 2006; 20 (10): 2432–2443. doi:10.1210/me.2006-0061.14. Fusco S, Maulucci G., Pani G. Sirt1: Defeating senescence? Cell. Cycle. 2012; 11 (22): 4135–4146. DOI:10.4161/cc.22074.15. Tseng P., Hou S., Chen R., Peng H., Hsieh C., Kuo M., Yen M. Resveratrol promotes osteogenesis of human mesenchymal stem cells by upregulating RUNX2 gene expression via the SIRT1/FOXO3A axis. J. Bone Miner. Res. 2011; 26 (10): 2552–2563. DOI:10.1002/jbmr.460.16. Shakibaei M., Buhrmann C., Mobasheri A. Resveratrol mediated SIRT-1 interactions with p300 modulate receptor activator of NF-kappaB Ligand (RANKL) activation of NF-kappaB signaling and inhibit osteoclastogenesis in bone derived cells. J. Biol. Chem. 2011; 286 (13): 11492–11505. DOI:10.1074/jbc.m110.198713.17. Edwards J., Perrien D., Fleming N., Nyman J., Ono K., Connelly L., Moore M., Lwin S., Yuii F., Mundy G., Elefteriou F. Silent information regulator (Sir)T1 inhibits NF-κB signaling to maintain normal skeletal remodeling. J. Bone Miner Res. 2013; 28 (4): 960–969. DOI:10.1002/jbmr.1824.18. Nakamura T., Kukita T., Shobuike T., Nagata K., Wu Z., Ogawa K., Hotokebuchi T., Kohashi O., Kukita A. Inhibition of histone deacetylase suppresses osteoclastogenesis and bone destruction by inducing IFN production. J. Immunol. 2005; 175 (9): 5809–5816. DOI:10.4049/jimmunol.175.9.5809.19. Takada Y. Suberoylanilide Hydroxamic acid potentiates apoptosis, inhibits invasion, and abolishes osteoclastogenesis by suppressing nuclear factor B activation. J. Biol. Chem. 2005; 281 (9): 5612–5622. DOI:10.1074/jbc.m507213200.20. Kim H., Lee J., Jin W., Ko S., Jung K., Ha H., Lee Z. MS-275, a benzamide histone deacetylase inhibitor, prevents osteoclastogenesis by down-regulating c-Fos expression and suppresses bone loss in mice. Eur. J. Pharmacol. 2012; 691 (1–3): 69–76. DOI:10.1016/j.ejphar.2012.07.034.21. Delgado–Calle J, Riancho J. The role of DNA methylation in common skeletal disorders. Biology. 2012; 1 (3): 698–713. doi:10.3390/biology1030698.22. Gibney E., Nolan C. Epigenetics and gene expression. Heredity. 2010; 105 (1): 4–13. DOI:10.1038/hdy.2010.54.23. Portela A., Esteller M. Epigenetic modifications and human disease. Nat. Biotechnol. 2010; 28 (10): 1057–1068. DOI:10.1038/nbt.1685.24. Delgado-Calle J., Sañudo C., Bolado A., Fernandez A., Arozanena J., Pascual-Carra M., Radriguez-Rey J., Fraga M.,Bonewald L., Riancho J. DNA methylation contributes to the regulation of sclerostin expression in human osteocytes. J. Bone Miner Res. 2012; 27 (4): 926–937. DOI:10.1002/jbmr.1491.25. Arnsdorf E., Tummala P., Castillo A., Zhang F., Jacobs C. The epigenetic mechanism of mechanically induced osteogenic differentiation. J. Biomech. 2010; 43 (15): 2881–2886. DOI:10.1016/j.jbiomech.2010.07.033.26. Delgado-Calle J., Sañudo C., Fernández A., García-Renedo R., Fraga M., Riancho J. Role of DNA methylation in the regulation of the RANKL–OPG system in human bone. Epigenetics. 2012; 7 (1):83–91. DOI:10.4161/epi.7.1.18753.27. Kitazawa S., Kitazawa R. Epigenetic control of mouse receptor activator of NF-κB ligand gene expression. Biochem. Biophys. Res. Commun. 2002; 293 (1): 126–131. DOI:10.1016/s0006-291x(02)00189-4.28. Kitazawa R., Kitazawa S. Methylation status of a single CpG locus 3 bases upstream of TATA box of receptor activator of nuclear factor κB ligand (RANKL) gene promoter modulates cell andtissue specific RANKL expression and osteoclastogenesis. Mol. Endocrinol. 2007; 21 (1): 148–158. DOI:10.1210/me.2006-0205.29. Markopoulou S., Nikolaidis G., Liloglou T. DNA methylation biomarkers in biological fluids for early detection of respiratory tract cancer. Clin. Chem. Lab. Med. 2012; 50 (10). doi:10.1515/cclm-2012-0124.30. Lacey D., Boyle W., Simonet W., Kostenuik P., Dougall W., Sullivan J., San Martin J., Dansey R. Bench to bedside: elucidation of the OPG–RANK–RANKL pathway and the development of denosumab. Nat. Rev. Drug. Discov. 2012; 11 (5): 401–419. DOI:10.1038/nrd3705.31. Monroe D., McGee-Lawrence M., Oursler M., Westendorf J. Update on Wnt signaling in bone cell biology and bone disease. Gene. 2012; 492 (1): 1–18. DOI:10.1016/j.gene.2011.10.044.32. Li X., Ominsky M.S., Warmington K.S., Morony S., Gong J., Cao J., Gao Y., Shalhoub V., Tipton B., Haldankar R., Chen Q., Winters A., Boone T., Geng Z., Niu Q.T., Ke H.Z., Kostenuik P.J., Simonet W.S., Lacey D.L., Paszty C. Sclerostin Antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis. J. Bone Miner Res. 2009; 24 (4): 578–588. DOI:10.1359/jbmr.081206.33. Centrella M., McCarthy T. Estrogen receptor dependent gene expression by osteoblasts – direct, indirect, circumspect, and speculative effects. Steroids. 2012; 77 (3): 174–184. DOI:10.1016/j.steroids.2011.10.016.34. Burgers T., Williams B. Regulation of Wnt/β-catenin signaling within and from osteocytes. Bone. 2013; 54 (2): 244–249. DOI:10.1016/j.bone.2013.02.022.35. Diarra D., Stolina M., Polzer K., Zwerina J., Ominsky M.S., Dwyer D., Korb A., Smolen J., Hoffmann M., Scheinecker C., van der Heide D., Landewe R., Lacey D., Richards W., Schett G. Dickkopf-1 is a master regulator of joint remodeling. Nat. Med. 2007; 13 (2): 156–163. DOI:10.1038/nm1538.36. Semenova E., Filatov M. Genetic and epigenetic markers of gliomas. Cell. Tiss. Biol. 2013; 7 (4): 303–313. DOI:10.1134/s1990519x13040123.37. Hassan M., Gordon J., Beloti M., Croce C.M., van Wijnen A.J., Stein J.L., Stein G.S., Lian J.B. A network connecting Runx2, SATB2, and the miR-23a 27a 24-2 cluster regulates the osteoblast differentiation program. Proc. Natl. Acad. Sci USA. 2010; 107 (46): 19879–19884. DOI:10.1073/pnas.1007698107.38. Wu T., Zhou H., Hong Y., Li J., Jiang X., Huang H. MiR–30 family members negatively regulate osteoblast differentiation. J. Biol. Chem. 2012; 287 (10): 7503–7511. DOI:10.1074/jbc.m111.292722.39. Li Z., Hassan M.Q., Volinia S., van Wijnen A.J., Stein J.L., Croce C.M., Lian J.B., Stein G.S. A microRNA signature for a BMP2 induced osteoblast lineage commitment program. Proc. Natl. Acad. Sci USA. 2008; 105 (37): 13906–13911. DOI:10.1073/ pnas.0804438105.40. Huang J., Zhao L., Xing L., Chen D. MicroRNA-204 regulates Runx2 protein expression and mesenchymal progenitor cell differentiation. Stem. Cells. 2010: 28 (2): 357–364. DOI:10.1002/stem.288.41. Tomé M., López-Romero P., Albo C., Sepúlveda J.C., Fernández-Gutiérrez B., Dopazo A., Bernad A., González M.A. miR-335 orchestrates cell proliferation, migration and differentiation in human mesenchymal stem cells. Cell Death Differ. 2010; 18 (6): 985–995. DOI:10.1038/cdd.2010.167.42. Kim E., Kang I., Lee J., Jang W., Koh J. MiR-433 mediates ERRγ suppressed osteoblast differentiation via direct targeting to Runx2 mRNA in C3H10T1/2 cells. Life Sci. 2013; 92 (10): 562–568. DOI:10.1016/j.lfs.2013.01.015.43. Zhang Y., Xie R.L., Croce C.M., Stein J.L., Lian J.B., van Wijnen A.J., Stein G.S. A program of microRNAs controls osteogenic lineage progression by targeting transcription factor Runx2. Proc. Natl. Acad. Sci USA. 2011; 108 (24): 9863–9868. DOI:10.1073/pnas.1018493108.44. Zhang Y., Xie R., Gordon J., LeBlanc K., Stein J.L., Lian J.B., van Wijnen A.J., Stein G.S. Control of mesenchymal lineage progression by MicroRNAs targeting skeletal gene regulators Trps1 and Runx2. J. Biol. Chem. 2012; 287 (26): 21926–21935. DOI:10.1074/jbc. m112.34039845. Li H., Xie H., Liu W., Hu R., Huang B., Tan Y.F., Xu K., Sheng Z.F., Zhou H.D., Wu X.P., Luo X.H. A novel microRNA targeting HDAC5 regulates osteoblast differentiation in mice and contributes to primary osteoporosis in humans. J. Clin. Invest. 2009; 119 (12): 3666–3677. DOI:10.1172/jci39832.46. Hu R., Liu W., Li H., Yang L., Chen C., Xia Z.Y., Guo L.J., Xie H., Zhou H.D., Wu X.P., Luo X.H. A Runx2/miR-3960/miR-2861 regulatory feedback loop during mouse osteoblast differentiation. J. Biol. Chem. 2011; 286 (14): 12328–12339. DOI:10.1074/jbc. m110.176099.47. Yang L., Cheng P., Chen C., He H.B., Xie G.Q., Zhou H.D., Xie H., Wu X.P., Luo X.H. miR-93/Sp7 function loop mediates osteoblast mineralization. J. Bone Miner. Res. 2012; 27 (7): 1598–1606. DOI:10.1002/jbmr.1621.48. Kapinas K., Kessler C., Ricks T., Gronowicz G., Delany A. MiR-29 modulates Wnt signaling in human osteoblasts through a positive feedback loop. J. Biol. Chem. 2010; 285 (33): 25221–25231. DOI:10.1074/jbc.m110.116137.49. Hassan M., Maeda Y., Taipaleenmaki H., Zhang W., Jafferji M., Gordon J.A., Li Z., Croce C.M., van Wijnen A.J., Stein J.L., Stein G.S., Lian J.B. MiR-218 directs a Wnt signaling circuit to promote differentiation of osteoblasts and osteomimicry of metastatic cancer cells. J. Biol. Chem. 2012; 287 (50): 42084–42092. DOI:10.1074/jbc.m112.377515.50. Zhang J., Tu Q., Bonewald L., He X., Stein G., Lian J., Chen J.. Effects of miR-335-5p in modulating osteogenic differentiation by specifically down regulating Wnt antagonist DKK1. J. Bone Miner. Res. 2011; 26 (8): 1953–1963. DOI:10.1002/jbmr.377.51. Wang T., Xu Z. MiR-27 promotes osteoblast differentiation by modulating Wnt signaling. Biochem Biophys Res Commun. 2010; 402 (2): 186–189. DOI:10.1016/j.bbrc.2010.08.031.52. Hu W., Ye Y., Zhang W., Wang J., Chen A., Guo F. MiR-142 3p promotes osteoblast differentiation by modulating Wnt signaling. Mol. Med. Rep. 2013; 7 (2):689-93. DOI:10.3892/mmr.2012.1207.53. Liao L, Yang X, Su X, Hu C, Zhu X, Yang N, Chen X, Shi S, Shi S, Jin Y. Redundant miR-3077-5p and miR-705 mediate the shift of mesenchymal stem cell lineage commitment to adipocyte in osteoporosis bone marrow. Cell Death Dis. 2013;4(4);e600. doi;10.1038/cddis.2013.130.54. Kapinas K., Kessler C., Delany A. MiR-29 suppression of osteonectin in osteoblasts: Regulation during differentiation and by canonical Wnt signaling. J. Cell. Biochem. 2009; 108 (1): 216–224. DOI:10.1002/jcb.22243.55. Li Z., Hassan M., Jafferji M., Aqeilan R.I., Garzon R., Croce C.M., van Wijnen A.J., Stein J.L., Stein G.S., Lian J.B. Biological functions of miR-29b contribute to positive regulation of osteoblast differentiation. J. Biol. Chem. 2009; 284 (23): 15676–15684. DOI:10.1074/jbc.m809787200.56. Wu T., Xie M., Wang X., Jiang X., Li J., Huang H. miR-155 modulates TNF-α inhibited osteogenic differentiation by targeting SOCS1 expression. Bone. 2012; 51 (3): 498–505. doi:10.1016/j. bone.2012.05.013.57. Mizoguchi F., Izu Y., Hayata T., Hemmi H., Nakashima K., Nakamura T., Kato S., Miyasaka N., Ezura Y., Noda M. Osteoclast specific Dicer gene deficiency suppresses osteoclastic bone resorption. J. Cell Biochem. 2010; 109(5): 866–875. DOI:10.1002/jcb.22228.58. Sugatani T., Hruska K. Impaired Micro-RNA Pathways diminishosteoclast differentiation and function. J. Biol. Chem. 2008; 284 (7):4667–4678. DOI:10.1074/jbc.m805777200.59. Sugatani T., Hruska K. MicroRNA-223 is a key factor in osteoclast differentiation. J. Cell Biochem. 2007; 101 (4): 996–999. DOI:10.1002/jcb.21335.60. Lian J., Stein G., van Wijnen A., Stein J.L., Hassan M.Q., Gaur T., Zhang Y. MicroRNA control of bone formation and homeostasis. Nat. Rev. Endocrinol. 2012; 8 (4): 212–227. DOI:10.1038/nrendo.2011.234.61. Wang Y., Li L., Moore B., Peng X.H., Fang X., Lappe J.M., Recker R.R., Xiao P. MiR-133a in human circulating monocytes: a potential biomarker associated with postmenopausal osteoporosis. PLoS ONE. 2012; 7 (4): 34641. DOI:10.1371/journal.pone.0034641.62. Cheng P., Chen C., He H., Hu R., Zhou H.D., Xie H., Zhu W., Dai R.C., Wu X.P., Liao E.Y., Luo X.H. miR-148 a regulates osteoclastogenesis by targeting V-maf musculoaponeurotic fibrosarcoma oncogene homolog B. J. Bone Miner Res. 2013; 28 (5): 1180–1190. DOI:10.1002/jbmr.1845.63. Mann M., Barad O., Agami R., Geiger B., Hornstein E. MiRNA based mechanism for the commitment of multipotent progenitors to a single cellular fate. Proc. Natl. Acad. Sci USA. 2010; 107 (36):15804–15809. DOI:10.1073/pnas.0915022107.64. Chen C., Cheng P., Xie H., Zhou H.D., Wu X.P., Liao E.Y., Luo X.H. MiR-503 Regulates Osteoclastogenesis via Targeting RANK. J. Bone Miner Res. 2014; 29 (2): 338–347. DOI:10.1002/jbmr.2032.65. Yang N., Wang G., Hu C., Shi Y., Liao L., Shi S., Cai Y., Cheng S., Wang X., Liu Y., Tang L., Ding Y., Jin Y. Tumor necrosis factor α suppresses the mesenchymal stem cell osteogenesis promoter miRflat21 in estrogen deficiency induced osteoporosis. J. Bone Miner. Res. 2013; 28 (3): 559–573. DOI:10.1002/jbmr.1798.66. Wang X., Guo B., Li Q., Peng J., Yang Z., Wang A., Li D., Hou Z., Lv K., Kan G., Cao H., Wu H., Song J., Pan X., Sun Q., Ling S., Li Y., Zhu M., Zhang P., Peng S., Xie X., Tang T., Hong A., Bian Z., Bai Y., Lu A., Li Y., He F., Zhang G., Li Y. MiR-214 targets ATF4 to inhibit bone formation. Nat. Med. 2012; 19 (1): 93–100. DOI:10.1038/nm.3026.67. Weber J., Baxter D., Zhang S., Huang D.Y., Huang K.H., Lee M.J., Galas D.J., Wang K. The MicroRNA Spectrum in 12 Body Fluids. Clin. Chem. 2010; 56 (11): 1733–1741. doi:10.1373/ clinchem.2010.147405.68. Gilad S., Meiri E., Yogev Y., Benjamin S., Lebanony D., Yerushalmi N., Benjamin H., Kushnir M., Cholakh H., Melamed N., Bentwich Z., Hod M., Goren Y., Chajut A. Serum MicroRNAs are promising novel biomarkers. PLoS ONE. 2008; 3 (9): 3148. DOI:10.1371/ journal.pone.0003148.69. Seeliger C., Karpinski K., Haug A., Vester H., Schmitt A., Bauer J.S., van Griensven M. Five freely circulating miRNAs and bone tissue miRNAs are associated with osteoporotic fractures. J. Bone Miner. Res. 2014; 29 (8): 1718–1728. DOI:10.1002/jbmr.2175.70. Heilmeier U., Hackl M., Skalicky S., Schroeder F., Vierlinger K., Burghardt A., Schwartz A., Grillari J., Link T. Blood circulating miRNAs are indicative of skeletal fractures in postmenopausal women with and without type 2 diabetes and may be promising candidates for general fracture risk prediction. Paper presented at: 4th Joint meeting of ECTS and IBMS. April 25–28, 2015. Netherlands, Rotterdam. URL: http://abstracts.ectsibms2015.org/ectsibms/0001/ectsibms0001OC6.6.htm (Available: 01.09.2015).71. Ell B., Mercatali L., Ibrahim T., Campbell N., Schwarzenbach H., Pantel K., Amadori D., Kang Y. Tumor induced osteoclast miRNA changes as regulators and biomarkers of osteolytic bone metastasis. Cancer Cell. 2013; 24 (4): 542–556. DOI:10.1016/j.ccr.2013.09.008.72. Wu K., Song W., Zhao L., Liu M., Yan J., Andersen M., Kjems J., Gao S., Zhang Y. MicroRNA functionalized microporous titanium oxide surface by lyophilization with enhanced osteogenic activity. ACS Appl. Mater Interfaces. 2013; 5 (7): 2733–2744. DOI:10.1021/am400374c.73. Wu K., Xu J., Liu M., Song W., Yan J., Gao S., Zhao L., Zhang Y. Induction of osteogenic differentiation of stem cells via a lyophilized microRNA reverse transfection formulation on a tissue culture plate. Int. J. Nanomedicine. 2013; 8: 1595. DOI:10.2147/ijn.s43244.74. Jing D., Hao J., Shen Y., Tang G., Li M.L., Huang S.H., Zhao Z.H. The role of microRNAs in bone remodeling. Int. J. Oral. Sci.2015; 7: 131–143. DOI:10.1038/ijos.2015.22.