vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/VJGB-23-48vavilov-3784Research ArticleБИОТЕХНОЛОГИЯ В ПОСТГЕНОМНУЮ ЭРУMEDICAL GENETICSЭпигенетическая регуляция ремоделирования костной ткани и ее роль в патогенезе первичного остеопорозаEpigenetic regulation of bone remodeling and its role in the pathogenesis of primary osteoporosishttps://orcid.org/0000-0003-4337-1736ЯлаевБ. И.YalaevB. I.

Уфа; Санкт-Петербург

Ufa; St. Petersburg

yalaev.bulat@yandex.ruhttps://orcid.org/0000-0002-8643-850XХусаиноваР. И.KhusainovaR. I.

Уфа; Санкт-Петербург

Ufa; St. Petersburg

Институт биохимии и генетики – обособленное структурное подразделение Уфимского федерального исследовательского центра Российской академии наук; Санкт-Петербургский государственный университетРоссияInstitute of Biochemistry and Genetics – Subdivision of the Ufa Federal Research Center of the Russian Academy of Sciences; Saint Petersburg State UniversityRussian FederationИнститут биохимии и генетики – обособленное структурное подразделение Уфимского федерального исследовательского центра Российской академии наук; Санкт-Петербургский государственный университет; Уфимский университет науки и технологийРоссияInstitute of Biochemistry and Genetics – Subdivision of the Ufa Federal Research Center of the Russian Academy of Sciences; Saint Petersburg State University; Ufa University of Science and TechnologyRussian Federation202314072023274401410Copyright © Ялаев Б.И., Хусаинова Р.И., 20232023Ялаев Б.И., Хусаинова Р.И.Yalaev B.I., Khusainova R.I.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/3784

Раскрытие молекулярных механизмов развития первичного остеопороза имеет фундаментальное значение как с точки зрения понимания патогенеза заболеваний опорно-двигательного аппарата в целом, так и для выявления ключевых звеньев генетической и эпигенетической регуляции экспрессии генов ремоделирования костной ткани. Количество обнаруженных молекулярно-генетических маркеров остеопороза продолжает расти, однако существует очевидная необходимость описания их функциональных взаимодействий. Установлено, что такие взаимодействия сопряжены с контролем экспрессии ряда факторов транскрипции и дифференцировки мезенхимальных стволовых клеток по пути остеобластогенеза и адипогенеза, а моноцитарных предшественников – по пути остеокластогенеза. Кроме того, результаты эпигенетических исследований значительно расширили понимание роли посттрансляционных модификаций гистонов, ДНК-метилирования и РНК-интерференции как в молекулярном патогенезе первичного остеопороза, так и в регуляции развития костной ткани. Несмотря на это, знания не систематизированы и нуждаются в обобщении данных исследований роли эпигенетических модификаторов в развитии первичного остеопороза, и, что не менее важно, в описании влияния каждого известного эпигенетического механизма на отдельные молекулярные звенья процесса формирования и резорбции костной ткани в течение онтогенеза человека, в том числе у лиц пожилого возраста. Понимание того, какие молекулярно-генетические механизмы и регуляторные системы вовлечены в развитие данной нозологии, представляет потенциальный интерес для создания таргетной терапии, поскольку уже сейчас рассматривается вопрос о возможности применения микроРНК для узконаправленной регуляции генов. Кроме того, систематизация этих данных важна для изучения разницы массивов эпигенетических маркеров, в зависимости от расовой и этнической принадлежности. В представленной обзорной статье проанализированы соответствующие систематические обзоры и оригинальные статьи, собрана и классифицирована информация о современных достижениях в области изучения эпигенетических механизмов и их аберраций при первичном остеопорозе, а также рассмотрены результаты исследований эпигенетических механизмов на отдельных функциональных звеньях ремоделирования костной ткани.

Discovery of molecular mechanisms of primary osteoporosis development is fundamental to understand the pathogenesis of musculoskeletal diseases in general and for identifying key links in the genetic and epigenetic regulation of bone remodelling genes. The number of identified molecular genetic markers for osteoporosis is increasing but there is a need to describe their functional interactions. These interactions have been determined to be associated with the control of expression of a number of transcription factors and the differentiation of mesenchymal stem cells through the pathway of osteoblastogenesis or adipogenesis, and monocytic precursors through the pathway of osteoclastogenesis. The results of epigenetic studies have significantly increased the understanding of the role of post-translational modifications of histones, DNA methylation and RNA interference in the osteoporosis pathogenesis and in bone remodelling. However, the knowledge should be systematised and generalised according to the results of research on the role of epigenetic modifiers in the development of osteoporosis, and the influence of each epigenetic mechanism on the individual links of bone remodelling during ontogenesis of humans in general, including the elderly, should be described. Understanding which mechanisms and systems are involved in the development of this nosology is of interest for the development of targeted therapies, as the possibility of using microRNAs to regulate genes is now being considered. Systematisation of these data is important to investigate the differences in epigenetic marker arrays by race and ethnicity. The review article analyses references to relevant reviews and original articles, classifies information on current advances in the study of epigenetic mechanisms in osteoporosis and reviews the results of studies of epigenetic mechanisms on individual links of bone remodelling.

остеопорозметилированиемикроРНКацетилированиеosteoporosismethylationmicroRNAacetylationThis work was carried out within the framework of the state assignment of the Ministry of Science and Higher Education of the Russian Federation (No. 122041400169-2), with partial support from the megagrant of the Government of the Russian Federation (agreement No. 075-15-2021-595), and the project of St. Petersburg University (No. 94034528).ReferencesAfzal F., Pratap J., Ito K., Ito Y., Stein J.L., Wijnen A.J., Stein G.S., Lian J.B., Javed A. Smad function and intranuclear targeting share a Runx2 motif required for osteogenic lineage induction and BMP2 responsive transcription. J. Cell. Physiol. 2005;204(1):63-72. DOI 10.1002/jcp.20258.Afzal F., Pratap J., Ito K., Ito Y., Stein J.L., Wijnen A.J., Stein G.S., Lian J.B., Javed A. Smad function and intranuclear targeting share a Runx2 motif required for osteogenic lineage induction and BMP2 responsive transcription. J. Cell. Physiol. 2005;204(1):63-72. DOI 10.1002/jcp.20258.Albright F., Bloomberg E., Smith P.H. Postmenopausal osteoporosis. Trans. Assoc. Am. Phys. 1940;55:298-305.Albright F., Bloomberg E., Smith P.H. Postmenopausal osteoporosis. Trans. Assoc. Am. Phys. 1940;55:298-305.Amjadi-Moheb F., Akhavan-Niaki H. Wnt signaling pathway in osteoporosis: Epigenetic regulation, interaction with other signaling pathways, and therapeutic promises. J. Cell. Physiol. 2019;234(9):14641-14650. DOI 10.1002/jcp.28207.Amjadi-Moheb F., Akhavan-Niaki H. Wnt signaling pathway in osteoporosis: Epigenetic regulation, interaction with other signaling pathways, and therapeutic promises. J. Cell. Physiol. 2019;234(9):14641-14650. DOI 10.1002/jcp.28207.Anastasilakis A.D., Makras P., Pikilidou M., Tournis S., Makris K., Bisbinas I., Tsave O., Yovos J.G., Yavropoulou M.P. Changes of circulating MicroRNAs in response to treatment with teriparatide or denosumab in postmenopausal osteoporosis. J. Clin. Endocrinol. Metab. 2018;103(3):1206-1213. DOI 10.1210/jc.2017-02406.Anastasilakis A.D., Makras P., Pikilidou M., Tournis S., Makris K., Bisbinas I., Tsave O., Yovos J.G., Yavropoulou M.P. Changes of circulating MicroRNAs in response to treatment with teriparatide or denosumab in postmenopausal osteoporosis. J. Clin. Endocrinol. Metab. 2018;103(3):1206-1213. DOI 10.1210/jc.2017-02406.Bedene A., Bedrac S.M., Jese L., Marc J., Vrtacnik P., Prezelj J., Kocjan T., Kranjc T., Ostanek B. MiR-148a the epigenetic regulator of bone homeostasis is increased in plasma of osteoporotic postmenopausal women. Wien. Klin. Wochenschr. 2016;128(7):519-526. DOI 10.1007/s00508-016-1141-3.Bedene A., Bedrac S.M., Jese L., Marc J., Vrtacnik P., Prezelj J., Kocjan T., Kranjc T., Ostanek B. MiR-148a the epigenetic regulator of bone homeostasis is increased in plasma of osteoporotic postmenopausal women. Wien. Klin. Wochenschr. 2016;128(7):519-526. DOI 10.1007/s00508-016-1141-3.Bolland M.J., Siu A.T., Mason B.H., Horne A.M., Ames R.W., Grey A.B., Gamble G.D., Reid I.R. Evaluation of the FRAX and Garvan fracture risk calculators in older women. J. Bone Miner. Res. 2011;26(2):420-427. DOI 10.1002/JBMR.215.Bolland M.J., Siu A.T., Mason B.H., Horne A.M., Ames R.W., Grey A.B., Gamble G.D., Reid I.R. Evaluation of the FRAX and Garvan fracture risk calculators in older women. J. Bone Miner. Res. 2011;26(2):420-427. DOI 10.1002/JBMR.215.Cheishvili D., Parashar S., Mahmood N., Arakelian A., Kremer R., Goltzman D., Szyf M., Rabbani S.A. Identification of an epigenetic signature of osteoporosis in blood DNA of postmenopausal women. J. Bone Miner. Res. 2018;33(11):1980-1989. DOI 10.1002/jbmr.3527.Cheishvili D., Parashar S., Mahmood N., Arakelian A., Kremer R., Goltzman D., Szyf M., Rabbani S.A. Identification of an epigenetic signature of osteoporosis in blood DNA of postmenopausal women. J. Bone Miner. Res. 2018;33(11):1980-1989. DOI 10.1002/jbmr.3527.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.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.Chen Y.H., Chung C.C., Liu Y.C., Yeh S.P., Hsu J.L., Hung M.Ch., Su H.L., Li L.Y. Enhancer of zeste homolog 2 and histone deacetylase 9c regulate age-dependent mesenchymal stem cell differentiation into osteoblasts and adipocytes. Stem Cells. 2016;34(8):2183-2193. DOI 10.1002/stem.2400.Chen Y.H., Chung C.C., Liu Y.C., Yeh S.P., Hsu J.L., Hung M.Ch., Su H.L., Li L.Y. Enhancer of zeste homolog 2 and histone deacetylase 9c regulate age-dependent mesenchymal stem cell differentiation into osteoblasts and adipocytes. Stem Cells. 2016;34(8):2183-2193. DOI 10.1002/stem.2400.Chen Y.H., Yeh F.L., Yeh S.P., Ma H.T., Hung S.C., Hung M.C., Li L.Y. Myocyte enhancer factor-2 interacting transcriptional repressor (MITR) is a switch that promotes osteogenesis and inhibits adipogenesis of mesenchymal stem cells by inactivating peroxisome proliferator-activated receptor γ-2. J. Biol. Chem. 2011;286(12):10671-10680. DOI 10.1074/jbc.M110.199612.Chen Y.H., Yeh F.L., Yeh S.P., Ma H.T., Hung S.C., Hung M.C., Li L.Y. Myocyte enhancer factor-2 interacting transcriptional repressor (MITR) is a switch that promotes osteogenesis and inhibits adipogenesis of mesenchymal stem cells by inactivating peroxisome proliferator-activated receptor γ-2. J. Biol. Chem. 2011;286(12):10671-10680. DOI 10.1074/jbc.M110.199612.Cheng P., Chen C., He H.B., Hu R., Zhou H.D., Xie H., Zhu W., Dai R.C., Wu X.P., Liao E.Y., Luo X.H. miR-148a 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.Cheng P., Chen C., He H.B., Hu R., Zhou H.D., Xie H., Zhu W., Dai R.C., Wu X.P., Liao E.Y., Luo X.H. miR-148a 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.Curtis E.M., Fuggle N.R., Cooper P., Harvey N.C. Epigenetic regulation of bone mass. Best Pract. Res. Clin. Endocrinol. Metab. 2022;36(2):101612. DOI 10.1016/j.beem.2021.101612.Curtis E.M., Fuggle N.R., Cooper P., Harvey N.C. Epigenetic regulation of bone mass. Best Pract. Res. Clin. Endocrinol. Metab. 2022;36(2):101612. DOI 10.1016/j.beem.2021.101612.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(1):83-91. DOI 10.4161/epi.7.1.18753.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(1):83-91. DOI 10.4161/epi.7.1.18753.Duan L., Zhao H., Xiong Y., Tang X., Yang Y., Hu Z., Li C., Chen S., Yu X. miR-16-2 ∗ interferes with WNT5A to regulate osteogenesis of mesenchymal stem cells. Cell. Physiol. Biochem. 2018;51(3):1087-1102. DOI 10.1159/000495489.Duan L., Zhao H., Xiong Y., Tang X., Yang Y., Hu Z., Li C., Chen S., Yu X. miR-16-2 ∗ interferes with WNT5A to regulate osteogenesis of mesenchymal stem cells. Cell. Physiol. Biochem. 2018;51(3):1087-1102. DOI 10.1159/000495489.Dudakovic A., Camilleri E.T., Riester S.M., Paradise C.R., Gluscevic M., O’Toole T.M., Thaler R., Evans J.M., Yan H., Subramaniam M., Hawse J.R., Stein G.S., Montecino M., McGee-Lawrence M.E., Westendorf J.J., Wijnen A.J. 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):24594-24606. DOI 10.1074/jbc.M116.740571.Dudakovic A., Camilleri E.T., Riester S.M., Paradise C.R., Gluscevic M., O’Toole T.M., Thaler R., Evans J.M., Yan H., Subramaniam M., Hawse J.R., Stein G.S., Montecino M., McGee-Lawrence M.E., Westendorf J.J., Wijnen A.J. 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):24594-24606. DOI 10.1074/jbc.M116.740571.Dudakovic A., Camilleri E.T., Xu F., Riester S.M., McGee-Lawrence M.E., Bradley E.W., Paradise C.R., Lewallen E.A., Thaler R., Deyle D.R., Larson A.N., Lewallen D.G., Dietz A.B., Stein G.S., Montecino M.A., Westendorf J.J., Wijnen A.J. Epigenetic control of skeletal development by the histone methyltransferase Ezh2. J. Biol. Chem. 2015;290(46):27604-27617. DOI 10.1074/jbc.M115.672345.Dudakovic A., Camilleri E.T., Xu F., Riester S.M., McGee-Lawrence M.E., Bradley E.W., Paradise C.R., Lewallen E.A., Thaler R., Deyle D.R., Larson A.N., Lewallen D.G., Dietz A.B., Stein G.S., Montecino M.A., Westendorf J.J., Wijnen A.J. Epigenetic control of skeletal development by the histone methyltransferase Ezh2. J. Biol. Chem. 2015;290(46):27604-27617. DOI 10.1074/jbc.M115.672345.Estrada K., Styrkarsdottir U., Evangelou E., … Ioannidis J.P.A., Kiel D.P., Rivadeneira F. Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. Nat. Genet. 2012;44(5):491-501. DOI 10.1038/ng.2249.Estrada K., Styrkarsdottir U., Evangelou E., … Ioannidis J.P.A., Kiel D.P., Rivadeneira F. Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. Nat. Genet. 2012;44(5):491-501. DOI 10.1038/ng.2249.Feng Y., Wan P., Yin L., Lou X. The inhibition of microRNA-139-5p promoted osteoporosis of bone marrow-derived mesenchymal stem cells by targeting Wnt/beta-catenin signaling pathway by Notch1. J. Microbiol. Biotechnol. 2020;30(3):448-458. DOI 10.4014/jmb.1908.08036.Feng Y., Wan P., Yin L., Lou X. The inhibition of microRNA-139-5p promoted osteoporosis of bone marrow-derived mesenchymal stem cells by targeting Wnt/beta-catenin signaling pathway by Notch1. J. Microbiol. Biotechnol. 2020;30(3):448-458. DOI 10.4014/jmb.1908.08036.Foger-Samwald U., Dovjak P., Azizi-Semrad U., Kerschan-Schindl K., Pietschmann P. Osteoporosis: pathophysiology and therapeutic options. EXCLI J. 2020;19:1017-1037. DOI 10.17179/excli2020-2591.Foger-Samwald U., Dovjak P., Azizi-Semrad U., Kerschan-Schindl K., Pietschmann P. Osteoporosis: pathophysiology and therapeutic options. EXCLI J. 2020;19:1017-1037. DOI 10.17179/excli2020-2591.Gao J., Yang T., Han J., Yan K., Qiu X., Zhou Y., Fan Q., Ma B. MicroRNA expression during osteogenic differentiation of human multipotent mesenchymal stromal cells from bone marrow. J. Cell. Biochem. 2011;112(7):1844-1856. DOI 10.1002/jcb.23106.Gao J., Yang T., Han J., Yan K., Qiu X., Zhou Y., Fan Q., Ma B. MicroRNA expression during osteogenic differentiation of human multipotent mesenchymal stromal cells from bone marrow. J. Cell. Biochem. 2011;112(7):1844-1856. DOI 10.1002/jcb.23106.Garmilla-Ezquerra P., Sanudo C., Delgado-Calle J., Perez-Nunez M.I., Sumillera M., Riancho J.A. Analysis of the bone MicroRNome in osteoporotic fractures. Calcif. Tissue Int. 2015;96(1):30-37. DOI 10.1007/s00223-014-9935-7.Garmilla-Ezquerra P., Sanudo C., Delgado-Calle J., Perez-Nunez M.I., Sumillera M., Riancho J.A. Analysis of the bone MicroRNome in osteoporotic fractures. Calcif. Tissue Int. 2015;96(1):30-37. DOI 10.1007/s00223-014-9935-7.Ge C., Xiao G., Jiang D., Franceschi R.T. Critical role of the extracellular signal-regulated kinase-MAPK pathway in osteoblast differentiation and skeletal development. J. Cell Biol. 2007;176(5):709-718. DOI 10.1083/JCB.200610046.Ge C., Xiao G., Jiang D., Franceschi R.T. Critical role of the extracellular signal-regulated kinase-MAPK pathway in osteoblast differentiation and skeletal development. J. Cell Biol. 2007;176(5):709-718. DOI 10.1083/JCB.200610046.Ge C., Xiao G., Jiang D., Yang Q., Hatch N.E., Roca H., Franceschi R.T. Identification and functional characterization of ERK/MAPK phosphorylation sites in the Runx2 transcription factor. J. Biol. Chem. 2009;284(47):32533-32543. DOI 10.1074/jbc.M109.040980.Ge C., Xiao G., Jiang D., Yang Q., Hatch N.E., Roca H., Franceschi R.T. Identification and functional characterization of ERK/MAPK phosphorylation sites in the Runx2 transcription factor. J. Biol. Chem. 2009;284(47):32533-32543. DOI 10.1074/jbc.M109.040980.Ge C., Yang Q., Zhao G., Yu H., Kirkwood K.L., Franceschi R.T. Interactions between extracellular signal-regulated kinase 1/2 and P38 Map kinase pathways in the control of RUNX2 phosphorylation and transcriptional activity. J. Bone Miner. Res. 2012;27(3):538-551. DOI 10.1002/JBMR.561.Ge C., Yang Q., Zhao G., Yu H., Kirkwood K.L., Franceschi R.T. Interactions between extracellular signal-regulated kinase 1/2 and P38 Map kinase pathways in the control of RUNX2 phosphorylation and transcriptional activity. J. Bone Miner. Res. 2012;27(3):538-551. DOI 10.1002/JBMR.561.Gomathi K., Akshaya N., Srinaath N., Moorthi A., Selvamurugan N. Regulation of Runx2 by post-translational modifications in osteoblast differentiation. Life Sci. 2020;245:117389. DOI 10.1016/J.LFS.2020.117389.Gomathi K., Akshaya N., Srinaath N., Moorthi A., Selvamurugan N. Regulation of Runx2 by post-translational modifications in osteoblast differentiation. Life Sci. 2020;245:117389. DOI 10.1016/J.LFS.2020.117389.Hassan M.Q., Tare R., Lee S.H., Mandeville M., Weiner B., Montecino M., Wijnen A.J., Stein J.L., Stein G.S., Lian J.B. HOXA10 controls osteoblastogenesis by directly activating bone regulatory and phenotypic genes. Mol. Cell. Biol. 2007;27(9):3337-3352. DOI 10.1128/mcb.01544-06.Hassan M.Q., Tare R., Lee S.H., Mandeville M., Weiner B., Montecino M., Wijnen A.J., Stein J.L., Stein G.S., Lian J.B. HOXA10 controls osteoblastogenesis by directly activating bone regulatory and phenotypic genes. Mol. Cell. Biol. 2007;27(9):3337-3352. DOI 10.1128/mcb.01544-06.Hu H., He X., Zhang Y., Wu R., Chen J., Lin Y., Shen B. MicroRNA alterations for diagnosis, prognosis, and treatment of osteoporosis: a comprehensive review and computational functional survey. Front. Genet. 2020;11:181. DOI 10.3389/FGENE.2020.00181/BIBTEX.Hu H., He X., Zhang Y., Wu R., Chen J., Lin Y., Shen B. MicroRNA alterations for diagnosis, prognosis, and treatment of osteoporosis: a comprehensive review and computational functional survey. Front. Genet. 2020;11:181. DOI 10.3389/FGENE.2020.00181/BIBTEX.Huang B., Li G., Jiang X.H. Fate determination in mesenchymal stem cells: A perspective from histone-modifying enzymes. Stem Cell Res. Ther. 2015;6(1):35. DOI 10.1186/s13287-015-0018-0.Huang B., Li G., Jiang X.H. Fate determination in mesenchymal stem cells: A perspective from histone-modifying enzymes. Stem Cell Res. Ther. 2015;6(1):35. DOI 10.1186/s13287-015-0018-0.Huang G., Shigesada K., Ito K., Wee H.J., Yokomizo T., Ito Y. Dimerization with PEBP2β protects RUNX1/AML1 from ubiquitin-proteasome-mediated degradation. EMBO J. 2001;20(4):723-733. DOI 10.1093/emboj/20.4.723.Huang G., Shigesada K., Ito K., Wee H.J., Yokomizo T., Ito Y. Dimerization with PEBP2β protects RUNX1/AML1 from ubiquitin-proteasome-mediated degradation. EMBO J. 2001;20(4):723-733. DOI 10.1093/emboj/20.4.723.Jing H., Liao L., An Y., Su X., Liu S., Shuai Y., Zhang X., Jin Y. Suppression of EZH2 prevents the shift of osteoporotic MSC fate to adipocyte and enhances bone formation during osteoporosis. Mol. Ther. 2016;24(2):217-229. DOI 10.1038/mt.2015.152.Jing H., Liao L., An Y., Su X., Liu S., Shuai Y., Zhang X., Jin Y. Suppression of EZH2 prevents the shift of osteoporotic MSC fate to adipocyte and enhances bone formation during osteoporosis. Mol. Ther. 2016;24(2):217-229. DOI 10.1038/mt.2015.152.Jing H., Su X., Gao B., Shuai Y., Chen J., Deng Z., Liao L., Jin Y. Epigenetic inhibition of Wnt pathway suppresses osteogenic differentiation of BMSCs during osteoporosis. Cell Death Dis. 2018;9(2):176. DOI 10.1038/s41419-017-0231-0.Jing H., Su X., Gao B., Shuai Y., Chen J., Deng Z., Liao L., Jin Y. Epigenetic inhibition of Wnt pathway suppresses osteogenic differentiation of BMSCs during osteoporosis. Cell Death Dis. 2018;9(2):176. DOI 10.1038/s41419-017-0231-0.Lei S.F., Papasian C.J., Deng H.W. Polymorphisms in predicted miRNA binding sites and osteoporosis. J. Bone Miner. Res. 2011;26(1):72-78. DOI 10.1002/jbmr.186.Lei S.F., Papasian C.J., Deng H.W. Polymorphisms in predicted miRNA binding sites and osteoporosis. J. Bone Miner. Res. 2011;26(1):72-78. DOI 10.1002/jbmr.186.Letarouilly J.G., Broux O., Clabaut A. New insights into the epigenetics of osteoporosis. Genomics. 2019;111(4):793-798. DOI 10.1016/J.YGENO.2018.05.001.Letarouilly J.G., Broux O., Clabaut A. New insights into the epigenetics of osteoporosis. Genomics. 2019;111(4):793-798. DOI 10.1016/J.YGENO.2018.05.001.Li B., Liu J., Zhao J., Ma J.X., Jia H.B., Zhang Y., Xing G.S., Ma X.L. LncRNA-H19 modulates Wnt/β-catenin signaling by targeting Dkk4 in hindlimb unloaded rat. Orthop. Surg. 2017;9(3):319-327. DOI 10.1111/os.12321.Li B., Liu J., Zhao J., Ma J.X., Jia H.B., Zhang Y., Xing G.S., Ma X.L. LncRNA-H19 modulates Wnt/β-catenin signaling by targeting Dkk4 in hindlimb unloaded rat. Orthop. Surg. 2017;9(3):319-327. DOI 10.1111/os.12321.Li D., Tian Y., Yin C., Huai Y., Zhao Y., Su P., Wang X., Pei J., Zhang K., Yang C., Dang K., Jiang S., Zhiping M., Li M., Hao Q., Zhang G., Qian A. Silencing of lncRNA AK045490 promotes osteoblast differentiation and bone formation via β-catenin/TCF1/Runx2 signaling axis. Int. J. Mol. Sci. 2019;20(24):6229. DOI 10.3390/ijms20246229.Li D., Tian Y., Yin C., Huai Y., Zhao Y., Su P., Wang X., Pei J., Zhang K., Yang C., Dang K., Jiang S., Zhiping M., Li M., Hao Q., Zhang G., Qian A. Silencing of lncRNA AK045490 promotes osteoblast differentiation and bone formation via β-catenin/TCF1/Runx2 signaling axis. Int. J. Mol. Sci. 2019;20(24):6229. DOI 10.3390/ijms20246229.Li H., Li T., Fan J., Li T., Fan L., Wang S., Weng X., Han Q., Zhao R.C. mIR-216a rescues dexamethasone suppression of osteogenesis, promotes osteoblast differentiation and enhances bone formation, by regulating c-Cbl-mediated PI3K/AKT pathway. Cell Death Differ. 2015;22(12):1935-1945. DOI 10.1038/cdd.2015.99.Li H., Li T., Fan J., Li T., Fan L., Wang S., Weng X., Han Q., Zhao R.C. mIR-216a rescues dexamethasone suppression of osteogenesis, promotes osteoblast differentiation and enhances bone formation, by regulating c-Cbl-mediated PI3K/AKT pathway. Cell Death Differ. 2015;22(12):1935-1945. DOI 10.1038/cdd.2015.99.Li H., Xiao Z., Quarles L.D., Li W. Osteoporosis: mechanism, molecular target and current status on drug development. Curr. Med. Chem. 2020;28(8):1489-1507. DOI 10.2174/0929867327666200330142432.Li H., Xiao Z., Quarles L.D., Li W. Osteoporosis: mechanism, molecular target and current status on drug development. Curr. Med. Chem. 2020;28(8):1489-1507. DOI 10.2174/0929867327666200330142432.Li J., He X., Wei W., Zhou X. MicroRNA-194 promotes osteoblast differentiation via downregulating STAT1. Biochem. Biophys. Res. Commun. 2015;460(2):482-488. DOI 10.1016/J.BBRC.2015.03.059.Li J., He X., Wei W., Zhou X. MicroRNA-194 promotes osteoblast differentiation via downregulating STAT1. Biochem. Biophys. Res. Commun. 2015;460(2):482-488. DOI 10.1016/J.BBRC.2015.03.059.Li Y., Ge C., Franceschi R.T. MAP kinase-dependent RUNX2 phosphorylation is necessary for epigenetic modification of chromatin during osteoblast differentiation. J. Cell. Physiol. 2017;232(9):2427-2435. DOI 10.1002/jcp.25517.Li Y., Ge C., Franceschi R.T. MAP kinase-dependent RUNX2 phosphorylation is necessary for epigenetic modification of chromatin during osteoblast differentiation. J. Cell. Physiol. 2017;232(9):2427-2435. DOI 10.1002/jcp.25517.Lorentzon M., Cummings S.R. Osteoporosis: the evolution of a diag nosis. J. Intern. Med. 2015;277(6):650-661. DOI 10.1111/joim.12369.Lorentzon M., Cummings S.R. Osteoporosis: the evolution of a diag nosis. J. Intern. Med. 2015;277(6):650-661. DOI 10.1111/joim.12369.Makitie R.E., Hackl M., Niinimaki R., Kakko S., Grillari J., Makitie O. Altered microRNA profile in osteoporosis caused by impaired WNT signaling. J. Clin. Endocrinol. Metab. 2018;103(5):1985-1996. DOI 10.1210/jc.2017-02585.Makitie R.E., Hackl M., Niinimaki R., Kakko S., Grillari J., Makitie O. Altered microRNA profile in osteoporosis caused by impaired WNT signaling. J. Clin. Endocrinol. Metab. 2018;103(5):1985-1996. DOI 10.1210/jc.2017-02585.Marshall D., Johnell O., Wedel H. Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. Br. Med. J. 1996;312(7041):1254-1259. DOI 10.1136/bmj.312.7041.1254.Marshall D., Johnell O., Wedel H. Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. Br. Med. J. 1996;312(7041):1254-1259. DOI 10.1136/bmj.312.7041.1254.Morris J.A., Tsai P.C., Joehanes R., Zheng J., Trajanoska K., Soerensen M., Forgetta V., Castillo-Fernandez J.E., Frost M., Spector T.D., Christensen K., Christiansen L., Rivadeneira F., Tobias J.H., Evans D.M., Kiel D.P., Hsu Y.H., Richards J.B., Bell J.T. Epi genome-wide association of DNA methylation in whole blood with bone mineral density. J. Bone Miner. Res. 2017;32(8):1644. DOI 10.1002/JBMR.3148.Morris J.A., Tsai P.C., Joehanes R., Zheng J., Trajanoska K., Soerensen M., Forgetta V., Castillo-Fernandez J.E., Frost M., Spector T.D., Christensen K., Christiansen L., Rivadeneira F., Tobias J.H., Evans D.M., Kiel D.P., Hsu Y.H., Richards J.B., Bell J.T. Epi genome-wide association of DNA methylation in whole blood with bone mineral density. J. Bone Miner. Res. 2017;32(8):1644. DOI 10.1002/JBMR.3148.Qadir A.S., Um S., Lee H., Baek K., Seo B.M., Lee G., Kim G.S., Woo K.M., Ryoo H.M., Baek J.H. miR-124 negatively regulates osteogenic differentiation and in vivo bone formation of mesenchymal stem cells. J. Cell. Biochem. 2015;116(5):730-742. DOI 10.1002/JCB.25026.Qadir A.S., Um S., Lee H., Baek K., Seo B.M., Lee G., Kim G.S., Woo K.M., Ryoo H.M., Baek J.H. miR-124 negatively regulates osteogenic differentiation and in vivo bone formation of mesenchymal stem cells. J. Cell. Biochem. 2015;116(5):730-742. DOI 10.1002/JCB.25026.Raisz L.G. Pathogenesis of osteoporosis: concepts, conflicts, and prospects. J. Clin. Invest. 2005;115(12):3318-3325. DOI 10.1172/JCI27071.Raisz L.G. Pathogenesis of osteoporosis: concepts, conflicts, and prospects. J. Clin. Invest. 2005;115(12):3318-3325. DOI 10.1172/JCI27071.Reppe S., Noer A., Grimholt R.M., Halldorsson B.V., Carolina M.G., Gautvik V.T., Olstad O.K., Berg J.P., Datta H., Estrada K., Hofman A., Uitterlinden A.G., Rivadeneira F., Lyle R., Collas P., Gautvik K.M. Methylation of bone SOST, its mRNA, and serum sclerostin levels correlate strongly with fracture risk in postmenopausal women. J. Bone Miner. Res. 2015;30(2):249-256. DOI 10.1002/JBMR.2342.Reppe S., Noer A., Grimholt R.M., Halldorsson B.V., Carolina M.G., Gautvik V.T., Olstad O.K., Berg J.P., Datta H., Estrada K., Hofman A., Uitterlinden A.G., Rivadeneira F., Lyle R., Collas P., Gautvik K.M. Methylation of bone SOST, its mRNA, and serum sclerostin levels correlate strongly with fracture risk in postmenopausal women. J. Bone Miner. Res. 2015;30(2):249-256. DOI 10.1002/JBMR.2342.Riggs B.L., Wahner H.W., Seeman E., Offord K.P., Dunn W.L., Mazess R.B., Johnson K.A., Melton L.J. Changes in bone mineral density of the proximal femur and spine with aging. Differences between the postmenopausal and senile osteoporosis syndromes. J. Clin. Invest. 1982;704(4):716-723. DOI 10.1172/JCI110667.Riggs B.L., Wahner H.W., Seeman E., Offord K.P., Dunn W.L., Mazess R.B., Johnson K.A., Melton L.J. Changes in bone mineral density of the proximal femur and spine with aging. Differences between the postmenopausal and senile osteoporosis syndromes. J. Clin. Invest. 1982;704(4):716-723. DOI 10.1172/JCI110667.Rivadeneira F., Styrkarsdottir U., Estrada K., … Stefansson K., Ioannidis J.P.A., Uitterlinden A.G. Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies. Nat. Genet. 2009;41(11):1199-1206. DOI 10.1038/ng.446.Rivadeneira F., Styrkarsdottir U., Estrada K., … Stefansson K., Ioannidis J.P.A., Uitterlinden A.G. Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies. Nat. Genet. 2009;41(11):1199-1206. DOI 10.1038/ng.446.Selvamurugan N., He Z., Rifkin D., Dabovic B., Partridge N. Pulsed electromagnetic field regulates microRNA 21 expression to activate TGF-β signaling in human bone marrow stromal cells to enhance osteoblast differentiation. Stem Cells Int. 2017;2017:2450327. DOI 10.1155/2017/2450327.Selvamurugan N., He Z., Rifkin D., Dabovic B., Partridge N. Pulsed electromagnetic field regulates microRNA 21 expression to activate TGF-β signaling in human bone marrow stromal cells to enhance osteoblast differentiation. Stem Cells Int. 2017;2017:2450327. DOI 10.1155/2017/2450327.Selvamurugan N., Pulumati M.R., Tyson D.R., Partridge N.C. Parathyroid hormone regulation of the rat collagenase-3 promoter by protein kinase A-dependent transactivation of core binding factor α1. J. Biol. Chem. 2000;275(7):5037-5042. DOI 10.1074/JBC.275.7.5037.Selvamurugan N., Pulumati M.R., Tyson D.R., Partridge N.C. Parathyroid hormone regulation of the rat collagenase-3 promoter by protein kinase A-dependent transactivation of core binding factor α1. J. Biol. Chem. 2000;275(7):5037-5042. DOI 10.1074/JBC.275.7.5037.Selvamurugan N., Shimizu E., Lee M., Liu T., Li H., Partridge N.C. Identification and characterization of Runx2 phosphorylation sites involved in matrix metalloproteinase-13 promoter activation. FEBS Lett. 2009;583(7):1141-1146. DOI 10.1016/J.FEBSLET.2009.02.040.Selvamurugan N., Shimizu E., Lee M., Liu T., Li H., Partridge N.C. Identification and characterization of Runx2 phosphorylation sites involved in matrix metalloproteinase-13 promoter activation. FEBS Lett. 2009;583(7):1141-1146. DOI 10.1016/J.FEBSLET.2009.02.040.Shi C., Huang P., Kang H., Hu B., Qi J., Jiang M., Zhou H., Guo L., Deng L. Glucocorticoid inhibits cell proliferation in differentiating osteoblasts by microRNA-199a targeting of WNT signaling. J. Mol. Endocrinol. 2015;54(3):325-337. DOI 10.1530/JME-14-0314.Shi C., Huang P., Kang H., Hu B., Qi J., Jiang M., Zhou H., Guo L., Deng L. Glucocorticoid inhibits cell proliferation in differentiating osteoblasts by microRNA-199a targeting of WNT signaling. J. Mol. Endocrinol. 2015;54(3):325-337. DOI 10.1530/JME-14-0314.Soltanoff C.S., Yang S., Chen W., Li Y.P. Signaling networks that control the lineage commitment and differentiation of bone cells. Crit. Rev. Eukaryot. Gene Expr. 2009;19(1):1-46. DOI 10.1615/CritRevEukarGeneExpr.v19.i1.10.Soltanoff C.S., Yang S., Chen W., Li Y.P. Signaling networks that control the lineage commitment and differentiation of bone cells. Crit. Rev. Eukaryot. Gene Expr. 2009;19(1):1-46. DOI 10.1615/CritRevEukarGeneExpr.v19.i1.10.Souza M.P.G. Osteoporosis diagnosis and treatment. Rev. Bras. Ortop. 2010;45(3):220-229. DOI 10.1016/S2255-4971(15)30361-X.Souza M.P.G. Osteoporosis diagnosis and treatment. Rev. Bras. Ortop. 2010;45(3):220-229. DOI 10.1016/S2255-4971(15)30361-X.Stein G.S., Lian J.B., Wijnen A.J., Stein J.L., Montecino M., Javed A., Zaidi S.K., Young D.W., Choi J.Y., Pockwinse S.M. Runx2 control of organization, assembly and activity of the regulatory machinery for skeletal gene expression. Oncogene. 2004;23(24):4315-4329. DOI 10.1038/sj.onc.1207676.Stein G.S., Lian J.B., Wijnen A.J., Stein J.L., Montecino M., Javed A., Zaidi S.K., Young D.W., Choi J.Y., Pockwinse S.M. Runx2 control of organization, assembly and activity of the regulatory machinery for skeletal gene expression. Oncogene. 2004;23(24):4315-4329. DOI 10.1038/sj.onc.1207676.Sun M., Cao Y., Yang X., An F., Wu H., Wang J. DNA methylation in the OPG/RANK/RANKL pathway is associated with steroid-induced osteonecrosis of the femoral head. BMC Musculoskelet. Disord. 2021;22(1):599. DOI 10.1186/s12891-021-04472-6.Sun M., Cao Y., Yang X., An F., Wu H., Wang J. DNA methylation in the OPG/RANK/RANKL pathway is associated with steroid-induced osteonecrosis of the femoral head. BMC Musculoskelet. Disord. 2021;22(1):599. DOI 10.1186/s12891-021-04472-6.Sveshnikov A.A. Mineral Density of Skeletal Bones, Muscle Mass, and Issues of Fracture Prevention. Moscow: Akademiya Yeste stvo znaniya Publ., 2013. (in Russian)Sveshnikov A.A. Mineral Density of Skeletal Bones, Muscle Mass, and Issues of Fracture Prevention. Moscow: Akademiya Yeste stvo znaniya Publ., 2013. (in Russian)Tang X., Lin J., Wang G., Lu J. MicroRNA-433-3p promotes osteoblast differentiation through targeting DKK1 expression. PLoS One. 2017;12(6):0179860. DOI 10.1371/JOURNAL.PONE.0179860.Tang X., Lin J., Wang G., Lu J. MicroRNA-433-3p promotes osteoblast differentiation through targeting DKK1 expression. PLoS One. 2017;12(6):0179860. DOI 10.1371/JOURNAL.PONE.0179860.Thomas P.A. Racial and ethnic differences in osteoporosis. J. Am. Acad. Orthop. Surg. 2007;15(1):26-30. DOI 10.5435/00124635-200700001-00008.Thomas P.A. Racial and ethnic differences in osteoporosis. J. Am. Acad. Orthop. Surg. 2007;15(1):26-30. DOI 10.5435/00124635-200700001-00008.Tobeiha M., Moghadasian M.H., Amin N., Jafarnejad S. RANKL/RANK/OPG pathway: a mechanism involved in exercise-induced bone remodeling. Biomed. Res. Int. 2020;2020:6910312. DOI 10.1155/2020/6910312.Tobeiha M., Moghadasian M.H., Amin N., Jafarnejad S. RANKL/RANK/OPG pathway: a mechanism involved in exercise-induced bone remodeling. Biomed. Res. Int. 2020;2020:6910312. DOI 10.1155/2020/6910312.Wang H., Sun Z., Wang Y., Hu Z., Zhou H., Zhang L., Hong B., Zhang S., Cao X. miR-33-5p, a novel mechano-sensitive microRNA promotes osteoblast differentiation by targeting Hmga2. Sci. Rep. 2016;6:23170. DOI 10.1038/SREP23170.Wang H., Sun Z., Wang Y., Hu Z., Zhou H., Zhang L., Hong B., Zhang S., Cao X. miR-33-5p, a novel mechano-sensitive microRNA promotes osteoblast differentiation by targeting Hmga2. Sci. Rep. 2016;6:23170. DOI 10.1038/SREP23170.Wang J., Guan X., Guo F., Zhou J., Chang A., Sun B., Cai Y., Ma Z., Dai C., Li X., Wang B. miR-30e reciprocally regulates the differentiation of adipocytes and osteoblasts by directly targeting low-density lipoprotein receptor-related protein 6. Cell Death Dis. 2013;4(10):845. DOI 10.1038/cddis.2013.356.Wang J., Guan X., Guo F., Zhou J., Chang A., Sun B., Cai Y., Ma Z., Dai C., Li X., Wang B. miR-30e reciprocally regulates the differentiation of adipocytes and osteoblasts by directly targeting low-density lipoprotein receptor-related protein 6. Cell Death Dis. 2013;4(10):845. DOI 10.1038/cddis.2013.356.Wang P., Cao Y., Zhan D., Wang D., Wang B., Liu Y., Li G., He W., Wang H., Xu L. Influence of DNA methylation on the expression of OPG/RANKL in primary osteoporosis. Int. J. Med. Sci. 2018;15(13):1480-1485. DOI 10.7150/ijms.27333.Wang P., Cao Y., Zhan D., Wang D., Wang B., Liu Y., Li G., He W., Wang H., Xu L. Influence of DNA methylation on the expression of OPG/RANKL in primary osteoporosis. Int. J. Med. Sci. 2018;15(13):1480-1485. DOI 10.7150/ijms.27333.Wee H.J., Huang G., Shigesada K., Ito Y. Serine phosphorylation of RUNX2 with novel potential functions as negative regulatory mechanisms. EMBO Rep. 2002;3(10):967-974. DOI 10.1093/embo-reports/kvf193.Wee H.J., Huang G., Shigesada K., Ito Y. Serine phosphorylation of RUNX2 with novel potential functions as negative regulatory mechanisms. EMBO Rep. 2002;3(10):967-974. DOI 10.1093/embo-reports/kvf193.Wei Y., Chen Y.H., Li L.Y., Lang J., Yeh S.P., Shi B., Yang C.C., Yang J.Y., Lin C.Y., Lai C.C., Hung M.C. CDK1-dependent phosphorylation of EZH2 suppresses methylation of H3K27 and promotes osteogenic differentiation of human mesenchymal stem cells. Nat. Cell Biol. 2011;13(1):87-94. DOI 10.1038/ncb2139.Wei Y., Chen Y.H., Li L.Y., Lang J., Yeh S.P., Shi B., Yang C.C., Yang J.Y., Lin C.Y., Lai C.C., Hung M.C. CDK1-dependent phosphorylation of EZH2 suppresses methylation of H3K27 and promotes osteogenic differentiation of human mesenchymal stem cells. Nat. Cell Biol. 2011;13(1):87-94. DOI 10.1038/ncb2139.Weilner S., Schraml E., Wieser M., Messner P., Schneider K., Wassermann K., Micutkova L., Fortschegger K., Maier A., Westendorp R., Resch H., Wolbank S., Redl H., Jansen-Durr P., Pietschmann P., Grillari-Voglauer R., Grillari J. Secreted microvesicular miR-31 inhibits osteogenic differentiation of mesenchymal stem cells. Aging Cell. 2016;15(4):744-754. DOI 10.1111/acel.12484.Weilner S., Schraml E., Wieser M., Messner P., Schneider K., Wassermann K., Micutkova L., Fortschegger K., Maier A., Westendorp R., Resch H., Wolbank S., Redl H., Jansen-Durr P., Pietschmann P., Grillari-Voglauer R., Grillari J. Secreted microvesicular miR-31 inhibits osteogenic differentiation of mesenchymal stem cells. Aging Cell. 2016;15(4):744-754. DOI 10.1111/acel.12484.Wein M.N., Liang Y., Goransson O., Sundberg T.B., Wang J., Williams E.A., O’Meara M.J., Govea N., Beqo B., Nishimori S., Nagano K., Brooks D.J., Martins J.S., Corbin B., Anselmo A., Sadreyev R., Wu J.Y., Sakamoto K., Foretz M., Xavier R.J., Baron R., Bouxsein M., Gardella T.J., Divieti-Pajevic P., Gray N.S., Kronenberg H.M. SIKs control osteocyte responses to parathyroid hormone. Nat. Commun. 2016;7:13176. DOI 10.1038/ncomms13176.Wein M.N., Liang Y., Goransson O., Sundberg T.B., Wang J., Williams E.A., O’Meara M.J., Govea N., Beqo B., Nishimori S., Nagano K., Brooks D.J., Martins J.S., Corbin B., Anselmo A., Sadreyev R., Wu J.Y., Sakamoto K., Foretz M., Xavier R.J., Baron R., Bouxsein M., Gardella T.J., Divieti-Pajevic P., Gray N.S., Kronenberg H.M. SIKs control osteocyte responses to parathyroid hormone. Nat. Commun. 2016;7:13176. DOI 10.1038/ncomms13176.Wein M., Spatz J., Nishimori S., Doench J., Root D., Babij P., Nagano K., Baron R., Brooks D., Bouxsein M., Pajevic P.D., Kronenberg H.M. HDAC5 controls MEF2C-driven sclerostin expression in osteocytes. J. Bone Miner. Res. 2015;30(3):400-411. DOI 10.1002/jbmr.2381.Wein M., Spatz J., Nishimori S., Doench J., Root D., Babij P., Nagano K., Baron R., Brooks D., Bouxsein M., Pajevic P.D., Kronenberg H.M. HDAC5 controls MEF2C-driven sclerostin expression in osteocytes. J. Bone Miner. Res. 2015;30(3):400-411. DOI 10.1002/jbmr.2381.Wiedl A., Forch S., Fenwick A., Mayr E. Fractures’ associated mortality risk in orthogeriatric inpatients: a prospective 2-year survey. Eur. Geriatr. Med. 2020;12(1):61-68. DOI 10.1007/s41999-020-00392-1.Wiedl A., Forch S., Fenwick A., Mayr E. Fractures’ associated mortality risk in orthogeriatric inpatients: a prospective 2-year survey. Eur. Geriatr. Med. 2020;12(1):61-68. DOI 10.1007/s41999-020-00392-1.Wood C.L., Stenson C., Embleton N. The developmental origins of osteoporosis. Curr. Genomics. 2015;16(6):411. DOI 10.2174/1389202916666150817202217.Wood C.L., Stenson C., Embleton N. The developmental origins of osteoporosis. Curr. Genomics. 2015;16(6):411. DOI 10.2174/1389202916666150817202217.Xu F., Li W., Yang X., Na L., Chen L., Liu G. The roles of epigenetics regulation in bone metabolism and osteoporosis. Front Cell Dev. Biol. 2020;8:619301. DOI 10.3389/fcell.2020.619301.Xu F., Li W., Yang X., Na L., Chen L., Liu G. The roles of epigenetics regulation in bone metabolism and osteoporosis. Front Cell Dev. Biol. 2020;8:619301. DOI 10.3389/fcell.2020.619301.Xu Y., Ma J., Xu G., Ma D. Recent advances in the epigenetics of bone metabolism. J. Bone Miner. Metab. 2021;39(6):914-924. DOI 10.1007/s00774-021-01249-8.Xu Y., Ma J., Xu G., Ma D. Recent advances in the epigenetics of bone metabolism. J. Bone Miner. Metab. 2021;39(6):914-924. DOI 10.1007/s00774-021-01249-8.Yalaev B.I., Khusainova R.I. Epigenetics of osteoporosis. Meditsin skaya Genetika = Medical Genetics. 2018;17(6):3-10. DOI 10.25557/2073-7998.2018.06.3-10. (in Russian)Yalaev B.I., Khusainova R.I. Epigenetics of osteoporosis. Meditsin skaya Genetika = Medical Genetics. 2018;17(6):3-10. DOI 10.25557/2073-7998.2018.06.3-10. (in Russian)Yalaev B.I., Khusainova R.I. Study of the rs2910164 polymorphic variant of miR-146a microRNA gene in patients with primary osteoporosis. Geny i Kletki = Genes and Cells. 2020;15(4):40-45. DOI 10.23868/202012007. (in Russian)Yalaev B.I., Khusainova R.I. Study of the rs2910164 polymorphic variant of miR-146a microRNA gene in patients with primary osteoporosis. Geny i Kletki = Genes and Cells. 2020;15(4):40-45. DOI 10.23868/202012007. (in Russian)Yalaev B.I., Tyurin A.V., Mirgalieva R.I., Khusnutdinova E.K., Khusainova R.I. Investigating the role of osteoprotegerin gene polymorphic variants in osteoporosis. Russ. Open Med. J. 2021;10(1):e0101. DOI 10.15275/RUSOMJ.2021.0101.Yalaev B.I., Tyurin A.V., Mirgalieva R.I., Khusnutdinova E.K., Khusainova R.I. Investigating the role of osteoprotegerin gene polymorphic variants in osteoporosis. Russ. Open Med. J. 2021;10(1):e0101. DOI 10.15275/RUSOMJ.2021.0101.Yang D., Okamura H., Nakashima Y., Haneji T. Histone demethylase Jmjd3 regulates osteoblast differentiation via transcription factors Runx2 and osterix. J. Biol. Chem. 2013;288(47):33530-33541. DOI 10.1074/jbc.M113.497040.Yang D., Okamura H., Nakashima Y., Haneji T. Histone demethylase Jmjd3 regulates osteoblast differentiation via transcription factors Runx2 and osterix. J. Biol. Chem. 2013;288(47):33530-33541. DOI 10.1074/jbc.M113.497040.Yang K., Tian N., Liu H., Tao X.Z., Wang M.X., Huang W. LncRNAp21 promotes osteogenic differentiation of mesenchymal stem cells in the rat model of osteoporosis by the Wnt/β-catenin signaling pathway. Eur. Rev. Med. Pharmacol. Sci. 2019;23(10):4303-4309. DOI 10.26355/EURREV_201905_17935.Yang K., Tian N., Liu H., Tao X.Z., Wang M.X., Huang W. LncRNAp21 promotes osteogenic differentiation of mesenchymal stem cells in the rat model of osteoporosis by the Wnt/β-catenin signaling pathway. Eur. Rev. Med. Pharmacol. Sci. 2019;23(10):4303-4309. DOI 10.26355/EURREV_201905_17935.Yang M., Pan Y., Zhou Y. miR-96 promotes osteogenic differentiation by suppressing HBEGF-EGFR signaling in osteoblastic cells. FEBS Lett. 2014;588(24):4761-4768. DOI 10.1016/J.FEBSLET.2014.11.008.Yang M., Pan Y., Zhou Y. miR-96 promotes osteogenic differentiation by suppressing HBEGF-EGFR signaling in osteoblastic cells. FEBS Lett. 2014;588(24):4761-4768. DOI 10.1016/J.FEBSLET.2014.11.008.Yang Y., Yujiao W., Fang W., Linhui Y., Ziqi G., Zhichen W., Zirui W., Shengwang W. The roles of miRNA, lncRNA and circRNA in the development of osteoporosis. Biol. Res. 2020;53(1):40. DOI 10.1186/s40659-020-00309-z.Yang Y., Yujiao W., Fang W., Linhui Y., Ziqi G., Zhichen W., Zirui W., Shengwang W. The roles of miRNA, lncRNA and circRNA in the development of osteoporosis. Biol. Res. 2020;53(1):40. DOI 10.1186/s40659-020-00309-z.Yin C., Tian Y., Yu Y., Wang H., Wu Z., Huang Z., Zhang Y., Li D., Yang C., Wang X., Li Y., Qian A. A novel long noncoding RNA AK016739 inhibits osteoblast differentiation and bone formation. J. Cell. Physiol. 2019;2347(7):11524-11536. DOI 10.1002/jcp.27815.Yin C., Tian Y., Yu Y., Wang H., Wu Z., Huang Z., Zhang Y., Li D., Yang C., Wang X., Li Y., Qian A. A novel long noncoding RNA AK016739 inhibits osteoblast differentiation and bone formation. J. Cell. Physiol. 2019;2347(7):11524-11536. DOI 10.1002/jcp.27815.Yu W., Wang H.L., Zhang J., Yin C. The effects of epigenetic modifications on bone remodeling in age-related osteoporosis. Connect. Tissue Res. 2022;1-12. DOI 10.1080/03008207.2022.2120392.Yu W., Wang H.L., Zhang J., Yin C. The effects of epigenetic modifications on bone remodeling in age-related osteoporosis. Connect. Tissue Res. 2022;1-12. DOI 10.1080/03008207.2022.2120392.Zhang J.G., Tan L.J., Xu C., He H., Tian Q., Zhou Y., Qiu C., Chen X.D., Deng H.W. Integrative analysis of transcriptomic and epigenomic data to reveal regulation patterns for BMD variation. PLoS One. 2015;10(9):0138524. DOI 10.1371/journal.pone.0138524.Zhang J.G., Tan L.J., Xu C., He H., Tian Q., Zhou Y., Qiu C., Chen X.D., Deng H.W. Integrative analysis of transcriptomic and epigenomic data to reveal regulation patterns for BMD variation. PLoS One. 2015;10(9):0138524. DOI 10.1371/journal.pone.0138524.Zhang R.F., Liu J.W., Yu S.P., Sun D., Wang X.H., Fu J.S., Xie Z. LncRNA UCA1 affects osteoblast proliferation and differentiation by regulating BMP-2 expression. Eur. Rev. Med. Pharmacol. Sci. 2019;23(16):6774-6782. DOI 10.26355/eurrev_201908_18715.Zhang R.F., Liu J.W., Yu S.P., Sun D., Wang X.H., Fu J.S., Xie Z. LncRNA UCA1 affects osteoblast proliferation and differentiation by regulating BMP-2 expression. Eur. Rev. Med. Pharmacol. Sci. 2019;23(16):6774-6782. DOI 10.26355/eurrev_201908_18715.Zhang W., Wu Y., Shiozaki Y., Sugimoto Y., Takigawa T., Tanaka M., Matsukawa A., Ozaki T. miRNA-133a-5p inhibits the expression of osteoblast differentiation-associated markers by targeting the 3′ UTR of RUNX2. DNA Cell Biol. 2018;37(3):199-209. DOI 10.1089/dna.2017.3936.Zhang W., Wu Y., Shiozaki Y., Sugimoto Y., Takigawa T., Tanaka M., Matsukawa A., Ozaki T. miRNA-133a-5p inhibits the expression of osteoblast differentiation-associated markers by targeting the 3′ UTR of RUNX2. DNA Cell Biol. 2018;37(3):199-209. DOI 10.1089/dna.2017.3936.Zhang Y., Gao Y., Cai L., Li F., Lou Y., Xu N., Kang Y., Yang H. MicroRNA-221 is involved in the regulation of osteoporosis through regulates RUNX2 protein expression and osteoblast differentiation. Am. J. Transl. Res. 2017;9(1):126-135.Zhang Y., Gao Y., Cai L., Li F., Lou Y., Xu N., Kang Y., Yang H. MicroRNA-221 is involved in the regulation of osteoporosis through regulates RUNX2 protein expression and osteoblast differentiation. Am. J. Transl. Res. 2017;9(1):126-135.

The authors declare that there are no conflicts of interest present.