Genes & CellsGenes & Cells2313-18292500-2562Human Stem Cells Institute12220710.23868/201903005Research ArticleMicroRNAs in the regulation of osteogenesis in vitro and in vivo: from fundamental mechanisms to bone diseases pathogenesisGalitsynaE. V-BukharovaT. B-VasilyevA. V-GoldshteinD. V-Research Centre for Medical GeneticsCentral Research Institute of Dental and Maxillofacial Surgery, Ministry of Health of the Russian FederationM.V. Lomonosov Moscow State University15032019141414816012023Copyright © 2019, Eco-Vector2019The review examined the participation of microRNA in the posttranscriptional regulation of the genes of the two main signaling pathways of osteogenic differentiation - canonical BMP/ SMAD and WNT/p-catenin. The positive and negative effects of microRNA on osteogenic differentiation in various cell cultures of humans and animals, including the choice of directions between adipo-, chondro- and osteogenesis, are indicated. The role of miRNA in the pathogenesis of bone tissue diseases and the prospects for developing methods for their diagnosis and therapy are described.Runx2OsterixmicroRNABMP/SMAD signaling pathwayWNT/p-catenin signaling pathwayosteogenic differentiationRunx2OsterixмикрорНКBMP/SMAD сигнальный путьWNT/p-катенин сигнальный путьостеогенная дифференцировка[Fire A., Xu S., Montgomery M.K. et al. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 1998; 391(6669): 806-11][Лебедев Т.Д., Спирин П.В., Прасолов В.С. Перенос и экспрессия малых интерферирующих РНКвклетках млекопитающих с помощью лентивирусных векторов. Acta naturae 2013; 2(17): 7-18][Monteys A.M., Spengler R.M., Wan J. et al. Structure and activity of putative intronic miRNA promoters. RNA 2010; 16(3): 495-505][Никитенко Н.А., Прасолов В.С. Невирусные методы доставки и терапевтическое применение малых интерферирующих РНК. Acta naturae 2013; 3(18): 36-56][Carthew R.W., Sontheimer E.J. Origins and Mechanisms of miR-NAs and siRNAs. Cell 2009; 136(4): 642-55][Alexander R., Lodish H., Sun L. MicroRNAs in adipogenesis and as therapeutic targets for obesity. Expert Opin. Ther. Targets 2011; 15(5): 623-36][Кожевникова М.Н., Микаелян А.С., Старостин В.И. Молекулярногенетические основы регуляции остеогенной дифференцировки мезенхимных стромальных клеток. Известия РАН. Серия биологическая 2008; 3: 261-71][Vishal M., Vimalraj S., Ajeetha R. et al. MicroRNA-590-5p Stabilizes Runx2 by Targeting Smad7 During Osteoblast Differentiation. Cell. Physiol. 2017; 232(2): 371-80.][Shen R., Chen M., Wang Y.J. et al. Smad6 interacts with Runx2 and mediates Smad ubiquitin regulatory factor 1-induced Runx2 degradation. Biol. Chem. 2006; 281(6): 3569-76.][Polakis P. Casein kinase 1: a Wnt’er of disconnect. Curr. Biol. 2002; 12(14): R499-R501.][Hart M., Concordet J.P., Lassot I. et al. The F-box protein beta-TrCP associates with phosphorylated beta-catenin and regulates its activity in the cell. Curr. Biol. 1999; 9(4): 207-10.][Cadigan K.M., Liu Y.I. Wnt signaling: complexity at the surface. Cell Sci. 2006; 119(Pt 3): 395-402.][Kapinas K., Kessler C., Ricks T. et al. MiR-29 modulates Wnt signaling in human osteoblasts through a positive feedback loop. Biol. Chem. 2010; 285(33): 25221-31.][Zhang W.B., Zhong W.J., Wang L. A signal-amplification circuit between miR-218 and Wnt/beta-catenin signal promotes human adipose tissue-derived stem cells osteogenic differentiation. Bone 2014; 58: 59-66.][Hassan M.Q., Maeda Y., Taipaleenmaki H. et al. miR-218 directs a Wnt signaling circuit to promote differentiation of osteoblasts and osteo-mimicry of metastatic cancer cells. Biol. Chem. 2012; 287(50): 42084-92.][Matsubara T., Kida K., Yamaguchi A. et al. BMP2 regulates Osterix through Msx2 and Runx2 during osteoblast differentiation. Biol. Chem. 2008; 283(43): 29119-25.][Dobreva G., Chahrour M., Dautzenberg M. et al. SATB2 is a multifunctional determinant of craniofacial patterning and osteoblast differentiation. Cell 2006; 125(5): 971-86.][Hassan M.Q., Tare R., Lee S.H. et al. HOXA10 Controls Osteoblasto-genesis by Directly Activating Bone Regulatory and Phenotypic Genes. Mol. Cell. Biol. 2007; 27(9): 3337-52.][Hwang S., Park S.K., Lee H.Y. et al. Mir-140-5p suppresses BMP2-mediated osteogenesis in undifferentiated human mesenchymal stem cells. FEBS Lett. 2014; 588(17): 2957-63.][Zhang Y., Wei Q.S., Ding W.B. et al. Increased microRNA-93-5p inhibits osteogenic differentiation by targeting bone morphogenetic protein-2. PLoS One 2017; 12(8): e0182678.][Liu K., Jing Y., Zhang W. et al. Silencing miR-106b accelerates osteogenesis of mesenchymal stem cells and rescues against glucocorticoid-induced osteoporosis by targeting BMP2. Bone 2017; 97: 130-8.][Itoh T., Ando M., Tsukamasa Y. et al. Expression of BMP-2 and Ets1 in BMP-2-stimulated mouse pre-osteoblast differentiation is regulated by microRNA-370. FEBS Lett. 2012; 586(12): 1693-701.][Kureel J., Dixit M., Tyagi A.M. et al. MiR-542-3p suppresses osteoblast cell proliferation and differentiation, targets BMP-7 signaling and inhibits bone formation. Cell Death Dis. 2014; 5: e1050.][Ju H., Yang Y., Sheng A. et al. MicroRNA-378 promotes myogenic differentiation by targeting BMP4. Mol. Med. Rep. 2016; 13(3): 2194-200.][Yao Y., Reheman A., Xu Y. et al. MiR-125b Contributes to Ovarian Granulosa Cell Apoptosis Through Targeting BMPR1B, a Major Gene for Sheep Prolificacy. Reprod. Sci. 2019; 26(2): 295-305.][Zeng Y., Qu X., Li H. et al. MicroRNA-100 regulates osteogenic differentiation of human adipose-derived mesenchymal stem cells by targeting BMPR2. FEBS lett. 2012; 586(16): 2375-81.][Cao Y., LV Q., LV C. MicroRNA-1 53 suppresses the osteogenic differentiation of human mesenchymal stem cells by targeting bone morphogenetic protein receptor type II. Int. J. Mol. Med. 2015; 36(3): 760-6.][Su X., Liao L., Shuai Y. et al. MiR-26a functions oppositely in osteogenic differentiation of BMSCs and ADSCs depending on distinct activation and roles of Wnt and BMP signaling pathway. Cell Death Dis. 2015; 6(8): e1851.][Wu T., Zhou H., Hong Y. et al. MiR-30 family members negatively regulate osteoblast differentiation. Biol. Chem. 2012; 287(10): 7503-11.][Li Z., Hassan M.Q., Volinia S. et al. A microRNA signature for a BMP2-induced osteoblast lineage commitment program. PNAS USA 2008; 105(37): 13906-11.][Fang T., Wu Q., Zhou L. et al. miR-106b-5p and miR-17-5p suppress osteogenic differentiation by targeting Smad5 and inhibit bone formation. Exp. Cell Res. 2016; 347(1): 74-82.][Wei F., Yang S., Guo Q. MicroRNA-21 regulates Osteogenic Differentiation of Periodontal Ligament Stem Cells by targeting Smad5. Sci. Rep. 2017; 7(1): 16608.][Li H., Yang F., Wang Z. et al. MicroRNA-21 promotes osteogenic differentiation by targeting small mothers against decapentaplegic 7. Mol. Med. Rep. 2015; 12(1): 1561-7.][Zhang Y., Huang X., Yuan Y. MicroRNA-410 promotes chon-drogenic differentiation of human bone marrow mesenchymal stem cells through down-regulating Wnt3a. Am. J. Transl. Res. 2017; 9(1): 136-145.][Zhang J., Tu Q., Bonewald L.F. et al. Effects of miR-335-5p in modulating osteogenic differentiation by specifically downregulating Wnt antagonist DKK1. Bone Miner. Res. 2011; 26(8): 1953-63.][Long H., Sun B., Cheng L. et al. miR-139-5p Represses BMSC Osteogenesis via Targeting Wnt/p-Catenin Signaling Pathway. DNA Cell Biol. 2017; 36(8): 715-24.][Li G., Luna C., Qiu J. et al. Role of miR-204 in the regulation of apoptosis, endoplasmic reticulum stress response, and inflammation in human trabecular meshwork cells. Invest. Ophthalmol. Vis. Sci. 2011; 52(6): 2999-3007.][Li T., Li H., Wang Y. et al. microRNA-23a inhibits osteogenic differentiation of human bone marrow-derived mesenchymal stem cells by targeting LRP5. Int. J. Biochem. Cell Biol. 2016; 72: 55-62.][Sun T., Li C.T., Xiong L. et al. MiR-375-3p negatively regulates osteogenesis by targeting and decreasing the expression levels of LRP5 and p-catenin. PLoS One 2017; 12(2): e0171281.][Elsafadi M., Manikandan M., Alajez N.M. et al. MicroRNA-4739 regulates osteogenic and adipocytic differentiation of immortalized human bone marrow stromal cells via targeting LRP3. Stem Cell Res. 2017; 20: 94-104.][Wang N., Zhou Z., Wu T. et al. TNF-alpha-induced NF-kappaB activation upregulates microRNA-150-3p and inhibits osteogenesis of mesenchymal stem cells by targeting beta-catenin. Open Biol. 2016; 6(3): 150258.][Huang J., Chen L. IL-1 p inhibits osteogenesis of human bone marrow-derived mesenchymal stem cells by activating FoxD3/ microRNA-496 to repress wnt signaling. Genesis 2017; 55(7).][Lin G., Liu B., Meng Z. et al. MiR-26a enhances invasive capacity by suppressing GSK3p in human lung cancer cells. Exp. Cell Res. 2017; 352(2): 364-74.][Wang Q., Cai J., Cai X.H. et al. MiR-346 Regulates Osteogenic Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells by Targeting the Wnt/b-Catenin Pathway. PLoS One 2013; 8(9): e72266.][Jia J., Feng X., Xu W. et al. MiR-17-5p modulates osteoblastic differentiation and cell proliferation by targeting SMAD7 in non-traumatic osteonecrosis. Exp. Mol. Med. 2014; 46: e107.][Zhang Y., Xie R.L., Croce C.M. et al. A program of microRNAs controls osteogenic lineage progression by targeting transcription factor Runx2. PNAS USA 2011; 108(24): 9863-8.][Zuo B., Zhu J.F., Li J. et al. MicroRNA-103a functions as a mechano-sensitive microRNA to inhibit bone formation through targeting Runx2. Bone Miner. Res. 2015; 30(2): 330-45.][Xie H., Lim B., Lodish H.F. MicroRNAs induced during adipogenesis that accelerate fat cell development are downregulated in obesity. Diabetes 2009; 58(5): 1050-7.][Huang J., Zhao L., Xing L. et al. MicroRNA-204 regulates Runx2 protein expression and mesenchymal progenitor cell differentiation. Stem Cells 2010; 28(2): 357-64.][Liao L., Yang X., Su X. et al. 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: e600.][Tome M., Lopez-Romero P., Albo C. et al. микрорНК-335 orchestrates cell proliferation, migration and differentiation in human mesenchymal stem cells. Cell Death Differ. 2011; 18(6): 985-95.][McCully M., Conde J., Baptista P.V. et al. Nanoparticle-antagomiR based targeting of miR-31 to induce osterix and osteocalcin expression in mesenchymal stem cells. PLoS One 2018; 13(2): e0192562.][Deng Y., Wu S., Zhou H. et al. Effects of a miR-31, Runx2 and Satb2 regulatory loop on the osteogenic differentiation of bone mesenchymal stem cells. Stem Cells Dev. 2013; 22(16): 2278-86.][Baglio S.R., Devescovi V., Granchi D. et al. MicroRNA expression profiling of human bone marrow mesenchymal stem cells during osteogenic differentiation reveals Osterix regulation by miR-31. Gene 2013; 527(1): 321-31.][Li E., Zhang J., Yuan T. et al. MiR-143 suppresses osteogenic differentiation by targeting Osterix. Mol. Cell. Biochem. 2014; 390(1-2): 69-74.][Jia J., Tian Q., Ling S. et al. miR-145 suppresses osteogenic differentiation by targeting Sp7. FEBS Lett. 2013; 587(18): 3027-31.][Shi K., Lu J., Zhao Y. et al. MicroRNA-214 suppresses osteogenic differentiation of C2C12 myoblast cells by targeting Osterix. Bone 2013; 55(2): 487-94.][Martinez-Sanchez A., Dudek K.A., Murphy C.L. Regulation of Human Chondrocyte Function through Direct Inhibition of Cartilage Master Regulator SOX9 by MicroRNA-145 (miRNA-145). Biol. Chem. 2012; 287(2): 916-24.][Dharap A., Pokrzywa C., Murali S. et al. Mutual induction of transcription factor PPARy and microRNAs miR-145 and miR-329. Neurochem. 2015; 135(1): 139-46.][Zhang J.F., Fu W.M., He M.L. et al. MiR-637 maintains the balance between adipocytes and osteoblasts by directly targeting Osterix. Mol. Biol. Cell 2011; 22(21): 3955-61.][Yang L., Cheng P., Chen C. et al. MiR-93/Sp7 function loop mediates osteoblast mineralization. Bone Miner. Res. 2012; 27(7): 1598-606.][Itoh T., Nozawa Y., Akao Y. MicroRNA-141 and -200a are involved in bone morphogenetic protein-2-induced mouse pre-osteoblast differentiation by targeting distal-less homeobox 5. Biol. Chem. 2009; 284(29): 19272-9.][Okamoto H., Matsumi Y., Hoshikawa Y. et al. Involvement of microRNAs in regulation of osteoblastic differentiation in mouse induced pluripotent stem cells. PLoS One 2012; 7(8): e43800.][Huang J., Meng Y., Liu Y. et al. MicroRNA-320a regulates the osteogenic differentiation of human bone marrow-derived mesenchymal stem cells by targeting HOXA10. Cell. Physiol. Biochem. 2016; 38(1): 40-8.][Wei J., Shi Y., Zheng L. et al. miR-34s inhibit osteoblast proliferation and differentiation in the mouse by targeting SATB2. J. Cell Biol. 2012; 197(4): 509-21.][Xie Q., Wang Z., Bi X. et al. Effects of miR-31 on the osteogenesis of human mesenchymal stem cells. Biochem. Biophys. Res. Commun. 2014; 446(1): 98-104.][Hu N., Feng C., Jiang Y. et al. Regulative Effect of Mir-205 on Osteogenic Differentiation of Bone Mesenchymal Stem Cells (BMSCs): Possible Role of SATB2/Runx2 and ERK/MAPK Pathway. Int. J. Mol. Sci. 201 5; 16(5): 10491-506.][Zhao W., Wu C., Dong Y. et al. MicroRNA-24 Regulates Osteogenic Differentiation via Targeting T-Cell Factor-1. Int. J. Mol. Sci. 2015; 16(5): 11699-712.][Amelio I., Lena A.M., Bonanno E. et al. miR-24 affects hair follicle morphogenesis targeting Tcf-3. Cell Death Dis. 2013; 4(11): e922.][Li H., Xie H., Liu W. et al. A novel microRNA targeting HDAC5 regulates osteoblast differentiation in mice and contributes to primary osteoporosis in humans. Clin. Invest. 2009; 119(12): 3666-77.][Hu R., Liu W., Li H. et al. A Runx2/miR-3960/miR-2861 regulatory feedback loop during mouse osteoblast differentiation. Biol. Chem. 2011; 286(14): 12328-39.][Wang X., Guo B., Li Q. et al. MiR-214 targets ATF4 to inhibit bone formation. Nat. Med. 2013; 19: 93-100.][Liu H., Liu Q., Wu X.P. et al. MiR-96 regulates bone metabolism by targeting osterix. Clin. Exp. Pharmacol. Physiol. 2018; 45(6): 602-13.][Yang N., Wang G., Hu C. et al. Tumor necrosis factor alpha suppresses the mesenchymal stem cell osteogenesis promoter miR-21 in estrogen deficiency-induced osteoporosis. Bone Miner. Res. 2013; 28(3): 559-73.][Wang Z., Lu Y., Zhang X. et al. Serum microRNA is a promising biomarker for osteogenesis imperfecta. Intractable Rare Dis. Res. 2012; 1(2): 81-5.][Sun K., Wang J., Liu F. et al. Ossotide promotes cell differentiation of human osteoblasts from osteogenesis imperfecta patients by up-regulating miR-145. Biomed. Pharmacother. 2016; 83: 1105-10.][Kaneto C.M., Lima P.S., Zanette D.L. et al. COL1A1 and miR-29b show lower expression levels during osteoblast differentiation of bone marrow stromal cells from Osteogenesis Imperfecta patients. BMC Med. Genet. 2014; 15: 45.][Chen P., Wei D., Xie B. et al. Effect and possible mechanism of network between microRNAs and RUNX2 gene on human dental follicle cells. J. Cell. Biochem. 2014; 115(2): 340-8.][Ge J., Guo S., Fu Y. et al. Dental Follicle Cells Participate in Tooth Eruption via the RUNX2-MiR-31-SATB2 Loop. Dent. Res. 2015; 94(7): 936-44.][Chang H., Wang Y., Liu H. et al. Mutant Runx2 regulates amelo-genesis and osteogenesis through a miR-185-5p-Dlx2 axis. Cell Death Dis. 2017; 8(12): 3221.][Rupaimoole R., Slack F.J. MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat. Rev. Drug Discov. 2017; 16(3): 203-22.]