The role of microRNAs in bone remodeling

Abstract

Short, non-coding microRNAs play a critical role in regulating bone remodeling and provide therapeutic targets for treating bone disease. In a review article, Zhi-He Zhao and colleagues from the State Key Laboratory of Oral Diseases at Sichuan University in Chengdu, China, examine the ways in which microRNAs control gene expression in various types of bone cells, including bone-forming osteoblasts and bone-resorbing osteoclasts. Through this regulatory function, microRNAs can help tip the balance toward bone synthesis or degradation to spur disease processes and affect healthy development. After highlighting some of the specific molecules and pathways impacted by microRNAs at various stages of bone remodeling, the authors discuss how microRNAs could be delivered into the body, either directly or through some kind of biomaterial, to correct skeletal disease, trauma, osteoporosis, cancer and other disorders affecting bone.

Keywords

bone remodeling / microRNAs / osteoclastogenesis / osteogenesis

References

[1] Dimitriou R, Jones E, McGonagle D. Bone regeneration: current concepts and future directions. BMC Med, 2011, 31(9): 66.

[2] Siddiqui NA, Owen JM. Clinical advances in bone regeneration. Curr Stem Cell Res Ther, 2013, 8(3): 192-200.

[3] Tezuka K, Yasuda M, Watanabe N. Stimulation of osteoblastic cell differentiation by Notch. J Bone Miner Res, 2002, 17(2): 231-239.

[4] Chen D, Zhao M, Mundy GR. Bone morphogenetic proteins. Growth Factors, 2004, 22(4): 233-241.

[5] Hu H, Hilton MJ, Tu X. Sequential roles of Hedgehog and Wnt signaling in osteoblast development. Development, 2005, 132(1): 49-60.

[6] Estrada K, Styrkarsdottir U, Evangelou E. 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.

[7] Zaidi SK, Young DW, Montecino M. Bookmarking the genome: maintenance of epigenetic information. J Biol Chem, 2011, 286(21): 18355-18361.

[8] Ghildiyal M, Zamore PD. Small silencing RNAs: an expanding universe. Nat Rev Genet, 2009, 10(2): 94-108.

[9] Iorio MV, Piovan C, Croce CM. Interplay between microRNAs and the epigenetic machinery: an intricate network. Biochim Biophys Acta, 2010, 1799(10/11/12): 694-701.

[10] Sims NA, Gooi JH. Bone remodeling: multiple cellular interactions required for coupling of bone formation and resorption. Semin Cell Dev Biol, 2008, 19(5): 444-451.

[11] Schaffler MB, Cheung WY, Majeska R. Osteocytes: master orchestrators of bone. Calcif Tissue Int, 2014, 94(1): 5-24.

[12] Kirk MD, Kahn AJ. Extracellular matrix synthesized by clonal osteogenic cells is osteoinductive in vivo and in vitro: role of transforming growth factor-beta 1 in osteoblast cell-matrix interaction. J Bone Miner Res, 1995, 10(8): 1203-1208.

[13] Lien CY, Lee OK, Su Y. Cbfb enhances the osteogenic differentiation of both human and mouse mesenchymal stem cells induced by Cbfa-1 via reducing its ubiquitination-mediated degradation. Stem Cells, 2007, 25(6): 1462-1468.

[14] Asagiri M, Takayanagi H. The molecular understanding of osteoclast differentiation. Bone, 2007, 40(2): 251-264.

[15] Sims NA, Martin TJ. Coupling the activities of bone formation and resorption: a multitude of signals within the basic multicellular unit. Bonekey Rep, 2014, 3: 481.

[16] Hobert O. Gene regulation by transcription factors and microRNAs. Science, 2008, 319(5871): 1785-1786.

[17] Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell, 2004, 116(2): 281-297.

[18] Borchert GM, Lanier W, Davidson BL. RNA polymerase III transcribes human microRNAs. Nat Struct Mol Biol, 2006, 13(12): 1097-1101.

[19] Kapinas K, Kessler CB, Delany AM. miR-29 suppression of osteonectin in osteoblasts: regulation during differentiation and by canonical Wnt signaling. J Cell Biochem, 2009, 108(1): 216-224.

[20] Guo H, Ingolia NT, Weissman JS. Mammalian microRNAs predominantly act to decrease target mRNA levels. Nature, 2010, 466(7308): 835-840.

[21] Ambros V, Chen X. The regulation of genes and genomes by small RNAs. Development, 2007, 134(9): 1635-1641.

[22] Cullen BR. Transcription and processing of human microRNA precursors. Mol Cell, 2004, 16(6): 861-865.

[23] Bentwich I, Avniel A, Karov Y. Identification of hundreds of conserved and nonconserved human microRNAs. Nat Genet, 2005, 37(7): 766-770.

[24] Langenberger D, Çakir MV, Hoffmann S. Dicer-processed small RNAs: rules and exceptions. J Exp Zool B Mol Dev Evol, 2013, 320(1): 35-46.

[25] Dalmay T. Mechanism of miRNA-mediated repression of mRNA translation. Essays Biochem, 2013, 54(1): 29-38.

[26] Titorencu I, Pruna V, Jinga VV. Osteoblast ontogeny and implications for bone pathology: an overview. Cell Tissue Res, 2014, 355(1): 23-33.

[27] Dalle Carbonare L, Innamorati G, Valenti MT. Transcription factor Runx2 and its application to bone tissue engineering. Stem Cell Rev, 2012, 8(3): 891-897.

[28] Ducy P, Zhang R, Geoffroy V. Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell, 1997, 89(5): 747-754.

[29] Cohen MM Jr. Perspectives on RUNX genes: an update. Am J Med Genet A, 2009, 149A(12): 2629-2646.

[30] He N, Xiao Z, Yin T. Inducible expression of Runx2 results in multiorgan abnormalities in mice. J Cell Biochem, 2011, 112(2): 653-665.

[31] Ylönen R, Kyrönlahti T, Sund M. Type XIII collagen strongly affects bone formation in transgenic mice. J Bone Miner Res, 2005, 20(8): 1381-1393.

[32] Huszar JM, Payne CJ. MIR146A inhibits JMJD3 expression and osteogenic differentiation in human mesenchymal stem cells. FEBS Lett, 2014, 588(9): 1850-1856.

[33] Zhang Y, Xie RL, Croce CM. A program of microRNAs controls osteogenic lineage progression by targeting transcription factor Runx2. Proc Natl Acad Sci U S A, 2011, 108(24): 9863-9868.

[34] Zhang Y, Xie RL, Gordon J. Control of mesenchymal lineage progression by microRNAs targeting skeletal gene regulators Trps1 and Runx2. J Biol Chem, 2012, 287(26): 21926-21935.

[35] Wu T, Zhou H, Hong Y. miR-30 family members negatively regulate osteoblast differentiation. J Biol Chem, 2012, 287(10): 7503-7511.

[36] Zaragosi LE, Wdziekonski B, Brigand KL. Small RNA sequencing reveals miR-642a-3p as a novel adipocyte-specific microRNA and miR-30 as a key regulator of human adipogenesis. Genome Biol, 2011, 12(7): R64.

[37] Huang J, Zhao L, Xing L. MicroRNA-204 regulates Runx2 protein expression and mesenchymal progenitor cell differentiation. Stem Cells, 2010, 28(2): 357-364.

[38] Cui RR, Li SJ, Liu LJ. MicroRNA-204 regulates vascular smooth muscle cell calcification in vitro and in vivo. Cardiovasc Res, 2012, 96(2): 320-329.

[39] Mizuno Y, Yagi K, Tokuzawa Y. miR-125b inhibits osteoblastic differentiation by down-regulation of cell proliferation. Biochem Biophys Res Commun, 2008, 368(2): 267-272.

[40] Huang K, Fu J, Zhou W. MicroRNA-125b regulates osteogenic differentiation of mesenchymal stem cells by targeting Cbfβ in vitro. Biochimie, 2014, 102: 47-55.

[41] Chen S, Yang L, Jie Q. MicroRNA-125b suppresses the proliferation and osteogenic differentiation of human bone marrow-derived mesenchymal stem cells. Mol Med Rep, 2014, 9(5): 1820-1826.

[42] Pinto MT, Nicolete LD, Rodrigues ES. Overexpression of hsa-miR-125b during osteoblastic differentiation does not influence levels of Runx2, osteopontin, and ALPL gene expression. Braz J Med Biol Res, 2013, 46(8): 676-680.

[43] Wei FL, Wang JH, Ding G. Mechanical force-induced specific MicroRNA expression in human periodontal ligament stem cells. Cells Tissues Organs, 2014, 199(5/6): 353-363.

[44] Chen Y, Mohammed A, Oubaidin M. Cyclic stretch and compression forces alter microRNA-29 expression of human periodontal ligament cells. Gene, 2015, 566(1): 13-17.

[45] Zuo B, Zhu J, Li J. microRNA-103a functions as a mechanosensitive microRNA to inhibit bone formation through targeting Runx2. J Bone Miner Res, 2015, 30(2): 330-345.

[46] Dobreva G, Chahrour M, Dautzenberg M. SATB2 is a multifunctional determinant of craniofacial patterning and osteoblast differentiation. Cell, 2006, 125(5): 971-986.

[47] Zhang J, Tu Q, Grosschedl R. Roles of SATB2 in osteogenic differentiation and bone regeneration. Tissue Eng Part A, 2011, 17(13/14): 1767-1776.

[48] Tang W, Li Y, Osimiri L. Osteoblast-specific transcription factor Osterix (Osx) is an upstream regulator of Satb2 during bone formation. J Biol Chem, 2011, 286(38): 32995-33002.

[49] Conner JR, Hornick JL. SATB2 is a novel marker of osteoblastic differentiation in bone and soft tissue tumours. Histopathology, 2013, 63(1): 36-49.

[50] Hassan MQ, Gordon JA, Beloti MM. A network connecting Runx2, SATB2, and the miR-23a∼27a∼24-2 cluster regulates the osteoblast differentiation program. Proc Natl Acad Sci U S A, 2010, 107(46): 19879-19884.

[51] Park J, Wada S, Ushida T et al. The microRNA-23a has limited roles in bone formation and homeostasis in vivo. Physiol Res 2015. [Epub ahead of print].

[52] Wei J, Shi Y, Zheng L. miR-34s inhibit osteoblast proliferation and differentiation in the mouse by targeting SATB2. J Cell Biol, 2012, 197(4): 509-521.

[53] Bae Y, Yang T, Zeng HC. miRNA-34c regulates Notch signaling during bone development. Hum Mol Genet, 2012, 21(13): 2991-3000.

[54] Deng Y, Bi X, Zhou H. Repair of critical-sized bone defects with anti-miR-31-expressing bone marrow stromal stem cells and poly(glycerol sebacate) scaffolds. Eur Cell Mater, 2014, 27: 13-24.

[55] Xie Q, Wang Z, Bi X. Effects of miR-31 on the osteogenesis of human mesenchymal stem cells. Biochem Biophys Res Commun, 2014, 446(1): 98-104.

[56] Deng Y, Wu S, Zhou H. 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): 2278-2286.

[57] Chen S, Feng J, Zhang H. Key role for the transcriptional factor, Osterix, in spine development. Spine J, 2014, 14(4): 683-694.

[58] Nakashima K, Zhou X, Kunkel G. The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell, 2002, 108(1): 17-29.

[59] Nishio Y, Dong Y, Paris M. Runx2-mediated regulation of the zinc finger Osterix/Sp7 gene. Gene, 2006, 372: 62-70.

[60] Celil AB, Campbell PG. BMP-2 and insulin-like growth factor-I mediate Osterix (Osx) expression in human mesenchymal stem cells via the MAPK and protein kinase D signaling pathways. J Biol Chem, 2005, 280(36): 31353-31359.

[61] Matsubara T, Kida K, Yamaguchi A. BMP2 regulates Osterix through Msx2 and Runx2 during osteoblast differentiation. J Biol Chem, 2008, 283(43): 29119-29125.

[62] Baglìo SR, Devescovi V, Granchi D. MicroRNA expression profiling of human bone marrow mesenchymal stem cells during osteogenic differentiation reveals Osterix regulation by miR-31. Gene, 2013, 527(1): 321-331.

[63] Yang L, Cheng P, Chen C. miR-93/Sp7 function loop mediates osteoblast mineralization. J Bone Miner Res, 2012, 27(7): 1598-1606.

[64] Li E, Zhang J, Yuan T. MiR-143 suppresses osteogenic differentiation by targeting Osterix. Mol Cell Biochem, 2014, 390(1/2): 69-74.

[65] Jia J, Tian Q, Ling S. miR-145 suppresses osteogenic differentiation by targeting Sp7. FEBS Lett, 2013, 587(18): 3027-3031.

[66] Liu H, Lin H, Zhang L. miR-145 and miR-143 regulate odontoblast differentiation through targeting Klf4 and Osx genes in a feedback loop. J Biol Chem, 2013, 288(13): 9261-9271.

[67] Zhang JF, Fu WM, He ML. MiR-637 maintains the balance between adipocytes and osteoblasts by directly targeting Osterix. Mol Biol Cell, 2011, 22(21): 3955-3961.

[68] Shi K, Lu J, Zhao Y. MicroRNA-214 suppresses osteogenic differentiation of C2C12 myoblast cells by targeting Osterix. Bone, 2013, 55(2): 487-494.

[69] Gámez B, Rodríguez-Carballo E, Bartrons R. MicroRNA-322 (miR-322) and its target protein Tob2 modulate Osterix (Osx) mRNA stability. J Biol Chem, 2013, 288(20): 14264-14275.

[70] Chen Q, Liu W, Sinha KM. Identification and characterization of microRNAs controlled by the osteoblast-specific transcription factor Osterix. PLoS One, 2013, 8(3): e58104.

[71] Chen G, Deng C, Li YP. TGF-β and BMP signaling in osteoblast differentiation and bone formation. Int J Biol Sci, 2012, 8(2): 272-288.

[72] Song B, Estrada KD, Lyons KM. Smad signaling in skeletal development and regeneration. Cytokine Growth Factor Rev, 2009, 20(5/6): 379-388.

[73] Afzal F, Pratap J, Ito K. 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.

[74] Kureel J, Dixit M, Tyagi AM. miR-542-3p suppresses osteoblast cell proliferation and differentiation, targets BMP-7 signaling and inhibits bone formation. Cell Death Dis, 2014, 5: e1050.

[75] Luzi E, Marini F, Sala SC. Osteogenic differentiation of human adipose tissue-derived stem cells is modulated by the miR-26a targeting of the SMAD1 transcription factor. J Bone Miner Res, 2008, 23(2): 287-295.

[76] Xu S, Cecilia Santini G, De Veirman K. Upregulation of miR-135b is involved in the impaired osteogenic differentiation of mesenchymal stem cells derived from multiple myeloma patients. PLoS One, 2013, 8(11): e79752.

[77] Li Z, Hassan MQ, Volinia S. A microRNA signature for a BMP2-induced osteoblast lineage commitment program. Proc Natl Acad Sci U S A, 2008, 105(37): 13906-13911.

[78] Schaap-Oziemlak AM, Raymakers RA, Bergevoet SM. MicroRNA hsa-miR-135b regulates mineralization in osteogenic differentiation of human unrestricted somatic stem cells. Stem Cells Dev, 2010, 19(6): 877-885.

[79] Li H, Li T, Wang S. miR-17-5p and miR-106a are involved in the balance between osteogenic and adipogenic differentiation of adipose-derived mesenchymal stem cells. Stem Cell Res, 2013, 10(3): 313-324.

[80] Zeng Y, Qu X, Li H. MicroRNA-100 regulates osteogenic differentiation of human adipose-derived mesenchymal stem cells by targeting BMPR2. FEBS Lett, 2012, 586(16): 2375-2381.

[81] Hwang S, Park SK, Lee HY. miR-140-5p suppresses BMP2-mediated osteogenesis in undifferentiated human mesenchymal stem cells. FEBS Lett, 2014, 588(17): 2957-2963.

[82] Jia J, Feng X, Xu W. MiR-17-5p modulates osteoblastic differentiation and cell proliferation by targeting SMAD7 in non-traumatic osteonecrosis. Exp Mol Med, 2014, 46: e107.

[83] Liu Tao, Fu Nan-Nan, Song Hong-Li, Wang Yu-Liang, Wu Ben-Juan, Shen Zhong-Yang. Suppression of MicroRNA-203 improves survival of rat bone marrow mesenchymal stem cells through enhancing PI3K-induced cellular activation. IUBMB Life, 2014, 66(3): 220-227.

[84] Day TF, Guo X, Garrett-Beal L. Wnt/beta-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis. Dev Cell, 2005, 8(5): 739-750.

[85] Rossini M, Gatti D, Adami S. Involvement of WNT/β-catenin signaling in the treatment of osteoporosis. Calcif Tissue Int, 2013, 93(2): 121-132.

[86] Liu G, Vijayakumar S, Grumolato L. Canonical Wnts function as potent regulators of osteogenesis by human mesenchymal stem cells. J Cell Biol, 2009, 185(1): 67-75.

[87] Liu W, Liu Y, Guo T. TCF3, a novel positive regulator of osteogenesis, plays a crucial role in miR-17 modulating the diverse effect of canonical Wnt signaling in different microenvironments. Cell Death Dis, 2013, 4: e539.

[88] Roberto VP, Tiago DM, Silva IA. MiR-29a is an enhancer of mineral deposition in bone-derived systems. Arch Biochem Biophys, 2014, 564: 173-183.

[89] Gaur T, Lengner CJ, Hovhannisyan H. Canonical WNT signaling promotes osteogenesis by directly stimulating Runx2 gene expression. J Biol Chem, 2005, 280(39): 33132-33140.

[90] Wang J, Guan X, Guo F. 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: e845.

[91] Qiu W, Kassem M. miR-141-3p inhibits human stromal (mesenchymal) stem cell proliferation and differentiation. Biochim Biophys Acta, 2014, 1843(9): 2114-2121.

[92] Yang X, Matsuda K, Bialek P. ATF4 is a substrate of RSK2 and an essential regulator of osteoblast biology; implication for Coffin-Lowry Syndrome. Cell, 2004, 117(3): 387-398.

[93] Makowski AJ, Uppuganti S, Wadeer SA. The loss of activating transcription factor 4 (ATF4) reduces bone toughness and fracture toughness. Bone, 2014, 62: 1-9.

[94] Xiao G, Jiang D, Ge C. Cooperative interactions between activating transcription factor 4 and Runx2/Cbfa1 stimulate osteoblast-specific osteocalcin gene expression. J Biol Chem, 2005, 280(35): 30689-30696.

[95] Liu TM, Lee EH. Transcriptional regulatory cascades in Runx2-dependent bone development. Tissue Eng Part B Rev, 2013, 19(3): 254-263.

[96] St-Arnaud R, Mandic V. FIAT control of osteoblast activity. J Cell Biochem, 2010, 109(3): 453-459.

[97] St-Arnaud R, Hekmatnejad B. Combinatorial control of ATF4-dependent gene transcription in osteoblasts. Ann N Y Acad Sci, 2011, 1237: 11-18.

[98] Hekmatnejad B, Gauthier C, St-Arnaud R. Control of Fiat (factor inhibiting ATF4-mediated transcription) expression by Sp family transcription factors in osteoblasts. J Cell Biochem, 2013, 114(8): 1863-1870.

[99] Matsuguchi T, Chiba N, Bandow K. JNK activity is essential for Atf4 expression and late-stage osteoblast differentiation. J Bone Miner Res, 2009, 24(3): 398-410.

[100] Karsenty G. Transcriptional control of skeletogenesis. Annu Rev Genomics Hum Genet, 2008, 9: 183-196.

[101] Wang X, Guo B, Li Q. miR-214 targets ATF4 to inhibit bone formation. Nat Med, 2013, 19(1): 93-100.

[102] Byun MR, Kim AR, Hwang JH. FGF2 stimulates osteogenic differentiation through ERK induced TAZ expression. Bone, 2014, 58: 72-80.

[103] Byun MR, Hwang JH, Kim AR. Canonical Wnt signalling activates TAZ through PP1A during osteogenic differentiation. Cell Death Differ, 2014, 21(6): 854-863.

[104] Byun MR, Kim AR, Hwang JH. Phorbaketal A stimulates osteoblast differentiation through TAZ mediated Runx2 activation. FEBS Lett, 2012, 586(8): 1086-1092.

[105] Jang EJ, Jeong H, Kang JO. TM-25659 enhances osteogenic differentiation and suppresses adipogenic differentiation by modulating the transcriptional co-activator TAZ. Br J Pharmacol, 2012, 165(5): 1584-1594.

[106] Hong JH, Hwang ES, McManus MT. TAZ, a transcriptional modulator of mesenchymal stem cell differentiation. Science, 2005, 309(5737): 1074-1078.

[107] Hong JH, Yaffe MB. TAZ: a beta-catenin-like molecule that regulates mesenchymal stem cell differentiation. Cell Cycle, 2006, 5(2): 176-179.

[108] Cho HH, Shin KK, Kim YJ. NF-κB activation stimulates osteogenic differentiation of mesenchymal stem cells derived from human adipose tissue by increasing TAZ expression. J Cell Physiol, 2010, 223(1): 168-177.

[109] Chaulk SG, Lattanzi VJ, Hiemer SE. The Hippo pathway effectors TAZ/YAP regulate dicer expression and microRNA biogenesis through Let-7. J Biol Chem, 2014, 289(4): 1886-1891.

[110] Hao J, Zhang Y, Jing D. Role of Hippo signaling in cancer stem cells. J Cell Physiol, 2014, 229(3): 266-270.

[111] Dupont S, Morsut L, Aragona M. Role of YAP/TAZ in mechanotransduction. Nature, 2011, 474(7350): 179-183.

[112] Hao J, Zhang Y, Wang Y. Role of extracellular matrix and YAP/TAZ in cell fate determination. Cell Signal, 2014, 26(2): 186-191.

[113] Eskildsen T, Taipaleenmäki H, Stenvang J. MicroRNA-138 regulates osteogenic differentiation of human stromal (mesenchymal) stem cells in vivo. Proc Natl Acad Sci U S A, 2011, 108(15): 6139-6144.

[114] Qu B, Xia X, Wu HH. PDGF-regulated miRNA-138 inhibits the osteogenic differentiation of mesenchymal stem cells. Biochem Biophys Res Commun, 2014, 448(3): 241-247.

[115] Guan X, Gao Y, Zhou J. miR-223 regulates adipogenic and osteogenic differentiation of mesenchymal stem cells through a C/EBPs/miR-223/FGFR2 regulatory feedback loop. Stem Cells, 2015, 33(5): 1589-1600.

[116] Liu H, Sun Q, Wan C. MicroRNA-338-3p regulates osteogenic differentiation of mouse bone marrow stromal stem cells by targeting Runx2 and Fgfr2. J Cell Physiol, 2014, 229(10): 1494-1502.

[117] Lecanda F, Warlow PM, Sheikh S. Connexin43 deficiency causes delayed ossification, craniofacial abnormalities, and osteoblast dysfunction. J Cell Biol, 2000, 151(4): 931-944.

[118] Kim HK, Lee YS, Sivaprasad U. Muscle-specific microRNA miR-206 promotes muscle differentiation. J Cell Biol, 2006, 174(5): 677-687.

[119] Inose H, Ochi H, Kimura A. A microRNA regulatory mechanism of osteoblast differentiation. Proc Natl Acad Sci U S A, 2009, 106(49): 20794-20799.

[120] 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. J Biol Chem, 2009, 284(29): 19272-19279.

[121] Sangani R, Periyasamy-Thandavan S, Kolhe R. MicroRNAs-141 and 200a regulate the SVCT2 transporter in bone marrow stromal cells. Mol Cell Endocrinol, 2015, 410: 19-26.

[122] Okamoto H, Matsumi Y, Hoshikawa Y. Involvement of microRNAs in regulation of osteoblastic differentiation in mouse induced pluripotent stem cells. PLoS One, 2012, 7(8): e43800.

[123] Qadir AS, Um S, Lee H. miR-124 negatively regulates osteogenic differentiation and in vivo bone formation of mesenchymal stem cells. J Cell Biochem, 2015, 116(5): 730-742.

[124] Tyagi S, Gupta P, Saini AS. The peroxisome proliferator-activated receptor: a family of nuclear receptors role in various diseases. J Adv Pharm Technol Res, 2011, 2(4): 236-240.

[125] James AW. Review of signaling pathways governing MSC osteogenic and adipogenic differentiation. Scientifica: Cairo, 2013, 2013: 684736.

[126] Sethi JK, Vidal-Puig AJ. Thematic review series: adipocyte biology. Adipose tissue function and plasticity orchestrate nutritional adaptation. J Lipid Res, 2007, 48(6): 1253-1262.

[127] Akune T, Ohba S, Kamekura S. PPARgamma insufficiency enhances osteogenesis through osteoblast formation from bone marrow progenitors. J Clin Invest, 2004, 113(6): 846-855.

[128] Jeon MJ, Kim JA, Kwon SH. Activation of peroxisome proliferator-activated receptor-γ inhibits the Runx2-mediated transcription of osteocalcin in osteoblasts. J Biol Chem, 2003, 278(26): 23270-23277.

[129] Liu J, Wang H, Zuo Y. Functional interaction between peroxisome proliferator-activated receptor γ and β-catenin. Mol Cell Biol, 2006, 26(15): 5827-5837.

[130] Zhao QH, Wang SG, Liu SX. PPARγ forms a bridge between DNA methylation and histone acetylation at the C/EBPα gene promoter to regulate the balance between osteogenesis and adipogenesis of bone marrow stromal cells. FEBS J, 2013, 280(22): 5801-5814.

[131] Kang Q, Song WX, Luo Q. A comprehensive analysis of the dual roles of BMPs in regulating adipogenic and osteogenic differentiation of mesenchymal progenitor cells. Stem Cells Dev, 2009, 18(4): 545-559.

[132] Sun J, Wang Y, Li Y. Downregulation of PPARγ by miR-548d-5p suppresses the adipogenic differentiation of human bone marrow mesenchymal stem cells and enhances their osteogenic potential. J Transl Med, 2014, 12: 168.

[133] He J, Zhang JF, Yi C. miRNA-mediated functional changes through co-regulating function related genes. PLoS One, 2010, 5(10): e13558.

[134] Zhang JF, Fu WM, He ML. MiRNA-20a promotes osteogenic differentiation of human mesenchymal stem cells by co-regulating BMP signaling. RNA Biol, 2011, 8(5): 829-838.

[135] Niehrs C. Function and biological roles of the Dickkopf family of Wnt modulators. Oncogene, 2006, 25(57): 7469-7481.

[136] Katoh M, Katoh M. WNT signaling pathway and stem cell signaling network. Clin Cancer Res, 2007, 13(14): 4042-4045.

[137] Zhang WB, Zhong WJ, Wang L. A signal-amplification circuit between miR-218 and Wnt/β-catenin signal promotes human adipose tissue-derived stem cells osteogenic differentiation. Bone, 2014, 58: 59-66.

[138] Hassan MQ, Maeda Y, Taipaleenmaki H. 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.

[139] Zhang J, Tu Q, Bonewald LF. Effects of miR-335-5p in modulating osteogenic differentiation by specifically downregulating Wnt antagonist DKK1. J Bone Miner Res, 2011, 26(8): 1953-1963.

[140] van Rooij E, Sutherland LB, Thatcher JE. Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29 in cardiac fibrosis. Proc Natl Acad Sci U S A, 2008, 105(35): 13027-13032.

[141] Li Z, Hassan MQ, Jafferji M. Biological functions of miR-29b contribute to positive regulation of osteoblast differentiation. J Biol Chem, 2009, 284(23): 15676-15684.

[142] Egea V, Zahler S, Rieth N. Tissue inhibitor of metalloproteinase-1 (TIMP-1) regulates mesenchymal stem cells through let-7f microRNA and Wnt/β-catenin signaling. Proc Natl Acad Sci U S A, 2012, 109(6): E309-E316.

[143] Wang T, Xu Z. miR-27 promotes osteoblast differentiation by modulating Wnt signaling. Biochem Biophys Res Commun, 2010, 402(2): 186-189.

[144] Guo D, Li Q, Lv Q. MiR-27a targets sFRP1 in hFOB cells to regulate proliferation, apoptosis and differentiation. PLoS One, 2014, 9(3): e91354.

[145] Jensen ED, Nair AK, Westendorf JJ. Histone deacetylase co-repressor complex control of Runx2 and bone formation. Crit Rev Eukaryot Gene Expr, 2007, 17(3): 187-196.

[146] Jeon EJ, Lee KY, Choi NS. Bone morphogenetic protein-2 stimulates Runx2 acetylation. J Biol Chem, 2006, 281(24): 16502-16511.

[147] Kang JS, Alliston T, Delston R. Repression of Runx2 function by TGF-beta through recruitment of class II histone deacetylases by Smad3. EMBO J, 2005, 24(14): 2543-2555.

[148] Liu T, Hou L, Zhao Y. Epigenetic silencing of HDAC1 by miR-449a upregulates Runx2 and promotes osteoblast differentiation. Int J Mol Med, 2015, 35(1): 238-246.

[149] Trompeter HI, Dreesen J, Hermann E. MicroRNAs miR-26a, miR-26b, and miR-29b accelerate osteogenic differentiation of unrestricted somatic stem cells from human cord blood. BMC Genomics, 2013, 14: 111.

[150] Li H, Xie H, Liu W. 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.

[151] Hu R, Liu W, Li H. A Runx2/miR-3960/miR-2861 regulatory feedback loop during mouse osteoblast differentiation. J Biol Chem, 2011, 286(14): 12328-12339.

[152] Zhang Y, Kwon S, Yamaguchi T. Mice lacking histone deacetylase 6 have hyperacetylated tubulin but are viable and develop normally. Mol Cell Biol, 2008, 28(5): 1688-1701.

[153] Huang S, Wang S, Bian C. Upregulation of miR-22 promotes osteogenic differentiation and inhibits adipogenic differentiation of human adipose tissue-derived mesenchymal stem cells by repressing HDAC6 protein expression. Stem Cells Dev, 2012, 21(13): 2531-2540.

[154] Li CJ, Cheng P, Liang MK. MicroRNA-188 regulates age-related switch between osteoblast and adipocyte differentiation. J Clin Invest, 2015, 125(4): 1509-1522.

[155] Bakhshandeh B, Hafizi M, Ghaemi N. Down-regulation of miRNA-221 triggers osteogenic differentiation in human stem cells. Biotechnol Lett, 2012, 34(8): 1579-1587.

[156] Bhushan R, Grünhagen J, Becker J. miR-181a promotes osteoblastic differentiation through repression of TGF-β signaling molecules. Int J Biochem Cell Biol, 2013, 45(3): 696-705.

[157] Mizuno Y, Tokuzawa Y, Ninomiya Y. miR-210 promotes osteoblastic differentiation through inhibition of AcvR1b. FEBS Lett, 2009, 583(13): 2263-2268.

[158] Cheung KS, Sposito N, Stumpf PS. MicroRNA-146a regulates human foetal femur derived skeletal stem cell differentiation by down-regulating SMAD2 and SMAD3. PLoS One, 2014, 9(6): e98063.

[159] Vimalraj S, Partridge NC, Selvamurugan N. A positive role of microRNA-15b on regulation of osteoblast differentiation. J Cell Physiol, 2014, 229(9): 1236-1244.

[160] Grünhagen J, Bhushan R, Degenkolbe E. MiR-497∼195 cluster microRNAs regulate osteoblast differentiation by targeting BMP signaling. J Bone Miner Res, 2015, 30(5): 796-808.

[161] Jeong BC, Kang IH, Hwang YC. MicroRNA-194 reciprocally stimulates osteogenesis and inhibits adipogenesis via regulating COUP-TFII expression. Cell Death Dis, 2014, 5: e1532.

[162] Kang IH, Jeong BC, Hur SW. MicroRNA-302a stimulates osteoblastic differentiation by repressing COUP-TFII expression. J Cell Physiol, 2015, 230(4): 911-921.

[163] 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.

[164] Yu S, Geng Q, Ma J. Heparin-binding EGF-like growth factor and miR-1192 exert opposite effect on Runx2-induced osteogenic differentiation. Cell Death Dis, 2013, 4: e868.

[165] Meng YB, Li X, Li ZY. microRNA-21 promotes osteogenic differentiation of mesenchymal stem cells by the PI3K/β-catenin pathway. J Orthop Res, 2015, 33(7): 957-964.

[166] Karsenty G, Wagner EF. Reaching a genetic and molecular understanding of skeletal development. Dev Cell, 2002, 2(4): 389-406.

[167] Del Fattore A, Teti A, Rucci N. Osteoclast receptors and signaling. Arch Biochem Biophys, 2008, 473(2): 147-160.

[168] Mizoguchi F, Izu Y, Hayata T. Osteoclast-specific Dicer gene deficiency suppresses osteoclastic bone resorption. J Cell Biochem, 2010, 109(5): 866-875.

[169] Sugatani T, Hildreth BE 3rd, Toribio RE. Expression of DGCR8-dependent microRNAs is indispensable for osteoclastic development and bone-resorbing activity. J Cell Biochem, 2014, 115(6): 1043-1047.

[170] Boyce BF. Advances in the regulation of osteoclasts and osteoclast functions. J Dent Res, 2013, 92(10): 860-867.

[171] Boyce BF. Advances in osteoclast biology reveal potential new drug targets and new roles for osteoclasts. J Bone Miner Res, 2013, 28(4): 711-722.

[172] Liu T, Qin AP, Liao B. A novel microRNA regulates osteoclast differentiation via targeting protein inhibitor of activated STAT3 (PIAS3). Bone, 2014, 67: 156-165.

[173] Boyce BF, Xing L. Biology of RANK, RANKL, and osteoprotegerin. Arthritis Res Ther, 2007, 9(Suppl 1): S1.

[174] Chen C, Cheng P, Xie H. MiR-503 regulates osteoclastogenesis via targeting RANK. J Bone Miner Res, 2014, 29(2): 338-347.

[175] Guo LJ, Liao L, Yang L. MiR-125a TNF receptor-associated factor 6 to inhibit osteoclastogenesis. Exp Cell Res, 2014, 321(2): 142-152.

[176] Lee Y, Kim HJ, Park CK. MicroRNA-124 regulates osteoclast differentiation. Bone, 2013, 56(2): 383-389.

[177] Mizoguchi F, Murakami Y, Saito T. miR-31 controls osteoclast formation and bone resorption by targeting RhoA. Arthritis Res Ther, 2013, 15(5): R102.

[178] Chellaiah MA, Soga N, Swanson S. Rho-A is critical for osteoclast podosome organization, motility, and bone resorption. J Biol Chem, 2000, 275(16): 11993-12002.

[179] Takayanagi H, Kim S, Matsuo K. RANKL maintains bone homeostasis through c-Fos-dependent induction of interferon-beta. Nature, 2002, 416(6882): 744-749.

[180] Grigoriadis AE, Wang ZQ, Cecchini MG. c-Fos: a key regulator of osteoclast-macrophage lineage determination and bone remodeling. Science, 1994, 266(5184): 443-448.

[181] Sugatani T, Vacher J, Hruska KA. A microRNA expression signature of osteoclastogenesis. Blood, 2011, 117(13): 3648-3657.

[182] Zhou Y, Liu Y, Cheng L. miR-21 expression is related to particle-induced osteolysis pathogenesis. J Orthop Res, 2012, 30(11): 1837-1842.

[183] Sugatani T, Hruska KA. Down-regulation of miR-21 biogenesis by estrogen action contributes to osteoclastic apoptosis. J Cell Biochem, 2013, 114(6): 1217-1222.

[184] Kim K, Kim JH, Lee J. MafB negatively regulates RANKL-mediated osteoclast differentiation. Blood, 2007, 109(8): 3253-3259.

[185] Takigawa M. CCN2: a master regulator of the genesis of bone and cartilage. J Cell Commun Signal, 2013, 7(3): 191-201.

[186] Kim K, Kim JH, Kim I. MicroRNA-26a regulates RANKL-induced osteoclast formation. Mol Cells, 2015, 38(1): 75-80.

[187] Sato K, Takayanagi H. Osteoclasts, rheumatoid arthritis, and osteoimmunology. Curr Opin Rheumatol, 2006, 18(4): 419-426.

[188] Blüml S, Bonelli M, Niederreiter B. Essential role of microRNA-155 in the pathogenesis of autoimmune arthritis in mice. Arthritis Rheum, 2011, 63(5): 1281-1288.

[189] Li YT, Chen SY, Wang CR. Brief report: amelioration of collagen-induced arthritis in mice by lentivirus-mediated silencing of microRNA-223. Arthritis Rheum, 2012, 64(10): 3240-3245.

[190] Sugatani T, Hruska KA. MicroRNA-223 is a key factor in osteoclast differentiation. J Cell Biochem, 2007, 101(4): 996-999.

[191] Shibuya H, Nakasa T, Adachi N. Overexpression of microRNA-223 in rheumatoid arthritis synovium controls osteoclast differentiation. Mod Rheumatol, 2013, 23(4): 674-685.

[192] Pauley KM, Cha S. miRNA-146a in rheumatoid arthritis: a new therapeutic strategy. Immunotherapy, 2011, 3(7): 829-831.

[193] Pauley KM, Satoh M, Chan AL. Upregulated miR-146a expression in peripheral blood mononuclear cells from rheumatoid arthritis patients. Arthritis Res Ther, 2008, 10(4): R101.

[194] Nakasa T, Miyaki S, Okubo A. Expression of microRNA-146 in rheumatoid arthritis synovial tissue. Arthritis Rheum, 2008, 58(5): 1284-1292.

[195] Zhao Q, Shao J, Chen W. Osteoclast differentiation and gene regulation. Front Biosci, 2007, 12: 2519-2529.

[196] Pixley FJ, Stanley ER. CSF-1 regulation of the wandering macrophage: complexity in action. Trends Cell Biol, 2004, 14(11): 628-638.

[197] Mellis DJ, Itzstein C, Helfrich MH. The skeleton: a multi-functional complex organ: the role of key signalling pathways in osteoclast differentiation and in bone resorption. J Endocrinol, 2011, 211(2): 131-143.

[198] Ross FP, Teitelbaum SL. α_vβ3 and macrophage colony-stimulating factor: partners in osteoclast biology. Immunol Rev, 2005, 208: 88-105.

[199] Kitaura H, Kimura K, Ishida M. Effect of cytokines on osteoclast formation and bone resorption during mechanical force loading of the periodontal membrane. Sci World J, 2014, 2014: 617032.

[200] Zhao C, Sun W, Zhang P. miR-214 promotes osteoclastogenesis by targeting Pten/PI3k/Akt pathway. RNA Biol, 2015, 12(3): 343-353.

[201] Osta B, Benedetti G, Miossec P. Classical and paradoxical effects of TNF-α on bone homeostasis. Front Immunol, 2014, 5: 48.

[202] Gilbert L, He X, Farmer P. Expression of the osteoblast differentiation factor RUNX2 (Cbfa₁/AML₃/Pebp2αA) is inhibited by tumor necrosis factor-α. J Biol Chem, 2002, 277(4): 2695-2701.

[203] Huang H, Zhao N, Xu X. Dose-specific effects of tumor necrosis factor alpha on osteogenic differentiation of mesenchymal stem cells. Cell Prolif, 2011, 44(5): 420-427.

[204] Gilbert LC, Chen H, Lu X. Chronic low dose tumor necrosis factor-α (TNF) suppresses early bone accrual in young mice by inhibiting osteoblasts without affecting osteoclasts. Bone, 2013, 56(1): 174-183.

[205] Hah YS, Kang HG, Cho HY. JNK signaling plays an important role in the effects of TNF-α and IL-1β on in vitro osteoblastic differentiation of cultured human periosteal-derived cells. Mol Biol Rep, 2013, 40(8): 4869-4881.

[206] Mukai T, Otsuka F, Otani H. TNF-α inhibits BMP-induced osteoblast differentiation through activating SAPK/JNK signaling. Biochem Biophys Res Commun, 2007, 356(4): 1004-1010.

[207] Thomson BM, Mundy GR, Chambers TJ. Tumor necrosis factors alpha and beta induce osteoblastic cells to stimulate osteoclastic bone resorption. J Immunol, 1987, 138(3): 775-779.

[208] Kitaura H, Kimura K, Ishida M. Immunological reaction in TNF-α-mediated osteoclast formation and bone resorption in vitro and in vivo. Clin Dev Immunol, 2013, 2013: 181849.

[209] Kohara H, Kitaura H, Fujimura Y. IFN-γ directly inhibits TNF-α-induced osteoclastogenesis in vitro and in vivo and induces apoptosis mediated by Fas/Fas ligand interactions. Immunol Lett, 2011, 137(1/2): 53-61.

[210] Wu T, Xie M, Wang X. miR-155 modulates TNF-α-inhibited osteogenic differentiation by targeting SOCS1 expression. Bone, 2012, 51(3): 498-505.

[211] Zhang J, Zhao H, Chen J. Interferon-β-induced miR-155 inhibits osteoclast differentiation by targeting SOCS1 and MITF. FEBS Lett, 2012, 586(19): 3255-3262.

[212] Kagiya T, Nakamura S. Expression profiling of microRNAs in RAW264.7 cells treated with a combination of tumor necrosis factor alpha and RANKL during osteoclast differentiation. J Periodont Res, 2013, 48(3): 373-385.

[213] Yang N, Wang G, Hu C. Tumor necrosis factor α suppresses the mesenchymal stem cell osteogenesis promoter miR-21 in estrogen deficiency-induced osteoporosis. J Bone Miner Res, 2013, 28(3): 559-573.

[214] Dong J, Cui X, Jiang Z. MicroRNA-23a modulates tumor necrosis factor-alpha-induced osteoblasts apoptosis by directly targeting Fas. J Cell Biochem, 2013, 114(12): 2738-2745.

[215] Mead TJ, Yutzey KE. Notch signaling and the developing skeleton. Adv Exp Med Biol, 2012, 727: 114-130.

[216] Hilton MJ, Tu X, Wu X. Notch signaling maintains bone marrow mesenchymal progenitors by suppressing osteoblast differentiation. Nat Med, 2008, 14(3): 306-314.

[217] Engin F, Yao Z, Yang T. Dimorphic effects of Notch signaling in bone homeostasis. Nat Med, 2008, 14(3): 299-305.

[218] Yamada T, Yamazaki H, Yamane T. Regulation of osteoclast development by Notch signaling directed to osteoclast precursors and through stromal cells. Blood, 2003, 101(6): 2227-2234.

[219] Chen L, Holmstrøm K, Qiu W. MicroRNA-34a inhibits osteoblast differentiation and in vivo bone formation of human stromal stem cells. Stem Cells, 2014, 32(4): 902-912.

[220] Krzeszinski JY, Wei W, Huynh H. miR-34a blocks osteoporosis and bone metastasis by inhibiting osteoclastogenesis and Tgif2. Nature, 2014, 512(7515): 431-435.

[221] Palmieri A, Pezzetti F, Brunelli G. Differences in osteoblast miRNA induced by cell binding domain of collagen and silicate-based synthetic bone. J Biomed Sci, 2007, 14(6): 777-782.

[222] Annalisa P, Furio P, Ilaria Z. Anorganic bovine bone and a silicate-based synthetic bone activate different microRNAs. J Oral Sci, 2008, 50(3): 301-307.

[223] Deng Y, Zhou H, Gu P. Repair of canine medial orbital bone defects with miR-31-modified bone marrow mesenchymal stem cells. Invest Ophthalmol Vis Sci, 2014, 55(9): 6016-6023.

[224] Wang Y, Jiang XL, Yang SC. MicroRNAs in the regulation of interfacial behaviors of MSCs cultured on microgrooved surface pattern. Biomaterials, 2011, 32(35): 9207-9217.

[225] Wu K, Song W, Zhao L. MicroRNA functionalized microporous titanium oxide surface by lyophilization with enhanced osteogenic activity. ACS Appl Mater Interfaces, 2013, 5(7): 2733-2744.

[226] Wu K, Xu J, Liu M. Induction of osteogenic differentiation of stem cells via a lyophilized microRNA reverse transfection formulation on a tissue culture plate. Int J Nanomedicine, 2013, 8: 1595-1607.

[227] Suh JS, Lee JY, Choi YS. Peptide-mediated intracellular delivery of miRNA-29b for osteogenic stem cell differentiation. Biomaterials, 2013, 34(17): 4347-4359.

[228] Qureshi AT, Monroe WT, Dasa V. miR-148b-nanoparticle conjugates for light mediated osteogenesis of human adipose stromal/stem cells. Biomaterials, 2013, 34(31): 7799-7810.

[229] Liu J, Dang L, Li D. A delivery system specifically approaching bone resorption surfaces to facilitate therapeutic modulation of microRNAs in osteoclasts. Biomaterials, 2015, 52: 148-160.

[230] Ding W, Li J, Singh J. miR-30e targets IGF2-regulated osteogenesis in bone marrow-derived mesenchymal stem cells, aortic smooth muscle cells, and ApoE^−/− mice. Cardiovasc Res, 2015, 106(1): 131-142.

[231] Wei J, Li H, Wang S. let-7 enhances osteogenesis and bone formation while repressing adipogenesis of human stromal/mesenchymal stem cells by regulating HMGA2. Stem Cells Dev, 2014, 23(13): 1452-1463.

[232] Trohatou O, Zagoura D, Bitsika V. Sox2 suppression by miR-21 governs human mesenchymal stem cell properties. Stem Cells Transl Med, 2014, 3(1): 54-68.

[233] Li J, He X, Wei W. MicroRNA-194 promotes osteoblast differentiation via downregulating STAT1. Biochem Biophys Res Commun, 2015, 460(2): 482-488.

[234] Kim YJ, Bae SW, Yu SS. miR-196a regulates proliferation and osteogenic differentiation in mesenchymal stem cells derived from human adipose tissue. J Bone Miner Res, 2009, 24(5): 816-825.

[235] Guo J, Ren F, Wang Y. miR-764-5p promotes osteoblast differentiation through inhibition of CHIP/STUB1 expression. J Bone Miner Res, 2012, 27(7): 1607-1618.

[236] Dou C, Zhang C, Kang F. MiR-7b directly targets DC-STAMP causing suppression of NFATc1 and c-Fos signaling during osteoclast fusion and differentiation. Biochim Biophys Acta, 2014, 1839(11): 1084-1096.