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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front Med    2011, Vol. 5 Issue (4) : 414-419     DOI: 10.1007/s11684-011-0168-0
MicroRNAs and their roles in osteoclast differentiation
Zhuying Xia, Chao Chen, Peng Chen, Hui Xie, Xianghang Luo()
Institute of Endocrinology and Metabolism, the Second Xiangya Hospital of Central South University, Changsha 410011, China
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Osteoclasts, which are derived from monocyte-macrophage precursors, are exclusive bone resorption cells. Limited evidence indicates that a class of small non-coding single-stranded RNAs known as “microRNAs” (miRNAs) is also involved in bone resorption. Although various miRNAs regulate cell proliferation and differentiation, few miRNAs have been reported to play a key role in the regulation of osteoclast differentiation. In this short review, the biology and functional mechanisms of miRNAs in osteoclastogenesis are summarized. The profiling, function, and target prediction of miRNAs are discussed as well.

Keywords miRNA      osteoclast differentiation      antagomirs     
Corresponding Authors: Luo Xianghang,   
Issue Date: 05 December 2011
URL:     OR
Fig.1  The biogenesis and function of miRNAs. miRNAs are initially transcribed into pri-miRNA in the nucleus. Pri-miRNA is processed by Drosha into stem-loop-structured pre-miRNAs. The pre-miRNA is further transported to cytoplasm by Exp 5 and then processed into the double-stranded mature miRNA by Dicer. The miRNA duplex (miRNA:miRNA*) is then incorporated into RISC. One strand of the miRNA duplex is rapidly removed and degraded, while the other strand is selected as a mature miRNA. The mature miRNA induces translation repression or degradation of mRNAs depending on the degree of complementarity with the target mRNA.
1 Suda T, Udagawa N, Nakamura I, Miyaura C, Takahashi N. Modulation of osteoclast differentiation by local factors. Bone 1995; 17(2 Suppl 1): S87–S91
doi: 10.1016/8756-3282(95)00185-G pmid:8579904
2 Karsenty G, Wagner EF. Reaching a genetic and molecular understanding of skeletal development. Dev Cell 2002; 2(4): 389–406
doi: 10.1016/S1534-5807(02)00157-0 pmid:11970890
3 Tanaka S, Nakamura K, Takahasi N, Suda T. Role of RANKL in physiological and pathological bone resorption and therapeutics targeting the RANKL-RANK signaling system. Immunol Rev 2005; 208(1): 30–49
doi: 10.1111/j.0105-2896.2005.00327.x pmid:16313339
4 Soriano P, Montgomery C, Geske R, Bradley A. Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice. Cell 1991; 64(4): 693–702
doi: 10.1016/0092-8674(91)90499-O pmid:1997203
5 Grigoriadis AE, Wang ZQ, Cecchini MG, Hofstetter W, Felix R, Fleisch HA, Wagner EF. c-Fos: a key regulator of osteoclast-macrophage lineage determination and bone remodeling. Science 1994; 266(5184): 443–448
doi: 7939685" target="_blank">10.1126/science. pmid:7939685 pmid:7939685
6 Tondravi MM, McKercher SR, Anderson K, Erdmann JM, Quiroz M, Maki R, Teitelbaum SL. Osteopetrosis in mice lacking haematopoietic transcription factor PU.1. Nature 1997; 386(6620): 81–84
doi: 10.1038/386081a0 pmid:9052784
7 Iotsova V, Caama?o J, Loy J, Yang Y, Lewin A, Bravo R. Osteopetrosis in mice lacking NF-κB1 and NF-κB2. Nat Med 1997; 3(11): 1285–1289
doi: 10.1038/nm1197-1285 pmid:9359707
8 Takayanagi H, Kim S, Koga T, Nishina H, Isshiki M, Yoshida H, Saiura A, Isobe M, Yokochi T, Inoue J, Wagner EF, Mak TW, Kodama T, Taniguchi T. Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev Cell 2002; 3(6): 889–901
doi: 10.1016/S1534-5807(02)00369-6 pmid:12479813
9 Kim VN. MicroRNA biogenesis: coordinated cropping and dicing. Nat Rev Mol Cell Biol 2005; 6(5): 376–385
doi: 10.1038/nrm1644 pmid:15852042
10 Mizuno Y, Yagi K, Tokuzawa Y, Kanesaki-Yatsuka Y, Suda T, Katagiri T, Fukuda T, Maruyama M, Okuda A, Amemiya T, Kondoh Y, Tashiro H, Okazaki Y. miR-125b inhibits osteoblastic differentiation by down-regulation of cell proliferation. Biochem Biophys Res Commun 2008; 368(2): 267–272
doi: 10.1016/j.bbrc.2008.01.073 pmid:18230348
11 Luzi E, Marini F, Sala SC, Tognarini I, Galli G, Brandi ML. 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
doi: 10.1359/jbmr.071011 pmid:18197755
12 Li ZY, Hassan MQ, Volinia S, van Wijnen AJ, Stein JL, Croce CM, Lian JB, Stein GS. A microRNA signature for a BMP2-induced osteoblast lineage commitment program. Proc Natl Acad Sci USA 2008; 105(37): 13906–13911
doi: 10.1073/pnas.0804438105 pmid:18784367
13 Huang J, Zhao L, Xing L, Chen D. MicroRNA-204 regulates Runx2 protein expression and mesenchymal progenitor cell differentiation. Stem Cells 2010; 28(2): 357–364
14 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
doi: 10.1002/jcb.22243 pmid:19565563
15 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
doi: 10.1074/jbc.M109.014001 pmid:19454767
16 Inose H, Ochi H, Kimura A, Fujita K, Xu R, Sato S, Iwasaki M, Sunamura S, Takeuchi Y, Fukumoto S, Saito K, Nakamura T, Siomi H, Ito H, Arai Y, Shinomiya K, Takeda S. A microRNA regulatory mechanism of osteoblast differentiation. Proc Natl Acad Sci USA 2009; 106(49): 20794–20799
doi: 10.1073/pnas.0909311106 pmid:19933329
17 Li ZY, Hassan MQ, Jafferji M, Aqeilan RI, Garzon R, Croce CM, van Wijnen AJ, Stein JL, Stein GS, Lian JB. Biological functions of miR-29b contribute to positive regulation of osteoblast differentiation. J Biol Chem 2009; 284(23): 15676–15684
doi: 10.1074/jbc.M809787200 pmid:19342382
18 Mizuno Y, Tokuzawa Y, Ninomiya Y, Yagi K, Yatsuka-Kanesaki Y, Suda T, Fukuda T, Katagiri T, Kondoh Y, Amemiya T, Tashiro H, Okazaki Y. miR-210 promotes osteoblastic differentiation through inhibition of AcvR1b. FEBS Lett 2009; 583(13): 2263–2268
doi: 10.1016/j.febslet.2009.06.006 pmid:19520079
19 Kim YJ, Bae SW, Yu SS, Bae YC, Jung JS. 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
doi: 10.1359/jbmr.081230 pmid:19063684
20 Li H, Xie H, Liu W, Hu R, Huang B, Tan YF, Xu K, Sheng ZF, Zhou HD, Wu XP, Luo XH. A novel microRNA targeting HDAC5 regulates osteoblast differentiation in mice and contributes to primary osteoporosis in humans. J Clin Invest 2009; 119(12): 3666–3677
doi: 10.1172/JCI39832 pmid:19920351
21 Xu XH, Dong SS, Guo Y, Yang TL, Lei SF, Papasian CJ, Zhao M, Deng HW. Molecular genetic studies of gene identification for osteoporosis: the 2009 update. Endocr Rev 2010; 31(4): 447–505
doi: 10.1210/er.2009-0032 pmid:20357209
22 Ambros V, Chen X. The regulation of genes and genomes by small RNAs. Development 2007; 134(9): 1635–1641
doi: 10.1242/dev.002006 pmid:17409118
23 Cullen BR. Transcription and processing of human microRNA precursors. Mol Cell 2004; 16(6): 861–865
doi: 10.1016/j.molcel.2004.12.002 pmid:15610730
24 Bentwich I, Avniel A, Karov Y, Aharonov R, Gilad S, Barad O, Barzilai A, Einat P, Einav U, Meiri E, Sharon E, Spector Y, Bentwich Z. Identification of hundreds of conserved and nonconserved human microRNAs. Nat Genet 2005; 37(7): 766–770
doi: 10.1038/ng1590 pmid:15965474
25 Lagos-Quintana M, Rauhut R, Lendeckel W, Tuschl T. Identification of novel genes coding for small expressed RNAs. Science 2001; 294(5543): 853–858
doi: 10.1126/science.1064921 pmid:11679670
26 Lee Y, Jeon K, Lee JT, Kim S, Kim VN. MicroRNA maturation: stepwise processing and subcellular localization. EMBO J 2002; 21(17): 4663–4670
doi: 10.1093/emboj/cdf476 pmid:12198168
27 Rodriguez A, Griffiths-Jones S, Ashurst JL, Bradley A. Identification of mammalian microRNA host genes and transcription units. Genome Res 2004; 14( 10A): 1902–1910
doi: 10.1101/gr.2722704 pmid:15364901
28 Carthew RW, Sontheimer EJ. Origins and mechanisms of miRNAs and siRNAs. Cell 2009; 136(4): 642–655
doi: 10.1016/j.cell.2009.01.035 pmid:19239886
29 Bushati N, Cohen SM. microRNA functions. Annu Rev Cell Dev Biol 2007; 23(1): 175–205
doi: 10.1146/annurev.cellbio.23.090506.123406 pmid:17506695
30 Gregory RI, Yan KP, Amuthan G, Chendrimada T, Doratotaj B, Cooch N, Shiekhattar R. The microprocessor complex mediates the genesis of microRNAs. Nature 2004; 432(7014): 235–240
doi: 10.1038/nature03120 pmid:15531877
31 Tan GS, Garchow BG, Liu X, Yeung J, Morris JP 4th, Cuellar TL, McManus MT, Kiriakidou M. Expanded RNA-binding activities of mammalian Argonaute 2. Nucleic Acids Res 2009; 37(22): 7533–7545
doi: 10.1093/nar/gkp812 pmid:19808937
32 Pillai RS, Bhattacharyya SN, Filipowicz W. Repression of protein synthesis by miRNAs: how many mechanisms? Trends Cell Biol 2007; 17(3): 118–126
doi: 10.1016/j.tcb.2006.12.007 pmid:17197185
33 Zeng Y, Yi R, Cullen BR. MicroRNAs and small interfering RNAs can inhibit mRNA expression by similar mechanisms. Proc Natl Acad Sci USA 2003; 100(17): 9779–9784
doi: 10.1073/pnas.1630797100 pmid:12902540
34 Yekta S, Shih IH, Bartel DP. MicroRNA-directed cleavage of HOXB8 mRNA. Science 2004; 304(5670): 594–596
doi: 10.1126/science.1097434 pmid:15105502
35 Krützfeldt J, Poy MN, Stoffel M. Strategies to determine the biological function of microRNAs. Nat Genet 2006; 38(Suppl): S14–S19
doi: 10.1038/ng1799 pmid:16736018
36 Castoldi M, Schmidt S, Benes V, Noerholm M, Kulozik AE, Hentze MW, Muckenthaler MU. A sensitive array for microRNA expression profiling (miChip) based on locked nucleic acids (LNA). RNA 2006; 12(5): 913–920
doi: 10.1261/rna.2332406 pmid:16540696
37 Kauppinen S, Vester B, Wengel J. Locked nucleic acid: high-affinity targeting of complementary RNA for RNomics. Handb Exp Pharmacol 2006; (173): 405–422
38 Auer H, Newsom DL, Kornacker K. Expression profiling using Affymetrix GeneChip microarrays. Methods Mol Biol 2009; 509: 35–46
doi: 10.1007/978-1-59745-372-1_3 pmid:19212713
39 Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, Sweet-Cordero A, Ebert BL, Mak RH, Ferrando AA, Downing JR, Jacks T, Horvitz HR, Golub TR. MicroRNA expression profiles classify human cancers. Nature 2005; 435(7043): 834–838
doi: 10.1038/nature03702 pmid:15944708
40 Schmittgen TD, Lee EJ, Jiang J, Sarkar A, Yang L, Elton TS, Chen C. Real-time PCR quantification of precursor and mature microRNA. Methods 2008; 44(1): 31–38
doi: 10.1016/j.ymeth.2007.09.006 pmid:18158130
41 Chen C, Ridzon DA, Broomer AJ, Zhou Z, Lee DH, Nguyen JT, Barbisin M, Xu NL, Mahuvakar VR, Andersen MR, Lao KQ, Livak KJ, Guegler KJ. Real-time quantification of microRNAs by stem-loop RT-PCR. Nucleic Acids Res 2005; 33(20): e179
doi: 10.1093/nar/gni178 pmid:16314309
42 Sugatani T, Vacher J, Hruska KA. A microRNA expression signature of osteoclastogenesis. Blood 2011; 117(13): 3648–3657
doi: 10.1182/blood-2010-10-311415 pmid:21273303
43 Marzia M, Sims NA, Voit S, Migliaccio S, Taranta A, Bernardini S, Faraggiana T, Yoneda T, Mundy GR, Boyce BF, Baron R, Teti A. Decreased c-Src expression enhances osteoblast differentiation and bone formation. J Cell Biol 2000; 151(2): 311–320
doi: 10.1083/jcb.151.2.311 pmid:11038178
44 Del Fattore A, Teti A, Rucci N. Osteoclast receptors and signaling. Arch Biochem Biophys 2008; 473(2): 147–160
doi: 10.1016/ pmid:18237538
45 Franzoso G, Carlson L, Xing L, Poljak L, Shores EW, Brown KD, Leonardi A, Tran T, Boyce BF, Siebenlist U. Requirement for NF-κB in osteoclast and B-cell development. Genes Dev 1997; 11(24): 3482–3496
doi: 10.1101/gad.11.24.3482 pmid:9407039
46 Ishida N, Hayashi K, Hoshijima M, Ogawa T, Koga S, Miyatake Y, Kumegawa M, Kimura T, Takeya T. Large scale gene expression analysis of osteoclastogenesis in vitro and elucidation of NFAT2 as a key regulator. J Biol Chem 2002; 277(43): 41147–41156
doi: 10.1074/jbc.M205063200 pmid:12171919
48 Takayanagi H, Kim S, Matsuo K, Suzuki H, Suzuki T, Sato K, Yokochi T, Oda H, Nakamura K, Ida N, Wagner EF, Taniguchi T. RANKL maintains bone homeostasis through c-Fos-dependent induction of interferon-beta. Nature 2002; 416(6882): 744–749
doi: 10.1038/416744a pmid:11961557
49 Weilbaecher KN, Motyckova G, Huber WE, Takemoto CM, Hemesath TJ, Xu Y, Hershey CL, Dowland NR, Wells AG, Fisher DE. Linkage of M-CSF signaling to Mitf, TFE3, and the osteoclast defect in Mitf(mi/mi) mice. Mol Cell 2001; 8(4): 749–758
doi: 10.1016/S1097-2765(01)00360-4 pmid:11684011
50 Sugatani T, Hruska KA. Impaired micro-RNA pathways diminish osteoclast differentiation and function. J Biol Chem 2009; 284(7): 4667–4678
doi: 10.1074/jbc.M805777200 pmid:19059913
51 Keen R. Osteoporosis: strategies for prevention and management. Best Pract Res Clin Rheumatol 2007; 21(1): 109–122
doi: 10.1016/j.berh.2006.10.004 pmid:17350547
52 Lakshmipathy U, Hart RP. Concise review: microRNA expression in multipotent mesenchymal stromal cells. Stem Cells 2008; 26(2): 356–363
doi: 10.1634/stemcells.2007-0625 pmid:17991914
53 Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell 2009; 136(2): 215–233
doi: 10.1016/j.cell.2009.01.002 pmid:19167326
54 Yue D, Liu H, Huang Y. Survey of computational algorithms for microRNA target prediction. Curr Genomics 2009; 10(7): 478–492
doi: 10.2174/138920209789208219 pmid:20436875
55 Lewis BP, Burge CB, Bartel DP. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 2005; 120(1): 15–20
doi: 10.1016/j.cell.2004.12.035 pmid:15652477
56 Krek A, Grün D, Poy MN, Wolf R, Rosenberg L, Epstein EJ, MacMenamin P, da Piedade I, Gunsalus KC, Stoffel M, Rajewsky N. Combinatorial microRNA target predictions. Nat Genet 2005; 37(5): 495–500
doi: 10.1038/ng1536 pmid:15806104
57 John B, Enright AJ, Aravin A, Tuschl T, Sander C, Marks DS. Human microRNA targets. PLoS Biol 2004; 2(11): e363
doi: 10.1371/journal.pbio.0020363 pmid:15502875
58 Griffiths-Jones S, Grocock RJ, van Dongen S, Bateman A, Enright AJ. miRBase: microRNA sequences, targets and gene nomenclature. Nucleic Acids Res 2006; 34(Suppl 1): D140–D144
doi: 10.1093/nar/gkj112 pmid:16381832
59 Hsu PW, Huang HD, Hsu SD, Lin LZ, Tsou AP, Tseng CP, Stadler PF, Washietl S, Hofacker IL. miRNAMap: genomic maps of microRNA genes and their target genes in mammalian genomes. Nucleic Acids Res 2006; 34(Suppl 1): D135–D139
doi: 10.1093/nar/gkj135 pmid:16381831
60 Megraw M, Sethupathy P, Corda B, Hatzigeorgiou AG. miRGen: a database for the study of animal microRNA genomic organization and function. Nucleic Acids Res 2007; 35(Suppl 1): D149–D155
doi: 10.1093/nar/gkl904 pmid:17108354
61 Meister G, Landthaler M, Dorsett Y, Tuschl T. Sequence-specific inhibition of microRNA- and siRNA-induced RNA silencing. RNA 2004; 10(3): 544–550
doi: 10.1261/rna.5235104 pmid:14970398
62 Krützfeldt J, Rajewsky N, Braich R, Rajeev KG, Tuschl T, Manoharan M, Stoffel M. Silencing of microRNAs in vivo with ‘antagomirs’. Nature 2005; 438(7068): 685–689
doi: 10.1038/nature04303 pmid:16258535
63 Krützfeldt J, Kuwajima S, Braich R, Rajeev KG, Pena J, Tuschl T, Manoharan M, Stoffel M. Specificity, duplex degradation and subcellular localization of antagomirs. Nucleic Acids Res 2007; 35: 2885–2892
doi: 10.1093/nar/gkm024 pmid:17439965
64 Horwich MD, Zamore PD. Design and delivery of antisense oligonucleotides to block microRNA function in cultured Drosophila and human cells. Nat Protoc 2008; 3(10): 1537–1549
doi: 10.1038/nprot.2008.145 pmid:18802435
65 Nasevicius A, Ekker SC. Effective targeted gene ‘knockdown’ in zebrafish. Nat Genet 2000; 26(2): 216–220
doi: 10.1038/79951 pmid:11017081
66 Zellweger T, Miyake H, Cooper S, Chi K, Conklin BS, Monia BP, Gleave ME. Antitumor activity of antisense clusterin oligonucleotides is improved in vitro and in vivo by incorporation of 2′-O-(2-methoxy)ethyl chemistry. J Pharmacol Exp Ther 2001; 298(3): 934–940
67 Dean NM, Bennett CF. Antisense oligonucleotide-based therapeutics for cancer. Oncogene 2003; 22(56): 9087–9096
doi: 10.1038/sj.onc.1207231 pmid:14663487
68 Kastelein JJ, Wedel MK, Baker BF, Su J, Bradley JD, Yu RZ, Chuang E, Graham MJ, Crooke RM. Potent reduction of apolipoprotein B and low-density lipoprotein cholesterol by short-term administration of an antisense inhibitor of apolipoprotein B. Circulation 2006; 114(16): 1729–1735
doi: 10.1161/CIRCULATIONAHA.105.606442 pmid:17030687
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