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MicroRNAs involved in bone formation

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Abstract

During skeletal development, mesenchymal progenitor cells undergo a multistage differentiation process in which they proliferate and become bone- and cartilage-forming cells. This process is tightly regulated by multiple levels of regulatory systems. The small non-coding RNAs, microRNAs (miRNAs), post-transcriptionally regulate gene expression. Recent studies have demonstrated that miRNAs play significant roles in all stages of bone formation, suggesting the possibility that miRNAs can be novel therapeutic targets for skeletal diseases. Here, we review the role and mechanism of action of miRNAs in bone formation. We discuss roles of specific miRNAs in major types of bone cells, osteoblasts, chondrocytes, osteoclasts, and their progenitors. Except a few, the current knowledge about miRNAs in bone formation has been obtained mainly by in vitro studies; further validation of these findings in vivo is awaited. We also discuss about several miRNAs of particular interest in the light of future therapies of bone diseases.

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Abbreviations

BMP:

Bone morphogenetic protein

MAPK:

Mitogen-activated protein kinase

FGF:

Fibroblast growth factor

FGFR:

Fibroblast growth factor receptor

CSF:

Colony-stimulating factor

RANK:

Receptor activator of NFκB

RANKL:

Ligand to receptor activator of NFκB

TRAP:

Tartrate-resistant acid phosphatase

TGF-β:

Transforming growth factor beta

IGF:

Insulin-like growth factor

HDAC:

Histone deacetylase

MEF:

Myocyte enhancer factor

MSC:

Mesenchymal stem cells

BMSC:

Bone marrow stromal cells

ADSC:

Adipose-derived stem cells

BMD:

Bone mineral density

ALP:

Alkaline phosphatase

TNF-α:

Tumor necrosis factor alpha

USSC:

Unrestricted somatic stem cells

References

  1. Kronenberg HM (2003) Developmental regulation of the growth plate. Nature 423:332–336

    CAS  PubMed  Google Scholar 

  2. Long F, Chung UI, Ohba S, McMahon J, Kronenberg HM, McMahon AP (2004) Ihh signaling is directly required for the osteoblast lineage in the endochondral skeleton. Development 131:1309–1318

    CAS  PubMed  Google Scholar 

  3. Yoon BS, Ovchinnikov DA, Yoshii I, Mishina Y, Behringer RR, Lyons KM (2005) Bmpr1a and Bmpr1b have overlapping functions and are essential for chondrogenesis in vivo. Proc Natl Acad Sci USA 102:5062–5067

    CAS  PubMed Central  PubMed  Google Scholar 

  4. Kobayashi T, Lyons KM, McMahon AP, Kronenberg HM (2005) BMP signaling stimulates cellular differentiation at multiple steps during cartilage development. Proc Natl Acad Sci USA 102:18023–18027

    CAS  PubMed Central  PubMed  Google Scholar 

  5. Pogue R, Lyons K (2006) BMP signaling in the cartilage growth plate. Curr Top Dev Biol 76:1–48

    CAS  PubMed  Google Scholar 

  6. Itoh N, Ornitz DM (2011) Fibroblast growth factors: from molecular evolution to roles in development, metabolism and disease. J Biochem 149:121–130

    CAS  PubMed Central  PubMed  Google Scholar 

  7. Long F (2012) Building strong bones: molecular regulation of the osteoblast lineage. Nat Rev Mol Cell Biol 13:27–38

    CAS  Google Scholar 

  8. Hu H, Hilton MJ, Tu X, Yu K, Ornitz DM, Long F (2005) Sequential roles of Hedgehog and Wnt signaling in osteoblast development. Development 132:49–60

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  10. Hill TP, Spater D, Taketo MM, Birchmeier W, Hartmann C (2005) Canonical Wnt/beta-catenin signaling prevents osteoblasts from differentiating into chondrocytes. Dev Cell 8:727–738

    CAS  PubMed  Google Scholar 

  11. Rodda SJ, McMahon AP (2006) Distinct roles for hedgehog and canonical Wnt signaling in specification, differentiation and maintenance of osteoblast progenitors. Development 133:3231–3244

    CAS  PubMed  Google Scholar 

  12. Canalis E (2013) Wnt signalling in osteoporosis: mechanisms and novel therapeutic approaches. Nat Rev Endocrinol 9:575–583

    CAS  PubMed  Google Scholar 

  13. van Amerongen R (2012) Alternative Wnt pathways and receptors. Cold Spring Harb Perspect Biol 4

  14. Rebay I, Fleming RJ, Fehon RG, Cherbas L, Cherbas P, Artavanis-Tsakonas S (1991) Specific EGF repeats of Notch mediate interactions with delta and serrate: implications for Notch as a multifunctional receptor. Cell 67:687–699

    CAS  PubMed  Google Scholar 

  15. Boyce BF (2013) Advances in the regulation of osteoclasts and osteoclast functions. J Dent Res 92:860–867

    CAS  PubMed Central  PubMed  Google Scholar 

  16. Bi W, Deng JM, Zhang Z, Behringer RR, de Crombrugghe B (1999) Sox9 is required for cartilage formation. Nat Genet 22:85–89

    CAS  PubMed  Google Scholar 

  17. Lefebvre V, Huang W, Harley VR, Goodfellow PN, de Crombrugghe B (1997) SOX9 is a potent activator of the chondrocyte-specific enhancer of the pro alpha1(II) collagen gene. Mol Cell Biol 17:2336–2346

    CAS  PubMed Central  PubMed  Google Scholar 

  18. Yamashita S, Miyaki S, Kato Y, Yokoyama S, Sato T, Barrionuevo F et al (2012) L-Sox5 and Sox6 proteins enhance chondrogenic miR-140 microRNA expression by strengthening dimeric Sox9 activity. J Biol Chem 287:22206–22215

    CAS  PubMed Central  PubMed  Google Scholar 

  19. Arnold MA, Kim Y, Czubryt MP, Phan D, McAnally J, Qi X et al (2007) MEF2C transcription factor controls chondrocyte hypertrophy and bone development. Dev Cell 12:377–389

    CAS  PubMed  Google Scholar 

  20. Yoshida CA, Yamamoto H, Fujita T, Furuichi T, Ito K, Inoue K et al (2004) Runx2 and Runx3 are essential for chondrocyte maturation, and Runx2 regulates limb growth through induction of Indian hedgehog. Genes Dev 18:952–963

    CAS  PubMed Central  PubMed  Google Scholar 

  21. Takeda S, Bonnamy JP, Owen MJ, Ducy P, Karsenty G (2001) Continuous expression of Cbfa1 in nonhypertrophic chondrocytes uncovers its ability to induce hypertrophic chondrocyte differentiation and partially rescues Cbfa1-deficient mice. Genes Dev 15:467–481

    CAS  PubMed Central  PubMed  Google Scholar 

  22. Otto F, Thornell AP, Crompton T, Denzel A, Gilmour KC, Rosewell IR et al (1997) Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell 89:765–771

    CAS  PubMed  Google Scholar 

  23. Komori T, Yagi H, Nomura S, Yamaguchi A, Sasaki K, Deguchi K et al (1997) Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 89:755–764

    CAS  PubMed  Google Scholar 

  24. Nakashima K, Zhou X, Kunkel G, Zhang Z, Deng JM, Behringer RR et al (2002) The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell 108:17–29

    CAS  PubMed  Google Scholar 

  25. Roodman GD (2006) Regulation of osteoclast differentiation. Ann N Y Acad Sci 1068:100–109

    CAS  PubMed  Google Scholar 

  26. Tetreault N, De Guire V (2013) miRNAs: their discovery, biogenesis and mechanism of action. Clin Biochem 46:842–845

    CAS  PubMed  Google Scholar 

  27. Harfe BD, McManus MT, Mansfield JH, Hornstein E, Tabin CJ (2005) The RNaseIII enzyme dicer is required for morphogenesis but not patterning of the vertebrate limb. Proc Natl Acad Sci USA 102:10898–10903

    CAS  PubMed Central  PubMed  Google Scholar 

  28. Kobayashi T, Lu J, Cobb BS, Rodda SJ, McMahon AP, Schipani E et al (2008) Dicer-dependent pathways regulate chondrocyte proliferation and differentiation. Proc Natl Acad Sci USA 105:1949–1954

    CAS  PubMed Central  PubMed  Google Scholar 

  29. Watanabe T, Sato T, Amano T, Kawamura Y, Kawamura N, Kawaguchi H et al (2008) Dnm3os, a non-coding RNA, is required for normal growth and skeletal development in mice. Dev Dyn 237:3738–3748

    CAS  PubMed  Google Scholar 

  30. Suomi S, Taipaleenmaki H, Seppanen A, Ripatti T, Vaananen K, Hentunen T et al (2008) MicroRNAs regulate osteogenesis and chondrogenesis of mouse bone marrow stromal cells. Gene Regul Syst Bio 2:177–191

    CAS  PubMed Central  PubMed  Google Scholar 

  31. Laine SK, Alm JJ, Virtanen SP, Aro HT, Laitala-Leinonen TK (2012) MicroRNAs miR-96, miR-124, and miR-199a regulate gene expression in human bone marrow-derived mesenchymal stem cells. J Cell Biochem 113:2687–2695

    CAS  PubMed  Google Scholar 

  32. Eberhart JK, He X, Swartz ME, Yan YL, Song H, Boling TC et al (2008) MicroRNA Mirn140 modulates Pdgf signaling during palatogenesis. Nat Genet 40:290–298

    CAS  PubMed Central  PubMed  Google Scholar 

  33. Miyaki S, Sato T, Inoue A, Otsuki S, Ito Y, Yokoyama S et al (2010) MicroRNA-140 plays dual roles in both cartilage development and homeostasis. Genes Dev 24:1173–1185

    CAS  PubMed Central  PubMed  Google Scholar 

  34. Nakamura Y, Inloes JB, Katagiri T, Kobayashi T (2011) Chondrocyte-specific microRNA-140 regulates endochondral bone development and targets Dnpep to modulate bone morphogenetic protein signaling. Mol Cell Biol 31:3019–3028

    CAS  PubMed Central  PubMed  Google Scholar 

  35. Nakamura Y, He X, Kato H, Wakitani S, Kobayashi T, Watanabe S et al (2012) Sox9 is upstream of microRNA-140 in cartilage. Appl Biochem Biotechnol 166:64–71

    CAS  PubMed Central  PubMed  Google Scholar 

  36. Tuddenham L, Wheeler G, Ntounia-Fousara S, Waters J, Hajihosseini MK, Clark I et al (2006) The cartilage specific microRNA-140 targets histone deacetylase 4 in mouse cells. FEBS Lett 580:4214–4217

    CAS  PubMed  Google Scholar 

  37. Yang J, Qin S, Yi C, Ma G, Zhu H, Zhou W et al (2011) MiR-140 is co-expressed with Wwp2-C transcript and activated by Sox9 to target Sp1 in maintaining the chondrocyte proliferation. FEBS Lett 585:2992–2997

    CAS  PubMed  Google Scholar 

  38. Pais H, Nicolas FE, Soond SM, Swingler TE, Clark IM, Chantry A et al (2010) Analyzing mRNA expression identifies Smad3 as a microRNA-140 target regulated only at protein level. RNA 16:489–494

    CAS  PubMed Central  PubMed  Google Scholar 

  39. Karlsen TA, Jakobsen RB, Mikkelsen TS, Brinchmann JE (2014) microRNA-140 targets RALA and regulates chondrogenic differentiation of human mesenchymal stem cells by translational enhancement of SOX9 and ACAN. Stem Cells Dev 23:290–304

    CAS  PubMed  Google Scholar 

  40. Papaioannou G, Inloes JB, Nakamura Y, Paltrinieri E, Kobayashi T (2013) let-7 and miR-140 microRNAs coordinately regulate skeletal development. Proc Natl Acad Sci USA 110:E3291–E3300

    CAS  PubMed Central  PubMed  Google Scholar 

  41. Dudek KA, Lafont JE, Martinez-Sanchez A, Murphy CL (2010) Type II collagen expression is regulated by tissue-specific miR-675 in human articular chondrocytes. J Biol Chem 285:24381–24387

    CAS  PubMed Central  PubMed  Google Scholar 

  42. Martinez-Sanchez A, Murphy CL (2013) miR-1247 functions by targeting cartilage transcription factor SOX9. J Biol Chem 288:30802–30814

    CAS  PubMed Central  PubMed  Google Scholar 

  43. Yang B, Guo H, Zhang Y, Chen L, Ying D, Dong S (2011) MicroRNA-145 regulates chondrogenic differentiation of mesenchymal stem cells by targeting Sox9. PLoS ONE 6:e21679

    CAS  PubMed Central  PubMed  Google Scholar 

  44. Ohgawara T, Kubota S, Kawaki H, Kondo S, Eguchi T, Kurio N et al (2009) Regulation of chondrocytic phenotype by micro RNA 18a: involvement of Ccn2/Ctgf as a major target gene. FEBS Lett 583:1006–1010

    CAS  PubMed  Google Scholar 

  45. Sumiyoshi K, Kubota S, Ohgawara T, Kawata K, Nishida T, Shimo T et al (2010) Identification of miR-1 as a micro RNA that supports late-stage differentiation of growth cartilage cells. Biochem Biophys Res Commun 402:286–290

    CAS  PubMed  Google Scholar 

  46. Zhong N, Sun J, Min Z, Zhao W, Zhang R, Wang W et al (2012) MicroRNA-337 is associated with chondrogenesis through regulating TGFBR2 expression. Osteoarthritis Cartilage 20:593–602

    CAS  PubMed  Google Scholar 

  47. Sumiyoshi K, Kubota S, Ohgawara T, Kawata K, Abd El Kader T, Nishida T et al (2013) Novel role of miR-181a in cartilage metabolism. J Cell Biochem 114:2094–2100

    CAS  PubMed  Google Scholar 

  48. Kim D, Song J, Jin EJ (2010) MicroRNA-221 regulates chondrogenic differentiation through promoting proteosomal degradation of slug by targeting Mdm2. J Biol Chem 285:26900–26907

    CAS  PubMed Central  PubMed  Google Scholar 

  49. Song J, Kim D, Chun CH, Jin EJ (2013) MicroRNA-375, a new regulator of cadherin-7, suppresses the migration of chondrogenic progenitors. Cell Signal 25:698–706

    PubMed  Google Scholar 

  50. Guerit D, Philipot D, Chuchana P, Toupet K, Brondello JM, Mathieu M et al (2013) Sox9-regulated miRNA-574-3p inhibits chondrogenic differentiation of mesenchymal stem cells. PLoS ONE 8:e62582

    CAS  PubMed Central  PubMed  Google Scholar 

  51. Paik S, Jung HS, Lee S, Yoon DS, Park MS, Lee JW (2012) miR-449a regulates the chondrogenesis of human mesenchymal stem cells through direct targeting of lymphoid enhancer-binding factor-1. Stem Cells Dev 21:3298–3308

    CAS  PubMed Central  PubMed  Google Scholar 

  52. Lin X, Wu L, Zhang Z, Yang R, Guan Q, Hou X et al (2013) MiR-335-5p Promotes Chondrogenesis in Mouse Mesenchymal Stem Cells and is Regulated Through Two Positive Feedback Loops. J Bone Miner Res 29:15751585

    Google Scholar 

  53. Gaur T, Hussain S, Mudhasani R, Parulkar I, Colby JL, Frederick D et al (2010) Dicer inactivation in osteoprogenitor cells compromises fetal survival and bone formation, while excision in differentiated osteoblasts increases bone mass in the adult mouse. Dev Biol 340:10–21

    CAS  PubMed Central  PubMed  Google Scholar 

  54. Raaijmakers MH, Mukherjee S, Guo S, Zhang S, Kobayashi T, Schoonmaker JA et al (2010) Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia. Nature 464:852–857

    CAS  PubMed Central  PubMed  Google Scholar 

  55. Li H, Xie H, Liu W, Hu R, Huang B, Tan YF et al (2009) A novel microRNA targeting HDAC5 regulates osteoblast differentiation in mice and contributes to primary osteoporosis in humans. J Clin Invest 119:3666–3677

    CAS  PubMed Central  PubMed  Google Scholar 

  56. Jeon EJ, Lee KY, Choi NS, Lee MH, Kim HN, Jin YH et al (2006) Bone morphogenetic protein-2 stimulates Runx2 acetylation. J Biol Chem 281:16502–16511

    CAS  PubMed  Google Scholar 

  57. Hu R, Liu W, Li H, Yang L, Chen C, Xia ZY et al (2011) A Runx2/miR-3960/miR-2861 regulatory feedback loop during mouse osteoblast differentiation. J Biol Chem 286:12328–12339

    CAS  PubMed Central  PubMed  Google Scholar 

  58. Wang X, Guo B, Li Q, Peng J, Yang Z, Wang A et al (2013) miR-214 targets ATF4 to inhibit bone formation. Nat Med 19:93–100

    PubMed  Google Scholar 

  59. Yang X, Matsuda K, Bialek P, Jacquot S, Masuoka HC, Schinke T et al (2004) ATF4 is a substrate of RSK2 and an essential regulator of osteoblast biology; implication for Coffin-Lowry Syndrome. Cell 117:387–398

    CAS  PubMed  Google Scholar 

  60. Shi K, Lu J, Zhao Y, Wang L, Li J, Qi B et al (2013) MicroRNA-214 suppresses osteogenic differentiation of C2C12 myoblast cells by targeting Osterix. Bone 55:487–494

    CAS  PubMed  Google Scholar 

  61. Inose H, Ochi H, Kimura A, Fujita K, Xu R, Sato S et al (2009) A microRNA regulatory mechanism of osteoblast differentiation. Proc Natl Acad Sci USA 106:20794–20799

    CAS  PubMed Central  PubMed  Google Scholar 

  62. He L, He X, Lim LP, de Stanchina E, Xuan Z, Liang Y et al (2007) A microRNA component of the p53 tumour suppressor network. Nature 447:1130–1134

    CAS  PubMed  Google Scholar 

  63. Bae Y, Yang T, Zeng HC, Campeau PM, Chen Y, Bertin T et al (2012) miRNA-34c regulates Notch signaling during bone development. Hum Mol Genet 21:2991–3000

    CAS  PubMed Central  PubMed  Google Scholar 

  64. Kim KM, Park SJ, Jung SH, Kim EJ, Jogeswar G, Ajita J et al (2012) miR-182 is a negative regulator of osteoblast proliferation, differentiation, and skeletogenesis through targeting FoxO1. J Bone Miner Res 27:1669–1679

    PubMed  Google Scholar 

  65. Rached MT, Kode A, Xu L, Yoshikawa Y, Paik JH, Depinho RA et al (2010) FoxO1 is a positive regulator of bone formation by favoring protein synthesis and resistance to oxidative stress in osteoblasts. Cell Metab 11:147–160

    CAS  PubMed Central  PubMed  Google Scholar 

  66. Ambrogini E, Almeida M, Martin-Millan M, Paik JH, Depinho RA, Han L et al (2010) FoxO-mediated defense against oxidative stress in osteoblasts is indispensable for skeletal homeostasis in mice. Cell Metab 11:136–146

    CAS  PubMed Central  PubMed  Google Scholar 

  67. Concepcion CP, Bonetti C, Ventura A (2012) The microRNA-17-92 family of microRNA clusters in development and disease. Cancer J 18:262–267

    CAS  PubMed Central  PubMed  Google Scholar 

  68. de Pontual L, Yao E, Callier P, Faivre L, Drouin V, Cariou S et al (2011) Germline deletion of the miR-17 approximately 92 cluster causes skeletal and growth defects in humans. Nat Genet 43:1026–1030

    PubMed Central  PubMed  Google Scholar 

  69. Tassano E, Di Rocco M, Signa S, Gimelli G (2013) De novo 13q31.1-q32.1 interstitial deletion encompassing the miR-17-92 cluster in a patient with Feingold syndrome-2. Am J Med Genet A 161A:894–896

    CAS  PubMed  Google Scholar 

  70. Kannu P, Campos-Xavier AB, Hull D, Martinet D, Ballhausen D, Bonafe L (2013) Post-axial polydactyly type A2, overgrowth and autistic traits associated with a chromosome 13q31.3 microduplication encompassing miR-17-92 and GPC5. Eur J Med Genet 56:452–457

    CAS  PubMed  Google Scholar 

  71. Hemmat M, Rumple MJ, Mahon LW, Strom CM, Anguiano A, Talai M et al (2014) Short stature, digit anomalies and dysmorphic facial features are associated with the duplication of miR-17 ~ 92 cluster. Mol Cytogenet 7:27

    PubMed Central  PubMed  Google Scholar 

  72. Zhou M, Ma J, Chen S, Chen X, Yu X (2013) MicroRNA-17-92 cluster regulates osteoblast proliferation and differentiation. Endocrine 45:302–310

    PubMed  Google Scholar 

  73. Liu Y, Liu W, Hu C, Xue Z, Wang G, Ding B et al (2011) MiR-17 modulates osteogenic differentiation through a coherent feed-forward loop in mesenchymal stem cells isolated from periodontal ligaments of patients with periodontitis. Stem Cells 29:1804–1816

    CAS  PubMed  Google Scholar 

  74. Li H, Li T, Wang S, Wei J, Fan J, Li J et al (2013) 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 10:313–324

    CAS  PubMed  Google Scholar 

  75. Li L, Shi JY, Zhu GQ, Shi B (2012) MiR-17-92 cluster regulates cell proliferation and collagen synthesis by targeting TGFB pathway in mouse palatal mesenchymal cells. J Cell Biochem 113:1235–1244

    CAS  PubMed  Google Scholar 

  76. Guo L, Xu J, Qi J, Zhang L, Wang J, Liang J et al (2013) MicroRNA-17-92a upregulation by estrogen leads to Bim targeting and inhibition of osteoblast apoptosis. J Cell Sci 126:978–988

    CAS  PubMed  Google Scholar 

  77. Chen L, Holmstrom K, Qiu W, Ditzel N, Shi K, Hokland LB et al (2013) MicroRNA-34a Inhibits osteoblast differentiation and in vivo bone formation of human stromal stem cells. Stem Cells 32:902–912

    Google Scholar 

  78. Tamura M, Uyama M, Sugiyama Y, Sato M (2013) Canonical Wnt signaling activates miR-34 expression during osteoblastic differentiation. Mol Med Rep 8:1807–1811

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed Central  PubMed  Google Scholar 

  80. Kapinas K, Kessler C, Ricks T, Gronowicz G, Delany AM (2010) miR-29 modulates Wnt signaling in human osteoblasts through a positive feedback loop. J Biol Chem 285:25221–25231

    CAS  PubMed Central  PubMed  Google Scholar 

  81. Chang TC, Yu D, Lee YS, Wentzel EA, Arking DE, West KM et al (2008) Widespread microRNA repression by Myc contributes to tumorigenesis. Nat Genet 40:43–50

    CAS  PubMed Central  PubMed  Google Scholar 

  82. Wang FS, Chuang PC, Lin CL, Chen MW, Ke HJ, Chang YH et al (2013) MicroRNA-29a protects against glucocorticoid-induced bone loss and fragility in rats by orchestrating bone acquisition and resorption. Arthritis Rheum 65:1530–1540

    CAS  PubMed  Google Scholar 

  83. Li Z, Hassan MQ, Jafferji M, Aqeilan RI, Garzon R, Croce CM et al (2009) Biological functions of miR-29b contribute to positive regulation of osteoblast differentiation. J Biol Chem 284:15676–15684

    CAS  PubMed Central  PubMed  Google Scholar 

  84. Li E, Zhang J, Yuan T, Ma B (2014) miR-143 suppresses osteogenic differentiation by targeting Osterix. Mol Cell Biochem 390:69–74

    CAS  PubMed  Google Scholar 

  85. Bhushan R, Grunhagen J, Becker J, Robinson PN, Ott CE, Knaus P (2013) miR-181a promotes osteoblastic differentiation through repression of TGF-beta signaling molecules. Int J Biochem Cell Biol 45:696–705

    CAS  PubMed  Google Scholar 

  86. Gamez B, Rodriguez-Carballo E, Bartrons R, Rosa JL, Ventura F (2013) MicroRNA-322 (miR-322) and its target protein Tob2 modulate Osterix (Osx) mRNA stability. J Biol Chem 288:14264–14275

    CAS  PubMed Central  PubMed  Google Scholar 

  87. Zhang J, Tu Q, Bonewald LF, He X, Stein G, Lian J et al (2011) Effects of miR-335-5p in modulating osteogenic differentiation by specifically downregulating Wnt antagonist DKK1. J Bone Miner Res 26:1953–1963

    CAS  PubMed  Google Scholar 

  88. Itoh T, Nozawa Y, Akao Y (2009) 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 284:19272–19279

    CAS  PubMed Central  PubMed  Google Scholar 

  89. Hassan MQ, Gordon JA, Beloti MM, Croce CM, van Wijnen AJ, Stein JL et al (2010) A network connecting Runx2, SATB2, and the miR-23a ~ 27a ~ 24-2 cluster regulates the osteoblast differentiation program. Proc Natl Acad Sci USA 107:19879–19884

    CAS  PubMed Central  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  91. Zhang Y, Xie RL, Croce CM, Stein JL, Lian JB, van Wijnen AJ et al (2011) A program of microRNAs controls osteogenic lineage progression by targeting transcription factor Runx2. Proc Natl Acad Sci USA 108:9863–9868

    CAS  PubMed Central  PubMed  Google Scholar 

  92. Lei SF, Papasian CJ, Deng HW (2011) Polymorphisms in predicted miRNA binding sites and osteoporosis. J Bone Miner Res 26:72–78

    CAS  PubMed Central  PubMed  Google Scholar 

  93. Lisse TS, Chun RF, Rieger S, Adams JS, Hewison M (2013) Vitamin D activation of functionally distinct regulatory miRNAs in primary human osteoblasts. J Bone Miner Res 28:1478–1488

    CAS  PubMed Central  PubMed  Google Scholar 

  94. Zhang JF, Fu WM, He ML, Wang H, Wang WM, Yu SC et al (2011) MiR-637 maintains the balance between adipocytes and osteoblasts by directly targeting Osterix. Mol Biol Cell 22:3955–3961

    CAS  PubMed Central  PubMed  Google Scholar 

  95. Chen Q, Liu W, Sinha KM, Yasuda H, de Crombrugghe B (2013) Identification and characterization of microRNAs controlled by the osteoblast-specific transcription factor Osterix. PLoS ONE 8:e58104

    CAS  PubMed Central  PubMed  Google Scholar 

  96. An JH, Ohn JH, Song JA, Yang JY, Park H, Choi HJ et al (2013) Changes of microRNA profile and microRNA-mRNA regulatory network in bones of ovariectomized mice. J Bone Miner Res 29:644–656

    Google Scholar 

  97. Seeliger C, Karpinski K, Haug A, Vester H, Schmitt A, Bauer J et al (2014) Five freely circulating miRNAs and bone tissue miRNAs are associated with osteoporotic fractures. J Bone Miner Res 29(1718):1728

    Google Scholar 

  98. Wang Q, Cai J, Cai XH, Chen L (2013) miR-346 regulates osteogenic differentiation of human bone marrow-derived mesenchymal stem cells by targeting the Wnt/beta-catenin pathway. PLoS ONE 8:e72266

    CAS  PubMed Central  PubMed  Google Scholar 

  99. Baglio SR, Devescovi V, Granchi D, Baldini N (2013) MicroRNA expression profiling of human bone marrow mesenchymal stem cells during osteogenic differentiation reveals Osterix regulation by miR-31. Gene 527:321–331

    CAS  PubMed  Google Scholar 

  100. Gao J, Yang T, Han J, Yan K, Qiu X, Zhou Y et al (2011) MicroRNA expression during osteogenic differentiation of human multipotent mesenchymal stromal cells from bone marrow. J Cell Biochem 112:1844–1856

    CAS  PubMed  Google Scholar 

  101. Deng Y, Wu S, Zhou H, Bi X, Wang Y, Hu Y et al (2013) Effects of a miR-31, Runx2, and Satb2 regulatory loop on the osteogenic differentiation of bone mesenchymal stem cells. Stem Cells Dev 22:2278–2286

    CAS  PubMed  Google Scholar 

  102. Eskildsen T, Taipaleenmaki H, Stenvang J, Abdallah BM, Ditzel N, Nossent AY et al (2011) MicroRNA-138 regulates osteogenic differentiation of human stromal (mesenchymal) stem cells in vivo. Proc Natl Acad Sci USA 108:6139–6144

    PubMed Central  PubMed  Google Scholar 

  103. Huang J, Zhao L, Xing L, Chen D (2010) MicroRNA-204 regulates Runx2 protein expression and mesenchymal progenitor cell differentiation. Stem Cells 28:357–364

    PubMed Central  PubMed  Google Scholar 

  104. Itoh T, Ando M, Tsukamasa Y, Akao Y (2012) Expression of BMP-2 and Ets1 in BMP-2-stimulated mouse pre-osteoblast differentiation is regulated by microRNA-370. FEBS Lett 586:1693–1701

    CAS  PubMed  Google Scholar 

  105. Liao L, Yang X, Su X, Hu C, Zhu X, Yang N et al (2013) 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 4:e600

    CAS  PubMed Central  PubMed  Google Scholar 

  106. Gong Y, Xu F, Zhang L, Qian Y, Chen J, Huang H et al (2014) MicroRNA expression signature for Satb2-induced osteogenic differentiation in bone marrow stromal cells. Mol Cell Biochem 387:227–239

    CAS  PubMed  Google Scholar 

  107. Mizuno Y, Tokuzawa Y, Ninomiya Y, Yagi K, Yatsuka-Kanesaki Y, Suda T et al (2009) miR-210 promotes osteoblastic differentiation through inhibition of AcvR1b. FEBS Lett 583:2263–2268

    CAS  PubMed  Google Scholar 

  108. Mizuno Y, Yagi K, Tokuzawa Y, Kanesaki-Yatsuka Y, Suda T, Katagiri T et al (2008) miR-125b inhibits osteoblastic differentiation by down-regulation of cell proliferation. Biochem Biophys Res Commun 368:267–272

    CAS  PubMed  Google Scholar 

  109. Fisher MC, Clinton GM, Maihle NJ, Dealy CN (2007) Requirement for ErbB2/ErbB signaling in developing cartilage and bone. Dev Growth Differ 49:503–513

    CAS  PubMed  Google Scholar 

  110. Okamoto H, Matsumi Y, Hoshikawa Y, Takubo K, Ryoke K, Shiota G (2012) Involvement of microRNAs in regulation of osteoblastic differentiation in mouse induced pluripotent stem cells. PLoS ONE 7:e43800

    CAS  PubMed Central  PubMed  Google Scholar 

  111. Schaap-Oziemlak AM, Raymakers RA, Bergevoet SM, Gilissen C, Jansen BJ, Adema GJ et al (2010) MicroRNA hsa-miR-135b regulates mineralization in osteogenic differentiation of human unrestricted somatic stem cells. Stem Cells Dev 19:877–885

    CAS  PubMed  Google Scholar 

  112. Bakhshandeh B, Soleimani M, Hafizi M, Paylakhi SH, Ghaemi N (2012) MicroRNA signature associated with osteogenic lineage commitment. Mol Biol Rep 39:7569–7581

    CAS  PubMed  Google Scholar 

  113. Luzi E, Marini F, Sala SC, Tognarini I, Galli G, Brandi ML (2008) 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 23:287–295

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  115. Zhang WB, Zhong WJ, Wang L (2014) A signal-amplification circuit between miR-218 and Wnt/beta-catenin signal promotes human adipose tissue-derived stem cells osteogenic differentiation. Bone 58:59–66

    CAS  PubMed  Google Scholar 

  116. Deng Y, Zhou H, Zou D, Xie Q, Bi X, Gu P et al (2013) The role of miR-31-modified adipose tissue-derived stem cells in repairing rat critical-sized calvarial defects. Biomaterials 34:6717–6728

    CAS  PubMed  Google Scholar 

  117. Dalle Carbonare L, Valenti MT, Zanatta M, Donatelli L, Lo Cascio V (2009) Circulating mesenchymal stem cells with abnormal osteogenic differentiation in patients with osteoporosis. Arthritis Rheum 60:3356–3365

    PubMed  Google Scholar 

  118. Yang N, Wang G, Hu C, Shi Y, Liao L, Shi S et al (2013) Tumor necrosis factor alpha suppresses the mesenchymal stem cell osteogenesis promoter miR-21 in estrogen deficiency-induced osteoporosis. J Bone Miner Res 28:559–573

    CAS  PubMed  Google Scholar 

  119. Sugatani T, Hruska KA (2009) Impaired micro-RNA pathways diminish osteoclast differentiation and function. J Biol Chem 284:4667–4678

    CAS  PubMed Central  PubMed  Google Scholar 

  120. Mizoguchi F, Izu Y, Hayata T, Hemmi H, Nakashima K, Nakamura T et al (2010) Osteoclast-specific dicer gene deficiency suppresses osteoclastic bone resorption. J Cell Biochem 109:866–875

    CAS  PubMed  Google Scholar 

  121. Sugatani T, Hildreth BE 3rd, Toribio RE, Malluche HH, Hruska KA (2014) Expression of DGCR8-Dependent MicroRNAs Is Indispensable for Osteoclastic Development and Bone-Resorbing Activity. J Cell Biochem 115:1043–1047

    CAS  PubMed  Google Scholar 

  122. Chen C, Cheng P, Xie H, Zhou HD, Wu XP, Liao EY et al (2014) MiR-503 regulates osteoclastogenesis via targeting RANK. J Bone Miner Res 29:338–347

    CAS  PubMed  Google Scholar 

  123. Cheng P, Chen C, He HB, Hu R, Zhou HD, Xie H et al (2013) miR-148a regulates osteoclastogenesis by targeting V-maf musculoaponeurotic fibrosarcoma oncogene homolog B. J Bone Miner Res 28:1180–1190

    CAS  PubMed  Google Scholar 

  124. Guo LJ, Liao L, Yang L, Li Y, Jiang TJ (2014) MiR-125a TNF receptor-associated factor 6 to inhibit osteoclastogenesis. Exp Cell Res 321:142–152

    CAS  PubMed  Google Scholar 

  125. Sugatani T, Vacher J, Hruska KA (2011) A microRNA expression signature of osteoclastogenesis. Blood 117:3648–3657

    CAS  PubMed Central  PubMed  Google Scholar 

  126. Mizoguchi F, Murakami Y, Saito T, Miyasaka N, Kohsaka H (2013) miR-31 controls osteoclast formation and bone resorption by targeting RhoA. Arthritis Res Ther 15:R102

    PubMed Central  PubMed  Google Scholar 

  127. Zhang J, Zhao H, Chen J, Xia B, Jin Y, Wei W et al (2012) Interferon-beta-induced miR-155 inhibits osteoclast differentiation by targeting SOCS1 and MITF. FEBS Lett 586:3255–3262

    CAS  PubMed  Google Scholar 

  128. Rossi M, Pitari MR, Amodio N, Di Martino MT, Conforti F, Leone E et al (2013) miR-29b negatively regulates human osteoclastic cell differentiation and function: implications for the treatment of multiple myeloma-related bone disease. J Cell Physiol 228:1506–1515

    CAS  PubMed  Google Scholar 

  129. Franceschetti T, Kessler CB, Lee SK, Delany AM (2013) miR-29 promotes murine osteoclastogenesis by regulating osteoclast commitment and migration. J Biol Chem 288:33347–33360

    CAS  PubMed  Google Scholar 

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Acknowledgments

This work is supported by the NIH grant, AR056645, to T.K.

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The authors declare that they have no conflict of interest.

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  1. Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Thier 1101, 50 Blossom Street, Boston, MA, 02114, USA

    Garyfallia Papaioannou, Fatemeh Mirzamohammadi & Tatsuya Kobayashi

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  1. Garyfallia Papaioannou
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  2. Fatemeh Mirzamohammadi
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  3. Tatsuya Kobayashi
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Correspondence to Tatsuya Kobayashi.

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Papaioannou, G., Mirzamohammadi, F. & Kobayashi, T. MicroRNAs involved in bone formation. Cell. Mol. Life Sci. 71, 4747–4761 (2014). https://doi.org/10.1007/s00018-014-1700-6

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  • DOI: https://doi.org/10.1007/s00018-014-1700-6

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