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microRNA Regulation of Skeletal Development

  • Skeletal Development (P Trainor and K Svoboda, Section Editors)
  • Published:
Current Osteoporosis Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Osteogenesis is a complex process involving the specification of multiple progenitor cells and their maturation and differentiation into matrix-secreting osteoblasts. Osteogenesis occurs not only during embryogenesis but also during growth, after an injury, and in normal homeostatic maintenance. While much is known about osteogenesis-associated regulatory genes, the role of microRNAs (miRNAs), which are epigenetic regulators of protein expression, is just beginning to be explored. While miRNAs do not abrogate all protein expression, their purpose is to finely tune it, allowing for a timely and temporary protein down-regulation.

Recent Findings

The last decade has unveiled a multitude of miRNAs that regulate key proteins within the osteogenic lineage, thus qualifying them as “ostemiRs.” These miRNAs may endogenously target an activator or inhibitor of differentiation, and depending on the target, may either lead to the prolongation of a progenitor maintenance state or to early differentiation. Interestingly, cellular identity seems intimately coupled to the expression of miRNAs, which participate in the suppression of previous and subsequent differentiation steps. In such cases where key osteogenic proteins were identified as direct targets of miRNAs in non-bone cell types, or through bioinformatic prediction, future research illuminating the activity of these miRNAs during osteogenesis will be extremely valuable.

Summary

Many bone-related diseases involve the dysregulation of transcription factors or other proteins found within osteoblasts and their progenitors, and the dysregulation of miRNAs, which target such factors, may play a pivotal role in disease etiology, or even as a possible therapy.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Park J, Gebhardt M, Golovchenko S, Perez-Branguli F, Hattori T, Hartmann C, et al. Dual pathways to endochondral osteoblasts: a novel chondrocyte-derived osteoprogenitor cell identified in hypertrophic cartilage. Biol Open. 2015;4(5):608–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Yang G, Zhu L, Hou N, Lan Y, Wu XM, Zhou B, et al. Osteogenic fate of hypertrophic chondrocytes. Cell Res. 2014;24(10):1266–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Yang L, Tsang KY, Tang HC, Chan D, Cheah KS. Hypertrophic chondrocytes can become osteoblasts and osteocytes in endochondral bone formation. Proc Natl Acad Sci U S A. 2014;111:12097–102.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Zhou X, von der Mark K, Henry S, Norton W, Adams H, de Crombrugghe B. Chondrocytes transdifferentiate into osteoblasts in endochondral bone during development, postnatal growth and fracture healing in mice. PLoS Genet. 2014;10:e1004820.

    PubMed  PubMed Central  Google Scholar 

  5. Gilbert SF. Osteogenesis: the development of bones. Dev Biol 10th ed. Sunderland: Sinauer Associates, Inc.; 2014. P. 432.

  6. Komori T, Yagi H, Nomura S, Yamaguchi A, Sasaki K, Deguchi K, et al. Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell. 1997;89:755–64.

    CAS  PubMed  Google Scholar 

  7. Otto F, Thornell AP, Crompton T, Denzel A, Gilmour KC, Rosewell IR, et al. Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell. 1997;89:765–71.

    CAS  PubMed  Google Scholar 

  8. Inada M, Yasui T, Nomura S, Miyake S, Deguchi K, Himeno M, et al. Maturational disturbance of chondrocytes in Cbfa1-deficient mice. Dev Dyn. 1999;214:279–90.

    CAS  PubMed  Google Scholar 

  9. • Ducy P, Zhang R, Geoffroy V, Ridall AL, Karsenty G. Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell. 1997;89:747–54. This paper was the first to identify and clone Runx2 , also known as Cbfa1 , identifying it as a master activator of osteoblast differentiation by showing transcription of osteoblastic genes in non-osteoblastic cells.

    CAS  PubMed  Google Scholar 

  10. Keller KC, zur Nieden NI. Osteogenesis from pluripotent stem cells: neural crest or mesodermal origin? In: Kallos MS, editor. Embryonic stem cells—differentiation and pluripotent alternatives, InTech; 2011. p. 323–48.

    Google Scholar 

  11. Huang B, Wang Y, Wang W, Chen J, Lai P, Liu Z, et al. mTORC1 prevents preosteoblast differentiation through the notch signaling pathway. PLoS Genet. 2015;11(8):e1005426.

    PubMed  PubMed Central  Google Scholar 

  12. • Bonewald LF. The amazing osteocyte. J Bone Miner Res. 2011;26(2):229–38. A comprehensive review on the function of osteocytes in bone, including a historic view on how osteocytogenesis was discovered to be an active process.

    CAS  PubMed  Google Scholar 

  13. Shkoukani MA, Chen M, Vong A. Cleft lip—a comprehensive review. Front Pediatr Frontiers Media SA. 2013;1:53.

    Google Scholar 

  14. Trejo P, Rauch F. Osteogenesis imperfecta in children and adolescents—new developments in diagnosis and treatment. Osteoporos Int. 2016;27(12):3427–37.

    CAS  PubMed  Google Scholar 

  15. Barkova E, Mohan U, Chitayat D, Keating S, Toi A, Frank J, et al. Fetal skeletal dysplasias in a tertiary care center: radiology, pathology, and molecular analysis of 112 cases. Clin Genet. 2015;87:330–7.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  17. Ducy P, Karsenty G. Two distinct osteoblast-specific cis-acting elements control expression of a mouse osteocalcin gene. Mol Cell Biol. 1995;15:1858–69.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Quack I, Vonderstrass B, Stock M, Aylsworth AS, Becker A, Brueton L, et al. Mutation analysis of core binding factor a1 in patients with cleidocranial dysplasia. Am J Hum Genet. 1999;65:1268–78.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Mundlos S. Cleidocranial dysplasia: clinical and molecular genetics. J Med Genet. 1999;36:177–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Woei Ng K, Speicher T, Dombrowski C, Helledie T, Haupt LM, Nurcombe V, et al. Osteogenic differentiation of murine embryonic stem cells is mediated by fibroblast growth factor receptors. Stem Cells Dev. 2007;16:305–18.

    PubMed  Google Scholar 

  21. Åberg T, Wang X-P, Kim J-H, Yamashiro T, Bei M, Rice R, et al. Runx2 mediates FGF signaling from epithelium to mesenchyme during tooth morphogenesis. Dev Biol. 2004;270:76–93.

    PubMed  Google Scholar 

  22. Zhang YW, Yasui N, Ito K, Huang G, Fujii M, Hanai J, et al. A RUNX2/PEBP2alpha a/CBFA1 mutation displaying impaired transactivation and Smad interaction in cleidocranial dysplasia. Proc Natl Acad Sci. 2000;97:10549–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Sinha KM, Zhou X. Genetic and molecular control of osterix in skeletal formation. J Cell Biochem. 2013;114:975–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Niger C, Luciotti MA, Buo AM, Hebert C, Ma V, Stains JP. The regulation of runt-related transcription factor 2 by fibroblast growth factor-2 and connexin43 requires the inositol polyphosphate/protein kinase Cδ cascade. J Bone Miner Res NIH Public Access. 2013;28:1468–77.

    CAS  Google Scholar 

  25. Gaur T, Lengner CJ, Hovhannisyan H, Bhat RA, Bodine PVN, Komm BS, et al. Canonical WNT signaling promotes osteogenesis by directly stimulating Runx2 gene expression. J Biol Chem. 2005;280:33132–40.

    CAS  PubMed  Google Scholar 

  26. • Karsenty G. Transcriptional control of skeletogenesis. Annu Rev Genomics Hum Genet. 2008;9:183–96. This review highlights many of the important transcriptional activators and repressors during differentiation of mesenchymal tissue into the osteochondral lineage and discusses the interaction between the two master osteogenic transcription factors RUNX2 and OSX.

    CAS  PubMed  Google Scholar 

  27. • Lee R, Feinbaum R, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell. 1993;75:843–54. This paper was the first to identify a small non-coding RNA molecule found to bind to the 3′UTR of a target mRNA, which suggested a translation regulation.

    CAS  PubMed  Google Scholar 

  28. Reinhart BJ, Slack FJ, Basson M, Pasquinelli AE, Bettinger JC, Rougvie AE, et al. The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature. 2000;403:901–6.

    CAS  PubMed  Google Scholar 

  29. Reinhart BJ, Weinstein EG, Rhoades MW, Bartel B, Bartel DP. MicroRNAs in plants. Genes Dev. 2002;16:1616–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Chen X. A microRNA as a translational repressor of APETALA2 in Arabidopsis flower development. Science. 2004;303:2022–5.

    CAS  PubMed  Google Scholar 

  31. Johnston RJ, Hobert O. A microRNA controlling left/right neuronal asymmetry in Caenorhabditis elegans. Nature. 2003;426:845–9.

    CAS  PubMed  Google Scholar 

  32. Li X, Carthew RW. A microRNA mediates EGF receptor signaling and promotes photoreceptor differentiation in the drosophila eye. Cell. 2005;123:1267–77.

    CAS  PubMed  Google Scholar 

  33. Heimberg AM, Sempere LF, Moy VN, Donoghue PCJ, Peterson KJ. MicroRNAs and the advent of vertebrate morphological complexity. Proc Natl Acad Sci. 2008;105:2946–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Ardekani AM, Naeini MM. The role of microRNAs in human diseases. Avicenna J Med Biotechnol. 2010;2:161–79.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Pasquinelli AE. MicroRNAs and their targets: recognition, regulation and an emerging reciprocal relationship. Nat Rev Genet. 2012;13:271–82.

    CAS  PubMed  Google Scholar 

  36. Wu L, Fan J, Belasco JG. MicroRNAs direct rapid deadenylation of mRNA. Proc Natl Acad Sci. 2006;103:4034–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Wahid F, Shehzad A, Khan T, Kim YY. MicroRNAs: synthesis, mechanism, function, and recent clinical trials. Biochim Biophys Acta. 1803;2010:1231–43.

    Google Scholar 

  38. Lin SL, Miller JD, Ying SY. Intronic microRNA (miRNA). J Biomed Biotechnol. 2006;2006:1–13.

    Google Scholar 

  39. Ruby JG, Jan CH, Bartel DP. Intronic microRNA precursors that bypass Drosha processing. Nature. 2007;448:83–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Bohnsack MT, Czaplinski K, Gorlich D. Exportin 5 is a RanGTP-dependent dsRNA-binding protein that mediates nuclear export of pre-miRNAs. RNA. 2004;10:185–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Sontheimer EJ. Assembly and functions of RNA silencing complexes. Nat Rev Mol Cell Biol. 2005;6:127–38.

    CAS  PubMed  Google Scholar 

  42. Ha M, Kim VN. Regulation of microRNA biogenesis. Nat Rev Mol Cell Biol. 2014;15:509–24.

    CAS  PubMed  Google Scholar 

  43. Olsen PH, Ambros V. The lin-4 regulatory RNA controls developmental timing in Caenorhabditis elegans by blocking LIN-14 protein synthesis after the initiation of translation. Dev Biol. 1999;216:671–80.

    CAS  PubMed  Google Scholar 

  44. Wu L, Fan J, Belasco JG. MicroRNAs direct rapid deadenylation of mRNA. Proc Natl Acad Sci U S A. 2006;103(11):4034–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Eulalio A, Rehwinkel J, Stricker M, Huntzinger E, Yang SF, Doerks T, et al. Target-specific requirements for enhancers of decapping in miRNA-mediated gene silencing. Genes Dev. 2007;21(20):2558–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Eulalio A, Huntzinger E, Nishihara T, Rehwinkel J, Fauser M, Izaurralde E. Deadenylation is a widespread effect of miRNA regulation. RNA. 2009;15(1):21–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Cai X, Hagedorn CH, Cullen BR. Human microRNAs are processed from capped, polyadenylated transcripts that can also function as mRNAs. RNA. 2004;10:1957–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Denli AM, Tops BBJ, Plasterk RHA, Ketting RF, Hannon GJ. Processing of primary microRNAs by the microprocessor complex. Nature. 2004;432:231–5.

    CAS  PubMed  Google Scholar 

  49. • Eguchi T, Watanabe K, Hara ES, Ono M, Kuboki T, Calderwood SK, et al. OstemiR: a novel panel of microRNA biomarkers in osteoblastic and osteocytic differentiation from mesenchymal stem cells. PLoS One. 2013;8:e58796. This paper reveals a number of miRNAs differentially expressed during osteoblastic and osteocytic differentiation denoted “ostemiRs,” which have been proposed to affect osteogenic differentiation, stemness as well as other important processes.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 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;108:216–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Zhou X, Luan X, Chen Z, Francis M, Gopinathan G, Li W, et al. MicroRNA-138 inhibits periodontal progenitor differentiation under inflammatory conditions. J Dent Res. 2016;95:230–7.

    PubMed  PubMed Central  Google Scholar 

  52. Laxman N, Rubin C-J, Mallmin H, Nilsson O, Pastinen T, Grundberg E, et al. Global miRNA expression and correlation with mRNA levels in primary human bone cells. RNA. 2015;21:1433–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Mohri T, Nakajima M, Takagi S, Komagata S, Yokoi T. MicroRNA regulates human vitamin D receptor. Int J Cancer. 2009;125:1328–33.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Chakrabarty A, Tranguch S, Daikoku T, Jensen K, Furneaux H, Dey SK. MicroRNA regulation of cyclooxygenase-2 during embryo implantation. Proc Natl Acad Sci. 2007;104:15144–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Li Z, Hassan MQ, Volinia S, van Wijnen AJ, Stein JL, Croce CM, et al. A microRNA signature for a BMP2-induced osteoblast lineage commitment program. Proc Natl Acad Sci. 2008;105:13906–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Shevde LA, Metge BJ, Mitra A, Xi Y, Ju J, King JA, et al. Spheroid-forming subpopulation of breast cancer cells demonstrates vasculogenic mimicry via hsa-miR-299-5p regulated de novo expression of osteopontin. J Cell Mol Med. 2010;14:1693–706.

    CAS  PubMed  Google Scholar 

  58. Tu M, Li Y, Zeng C, Deng Z, Gao S, Xiao W, et al. MicroRNA-127-5p regulates osteopontin expression and osteopontin-mediated proliferation of human chondrocytes. Sci Rep. 2016;6:25032.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Sekiya Y, Ogawa T, Yoshizato K, Ikeda K, Kawada N. Suppression of hepatic stellate cell activation by microRNA-29b. Biochem Biophys Res Commun. 2011;412:74–9.

    CAS  PubMed  Google Scholar 

  60. Tang O, Chen X-M, Shen S, Hahn M, Pollock CA. MiRNA-200b represses transforming growth factor-β1-induced EMT and fibronectin expression in kidney proximal tubular cells. Am J Physiol Renal Physiol. 2013;304:1266–73.

    Google Scholar 

  61. Wang Q, Wang Y, Minto AW, Wang J, Shi Q, Li X, et al. MicroRNA-377 is up-regulated and can lead to increased fibronectin production in diabetic nephropathy. FASEB J. 2008;22:4126–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Bonnin N, Armandy E, Carras J, Ferrandon S, Foy J-P, Saintigny P, et al. MiR-422a promotes loco-regional recurrence by targeting NT5E/CD73 in head and neck squamous cell carcinoma. Oncotarget. 2016; doi:10.18632/oncotarget.9829.

  63. Chen XP, Chen YG, Lan JY, Shen ZJ. MicroRNA-370 suppresses proliferation and promotes endometrioid ovarian cancer chemosensitivity to cDDP by negatively regulating ENG. Cancer Lett. 2014;353:201–10.

    CAS  PubMed  Google Scholar 

  64. Yu G, Li H, Wang J, Gumireddy K, Li A, Yao W, et al. miRNA-34a suppresses cell proliferation and metastasis by targeting CD44 in human renal carcinoma cells. J Urol. 2014;192:1229–37.

    CAS  PubMed  Google Scholar 

  65. Wang P, Luo Y, Duan H, Xing S, Zhang J, Lu D, et al. MicroRNA 329 suppresses angiogenesis by targeting CD146. Mol Cell Biol. 2013;33:3689–99.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Liu H, Lin H, Zhang L, Sun Q, Yuan G, Zhang L, et al. miR-145 and miR-143 regulate odontoblast differentiation through targeting Klf4 and Osx genes in a feedback loop. J Biol Chem. 2013;288:9261–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Li E, Zhang J, Yuan T, Ma B. MiR-143 suppresses osteogenic differentiation by targeting Osterix. Mol Cell Biochem. 2014;390:69–74.

    CAS  PubMed  Google Scholar 

  68. Shi K, Lu J, Zhao Y, Wang L, Li J, Qi B, et al. MicroRNA-214 suppresses osteogenic differentiation of C2C12 myoblast cells by targeting Osterix. Bone. 2013;55:487–94.

    CAS  PubMed  Google Scholar 

  69. Zhang J, Fu W, He M, Wang H, Wang W, Yu S, et al. MiR-637 maintains the balance between adipocytes and osteoblasts by directly targeting osterix. Mol Biol Cell. 2011;22:3955–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Gámez B, Rodríguez-Carballo E, Bartrons R, Rosa JL, Ventura F. MicroRNA-322 (miR-322) and its target protein Tob2 modulate Osterix (Osx) mRNA stability. J Biol Chem. 2013;288:14264–75.

    PubMed  PubMed Central  Google Scholar 

  71. • Huang J, Zhao L, Xing L, Chen D. MicroRNA-204 regulates Runx2 protein expression and mesenchymal progenitor cell differentiation. Stem Cells. 2010;28:357–64. This paper demonstrates the direct binding of miR-204 to the 3′UTR of Runx2 within the osteogenic lineage to inhibit osteogenesis and promote adipogenesis.

    PubMed  PubMed Central  Google Scholar 

  72. Kim E-J, Kang I-H, Lee JW, Jang W-G, Koh J-T. MiR-433 mediates ERRγ-suppressed osteoblast differentiation via direct targeting to Runx2 mRNA in C3H10T1/2 cells. Life Sci. 2013;92:562–8.

    CAS  PubMed  Google Scholar 

  73. Chen H, Ji X, She F, Gao Y, Tang P. miR-628-3p regulates osteoblast differentiation by targeting RUNX2: possible role in atrophic non-union. Int J Mol Med Spandidos Publications. 2017;39:279–86.

    CAS  Google Scholar 

  74. Liu H, Sun Q, Wan C, Li L, Zhang L, Chen Z. MicroRNA-338-3p regulates osteogenic differentiation of mouse bone marrow stromal stem cells by targeting Runx2 and Fgfr2. J Cell Physiol. 2014;229:1494–502.

    CAS  PubMed  Google Scholar 

  75. Du F, Wu H, Zhou Z, Liu YU. microRNA-375 inhibits osteogenic differentiation by targeting runt-related transcription factor 2. Exp Ther Med. 2015;10:207–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Hassan MQ, Gordon JAR, Beloti MM, Croce CM, van Wijnen AJ, Stein JL, et al. A network connecting Runx2, SATB2, and the miR-23a~27a~24-2 cluster regulates the osteoblast differentiation program. Proc Natl Acad Sci. 2010;107:19879–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Hu N, Feng C, Jiang Y, Sekiya Q, Liu H. 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. 2015;16:10491–506.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Kim S, Koga T, Isobe M, Kern BE, Yokochi T, Chin YE, et al. Stat1 functions as a cytoplasmic attenuator of Runx2 in the transcriptional program of osteoblast differentiation. Genes Dev. 2003;17:1979–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Wei J, Shi Y, Zheng L, Zhou B, Inose H, Wang J, et al. miR-34s inhibit osteoblast proliferation and differentiation in the mouse by targeting SATB2. J Cell Biol. 2012;197:509–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Brennan-Speranza TC, Conigrave AD. Osteocalcin: an osteoblast-derived polypeptide hormone that modulates whole body energy metabolism. Calcif Tissue Int. 2015;96:1–10.

    CAS  PubMed  Google Scholar 

  81. van Leeuwen J, van Driel M, van den Bemd G, Pols HA. Vitamin D control of osteoblast function and bone extracellular matrix mineralization. Crit Rev Eukaryot Gene Expr. 2001;11:199–226.

    PubMed  Google Scholar 

  82. Mizuno Y, Yagi K, Tokuzawa Y, Kanesaki-Yatsuka Y, Suda T, Katagiri T, et al. miR-125b inhibits osteoblastic differentiation by down-regulation of cell proliferation. Biochem Biophys Res Commun. 2008;368:267–72.

    CAS  PubMed  Google Scholar 

  83. Yin JJ, Pollock CB, Kelly K. Mechanisms of cancer metastasis to the bone. Cell Res. 2005;15:57–62.

    CAS  PubMed  Google Scholar 

  84. Forwood MR. Inducible cyclo-oxygenase (COX-2) mediates the induction of bone formation by mechanical loading in vivo. J Bone Miner Res. 1996;11:1688–93.

    CAS  PubMed  Google Scholar 

  85. Wadhwa S, Choudhary S, Voznesensky M, Epstein M, Raisz L, Pilbeam C. Fluid flow induces COX-2 expression in MC3T3-E1 osteoblasts via a PKA signaling pathway. Biochem Biophys Res Commun. 2002;297:46–51.

    CAS  PubMed  Google Scholar 

  86. Greenhough A, Smartt HJM, Moore AE, Roberts HR, Williams AC, Paraskeva C, et al. The COX-2/PGE2 pathway: key roles in the hallmarks of cancer and adaptation to the tumour microenvironment. Carcinogenesis. 2009;30:377–86.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Yu S, Geng Q, Pan Q, Liu Z, Ding S, Xiang Q, et al. MiR-690, a Runx2-targeted miRNA, regulates osteogenic differentiation of C2C12 myogenic progenitor cells by targeting NF-kappaB p65. Cell Biosci. 2016;6:10.

    PubMed  PubMed Central  Google Scholar 

  89. Guo Y, Wang Y, Liu Y, Liu Y, Zeng Q, Zhao Y, et al. MicroRNA-218, microRNA-191*, microRNA-3070a and microRNA-33 are responsive to mechanical strain exerted on osteoblastic cells. Mol Med Rep. 2015;12:3033–8.

    CAS  PubMed  Google Scholar 

  90. Sodek J, Ganss B, McKee MD. Osteopontin. Crit Rev Oral Biol Med. 2000;11:279–303.

    CAS  PubMed  Google Scholar 

  91. Sun C, Huang F, Liu X, Xiao X, Yang M, Hu G, et al. miR-21 regulates triglyceride and cholesterol metabolism in non-alcoholic fatty liver disease by targeting HMGCR. Int J Mol Med. 2015;35:847–53.

    CAS  PubMed  Google Scholar 

  92. Tsipouras P, Myers JC, Ramirez F, Prockop DJ. Restriction fragment length polymorphism associated with the pro alpha 2(I) gene of human type I procollagen. Application to a family with an autosomal dominant form of osteogenesis imperfecta. J Clin Invest. 1983;72:1262–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Byers PH, Shapiro JR, Rowe DW, David KE, Holbrook KA. Abnormal alpha 2-chain in type I collagen from a patient with a form of osteogenesis imperfecta. J Clin Invest. 1983;71:689–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Kalajzic I, Staal A, Yang W-P, Wu Y, Johnson SE, Feyen JHM, et al. Expression profile of osteoblast lineage at defined stages of differentiation. J Biol Chem. 2005;280:24618–26.

    CAS  PubMed  Google Scholar 

  95. Li C, Nguyen HT, Zhuang Y, Lin Y, Flemington EK, Guo W, et al. Post-transcriptional up-regulation of miR-21 by type I collagen. Mol Carcinog. 2011;50:563–70.

    CAS  PubMed  Google Scholar 

  96. • Davis BN, Hilyard AC, Lagna G, Hata A. SMAD proteins control DROSHA-mediated microRNA maturation. Nature. 2008;454:56–61. This paper highlights the fact that signaling cascades cannot only activate the transcription of microRNAs through downstream transcription factors but also by affecting microRNA processing.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Kawakita A, Yanamoto S, Yamada S-I, Naruse T, Takahashi H, Kawasaki G, et al. MicroRNA-21 promotes oral cancer invasion via the Wnt/β-catenin pathway by targeting DKK2. Pathol Oncol Res. 2014;20:253–61.

    CAS  PubMed  Google Scholar 

  98. Lenselink EA. Role of fibronectin in normal wound healing. Int Wound J. 2015;12:313–6.

    PubMed  Google Scholar 

  99. Liu F, Lv Q, Du WW, Li H, Yang X, Liu D, et al. Specificity of miR-378a-5p targeting rodent fibronectin. Biochim Biophys Acta. 1833;2013:3272–85.

    Google Scholar 

  100. Vasanthan P, Govindasamy V, Gnanasegaran N, Kunasekaran W, Musa S, Abu Kasim NH. Differential expression of basal microRNAs’ patterns in human dental pulp stem cells. J Cell Mol Med. 2015;19:566–80.

    CAS  PubMed  Google Scholar 

  101. Palmieri A, Pezzetti F, Brunelli G, Martinelli M, Scapoli L, Arlotti M, et al. Medpor regulates osteoblast’s microRNAs. Biomed Mater Eng. 2008;18:91–7.

    CAS  PubMed  Google Scholar 

  102. Palmieri A, Pezzetti F, Brunelli G, Martinelli M, Lo Muzio L, Scarano A, et al. Anorganic bovine bone (Bio-Oss) regulates miRNA of osteoblast-like cells. Int J Periodontics Restorative Dent. 2010;30:83–7.

    PubMed  Google Scholar 

  103. Vodyanik MA, Yu J, Zhang X, Tian S, Stewart R, Thomson JA, et al. A mesoderm-derived precursor for mesenchymal stem and endothelial cells. Cell Stem Cell. 2010;7:718–29.

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The international society for cellular therapy position statement. Cytotherapy. 2006;8:315–7.

    CAS  PubMed  Google Scholar 

  105. Spaeth EL, Labaff AM, Toole BP, Klopp A, Andreeff M, Marini FC. Mesenchymal CD44 expression contributes to the acquisition of an activated fibroblast phenotype via TWIST activation in the tumor microenvironment. Cancer Res. 2013;73:5347–59.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Fan J, Im CS, Guo M, Cui Z-K, Fartash A, Kim S, et al. Enhanced osteogenesis of adipose-derived stem cells by regulating bone morphogenetic protein signaling antagonists and agonists. Stem Cells Transl Med. 2016;5:539–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Harkness L, Zaher W, Ditzel N, Isa A, Kassem M. CD146/MCAM defines functionality of human bone marrow stromal stem cell populations. Stem Cell Res Ther. 2016;7:4.

    PubMed  PubMed Central  Google Scholar 

  108. Nishihira S, Okubo N, Takahashi N, Ishisaki A, Sugiyama Y, Chosa N. High-cell density-induced VCAM1 expression inhibits the migratory ability of mesenchymal stem cells. Cell Biol Int. 2011;35:475–81.

    CAS  PubMed  Google Scholar 

  109. Harris TA, Yamakuchi M, Ferlito M, Mendell JT, Lowenstein CJ. MicroRNA-126 regulates endothelial expression of vascular cell adhesion molecule 1. Proc Natl Acad Sci. 2008;105:1516–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Hwang S, Park S-K, Lee HY, Kim SW, Lee JS, Choi EK, et al. miR-140-5p suppresses BMP2-mediated osteogenesis in undifferentiated human mesenchymal stem cells. FEBS Lett. 2014;588:2957–63.

    CAS  PubMed  Google Scholar 

  111. Niu T, Liu N, Zhao M, Xie G, Zhang L, Li J, et al. Identification of a novel FGFRL1 microRNA target site polymorphism for bone mineral density in meta-analyses of genome-wide association studies. Hum Mol Genet. 2015;24:4710–27.

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Gan S, Huang Z, Liu N, Su R, Xie G, Zhong B, et al. MicroRNA-140-5p impairs zebrafish embryonic bone development via targeting BMP-2. FEBS Lett. 2016;590:1438–46.

    CAS  PubMed  Google Scholar 

  113. Yu X, Cohen DM, Chen CS. miR-125b is an adhesion-regulated microRNA that protects mesenchymal stem cells from anoikis. Stem Cells. 2012;30:956–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Chen S, Yang L, Jie Q, Lin Y-S, Meng G-L, Fan J-Z, et al. MicroRNA-125b suppresses the proliferation and osteogenic differentiation of human bone marrow-derived mesenchymal stem cells. Mol Med Rep. 2014;9:1820–6.

    CAS  PubMed  Google Scholar 

  115. Karsenty G, Wagner EF. Reaching a genetic and molecular understanding of skeletal development. Dev Cell. 2002;2:389–406.

    CAS  PubMed  Google Scholar 

  116. Komori T. Regulation of osteoblast differentiation by transcription factors. J Cell Biochem. 2006;99:1233–9.

    CAS  PubMed  Google Scholar 

  117. Liu L-L, Lu S-X, Li M, Li L-Z, Fu J, Hu W, et al. FoxD3-regulated microRNA-137 suppresses tumour growth and metastasis in human hepatocellular carcinoma by targeting AKT2. Oncotarget. 2014;5:5113–24.

    PubMed  PubMed Central  Google Scholar 

  118. Farina NH, Zingiryan A, Akech JA, Callahan CJ, Lu H, Stein JL, et al. A microRNA/Runx1/Runx2 network regulates prostate tumor progression from onset to adenocarcinoma in TRAMP mice. Oncotarget. 2016; doi:10.18632/oncotarget.11992.

  119. Xiao WZ, Gu XC, Hu B, Liu XW, Zi Y, Li M. Role of microRNA-129-5p in osteoblast differentiation from bone marrow mesenchymal stem cells. Cell Mol Biol. 2016;62:95–9.

    CAS  PubMed  Google Scholar 

  120. Yu S, Geng Q, Ma J, Sun F, Yu Y, Pan Q, et al. Heparin-binding EGF-like growth factor and miR-1192 exert opposite effect on Runx2-induced osteogenic differentiation. Cell Death Dis. 2013;4:e868.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Dobreva G, Chahrour M, Dautzenberg M, Chirivella L, Kanzler B, Fariñas I, et al. SATB2 is a multifunctional determinant of craniofacial patterning and osteoblast differentiation. Cell. 2006;125:971–86.

    CAS  PubMed  Google Scholar 

  122. Tang W, Li Y, Osimiri L, Zhang C. Osteoblast-specific transcription factor Osterix (Osx) is an upstream regulator of Satb2 during bone formation. J Biol Chem. 2011;286:32995–3002.

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Deng Y, Wu S, Zhou H, Bi X, Wang Y, Hu Y, 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;22:2278–86.

    CAS  PubMed  Google Scholar 

  124. Mi W, Shi Q, Chen X, Wu T, Huang H. miR-33a-5p modulates TNF-α-inhibited osteogenic differentiation by targeting SATB2 expression in hBMSCs. FEBS Lett. 2016;590:396–407.

    CAS  PubMed  Google Scholar 

  125. Ge J, Guo S, Fu Y, Zhou P, Zhang P, Du Y, et al. Dental follicle cells participate in tooth eruption via the RUNX2-miR-31-SATB2 loop. J Dent Res. 2015;94:936–44.

    CAS  PubMed  Google Scholar 

  126. Le Douarin NM, Dupin E. Multipotentiality of the neural crest. Curr Opin Genet Dev. 2003;13:529–36.

    PubMed  Google Scholar 

  127. • Nie X, Wang Q, Jiao K. Dicer activity in neural crest cells is essential for craniofacial organogenesis and pharyngeal arch artery morphogenesis. Mech Dev. 2011;128:200–7. This paper signifies the importance of miRNA regulation within neural crest cells during early craniofacial development, with no defects in the migration of cranial and cardia neural crest cells, but to subsequent development.

    CAS  PubMed  PubMed Central  Google Scholar 

  128. • Simões-Costa M, Bronner ME. Establishing neural crest identity: a gene regulatory recipe. Development. 2015;142:242–57. This review highlights the complex genetic regulations and pathways, identified as the gene regulatory network, in which neural crest cells undergo in order to become specified, maintained, migratory, and further differentiated.

    PubMed  PubMed Central  Google Scholar 

  129. Betel D, Wilson M, Gabow A, Marks DS, Sander C. The microRNA.org resource: targets and expression. Nucleic Acids Res. 2008;36:D149–53.

    CAS  PubMed  Google Scholar 

  130. Crane JF, Trainor PA. Neural crest stem and progenitor cells. Annu Rev Cell Dev Biol. 2006;22:267–86.

    CAS  PubMed  Google Scholar 

  131. • Basch ML, Bronner-Fraser M, García-Castro MI. Specification of the neural crest occurs during gastrulation and requires Pax7. Nature. 2006;441:218–22. This paper challenged the prior notion that neural crest specification occurs after gastrulation and introduced Pax7 as a border specifier gene.

    CAS  PubMed  Google Scholar 

  132. Monsoro-Burq AH. PAX transcription factors in neural crest development. Semin Cell Dev Biol. 2015;44:87–96.

    CAS  PubMed  Google Scholar 

  133. Sambasivan R, Yao R, Kissenpfennig A, Van Wittenberghe L, Paldi A, Gayraud-morel B, et al. Pax7-expressing satellite cells are indispensable for adult skeletal muscle regeneration. Development. 2011;4333:3647–56.

    Google Scholar 

  134. Wu R, Li H, Zhai L, Zou X, Meng J, Zhong R, et al. MicroRNA-431 accelerates muscle regeneration and ameliorates muscular dystrophy by targeting Pax7 in mice. Nat Commun. 2015;6:7713.

    PubMed  Google Scholar 

  135. Yang B, Jia L, Guo Q, Ren H, Hu D, Zhou X, et al. MiR-564 functions as a tumor suppressor in human lung cancer by targeting ZIC3. Biochem Biophys Res Commun. 2015;467:690–6.

    CAS  PubMed  Google Scholar 

  136. Penna E, Orso F, Cimino D, Vercellino I, Grassi E, Quaglino E, et al. miR-214 coordinates melanoma progression by upregulating ALCAM through TFAP2 and miR-148b downmodulation. Cancer Res. 2013;73:4098–111.

    CAS  PubMed  Google Scholar 

  137. Pieper M, Ahrens K, Rink E, Peter A, Schlosser G. Differential distribution of competence for panplacodal and neural crest induction to non-neural and neural ectoderm. Dev. 2012;139:1175–87.

    CAS  Google Scholar 

  138. Otsubo T, Akiyama Y, Hashimoto Y, Shimada S, Goto K, Yuasa Y. MicroRNA-126 inhibits sox2 expression and contributes to gastric carcinogenesis. PLoS One. 2011;6

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Yan B, Liu B, Zhu C-D, Li K-L, Yue L-J, Zhao J-L, et al. MicroRNA regulation of skin pigmentation in fish. J Cell Sci. 2013;126:3401–8.

    CAS  PubMed  Google Scholar 

  140. Duband JL, Monier F, Delannet M, Newgreen D. Epithelium-mesenchyme transition during neural crest development. Acta Anat. 1995;154:63–78.

    CAS  PubMed  Google Scholar 

  141. Shook D, Keller R. Mechanisms, mechanics and function of epithelial-mesenchymal transitions in early development. Mech Dev. 2003;120:1351–83.

    CAS  PubMed  Google Scholar 

  142. Thiery JP, Sleeman JP. Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol. 2006;7:131–42.

    CAS  PubMed  Google Scholar 

  143. Vincentz JW, Firulli BA, Lin A, Spicer DB, Howard MJ, Firulli AB. Twist1 controls a cell-specification switch governing cell fate decisions within the cardiac neural crest. PLoS Genet. 2013;9:e1003405.

    CAS  PubMed  PubMed Central  Google Scholar 

  144. MacKenzie A, Ferguson MW, Sharpe PT. Hox-7 expression during murine craniofacial development. Development. 1991;113:601–11.

    CAS  PubMed  Google Scholar 

  145. Takahashi K, Nuckolls GH, Takahashi I, Nonaka K, Nagata M, Ikura T, et al. Msx2 is a repressor of chondrogenic differentiation in migratory cranial neural crest cells. Dev Dyn. 2001;222:252–62.

    CAS  PubMed  Google Scholar 

  146. McCusker C, Cousin H, Neuner R, Alfandari D. Extracellular cleavage of cadherin-11 by ADAM metalloproteases is essential for Xenopus cranial neural crest cell migration. Mol Biol Cell. 2009;20:78–89.

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Liu H, Wang H, Liu X, Yu T. miR-1271 inhibits migration, invasion and epithelial-mesenchymal transition by targeting ZEB1 and TWIST1 in pancreatic cancer cells. Biochem Biophys Res Commun. 2016;472:346–52.

    CAS  PubMed  Google Scholar 

  148. Bildsoe H, Loebel DAF, Jones VJ, Chen Y-T, Behringer RR, Tam PPL. Requirement for Twist1 in frontonasal and skull vault development in the mouse embryo. Dev Biol. 2009;331:176–88.

    CAS  PubMed  Google Scholar 

  149. Davideau JL, Demri P, Hotton D, Gu TT, MacDougall M, Sharpe P, et al. Comparative study of MSX-2, DLX-5, and DLX-7 gene expression during early human tooth development. Pediatr Res. 1999;46:650–6.

    CAS  PubMed  Google Scholar 

  150. 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;284:19272–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Shirakabe K, Terasawa K, Miyama K, Shibuya H, Nishida E. Regulation of the activity of the transcription factor Runx2 by two homeobox proteins, Msx2 and Dlx5. Genes Cells. 2001;6:851–6.

    CAS  PubMed  Google Scholar 

  152. Ishii M, Han J, Yen H-Y, Sucov HM, Chai Y, Maxson RE. Combined deficiencies of Msx1 and Msx2 cause impaired patterning and survival of the cranial neural crest. Development. 2005;132:4937–50.

    CAS  PubMed  Google Scholar 

  153. Mayanil CS. Transcriptional and epigenetic regulation of neural crest induction during neurulation. Dev Neurosci. 2013;35:361–72.

    CAS  PubMed  Google Scholar 

  154. Sauka-Spengler T, Bronner-Fraser M. A gene regulatory network orchestrates neural crest formation. Nat Rev Mol Cell Biol. 2008;9:557–68.

    CAS  PubMed  Google Scholar 

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Acknowledgments

We apologize to the authors of many excellent research studies who we could not cite here due to space constraints. This work was supported by a grant from the National Institute of Dental and Craniofacial Research of the National Institutes of Health (R01 DE025330-01A1) and a grant from the Tobacco Related Disease Research Program (25IP-0018, award no. 392351) to NzN.

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Steven R. Sera and Nicole I. zur Nieden declare that they have no conflict of interest.

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Sera, S.R., zur Nieden, N.I. microRNA Regulation of Skeletal Development. Curr Osteoporos Rep 15, 353–366 (2017). https://doi.org/10.1007/s11914-017-0379-7

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