Skip to main content

Advertisement

SpringerLink
Log in

MicroRNAs and Fracture Healing

  • Review
  • Published:
Calcified Tissue International Aims and scope Submit manuscript

Abstract

MicroRNAs (miRNAs) are small molecules found to have major regulatory roles in many biological processes. This review aims to provide an overview of the recent advances in knowledge of the role of miRNAs in fracture healing and bone repair. A search of the published literature was performed (using the PubMed database) to include all relevant studies published in English. These studies were then reviewed and the results condensed into this review paper. MiRNAs have now been shown to have significant alterations in expression levels in bone tissue in the presence of fractures. This is thought to be related to the process of fracture healing through effects on osteoblasts and bone growth factors. These small molecules are also detectable in the circulation where their expression appears to be altered by the presence of fractures. Although further research is required in this area, miRNAs may present an opportunity for future clinical applications in fracture management.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116(2):281–297

    Article  CAS  PubMed  Google Scholar 

  2. Lee RC, Feinbaum RL, Ambros V (1993) The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75(5):843–854

    Article  CAS  PubMed  Google Scholar 

  3. Ambros V, Bartel B, Bartel DP, Burge CB, Carrington JC, Chen X et al (2003) A uniform system for microRNA annotation. RNA 9(3):277–279

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Griffiths-Jones S (2010) miRBase: microRNA sequences and annotation. Curr Protoc Bioinform. doi:10.1002/0471250953.bi1209s29

    Google Scholar 

  5. Valencia-Sanchez MA, Liu J, Hannon GJ, Parker R (2006) Control of translation and mRNA degradation by miRNAs and siRNAs. Genes Dev 20(5):515–524. doi:10.1101/gad.1399806

    Article  CAS  PubMed  Google Scholar 

  6. Winter J, Jung S, Keller S, Gregory RI, Diederichs S (2009) Many roads to maturity: microRNA biogenesis pathways and their regulation. Nat Cell Biol 11(3):228–234. doi:10.1038/ncb0309-228

    Article  CAS  PubMed  Google Scholar 

  7. He L, Hannon GJ (2004) MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet 5(7):522–531. doi:10.1038/nrg1379

    Article  CAS  PubMed  Google Scholar 

  8. Hammond SM, Caudy AA, Hannon GJ (2001) Post-transcriptional gene silencing by double-stranded RNA. Nat Rev Genet 2(2):110–119. doi:10.1038/35052556

    Article  CAS  PubMed  Google Scholar 

  9. Fakhry M, Hamade E, Badran B, Buchet R, Magne D (2013) Molecular mechanisms of mesenchymal stem cell differentiation towards osteoblasts. World J Stem Cells 5(4):136–148. doi:10.4252/wjsc.v5.i4.136

    Article  PubMed  PubMed Central  Google Scholar 

  10. Lian JB, Stein GS, van Wijnen AJ, Stein JL, Hassan MQ, Gaur T et al (2012) MicroRNA control of bone formation and homeostasis. Nat Rev Endocrinol 8(4):212–227. doi:10.1038/nrendo.2011.234

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Taipaleenmaki H, Bjerre Hokland L, Chen L, Kauppinen S, Kassem M (2012) Mechanisms in endocrinology: micro-RNAs: targets for enhancing osteoblast differentiation and bone formation. Eur J Endocrinol 166(3):359–371. doi:10.1530/EJE-11-0646

    Article  CAS  PubMed  Google Scholar 

  12. Nugent M (2014) MicroRNA function and dysregulation in bone tumors: the evidence to date. Cancer Manag Res 6:15–25. doi:10.2147/CMAR.S53928

    Article  PubMed  PubMed Central  Google Scholar 

  13. Nugent M (2015) MicroRNAs: exploring new horizons in osteoarthritis. Osteoarthr Cartil. doi:10.1016/j.joca.2015.10.018

    PubMed  Google Scholar 

  14. Nugent M (2015) microRNA and bone cancer. Adv Exp Med Biol 889:201–230. doi:10.1007/978-3-319-23730-5_11

    Article  CAS  PubMed  Google Scholar 

  15. Nugent M, Miller N, Kerin MJ (2011) MicroRNAs in colorectal cancer: function, dysregulation and potential as novel biomarkers. Eur J Surg Oncol 37(8):649–654. doi:10.1016/j.ejso.2011.05.005

    Article  CAS  PubMed  Google Scholar 

  16. Nigro JM, Cho KR, Fearon ER, Kern SE, Ruppert JM, Oliner JD et al (1991) Scrambled exons. Cell 64(3):607–613

    Article  CAS  PubMed  Google Scholar 

  17. Dou C, Cao Z, Yang B, Ding N, Hou T, Luo F et al (2016) Changing expression profiles of lncRNAs, mRNAs, circRNAs and miRNAs during osteoclastogenesis. Sci Rep 6:21499. doi:10.1038/srep21499

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Memczak S, Jens M, Elefsinioti A, Torti F, Krueger J, Rybak A et al (2013) Circular RNAs are a large class of animal RNAs with regulatory potency. Nature 495(7441):333–338. doi:10.1038/nature11928

    Article  CAS  PubMed  Google Scholar 

  19. Ernst C, Morton CC (2013) Identification and function of long non-coding RNA. Front Cell Neurosci 7:168. doi:10.3389/fncel.2013.00168

    Article  PubMed  PubMed Central  Google Scholar 

  20. Liang WC, Fu WM, Wang YB, Sun YX, Xu LL, Wong CW et al (2016) H19 activates Wnt signaling and promotes osteoblast differentiation by functioning as a competing endogenous RNA. Sci Rep 6:20121. doi:10.1038/srep20121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Huang Y, Zheng Y, Jia L, Li W (2015) Long noncoding RNA H19 promotes osteoblast differentiation via TGF-beta1/Smad3/HDAC signaling pathway by deriving miR-675. Stem Cells 33(12):3481–3492. doi:10.1002/stem.2225

    Article  CAS  PubMed  Google Scholar 

  22. Wang L, Wang Y, Li Z, Li Z, Yu B (2015) Differential expression of long noncoding ribonucleic acids during osteogenic differentiation of human bone marrow mesenchymal stem cells. Int Orthop 39(5):1013–1019. doi:10.1007/s00264-015-2683-0

    Article  PubMed  Google Scholar 

  23. De-Ugarte L, Yoskovitz G, Balcells S, Guerri-Fernandez R, Martinez-Diaz S, Mellibovsky L et al (2015) MiRNA profiling of whole trabecular bone: identification of osteoporosis-related changes in MiRNAs in human hip bones. BMC Med Genom 8(1):75. doi:10.1186/s12920-015-0149-2

    Article  Google Scholar 

  24. Garmilla-Ezquerra P, Sanudo C, Delgado-Calle J, Perez-Nunez MI, Sumillera M, Riancho JA (2015) Analysis of the bone microRNome in osteoporotic fractures. Calcif Tissue Int 96(1):30–37. doi:10.1007/s00223-014-9935-7

    Article  CAS  PubMed  Google Scholar 

  25. Jones SW, Watkins G, Le Good N, Roberts S, Murphy CL, Brockbank SM et al (2009) The identification of differentially expressed microRNA in osteoarthritic tissue that modulate the production of TNF-alpha and MMP13. Osteoarthr Cartil 17(4):464–472. doi:10.1016/j.joca.2008.09.012

    Article  CAS  PubMed  Google Scholar 

  26. Watson L, Elliman SJ, Coleman CM (2014) From isolation to implantation: a concise review of mesenchymal stem cell therapy in bone fracture repair. Stem Cell Res Ther 5(2):51. doi:10.1186/scrt439

    Article  PubMed  PubMed Central  Google Scholar 

  27. Huang J, Zhao L, Xing L, Chen D (2010) MicroRNA-204 regulates Runx2 protein expression and mesenchymal progenitor cell differentiation. Stem Cells 28(2):357–364. doi:10.1002/stem.288

    PubMed  PubMed Central  Google Scholar 

  28. 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(3):313–324. doi:10.1016/j.scr.2012.11.007

    Article  CAS  PubMed  Google Scholar 

  29. 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(49):20794–20799. doi:10.1073/pnas.0909311106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Almeida MI, Silva AM, Vasconcelos DM, Almeida CR, Caires H, Pinto MT et al (2015) miR-195 in human primary mesenchymal stromal/stem cells regulates proliferation, osteogenesis and paracrine effect on angiogenesis. Oncotarget. doi:10.18632/oncotarget.6589

    Google Scholar 

  31. Li Z, Hassan MQ, Volinia S, van Wijnen AJ, Stein JL, Croce CM et al (2008) A microRNA signature for a BMP2-induced osteoblast lineage commitment program. Proc Natl Acad Sci USA 105(37):13906–13911. doi:10.1073/pnas.0804438105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kim EJ, Kang IH, Lee JW, Jang WG, Koh JT (2013) MiR-433 mediates ERRgamma-suppressed osteoblast differentiation via direct targeting to Runx2 mRNA in C3H10T1/2 cells. Life Sci 92(10):562–568. doi:10.1016/j.lfs.2013.01.015

    Article  CAS  PubMed  Google Scholar 

  33. Schmidt Y, Simunovic F, Strassburg S, Pfeifer D, Stark GB, Finkenzeller G (2015) miR-126 regulates platelet-derived growth factor receptor-alpha expression and migration of primary human osteoblasts. Biol Chem 396(1):61–70. doi:10.1515/hsz-2014-0168

    Article  CAS  PubMed  Google Scholar 

  34. Schoolmeesters A, Eklund T, Leake D, Vermeulen A, Smith Q, Force Aldred S et al (2009) Functional profiling reveals critical role for miRNA in differentiation of human mesenchymal stem cells. PLoS ONE 4(5):e5605. doi:10.1371/journal.pone.0005605

    Article  PubMed  PubMed Central  Google Scholar 

  35. 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(12):3666–3677. doi:10.1172/JCI39832

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 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(8):1953–1963. doi:10.1002/jbmr.377

    Article  CAS  PubMed  Google Scholar 

  37. Kapinas K, Delany AM (2011) MicroRNA biogenesis and regulation of bone remodeling. Arthritis Res Ther 13(3):220. doi:10.1186/ar3325

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 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(21):3955–3961. doi:10.1091/mbc.E11-04-0356

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Li H, Li T, Fan J, Fan L, Wang S, Weng X et al (2015) miR-216a rescues dexamethasone suppression of osteogenesis, promotes osteoblast differentiation and enhances bone formation, by regulating c-Cbl-mediated PI3K/AKT pathway. Cell Death Differ 22(12):1935–1945. doi:10.1038/cdd.2015.99

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Sun Y, Xu L, Huang S, Hou Y, Liu Y, Chan KM et al (2015) mir-21 overexpressing mesenchymal stem cells accelerate fracture healing in a rat closed femur fracture model. Biomed Res Int 2015:412327. doi:10.1155/2015/412327

    PubMed  PubMed Central  Google Scholar 

  41. Tu M, Tang J, He H, Cheng P, Chen C (2016) MiR-142-5p promotes bone repair by maintaining osteoblast activity. J Bone Miner Metab. doi:10.1007/s00774-016-0757-8

    PubMed  Google Scholar 

  42. 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(1):93–100. doi:10.1038/nm.3026

    Article  PubMed  Google Scholar 

  43. Li KC, Chang YH, Yeh CL, Hu YC (2016) Healing of osteoporotic bone defects by baculovirus-engineered bone marrow-derived MSCs expressing MicroRNA sponges. Biomaterials 74:155–166. doi:10.1016/j.biomaterials.2015.09.046

    Article  CAS  PubMed  Google Scholar 

  44. Wang S, Tang C, Zhang Q, Chen W (2014) Reduced miR-9 and miR-181a expression down-regulates Bim concentration and promote osteoclasts survival. Int J Clin Exp Pathol 7(5):2209–2218

    PubMed  PubMed Central  Google Scholar 

  45. Hadjiargyrou M, Zhi J, Komatsu DE (2016) Identification of the microRNA transcriptome during the early phases of mammalian fracture repair. Bone 87:78–88. doi:10.1016/j.bone.2016.03.011

    Article  CAS  PubMed  Google Scholar 

  46. Waki T, Lee SY, Niikura T, Iwakura T, Dogaki Y, Okumachi E et al (2016) Profiling microRNA expression during fracture healing. BMC Musculoskelet Disord 17:83. doi:10.1186/s12891-016-0931-0

    Article  PubMed  PubMed Central  Google Scholar 

  47. Waki T, Lee SY, Niikura T, Iwakura T, Dogaki Y, Okumachi E et al (2015) Profiling microRNA expression in fracture nonunions: Potential role of microRNAs in nonunion formation studied in a rat model. Bone Joint J 97-B(8):1144–1151. doi:10.1302/0301-620X.97B8.34966

    Article  CAS  PubMed  Google Scholar 

  48. Xiao W, Bao ZX, Zhang CY, Zhang XY, Shi LJ, Zhou ZT et al (2012) Upregulation of miR-31* is negatively associated with recurrent/newly formed oral leukoplakia. PLoS ONE 7(6):e38648. doi:10.1371/journal.pone.0038648

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. 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(1):321–331. doi:10.1016/j.gene.2013.06.021

    Article  CAS  PubMed  Google Scholar 

  50. Xie Q, Wang Z, Bi X, Zhou H, Wang Y, Gu P et al (2014) Effects of miR-31 on the osteogenesis of human mesenchymal stem cells. Biochem Biophys Res Commun 446(1):98–104. doi:10.1016/j.bbrc.2014.02.058

    Article  CAS  PubMed  Google Scholar 

  51. Yamagishi M, Nakano K, Miyake A, Yamochi T, Kagami Y, Tsutsumi A et al (2012) Polycomb-mediated loss of miR-31 activates NIK-dependent NF-kappaB pathway in adult T cell leukemia and other cancers. Cancer Cell 21(1):121–135. doi:10.1016/j.ccr.2011.12.015

    Article  CAS  PubMed  Google Scholar 

  52. 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(7):1844–1856. doi:10.1002/jcb.23106

    Article  CAS  PubMed  Google Scholar 

  53. Taganov KD, Boldin MP, Chang KJ, Baltimore D (2006) NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci USA 103(33):12481–12486. doi:10.1073/pnas.0605298103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Chen Q, Wang H, Liu Y, Song Y, Lai L, Han Q et al (2012) Inducible microRNA-223 down-regulation promotes TLR-triggered IL-6 and IL-1beta production in macrophages by targeting STAT3. PLoS ONE 7(8):e42971. doi:10.1371/journal.pone.0042971

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Haneklaus M, Gerlic M, O’Neill LA, Masters SL (2013) miR-223: infection, inflammation and cancer. J Intern Med 274(3):215–226. doi:10.1111/joim.12099

    Article  CAS  PubMed  Google Scholar 

  56. He B, Zhang ZK, Liu J, He YX, Tang T, Li J et al (2016) Bioinformatics and microarray analysis of miRNAs in aged female mice model implied new molecular mechanisms for impaired fracture healing. Int J Mol Sci. doi:10.3390/ijms17081260

    Google Scholar 

  57. Turchinovich A, Weiz L, Burwinkel B (2012) Extracellular miRNAs: the mystery of their origin and function. Trends Biochem Sci 37(11):460–465. doi:10.1016/j.tibs.2012.08.003

    Article  CAS  PubMed  Google Scholar 

  58. Heneghan HMMN, Lowery AJ, Sweeney KJ, Kerin MJ (2009) Circulating microRNAs as novel minimally invasive biomarkers for breast cancer. Ann Surg 251:499–505

    Article  Google Scholar 

  59. Nugent M, Miller N, Kerin MJ (2012) Circulating miR-34a levels are reduced in colorectal cancer. J Surg Oncol 106(8):947–952. doi:10.1002/jso.23174

    Article  CAS  PubMed  Google Scholar 

  60. Chen X, Ba Y, Ma L, Cai X, Yin Y, Wang K et al (2008) Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res 18(10):997–1006. doi:10.1038/cr.2008.282

    Article  CAS  PubMed  Google Scholar 

  61. Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman SK, Pogosova-Agadjanyan EL et al (2008) Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci USA 105(30):10513–10518. doi:10.1073/pnas.0804549105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Cai H, Zhao H, Tang J, Wu H (2014) Serum miR-195 is a diagnostic and prognostic marker for osteosarcoma. J Surg Res. doi:10.1016/j.jss.2014.11.025

    Google Scholar 

  63. Panach L, Mifsut D, Tarin JJ, Cano A, Garcia-Perez MA (2015) Serum circulating microRNAs as biomarkers of osteoporotic fracture. Calcif Tissue Int 97(5):495–505. doi:10.1007/s00223-015-0036-z

    Article  CAS  PubMed  Google Scholar 

  64. Seeliger C, Karpinski K, Haug AT, Vester H, Schmitt A, Bauer JS et al (2014) Five freely circulating miRNAs and bone tissue miRNAs are associated with osteoporotic fractures. J Bone Miner Res 29(8):1718–1728. doi:10.1002/jbmr.2175

    Article  CAS  PubMed  Google Scholar 

  65. Weilner S, Skalicky S, Salzer B, Keider V, Wagner M, Hildner F et al (2015) Differentially circulating miRNAs after recent osteoporotic fractures can influence osteogenic differentiation. Bone 79:43–51. doi:10.1016/j.bone.2015.05.027

    Article  CAS  PubMed  Google Scholar 

  66. Murata K, Ito H, Yoshitomi H, Yamamoto K, Fukuda A, Yoshikawa J et al (2014) Inhibition of miR-92a enhances fracture healing via promoting angiogenesis in a model of stabilized fracture in young mice. J Bone Miner Res 29(2):316–326. doi:10.1002/jbmr.2040

    Article  CAS  PubMed  Google Scholar 

  67. Kocijan R, Muschitz C, Geiger E, Skalicky S, Baierl A, Dormann R et al (2016) Circulating microRNA signatures in patients with idiopathic and postmenopausal osteoporosis and fragility fractures. J Clin Endocrinol Metab 101(11):4125–4134. doi:10.1210/jc.2016-2365

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

There is no funding source.

Author information

Authors and Affiliations

  1. Department of Orthopaedic Surgery, Merlin Park Hospital, Galway University Hospitals, Galway, Ireland

    Mary Nugent

Authors
  1. Mary Nugent
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mary Nugent.

Ethics declarations

Conflict of interest

Mary Nugent declares that she has no conflict of interest.

Ethical Approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nugent, M. MicroRNAs and Fracture Healing. Calcif Tissue Int 101, 355–361 (2017). https://doi.org/10.1007/s00223-017-0296-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00223-017-0296-x

Keywords

Search

Navigation