Skip to main content

Advertisement

SpringerLink
Log in

MiR-142-5p promotes bone repair by maintaining osteoblast activity

  • Original Article
  • Published:
Journal of Bone and Mineral Metabolism Aims and scope Submit manuscript

Abstract

MicroRNAs play important roles in regulating bone regeneration and remodeling. However, the pathophysiological roles of microRNAs in bone repair remain unclear. Here we identify a significant upregulation of miR-142-5p correlated with active osteoblastogenesis during the bone healing process. In vitro, miR-142-5p promoted osteoblast activity and matrix mineralization by targeting the gene encoding WW-domain-containing E3 ubiquitin protein ligase 1. We also found that the expression of miR-142-5p in the callus of aged mice was lower than that in the callus of young mice and directly correlated with the age-related delay in bone healing. Furthermore, treatment with agomir-142-5p in the fracture areas stimulated osteoblast activity which repaired the bone fractures in aged mice. Thus, our study revealed that miR-142-5p plays a crucial role in healing fractures by maintaining osteoblast activity, and provided a new molecular target therapeutic strategy for bone healing.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Gardner MJ, Demetrakopoulos D, Shindle MK, Griffith MH, Lane JM (2006) Osteoporosis and skeletal fractures. HSS J 2:62–69

    Article  PubMed  PubMed Central  Google Scholar 

  2. Chrischilles EA, Butler CD, Davis CS, Wallace RB (1991) A model of lifetime osteoporosis impact. Arch Intern Med 151:2026–2032

    Article  CAS  PubMed  Google Scholar 

  3. Riggs BL, Melton LJ 3rd (1995) The worldwide problem of osteoporosis: insights afforded by epidemiology. Bone 17:505S–511S

    Article  CAS  PubMed  Google Scholar 

  4. Nelson FR, Brighton CT, Ryaby J, Simon BJ, Nielson JH, Lorich DG, Bolander M, Seelig J (2003) Use of physical forces in bone healing. J Am Acad Orthop Surg 11:344–354

    Article  PubMed  Google Scholar 

  5. Rozen N, Lewinson D, Bick T, Meretyk S, Soudry M (2007) Role of bone regeneration and turnover modulators in control of fracture. Crit Rev Eukaryot Gene Expr 17:197–213

    Article  CAS  PubMed  Google Scholar 

  6. Mehta M, Strube P, Peters A, Perka C, Hutmacher D, Fratzl P, Duda GN (2010) Influences of age and mechanical stability on volume, microstructure, and mineralization of the fracture callus during bone healing: is osteoclast activity the key to age-related impaired healing? Bone 47:219–228

    Article  CAS  PubMed  Google Scholar 

  7. Claes L, Recknagel S, Ignatius A (2012) Fracture healing under healthy and inflammatory conditions. Nat Rev Rheumatol 8:133–143

    Article  CAS  PubMed  Google Scholar 

  8. Ai-Aql ZS, Alagl AS, Graves DT, Gerstenfeld LC, Einhorn TA (2008) Molecular mechanisms controlling bone formation during fracture healing and distraction osteogenesis. J Dent Res 87:107–118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Nilsson BE, Edwards P (1969) Age and fracture healing: a statistical analysis of 418 cases of tibial shaft fractures. Geriatrics 24:112–117

    CAS  PubMed  Google Scholar 

  10. Ekeland A, Engesoeter LB, Langeland N (1982) Influence of age on mechanical properties of healing fractures and intact bones in rats. Acta Orthop Scand 53:527–534

    Article  CAS  PubMed  Google Scholar 

  11. Meyer RA Jr, Tsahakis PJ, Martin DF, Banks DM, Harrow ME, Kiebzak GM (2001) Age and ovariectomy impair both the normalization of mechanical properties and the accretion of mineral by the fracture callus in rats. J Orthop Res 19:428–435

    Article  PubMed  Google Scholar 

  12. Naik AA, Xie C, Zuscik MJ, Kingsley P, Schwarz EM, Awad H, Guldberg R, Drissi H, Puzas JE, Boyce B et al (2009) Reduced COX-2 expression in aged mice is associated with impaired fracture healing. J Bone Miner Res 24:251–264

    Article  CAS  PubMed  Google Scholar 

  13. Meyer RA, Meyer MH, Phieffer LS, Banks DM (2001) Delayed union of femoral fractures in older rats: decreased gene expression. BMC Musculoskelet Disord 2:2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Carthew RW, Sontheimer EJ (2009) Origins and mechanisms of miRNAs and siRNAs. Cell 136:642–655

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Inose H, Ochi H, Kimura A, Fujita K, Xu R, Sato S, Iwasaki M, Sunamura S, Takeuchi Y, Fukumoto S et al (2009) A microRNA regulatory mechanism of osteoblast differentiation. Proc Natl Acad Sci U S A 106:20794–20799

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Li Z, Hassan MQ, Volinia S, van Wijnen AJ, Stein JL, Croce CM, Lian JB, Stein GS (2008) A microRNA signature for a BMP2-induced osteoblast lineage commitment program. Proc Natl Acad Sci U S A 105:13906–13911

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kobayashi T, Lu J, Cobb BS, Rodda SJ, McMahon AP, Schipani E, Merkenschlager M, Kronenberg HM (2008) Dicer-dependent pathways regulate chondrocyte proliferation and differentiation. Proc Natl Acad Sci U S A 105:1949–1954

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Wei J, Shi Y, Zheng L, Zhou B, Inose H, Wang J, Guo XE, Grosschedl R, Karsenty G (2012) miR-34s inhibit osteoblast proliferation and differentiation in the mouse by targeting SATB2. J Cell Biol 197:509–521

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Li H, Xie H, Liu W, Hu R, Huang B, Tan YF, Xu K, Sheng ZF, Zhou HD, Wu XP 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

  22. Murata K, Ito H, Yoshitomi H, Yamamoto K, Fukuda A, Yoshikawa J, Furu M, Ishikawa M, Shibuya H, Matsuda S (2014) Inhibition of miR-92a enhances fracture healing via promoting angiogenesis in a model of stabilized fracture in young mice. J Bone Miner Res 29:316–326

    Article  CAS  PubMed  Google Scholar 

  23. Zhang X, Yan Z, Zhang J, Gong L, Li W, Cui J, Liu Y, Gao Z, Li J, Shen L et al (2011) Combination of hsa-miR-375 and hsa-miR-142-5p as a predictor for recurrence risk in gastric cancer patients following surgical resection. Ann Oncol 22:2257–2266

    Article  CAS  PubMed  Google Scholar 

  24. Schaefer JS, Montufar-Solis D, Vigneswaran N, Klein JR (2011) Selective upregulation of microRNA expression in peripheral blood leukocytes in IL-10−/− mice precedes expression in the colon. J Immunol 187:5834–5841

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Chaudhuri AD, Yelamanchili SV, Marcondes MC, Fox HS (2013) Up-regulation of microRNA-142 in simian immunodeficiency virus encephalitis leads to repression of sirtuin1. FASEB J 27:3720–3729

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Xu R, Bi C, Song J, Wang L, Ge C, Liu X, Zhang M (2015) Upregulation of miR-142-5p in atherosclerotic plaques and regulation of oxidized low-density lipoprotein-induced apoptosis in macrophages. Mol Med Rep 11:3229–3234

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Jones KB, Salah Z, Del Mare S, Galasso M, Gaudio E, Nuovo GJ, Lovat F, LeBlanc K, Palatini J, Randall RL et al (2012) miRNA signatures associate with pathogenesis and progression of osteosarcoma. Cancer Res 72:1865–1877

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Zhao R, Zhu Y, Sun B (2015) Exploration of the effect of mmu-miR-142-5p on osteoblast and the mechanism. Cell Biochem Biophys 71:255–260

    Article  CAS  PubMed  Google Scholar 

  29. Manigrasso MB, O’Connor JP (2004) Characterization of a closed femur fracture model in mice. J Orthop Trauma 18:687–695

    Article  PubMed  Google Scholar 

  30. Cho TJ, Gerstenfeld LC, Einhorn TA (2002) Differential temporal expression of members of the transforming growth factor beta superfamily during murine fracture healing. J Bone Miner Res 17:513–520

    Article  CAS  PubMed  Google Scholar 

  31. Garcia DM, Baek D, Shin C, Bell GW, Grimson A, Bartel DP (2011) Weak seed-pairing stability and high target-site abundance decrease the proficiency of lsy-6 and other microRNAs. Nat Struct Mol Biol 18:1139–1146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Shu L, Zhang H, Boyce BF, Xing L (2013) Ubiquitin E3 ligase Wwp1 negatively regulates osteoblast function by inhibiting osteoblast differentiation and migration. J Bone Miner Res 28:1925–1935

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Phillips AM (2005) Overview of the fracture healing cascade. Injury 36:S5–S7

    Article  PubMed  Google Scholar 

  34. Ferguson CM, Miclau T, Hu D, Alpern E, Helms JA (1998) Common molecular pathways in skeletal morphogenesis and repair. Ann N Y Acad Sci 857:33–42

    Article  CAS  PubMed  Google Scholar 

  35. Einhorn TA (1998) The cell and molecular biology of fracture healing. Clin Orthop Relat Res (355 Suppl):S7–S21

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Li Z, Hassan MQ, Jafferji M, Aqeilan RI, Garzon R, Croce CM, van Wijnen AJ, Stein JL, Stein GS, Lian JB (2009) Biological functions of miR-29b contribute to positive regulation of osteoblast differentiation. J Biol Chem 284:15676–15684

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Yang L, Cheng P, Chen C, He HB, Xie GQ, Zhou HD, Xie H, Wu XP, Luo XH (2012) miR-93/Sp7 function loop mediates osteoblast mineralization. J Bone Miner Res 27:1598–1606

    Article  CAS  PubMed  Google Scholar 

  40. Vimalraj S, Selvamurugan N (2013) MicroRNAs: synthesis, gene regulation and osteoblast differentiation. Curr Issues Mol Biol 15:7–18

    CAS  PubMed  Google Scholar 

  41. Brennecke J, Hipfner DR, Stark A, Russell RB, Cohen SM (2003) bantam encodes a developmentally regulated microRNA that controls cell proliferation and regulates the proapoptotic gene hid in Drosophila. Cell 113:25–36

    Article  CAS  PubMed  Google Scholar 

  42. Chen X (2004) A microRNA as a translational repressor of APETALA2 in Arabidopsis flower development. Science 303:2022–2025

    Article  CAS  PubMed  Google Scholar 

  43. Olsen PH, Ambros V (1999) The lin-4 regulatory RNA controls developmental timing in Caenorhabditis elegans by blocking LIN-14 protein synthesis after the initiation of translation. Dev Biol 216:671–680

    Article  CAS  PubMed  Google Scholar 

  44. Zhao L, Huang J, Zhang H, Wang Y, Matesic LE, Takahata M, Awad H, Chen D, Xing L (2011) Tumor necrosis factor inhibits mesenchymal stem cell differentiation into osteoblasts via the ubiquitin E3 ligase Wwp1. Stem Cells 29:1601–1610

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from China: Specialized Research Fund for the Doctoral Program of High Education (grant 20110162110038), the Fundamental Research Funds for the Central Universities of Central South University (grant 2012zzts033), and the National Natural Scientific Foundation (grant 81371955).

Author information

Authors and Affiliations

  1. Institute of Endocrinology and Metabolism, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, People’s Republic of China

    Manli Tu

  2. Department of Endocrinology and Metabolism, The First Affiliated Hospital of Soochow University, Suzhou, 215006, Jiangsu, People’s Republic of China

    Chao Chen

  3. Department of Gerontology, The First Hospital Affiliated to Nanjing Medical University, Nanjing, 210029, Jiangsu, People’s Republic of China

    Peng Cheng

  4. Department of Gynaecology and Obstetrics, The First Hospital Affiliated to Nanjing Medical University, Nanjing, 210029, Jiangsu, People’s Republic of China

    Juanjuan Tang

  5. Department of Orthopedics, Xiangya Hospital of Central South University, 87# Xiangya Road, Changsha, 410008, Hunan, People’s Republic of China

    Hongbo He

Authors
  1. Manli Tu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Juanjuan Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hongbo He
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Peng Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chao Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Peng Cheng or Chao Chen.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 25 kb)

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tu, M., Tang, J., He, H. et al. MiR-142-5p promotes bone repair by maintaining osteoblast activity. J Bone Miner Metab 35, 255–264 (2017). https://doi.org/10.1007/s00774-016-0757-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00774-016-0757-8

Keywords

Search

Navigation