Current Osteoporosis Reports

, Volume 11, Issue 2, pp 72–82 | Cite as

MicroRNA Functions in Osteogenesis and Dysfunctions in Osteoporosis

  • Andre J. van Wijnen
  • Jeroen van de Peppel
  • Johannes P. van Leeuwen
  • Jane B. Lian
  • Gary S. Stein
  • Jennifer J. Westendorf
  • Merry-Jo Oursler
  • Hee-Jeong Im
  • Hanna Taipaleenmäki
  • Eric Hesse
  • Scott Riester
  • Sanjeev Kakar
Skeletal Biology (DB Burr, Section Editor)

Abstract

MicroRNAs (miRNAs) are critical post-transcriptional regulators of gene expression that control osteoblast mediated bone formation and osteoclast-related bone remodeling. Deregulation of miRNA mediated mechanisms is emerging as an important pathological factor in bone degeneration (eg, osteoporosis) and other bone-related diseases. MiRNAs are intriguing regulatory molecules that are networked with cell signaling pathways and intricate transcriptional programs through ingenuous circuits with remarkably simple logic. This overview examines key principles by which miRNAs control differentiation of osteoblasts as they evolve from mesenchymal stromal cells during osteogenesis, or of osteoclasts as they originate from monocytic precursors in the hematopoietic lineage during osteoclastogenesis. Of particular note are miRNAs that are temporally upregulated during osteoblastogenesis (eg, miR-218) or osteoclastogenesis (eg, miR-148a). Each miRNA stimulates differentiation by suppressing inhibitory signaling pathways (‘double-negative’ regulation). The excitement surrounding miRNAs in bone biology stems from the prominent effects that individual miRNAs can have on biological transitions during differentiation of skeletal cells and correlations of miRNA dysfunction with bone diseases. MiRNAs have significant clinical potential which is reflected by their versatility as disease-specific biomarkers and their promise as therapeutic agents to ameliorate or reverse bone tissue degeneration.

Keywords

Osteoblast Osteoclast Osteoporosis Skeletal development Bone mineral density Osteogenesis Mesenchymal stem cell miRNA 

References

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

  1. 1.
    Ambros V. MicroRNAs: tiny regulators with great potential. Cell. 2001;107:823–6. Review. PubMed PMID: 11779458.PubMedCrossRefGoogle Scholar
  2. 2.
    •• Lian JB, Stein GS, van Wijnen AJ, Stein JL, Hassan MQ, Gaur T, Zhang Y. MicroRNA control of bone formation and homeostasis. Nat Rev Endocrinol. 2012;8:212–27. doi:10.1038/nrendo.2011.234. Review. PubMed PMID: 22290358. Comprehensive review of the microRNA literature on skeletal development and disease.
  3. 3.
    Miyaki S, Asahara H. Macro view of microRNA function in osteoarthritis. Nat Rev Rheumatol. 2012;8:543–52. doi:10.1038/nrrheum.2012.128. Epub 2012 Aug 14. Review. PubMed PMID: 22890245; PubMed Central PMCID: PMC3572197.PubMedCrossRefGoogle Scholar
  4. 4.
    Xia Z, Chen C, Chen P, Xie H, Luo X. MicroRNAs and their roles in osteoclast differentiation. Front Med. 2011;5:414–9. doi:10.1007/s11684-011-0168-0.Epub2011 Dec 27. Review. PubMed PMID: 22198753.PubMedCrossRefGoogle Scholar
  5. 5.
    Goldring MB, Marcu KB. Epigenomic and microRNA-mediated regulation in cartilage development, homeostasis, and osteoarthritis. Trends Mol Med. 2012;18:109–18. doi:10.1016/j.molmed.2011.11.005.Epub2011 Dec 17. Review. PubMed PMID: 22178468; PubMed Central PMCID: PMC3282171.PubMedCrossRefGoogle Scholar
  6. 6.
    Taipaleenmäki H, Bjerre Hokland L, Chen L, Kauppinen S, Kassem M. Mechanisms in endocrinology: micro-RNAs: targets for enhancing osteoblast differentiation and bone formation. Eur J Endocrinol. 2012;166:359–71. doi:10.1530/EJE-11-0646.Epub2011 Nov 14. Review. PubMed PMID: 22084154.PubMedCrossRefGoogle Scholar
  7. 7.
    • Laine SK, Hentunen T, Laitala-Leinonen T. Do microRNAs regulate bone marrow stem cell niche physiology? Gene. 2012;497:1–9. doi:10.1016/j.gene.2012.01.045. Epub 2012 Jan 28. Review. PubMed PMID: 22306262. Important review that addresses miRNA dependent cell/cell communication in the bone marrow micro-environment.
  8. 8.
    Bernstein E, Kim SY, Carmell MA, Murchison EP, Alcorn H, Li MZ, et al. Dicer is essential for mouse development. Nat Genet. 2003;35:215–7. Epub 2003 Oct 5. Erratum in: Nat Genet. 2003;35:287. PubMed PMID: 14528307.PubMedCrossRefGoogle Scholar
  9. 9.
    Harfe BD, McManus MT, Mansfield JH, Hornstein E, Tabin CJ. The RNaseIII enzyme Dicer is required for morphogenesis but not patterning of the vertebrate limb. Proc Natl Acad Sci U S A. 2005;102:10898–903. Epub 2005 Jul 22. PubMed PMID: 16040801; PubMed Central PMCID: PMC1182454.PubMedCrossRefGoogle Scholar
  10. 10.
    Mudhasani R, Zhu Z, Hutvagner G, Eischen CM, Lyle S, Hall LL, et al. Loss of miRNA biogenesis induces p19Arf-p53 signaling and senescence in primary cells. J Cell Biol. 2008;181:1055–63. doi:10.1083/jcb.200802105. PubMed PMID: 18591425; PubMed Central PMCID: PMC2442212.PubMedCrossRefGoogle Scholar
  11. 11.
    •• Gaur T, Hussain S, Mudhasani R, Parulkar I, Colby JL, Frederick D, et al. 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. 2010;340:10–21. doi:10.1016/j.ydbio.2010.01.008. Epub 2010 Jan 15. PubMed PMID: 20079730; PubMed Central PMCID: PMC2840721. Key study showing a post-natal bone phenotype in microRNA deficient mice.
  12. 12.
    Raaijmakers MH, Mukherjee S, Guo S, Zhang S, Kobayashi T, Schoonmaker JA, et al. Bone progenitor dysfunction induces myelodysplasia and secondary leukemia. Nature. 2010;464:852–7. doi:10.1038/nature08851. Epub 2010 Mar 21. PubMed PMID: 20305640; PubMed Central PMCID: PMC3422863.PubMedCrossRefGoogle Scholar
  13. 13.
    •• Sugatani T, Hruska KA. Impaired micro-RNA pathways diminish osteoclast differentiation and function. J Biol Chem. 2009;284:4667–78. doi:10.1074/jbc.M805777200. Epub 2008 Dec 5. PubMed PMID: 19059913; PubMed Central PMCID: PMC2640963. First in vivo demonstration of a requirement for Dicer in osteoclast-related bone remodeling.
  14. 14.
    • Mizoguchi F, Izu Y, Hayata T, Hemmi H, Nakashima K, Nakamura T, et al. Osteoclast-specific Dicer gene deficiency suppresses osteoclastic bone resorption. J Cell Biochem. 2010;109:866–75. doi:10.1002/jcb.22228. PubMed PMID: 20039311. Important study revealing the biological contribution of Dicer to mature osteoclasts.
  15. 15.
    Suomi S, Taipaleenmäki H, Seppänen A, Ripatti T, Väänänen K, Hentunen T, et al. MicroRNAs regulate osteogenesis and chondrogenesis of mouse bone marrow stromal cells. Gene Regul Syst Bio. 2008;2:177–91. PubMed PMID: 19787082; PubMed Central PMCID: PMC2733092.PubMedGoogle Scholar
  16. 16.
    Laine SK, Alm JJ, Virtanen SP, Aro HT, Laitala-Leinonen TK. MicroRNAs miR-96, miR-124, and miR-199a regulate gene expression in human bone marrow-derived mesenchymal stem cells. J Cell Biochem. 2012;113:2687–95. doi:10.1002/jcb.24144.PubMedCrossRefGoogle Scholar
  17. 17.
    •• Eskildsen T, Taipaleenmäki H, Stenvang J, Abdallah BM, Ditzel N, Nossent AY, et al. MicroRNA-138 regulates osteogenic differentiation of human stromal (mesenchymal) stem cells in vivo. Proc Natl Acad Sci U S A. 2011;108:6139–44. doi:10.1073/pnas.1016758108.Epub2011 Mar 28. PubMed PMID: 21444814; PubMed Central PMCID: PMC3076836. Major study providing proof for miRNA effects on mesenchymal lineage-differentiation in mice using a subcutaneous growth model.
  18. 18.
    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 U S A. 2008;105:13906–11. doi:10.1073/pnas.0804438105. Epub 2008 Sep 10. PubMed PMID: 18784367; PubMed Central PMCID: PMC2544552.PubMedCrossRefGoogle Scholar
  19. 19.
    Li Z, Hassan MQ, Jafferji M, Aqeilan RI, Garzon R, Croce CM, et al. Biological functions of miR-29b contribute to positive regulation of osteoblast differentiation. J Biol Chem. 2009;284:15676–84. doi:10.1074/jbc.M809787200. Epub 2009 Apr 2. PubMed PMID: 19342382; PubMed Central PMCID: PMC2708864.PubMedCrossRefGoogle Scholar
  20. 20.
    Hassan MQ, Gordon JA, 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 U S A. 2010;107:19879–84. doi:10.1073/pnas.1007698107. Epub 2010 Oct 27. PubMed PMID: 20980664; PubMed Central PMCID: PMC2993380.PubMedCrossRefGoogle Scholar
  21. 21.
    •• Hassan MQ, Maeda Y, Taipaleenmaki H, Zhang W, Jafferji M, Gordon JA, et al. miR-218 directs a Wnt signaling circuit to promote differentiation of osteoblasts and osteomimicry of metastatic cancer cells. J Biol Chem. 2012;287:42084–92. doi:10.1074/jbc.M112.377515. Epub 2012 Oct 11. PubMed PMID: 23060446; PubMed Central PMCID: PMC3516754. First identification of a miRNA with osteogenic or osteomimetic properties in, respectively, osseous and non-osseous cells.
  22. 22.
    Sugatani T, Hruska KA. MicroRNA-223 is a key factor in osteoclast differentiation. J Cell Biochem. 2007;101:996–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Sugatani T, Vacher J, Hruska KA. A microRNA expression signature of osteoclastogenesis. Blood. 2011;117:3648–57. doi:10.1182/blood-2010-10-311415.Epub2011 Jan 27. PubMed PMID: 21273303; PubMed Central PMCID: PMC3072882.PubMedCrossRefGoogle Scholar
  24. 24.
    •• Sugatani T, Hruska KA. Down-regulation of miR-21 biogenesis by estrogen action contributes to osteoclastic apoptosis. J Cell Biochem. 2012. [Epub ahead of print]. doi:10.1002/jcb.24471. PubMed PMID: 23238785. Exciting study that clarifies the interplay between miRNAs and estrogen levels.
  25. 25.
    Kagiya T, Nakamura S. Expression profiling of microRNAs in RAW264.7 cells treated with a combination of tumor necrosis factor alpha and RANKL during osteoclast differentiation. J Periodontal Res. 2012. [Epub ahead of print]. doi:10.1111/jre.12017.
  26. 26.
    Zhang J, Zhao H, Chen J, Xia B, Jin Y, Wei W, et al. Interferon-β-induced miR-155 inhibits osteoclast differentiation by targeting SOCS1 and MITF. FEBS Lett. 2012;586:3255–62. doi:10.1016/j.febslet.2012.06.047. Epub 2012 Jul 4.PubMedCrossRefGoogle Scholar
  27. 27.
    Rossi M, Pitari MR, Amodio N, Di Martino MT, Conforti F, Leone E, et al. miR-29b negatively regulates human osteoclastic cell differentiation and function: implications for the treatment of multiple myeloma-related bone disease. J Cell Physiol. 2012. [Epub ahead of print]. doi:10.1002/jcp.24306. PubMed PMID: 23254643.
  28. 28.
    Saltman LH, Javed A, Ribadeneyra J, Hussain S, Young DW, Osdoby P, et al. Organization of transcriptional regulatory machinery in osteoclast nuclei: compartmentalization of Runx1. J Cell Physiol. 2005;204:871–80.PubMedCrossRefGoogle Scholar
  29. 29.
    • Collino F, Deregibus MC, Bruno S, Sterpone L, Aghemo G, Viltono L, et al. Microvesicles derived from adult human bone marrow and tissue specific mesenchymal stem cells shuttle selected pattern of miRNAs. PLoS One. 2010;5:e11803. doi:10.1371/journal.pone.0011803. PubMed PMID: 20668554; PubMed Central PMCID: PMC2910725. Early study that provides evidence for cell/cell contact through miRNA containing microvesicles.
  30. 30.
    • Chen TS, Lai RC, Lee MM, Choo AB, Lee CN, Lim SK. Mesenchymal stem cell secretes microparticles enriched in pre-microRNAs. Nucleic Acids Res. 2010;38:215–24. doi:10.1093/nar/gkp857. Epub 2009 Oct 22. PubMed PMID: 19850715; PubMed Central PMCID: PMC2800221. Concurrent early study also showing microvesicle-related secretuib of miRNAs.
  31. 31.
    Li X, Gibson G, Kim JS, Kroin J, Xu S, van Wijnen AJ, et al. MicroRNA-146a is linked to pain-related pathophysiology of osteoarthritis. Gene. 2011;480:34–41. doi:10.1016/j.gene.2011.03.003.Epub2011 Mar 21. PubMed PMID: 21397669; PubMed Central PMCID: PMC3095758.PubMedCrossRefGoogle Scholar
  32. 32.
    Huang X, Le QT, Giaccia AJ. MiR-210--micromanager of the hypoxia pathway. Trends Mol Med. 2010;16:230–7. doi:10.1016/j.molmed.2010.03.004. Epub 2010 Apr 29. Review. PubMed PMID: 20434954; PubMed Central PMCID: PMC3408219.PubMedCrossRefGoogle Scholar
  33. 33.
    •• Cheng P, Chen C, He HB, Hu R, Zhou HD, Xie H, et al. MiR-148a regulates osteoclastogenesis via targeting MAFB. J Bone Miner Res. 2012. [Epub ahead of print]. doi:10.1002/jbmr.1845. PubMed PMID: 23225151. Compelling paper providing evidence for a ‘double negative’ circuit that promotes osteoclast differentiation.
  34. 34.
    • Zhang Y, Xie RL, Croce CM, Stein JL, Lian JB, van Wijnen AJ, et al. A program of microRNAs controls osteogenic lineage progression by targeting transcription factor Runx2. Proc Natl Acad Sci U S A. 2011;108:9863–8. doi:10.1073/pnas.1018493108.Epub2011 May 31. PubMed PMID: 21628588; PubMed Central PMCID: PMC3116419. Comprehensive study showing that osteogenic activity of transcription factor Runx2 is controlled by a multiplicity of miRNAs. Google Scholar
  35. 35.
    •• Zhang Y, Xie RL, Gordon J, LeBlanc K, Stein JL, Lian JB, et al. Control of mesenchymal lineage progression by microRNAs targeting skeletal gene regulators Trps1 and Runx2. J Biol Chem. 2012;287:21926–35. doi:10.1074/jbc.M112.340398. Epub 2012 Apr 27. PubMed PMID: 22544738; PubMed Central PMCID: PMC3381153. Key paper revealing a miRNA-transcription factor network that regulates mesenchymal lineage allocation.
  36. 36.
    •• 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. doi:10.1083/jcb.201201057. Epub 2012 May 7. PubMed PMID: 22564414; PubMed Central PMCID: PMC3352956. First paper to demonstrate a skeletal phenotype linked to a specific microRNA expressed in osteogenic cells.
  37. 37.
    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. doi:10.1002/stem.288. PubMed PMID: 20039258; PubMed Central PMCID: PMC2837600.PubMedGoogle Scholar
  38. 38.
    Hu R, Liu W, Li H, Yang L, Chen C, Xia ZY, et al. A Runx2/miR-3960/miR-2861 regulatory feedback loop during mouse osteoblast differentiation. J Biol Chem. 2011;286:12328–39. doi:10.1074/jbc.M110.176099.Epub2011 Feb 15. PubMed PMID: 21324897; PubMed Central PMCID: PMC3069436.PubMedCrossRefGoogle Scholar
  39. 39.
    Zhang JF, Fu WM, He ML, Xie WD, Lv Q, Wan G, et al. MiRNA-20a promotes osteogenic differentiation of human mesenchymal stem cells by co-regulating BMP signaling. RNA Biol. 2011;8:829–38. doi:10.4161/rna.8.5.16043.Epub2011Jul28.PubMedCrossRefGoogle Scholar
  40. 40.
    Yang L, Cheng P, Chen C, He HB, Xie GQ, Zhou HD, et al. miR-93/Sp7 function loop mediates osteoblast mineralization. J Bone Miner Res. 2012;27:1598–606. doi:10.1002/jbmr.1621. PubMed PMID: 22467200.PubMedCrossRefGoogle Scholar
  41. 41.
    Zhang JF, Fu WM, He ML, Wang H, Wang WM, Yu SC, et al. MiR-637 maintains the balance between adipocytes and osteoblasts by directly targeting Osterix. Mol Biol Cell. 2011;22:3955–61. doi:10.1091/mbc.E11-04-0356.Epub2011 Aug 31. PubMed PMID: 21880893; PubMed Central PMCID: PMC3204058.PubMedCrossRefGoogle Scholar
  42. 42.
    Wang X, Guo B, Li Q, Peng J, Yang Z, Wang A, et al. miR-214 targets ATF4 to inhibit bone formation. Nat Med. 2013;19:93–100. doi:10.1038/nm.3026. Epub 2012 Dec 9. PubMed PMID: 23223004.PubMedCrossRefGoogle Scholar
  43. 43.
    Li H, Xie H, Liu W, Hu R, Huang B, Tan YF, et al. A novel microRNA targeting HDAC5 regulates osteoblast differentiation in mice and contributes to primary osteoporosis in humans. J Clin Invest. 2009;119:3666–77. doi:10.1172/JCI39832. Epub 2009 Nov 16. Erratum in: J Clin Invest. 2010;120:395. Liao, Er-Yuan [removed]. PubMed PMID: 19920351; PubMed Central PMCID: PMC2786801.PubMedCrossRefGoogle Scholar
  44. 44.
    • Lei SF, Papasian CJ, Deng HW. Polymorphisms in predicted miRNA binding sites and osteoporosis. J Bone Miner Res. 2011;26:72–8. doi:10.1002/jbmr.186. PubMed PMID: 20641033; PubMed Central PMCID: PMC3179316. Solid study that characterizes a miRNA dependent polymorphisms linked to bone mineral density in human patients.
  45. 45.
    Xiao G, Jiang D, Gopalakrishnan R, Franceschi RT. Fibroblast growth factor 2 induction of the osteocalcin gene requires MAPK activity and phosphorylation of the osteoblast transcription factor, Cbfa1/Runx2. J Biol Chem. 2002;277:36181–7. Epub 2002 Aug 28. PubMed PMID: 12110689.PubMedCrossRefGoogle Scholar
  46. 46.
    Teplyuk NM, Haupt LM, Ling L, Dombrowski C, Mun FK, Nathan SS, et al. The osteogenic transcription factor Runx2 regulates components of the fibroblast growth factor/proteoglycan signaling axis in osteoblasts. J Cell Biochem. 2009;107:144–54. doi:10.1002/jcb.22108. PubMed PMID: 19259985; PubMed Central PMCID: PMC2918404.PubMedCrossRefGoogle Scholar
  47. 47.
    • Bae Y, Yang T, Zeng HC, Campeau PM, Chen Y, Bertin T, et al. miRNA-34c regulates Notch signaling during bone development. Hum Mol Genet. 2012;21:2991–3000. doi:10.1093/hmg/dds129. Epub 2012 Apr 12. PubMed PMID: 22498974; PubMed Central PMCID: PMC3373245.Compelling paper that examines the miRNA dependent interplay between osteoclasts and osteoblasts. Google Scholar
  48. 48.
    Pratap J, Galindo M, Zaidi SK, Vradii D, Bhat BM, Robinson JA, et al. Cell growth regulatory role of Runx2 during proliferative expansion of preosteoblasts. Cancer Res. 2003;63:5357–62.PubMedGoogle Scholar
  49. 49.
    Teplyuk NM, Galindo M, Teplyuk VI, Pratap J, Young DW, Lapointe D, et al. Runx2 regulates G protein-coupled signaling pathways to control growth of osteoblast progenitors. J Biol Chem. 2008;283:27585–97. doi:10.1074/jbc.M802453200. Epub 2008 Jul 14. PubMed PMID: 18625716; PubMed Central PMCID: PMC2562077.PubMedCrossRefGoogle Scholar
  50. 50.
    He L, He X, Lowe SW, Hannon GJ. microRNAs join the p53 network-another piece in the tumor-suppression puzzle. Nat Rev Cancer. 2007;7:819–22. Review. PubMed PMID: 17914404.PubMedCrossRefGoogle Scholar
  51. 51.
    Gilad S, Meiri E, Yogev Y, Benjamin S, Lebanony D, Yerushalmi N, et al. Serum microRNAs are promising novel biomarkers. PLoS One. 2008;3:e3148. doi:10.1371/journal.pone.0003148. PubMed PMID: 18773077; PubMed Central PMCID: PMC2519789.PubMedCrossRefGoogle Scholar
  52. 52.
    Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman SK, Pogosova-Agadjanyan EL, et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci U S A. 2008;105:10513–8. doi:10.1073/pnas.0804549105. Epub2008Jul28. PubMed PMID: 18663219; PubMed Central PMCID: PMC2492472.PubMedCrossRefGoogle Scholar
  53. 53.
    •• Wang Y, Li L, Moore BT, Peng XH, Fang X, Lappe JM, et al. MiR-133a in human circulating monocytes: a potential biomarker associated with postmenopausal osteoporosis. PLoS One. 2012;7:e34641. doi:10.1371/journal.pone.0034641. Epub 2012 Apr 10. PubMed PMID: 22506038; PubMed Central PMCID: PMC3323546. First clinically relevant paper indicating the potential utility of circulating microRNAs in predicting differences in bone mineral density in human patients.

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Andre J. van Wijnen
    • 1
  • Jeroen van de Peppel
    • 2
  • Johannes P. van Leeuwen
    • 2
  • Jane B. Lian
    • 3
  • Gary S. Stein
    • 3
  • Jennifer J. Westendorf
    • 1
  • Merry-Jo Oursler
    • 1
  • Hee-Jeong Im
    • 4
  • Hanna Taipaleenmäki
    • 5
  • Eric Hesse
    • 5
  • Scott Riester
    • 1
  • Sanjeev Kakar
    • 1
  1. 1.Departments of Orthopedic Surgery & Biochemistry and Molecular BiologyCenter of Regenerative MedicineRochesterUSA
  2. 2.Department of Internal MedicineErasmus Medical Centre RotterdamRotterdamThe Netherlands
  3. 3.Department of Biochemistry, HSRF 326, Vermont Cancer Center for Basic and Translational ResearchUniversity of Vermont Medical SchoolBurlingtonUSA
  4. 4.Departments of Biochemistry, Internal Medicine (Rheumatology) and Department of Orthopedic SurgeryRush University Medical CenterChicagoUSA
  5. 5.Heisenberg-Group for Molecular Skeletal Biology, Department of Trauma, Hand and Reconstructive SurgeryUniversity Medical Center Hamburg-EppendorfHamburgGermany

Personalised recommendations