Skip to main content

Advertisement

SpringerLink
Log in

Transcription Factor Runx2 and its Application to Bone Tissue Engineering

  • Published:
Stem Cell Reviews and Reports Aims and scope Submit manuscript

Abstract

Cbfa1/Runx2 is a bone transcription factor homologous to the Drosophila protein, Runt. Runx2 is a master gene that encodes for a protein involved in the osteogenic differentiation process from mesenchymal precursors. It is known that in Cbfa1 deficient mice (Cbfa1−/−) the lack of mature osteoblasts is associated to incomplete bone mineralization. An important aim of modern biology is the development of new molecular tools for identification of therapeutic approaches. Recent discoveries in cell and molecular biology enabled researchers in the bone tissue-engineering field to develop new strategies for gene and cell-based therapies. This review summarizes the process of osteogenic differentiation from mesenchymal stem cells and the importance of bone regeneration is discussed. In particular, given the increasing interest in the study of the transcription factor Runx2, this review highlights the role of this target gene and addresses recent strategies using Runx2 for bone regeneration.

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

Similar content being viewed by others

References

  1. Lemaire, V., Tobin, F. L., Greller, L. D., et al. (2004). Modeling the interactions between osteoblast and osteoclast activities in bone remodelling. Journal of Theoretical Biology, 229, 293–309.

    Article  PubMed  CAS  Google Scholar 

  2. Neve, A., Corrado, F., & Cantatore, P. (2011). Osteoblast physiology in normal and pathological conditions. Cell and Tissue Research, 343, 289–302.

    Article  PubMed  CAS  Google Scholar 

  3. Jilka, R. L., O’Brien, C. A., Bartell, S. M., et al. (2010). Continuous elevation of PTH increases the number of osteoblasts via both osteoclast-dependent and -independent mechanisms. Journal of Bone and Mineral Research, 25, 2427–2437.

    Article  PubMed  CAS  Google Scholar 

  4. Dominici, M., Le Blanc, K., Mueller, I., et al. (2006). Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy, 8, 315–317.

    Article  PubMed  CAS  Google Scholar 

  5. Abdallah, B. M., & Kassem, M. (2008). Human mesenchymal stem cells: From basic biology to clinical applications. Gene Therapy, 15, 109–116.

    Article  PubMed  CAS  Google Scholar 

  6. Dezawa, M., Kanno, H., Hoshino, M., et al. (2004). Specific induction of neuronal cells from bone marrow stromal cells and application for autologous transplantation. The Journal of Clinical Investigation, 113, 1701–1710.

    PubMed  CAS  Google Scholar 

  7. Luk, J. M., Wang, P. P., Lee, C. K., et al. (2005). Hepatic potential of bone marrow stromal cells: Development of in vitro co-culture and intra-portal transplantation models. Journal of Immunological Methods, 305, 39–47.

    Article  PubMed  CAS  Google Scholar 

  8. Himburg, H. A., Muramoto, G. G., Daher, P., et al. (2010). Pleiotrophin regulates the expansion and regeneration of hematopoietic stem cells. Nature Medicine, 16, 475–482.

    Article  PubMed  CAS  Google Scholar 

  9. Janicki, P., Boeuf, S., Steck, E., et al. (2011). Prediction of in vivo bone forming potency of bone marrow-derived human mesenchymal stem cells. European Cells & Materials, 20, 488–507.

    Google Scholar 

  10. Charbord, P. (2010). Bone marrow mesenchymal stem cells. Historical overview and concepts. Human Gene Therapy, 21, 1045–1056.

    Article  PubMed  CAS  Google Scholar 

  11. Luria, E. A., Panasyuk, A. F., & Friedenstein, A. Y. (1971). Fibroblast colony formation from monolayer cultures of blood cells. Transfusion, 11, 345–349.

    Article  PubMed  CAS  Google Scholar 

  12. Foster, L. J., Zeemann, P. A., Li, C., et al. (2005). Differential expression profiling of membrane proteins by quantitative proteomics in a human mesenchymal stem cell line undergoing osteoblast differentiation. Stem Cells, 23, 1367–1377.

    Article  PubMed  CAS  Google Scholar 

  13. Valenti, M. T., Dalle Carbonare, L., Donatelli, L., et al. (2008). Gene expression analysis in osteoblastic differentiation from peripheral blood mesenchymal stem cells. Bone, 43, 1084–1092.

    Article  PubMed  CAS  Google Scholar 

  14. Rosada, C., Justesen, J., Melsvik, D., et al. (2003). The human umbilical cord blood: A potential source for osteoblast progenitor cells. Calcified Tissue International, 72, 135–142.

    Article  PubMed  CAS  Google Scholar 

  15. De Bari, C., Dell’Accio, F., Tylzanowski, P., & Luyten, F. P. (2001). Multipotent mesenchymal stem cells from adult human synovial membrane. Arthritis and Rheumatism, 44, 1928–1942.

    Article  PubMed  Google Scholar 

  16. Miura, M., Gronthos, S., Zhao, M., et al. (2003). Stem cells from human exfoliated deciduous teeth. Proceedings of the National Academy of Sciences of the United States of America, 100, 5807–5812.

    Article  PubMed  CAS  Google Scholar 

  17. De Coppi, P., Bartsch, G., Jr., Siddiqui, M. M., et al. (2007). Isolation of amniotic stem cell lines with potential for therapy. Nature Biotechnology, 25, 100–106.

    Article  PubMed  Google Scholar 

  18. Wagner, W., Wein, F., Seckinger, A., et al. (2005). Comparative characteristics of mesenchymal stem cells from human bone marrow, adipose tissue, and umbilical cord blood. Experimental Hematology, 33, 1402–1416.

    Article  PubMed  CAS  Google Scholar 

  19. Karsenty, G. (1999). The genetic transformation of bone biology. Genes & Development, 13, 3037–3051.

    Article  CAS  Google Scholar 

  20. Jensen, E. D., Gopalakrishnan, R., & Westendorf, J. J. (2010). Regulation of gene expression in osteoblasts. Biofactors, 36, 25–32.

    PubMed  CAS  Google Scholar 

  21. Olsen, B. R., Reginato, A. M., & Wang, W. (2000). Bone development. Annual Review of Cell and Developmental Biology, 16, 191–220.

    Article  PubMed  CAS  Google Scholar 

  22. Franceschi, R. T., Ge, C., & Xiao, G. (2007). Transcriptional regulation of osteoblasts. Annals of the New York Academy of Sciences, 1116, 196–207.

    Article  PubMed  CAS  Google Scholar 

  23. Deng, Z. L., Sharff, K. A., Tang, N., et al. (2008). Regulation of osteogenic differentiation during skeletal development. Frontiers in Bioscience, 13, 2001–2021.

    Article  PubMed  CAS  Google Scholar 

  24. Lian, J. B., Javed, A., Zaidi, S. K., et al. (2004). Regulatory controls for osteoblast growth and differentiation: Role of Runx/Cbfa/AML factors. Critical Reviews in Eukaryotic Gene Expression, 14, 1–41.

    Article  PubMed  CAS  Google Scholar 

  25. Cohen, M. M., Jr. (2009). Perspectives on RUNX genes: An update. American Journal of Medical Genetics, Part A, 149A, 2629–2646.

    Article  CAS  Google Scholar 

  26. Yang, X., Matsuda, K., Bialek, P., et al. (2004). ATF4 is a substrate of RSK2 and an essential regulator of osteoblast biology; implication for Coffin-Lowry syndrome. Cell, 117, 387–398.

    Article  PubMed  CAS  Google Scholar 

  27. Xiao, G., Wang, D., Benson, M. D., et al. (1998). Role of the alpha2-integrin in osteoblast-specific gene expression and activation of the Osf2 transcription factor. Journal of Biological Chemistry, 273, 32988–32994.

    Article  PubMed  CAS  Google Scholar 

  28. Roca, H., Phimphilai, M., Gopalakrishnan, R., et al. (2005). Cooperative interactions between RUNX2 and homeodomain protein-binding sites are critical for the osteoblast-specific expression of the bone sialoprotein gene. Journal of Biological Chemistry, 35, 30845–30855.

    Article  Google Scholar 

  29. Imai, Y., Kurokawa, M., Yamaguchi, Y., et al. (2004). The corepressor mSin3A regulates phosphorylation-induced activation, intranuclear location, and stability of AML1. Molecular and Cellular Biology, 24, 1033–1043.

    Article  PubMed  CAS  Google Scholar 

  30. Shen, Q., & Christakos, S. (2005). The vitamin D receptor, Runx2, and the Notch signaling pathway cooperate in the transcriptional regulation of osteopontin. Journal of Biological Chemistry, 280(49), 40589–40598.

    Article  PubMed  CAS  Google Scholar 

  31. Ylönen, R., Kyrönlahti, T., Sund, M., et al. (2005). Type XIII collagen strongly affects bone formation in transgenic mice. Journal of Bone and Mineral Research, 20, 1381–1393.

    Article  PubMed  Google Scholar 

  32. Otto, F., Lubbert, M., & Stock, M. (2003). Upstream and downstream targets of RUNX proteins. Journal of Cellular Biochemistry, 89, 9–18.

    Article  PubMed  CAS  Google Scholar 

  33. Quarto, N., Behr, B., & Longaker, M. T. (2010). Opposite spectrum of activity of canonical Wnt signaling in the osteogenic context of undifferentiated and differentiated mesenchymal cells: Implications for tissue engineering. Tissue Engineering, Part A, 16, 3185–3197.

    Google Scholar 

  34. Shui, C., Spelsberg, T. C., Riggs, B. L., & Khosla, S. (2003). Changes in Runx2/Cbfa1 expression and activity during osteoblastic differentiation of human bone marrow stromal cells. Journal of Bone and Mineral Research, 18, 213–221.

    Article  PubMed  CAS  Google Scholar 

  35. Hu, R., Liu, W., Li, H., et al. (2011). A RUNX2/MIR-3960/MIR-2861 regulatory feedback loop during mouse osteoblast differentiation. Journal of Biological Chemistry, 286, 12328–12339.

    Article  PubMed  CAS  Google Scholar 

  36. Jensen, E. D., Schroeder, T. M., Bailey, J., et al. (2008). Histone deacetylase 7 associates with Runx2 and represses its activity during osteoblast maturation in a deacetylation-independent manner. Journal of Bone and Mineral Research, 23, 361–372.

    Article  PubMed  CAS  Google Scholar 

  37. Howard, T. D., Paznekas, W. A., Green, E. D., et al. (1997). Mutations in TWIST, a basic helix-loop-helix transcription factor, in Saethre-Chotzen syndrome. Nature Genetics, 15, 36–41.

    Article  PubMed  Google Scholar 

  38. Bialek, P., Kern, B., Yang, X., et al. (2004). A twist code determines the onset of osteoblast differentiation. Developmental Cell, 6, 423–435.

    Article  PubMed  CAS  Google Scholar 

  39. Xiao, G., Jiang, D., Thomas, P., et al. (2000). MAPK pathways activate and phosphorylate the osteoblast-specific transcription factor, Cbfa1. Journal of Biological Chemistry, 11, 4453–4459.

    Article  Google Scholar 

  40. Ge, C., Xiao, G., Jiang, D., et al. (2009). Identification and functional characterization of ERK/MAPK phosphorylation sites in the Runx2 transcription factor. Journal of Biological Chemistry, 20, 32533–32543.

    Article  Google Scholar 

  41. Ogawa, E., Maruyama, M., Kagoshima, H., et al. (1993). PEBP2/PEA2 represents a family of transcription factors homologous to the products of the Drosophila runt gene and the human AML1 gene. Proceedings of the National Academy of Sciences of the United States of America, 90(14), 6859–6863.

    Article  PubMed  CAS  Google Scholar 

  42. Jeong, J. H., Jin, J. S., Kim, H. N., et al. (2008). Expression of Runx2 transcription factor in non-skeletal tissues, sperm and brain. Journal of Cellular Physiology, 217(2), 511–517.

    Article  PubMed  CAS  Google Scholar 

  43. Harada, H., Tagashira, S., Fujiwara, M., et al. (1999). Cbfa1 isoforms exert functional differences in osteoblast differentiation. Journal of Biological Chemistry, 274, 6972–6978.

    Article  PubMed  CAS  Google Scholar 

  44. Geoffroy, V., Corral, D. A., Zhou, L., et al. (1998). Genomic organization, expression of the human CBFA1 gene, and evidence for an alternative splicing event affecting protein function. Mammalian Genome, 9, 54–57.

    Article  PubMed  CAS  Google Scholar 

  45. Caetano-Lopes, J., Canhão, H., & Fonseca, J. E. (2007). Osteoblasts and bone formation. Acta Reumatológica Portuguesa, 32, 103–110.

    PubMed  Google Scholar 

  46. Marie, P., Debiais, F., Cohen-Solal, M., & de Vernejoul, M. C. (2000). New factors controlling bone remodeling. Joint, Bone, Spine, 67, 150–156.

    PubMed  CAS  Google Scholar 

  47. Enomoto, H., Enomoto-Iwamoto, M., Iwamoto, M., et al. (2000). Cbfa1 is a positive regulatory factor in chondrocyte maturation. Journal of Biological Chemistry, 275, 8695–8702.

    Article  PubMed  CAS  Google Scholar 

  48. Park, M. H., Shin, H. I., Choi, J. Y., et al. (2001). Differential expression patterns of Runx2 isoforms in cranial suture morphogenesis. Journal of Bone and Mineral Research, 16, 885–892.

    Article  PubMed  CAS  Google Scholar 

  49. Banerjee, C., Javed, A., Choi, J. Y., et al. (2001). Differential regulation of the two principal Runx2/Cbfa1 n-terminal isoforms in response to bone morphogenetic protein-2 during development of the osteoblast phenotype. Endocrinology, 142, 4026–4039.

    Article  PubMed  CAS  Google Scholar 

  50. Prince, M., Banerjee, C., Javed, A., et al. (2001). Expression and regulation of Runx2/Cbfa1 and osteoblast phenotypic markers during the growth and differentiation of human osteoblasts. Journal of Cellular Biochemistry, 80, 424–440.

    Article  PubMed  CAS  Google Scholar 

  51. Sudhakar, S., Li, Y., Katz, M. S., & Elango, N. (2001). Translational regulation is a control point in RUNX2/Cbfa1 gene expression. Biochemical and Biophysical Research Communications, 289, 616–622.

    Article  PubMed  CAS  Google Scholar 

  52. Drissi, H., Pouliot, A., Koolloos, C., et al. (2002). 1,25-(OH)2-vitamin D3 suppresses the bone-related Runx2/Cbfa1 gene promoter. Experimental Cell Research, 274, 323–333.

    Article  PubMed  CAS  Google Scholar 

  53. Tou, L., Quibria, N., & Alexander, J. M. (2001). Regulation of human cbfa1 gene transcription in osteoblasts by selective estrogen receptor modulators (SERMs). Molecular and Cellular Endocrinology, 183, 71–79.

    Article  PubMed  CAS  Google Scholar 

  54. Nojiri, C., Okano, T., Koyanagi, H., et al. (1992). In vivo protein adsorption on polymers: Visualization of adsorbed proteins on vascular implants in dogs. Journal of Biomaterials Science, Polymer Edition, 4, 75–88.

    CAS  Google Scholar 

  55. Tsaryk, R., Kalbacova, M., Hempel, U., et al. (2007). Response of human endothelial cells to oxidative stress on Ti6Al4V alloy. Biomaterials, 28, 806–813.

    Article  PubMed  CAS  Google Scholar 

  56. LeGeros, R. Z. (1993). Biodegradation and bioresorption of calcium phosphate ceramics. Clinical Materials, 14, 65–88.

    Article  PubMed  CAS  Google Scholar 

  57. Meyer, U., Büchter, A., Wiesmann, H. P., et al. (2005). Basic reactions of osteoblasts on structured material surfaces. European Cells & Materials, 9, 39–49.

    CAS  Google Scholar 

  58. Lucas, N., Bienaime, C., Belloy, C., et al. (2008). Polymer biodegradation: Mechanisms and estimation techniques. Chemosphere, 73, 429–442.

    Article  PubMed  CAS  Google Scholar 

  59. Vallés, G., González-Melendi, P., González-Carrasco, J. L., et al. (2006). Differential inflammatory macrophage response to rutile and titanium particles. Biomaterials, 27, 5199–5211.

    Article  PubMed  Google Scholar 

  60. Sreejalekshmi, K. G., & Nair, P. D. (2011). Biomimeticity in tissue engineering scaffolds through synthetic peptide modifications-altering chemistry for enhanced biological response. Journal of Biomedical Materials Research, Part A, 96, 477–491.

    Article  Google Scholar 

  61. Søballe, K., Hansen, E. S., B-Rasmussen, H., et al. (1992). Tissue ingrowth into titanium and hydroxyapatite-coated implants during stable and unstable mechanical conditions. Journal of Orthopaedic Research, 10, 285–299.

    Article  PubMed  Google Scholar 

  62. Janatova, J. (2000). Activation and control of complement, inflammation, and infection associated with the use of biomedical polymers. ASAIO Journal, 46, S53–S62.

    Article  PubMed  CAS  Google Scholar 

  63. Laurencin, C. T., Ambrosio, A. M., Borden, M. D., & Cooper, J. A., Jr. (1999). Tissue engineering: Orthopedic applications. Annual Review of Biomedical Engineering, 1, 19–46.

    Article  PubMed  CAS  Google Scholar 

  64. Fang, J., Zhu, Y. Y., Smiley, E., et al. (1996). Stimulation of new bone formation by direct transfer of osteogenic plasmid genes. Proceedings of the National Academy of Sciences of the United States of America, 93, 5753–5758.

    Article  PubMed  CAS  Google Scholar 

  65. Franceschi, R. T. (2005). Biological approaches to bone regeneration by gene therapy. Journal of Dental Research, 12, 1093–1103.

    Article  Google Scholar 

  66. Ishihara, A., Zekas, L. J., Weisbrode, S. E., & Bertone, A. L. (2010). Comparative efficacy of dermal fibroblast-mediated and direct adenoviral bone morphogenetic protein-2 gene therapy for bone regeneration in an equine rib model. Gene Therapy, 17, 733–744.

    Article  PubMed  CAS  Google Scholar 

  67. Ishaug-Riley, S. L., Crane-Kruger, G. M., Yaszemski, M. J., & Mikos, A. G. (1998). Three-dimensional culture of rat calvarial osteoblasts in porous biodegradable polymers. Biomaterials, 19, 1405–1412.

    Article  PubMed  CAS  Google Scholar 

  68. Cartmell, S. H., Porter, B. D., García, A. J., & Guldberg, R. E. (2003). Effects of medium perfusion rate on cell seeded three dimensional bone constructs in vitro. Tissue Engineering, 9, 1197–1203.

    Article  PubMed  CAS  Google Scholar 

  69. Buckley, C. T., & O’Kelly, K. U. (2010). Fabrication and characterization of a porous multidomain hydroxyapatite scaffold for bone tissue engineering investigations. Journal of Biomedical Materials Research, Part B, Applied Biomaterials, 2, 459–467.

    Article  Google Scholar 

  70. Kretlow, J. D., & Mikos, A. G. (2008). From material to tissue: Biomaterial development, scaffold fabrication, and tissue engineering. AIChE Journal, 54, 3048–3067.

    Article  PubMed  CAS  Google Scholar 

  71. Cai, X., Tong, H., Shen, X., et al. (2009). Preparation and characterization of homogeneous chitosan–polylactic acid/hydroxyapatite nanocomposite for bone tissue engineering and evaluation of its mechanical properties. Acta Biomaterialia, 5, 2693–2703.

    Article  PubMed  CAS  Google Scholar 

  72. Jose, M. V., Thomas, V., Johnson, K. T., et al. (2009). Aligned PLGA/HA nanofibrous nanocomposite scaffolds for bone tissue engineering. Acta Biomaterialia, 5, 305–315.

    Article  PubMed  CAS  Google Scholar 

  73. Zhao, M., Qiao, M., Harris, S. E., et al. (2004). Smurf1 inhibits osteoblast differentiation and bone formation in vitro and in vivo. Journal of Biological Chemistry, 279, 12854–12859.

    Article  PubMed  CAS  Google Scholar 

  74. Bae, S. & Ryoo, H. (2008). Method to enhance the bone formation activity of Bmp by Runx2 acetylation. U.S. Patent 20080219962.

  75. Jeon, E. J., Lee, K. Y., Choi, N. S., et al. (2006). Bone morphogenetic protein-2 stimulates Runx2 acetylation. Journal of Biological Chemistry, 281(24), 16502–16511.

    Article  PubMed  CAS  Google Scholar 

  76. Byers, B. A., Guldberg, R. E., & García, A. J. (2004). Synergy between genetic and tissue engineering: Runx2 overexpression and in vitro construct development enhance in vivo mineralization. Tissue Engineering, 10, 1757–1766.

    Article  PubMed  CAS  Google Scholar 

  77. Doll, B., Fu, H., Hollinger, J., & Sfeir, C. (2003). Compositions and devices comprising or encoding the Runx2 protein and method of use. U.S. Patent 20030235564.

  78. Ogawa, T. & Jewett, A. (2009). Osteogenic enhancer composit. U.S. Patent 20090324669.

  79. Gillissen, M., Jaworska, M., Orth, M., et al. (1997). Nacystelyn, a novel lysine salt of N-acetylcysteine, to augment cellular antioxidant defence in vitro. Respiratory Medicine, 91, 159–168.

    Article  PubMed  CAS  Google Scholar 

  80. Strong Donna, D., Linkhart Thomas, A., & Dean David, A. (2006). U.S. Patent 7741113.

Download references

Acknowledgment

The authors acknowledge Miss Lucy Percival for revising the English language.

Statement of Interest

The authors have no conflicts of interest to declare.

Author information

Authors and Affiliations

  1. Department of Medicine, Clinic of Internal Medicine, section D, University of Verona, Piazzale Scuro, 10, 37134, Verona, Italy

    Luca Dalle Carbonare & Maria Teresa Valenti

  2. L.U.R.M. University Laboratory for Medical Research, University of Verona, Piazzale Scuro, 10, 37134, Verona, Italy

    Luca Dalle Carbonare, Giulio Innamorati & Maria Teresa Valenti

Authors
  1. Luca Dalle Carbonare
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Giulio Innamorati
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maria Teresa Valenti
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Maria Teresa Valenti.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dalle Carbonare, L., Innamorati, G. & Valenti, M.T. Transcription Factor Runx2 and its Application to Bone Tissue Engineering. Stem Cell Rev and Rep 8, 891–897 (2012). https://doi.org/10.1007/s12015-011-9337-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12015-011-9337-4

Keywords

Search

Navigation