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Gene Transfer Approaches to Enhancing Bone Healing

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Bone Regeneration and Repair

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Abstract

Although bone is one of the few organs in the body that can heal spontaneously and restore function without scarring, it has been recognized since the time of Hippocrates that repair is not always satisfactory.Bone healing is inadequate when the loss of bone through, for example, tumor resection or traumatic injury, is extensive enough to produce a critical-sized defect.Healing may also be impaired in much smaller defects, and nonunion following fracture occurs in 5–10%of cases (1–3).

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References

  1. Fernandez, D. L., Ring, D., and Jupiter, J. B. (2001) Surgical management of delayed union and nonunion of distal radius fractures. J. Hand Surg. 26(2), 201–209.

    Article  CAS  Google Scholar 

  2. Rommens, P. M., Coosemans, W., and Broos, P. L. (1989) The difficult healing of segmental fractures of the tibial shaft. Arch. Orthop. Trauma Surg. 108(4), 238–242.

    Article  PubMed  CAS  Google Scholar 

  3. Buchler, U. and Nagy, L. (1995) The issue of vascularity in fractures and non-union of the scaphoid. J. Hand Surg. [Br.] 20(6), 726–735.

    Article  CAS  Google Scholar 

  4. Einhorn, T. A. and Lane, J. M. (1998) Fracture Healing Enhancement. Clin. Orthop. Rel. Res. 335S, 365.

    Google Scholar 

  5. Arrington, E. D., et al. (1996) Complications of iliac crest bone graft harvesting. Clin. Orthop. 329, 300–309.

    Article  PubMed  Google Scholar 

  6. Colterjohn, N. R. and Bednar, D. A. (1997) Procurement of bone graft from the iliac crest. An operative approach with decreased morbidity. J. Bone Joint Surg. 79(5), 756–759.

    PubMed  CAS  Google Scholar 

  7. Kwong, L. M., Jasty, M., and Harris, W. H. (1993) High failure rate of bulk femoral head allografts in total hip acetabular reconstructions at 10 years. J. Arthroplasty 8(4), 341–346.

    Article  PubMed  CAS  Google Scholar 

  8. Bonnarens, F. and Einhorn, T. A. (1984) Production of a standard closed fracture in laboratory animal bone. J. Orthop. Res. 2(1), 97–101.

    Article  PubMed  CAS  Google Scholar 

  9. Einhorn, T. A. (1998) The cell and molecular biology of fracture healing. Clin. Orthop. 355(Suppl), S7–S21.

    PubMed  Google Scholar 

  10. Reddi, A. H. (2001) Bone morphogenetic proteins:from basic science to clinical applications. J. Bone Joint Surg. 83A(Suppl 1, pt 1), S1–S6.

    Google Scholar 

  11. Li, R. H. and Wozney, J. M. (2001) Delivering on the promise of bone morphogenetic proteins. Trends Biotechnol. 19(7), 255–265.

    Article  PubMed  CAS  Google Scholar 

  12. Lieberman, J. R., Daluiski, A., and Einhorn, T. A. (2002) The role of growth factors in the repair of bone. Biology and clinical applications. J. Bone Joint Surg. 84A(6), 1032–1044.

    Google Scholar 

  13. Valentin-Opran, A., et al. (2002) Clinical evaluation of recombinant human bone morphogenetic protein-2. Clin. Orthop. 395, 110–120.

    Article  PubMed  Google Scholar 

  14. Salkeld, S. L., et al. (2001) The effect of osteogenic protein-1 on the healing of segmental bone defects treated with autograft or allograft bone. J. Bone Joint Surg. 83A(6), 803–816.

    Google Scholar 

  15. Bouxsein, M. L., et al. (2001) Recombinant human bone morphogenetic protein-2 accelerates healing in a rabbit ulnar osteotomy model. J. Bone Joint Surg. 83A(8), 1219–1230.

    Google Scholar 

  16. Uludag, H., et al. (2001) Delivery systems for BMPs:factors contributing to protein retention at an application site. J. Bone Joint Surg. 83A(Suppl 1, pt 2), S128–S135.

    Google Scholar 

  17. Talwar, R., et al. (2001) Effects of carrier release kinetics on bone morphogenetic protein-2-induced periodontal regeneration in vivo. J. Clin. Periodontol. 28(4), 340–347.

    Article  PubMed  CAS  Google Scholar 

  18. Niyibizi, C., et al. (1998) Potential role for gene therapy in the enhancement of fracture healing. Clin. Orthop. 355 (Suppl), S148–S153.

    PubMed  Google Scholar 

  19. Lieberman, J., Ghivizzani, S., and Evans, C. (2002) Gene transfer approaches to the healing of bone and cartilage. Mol. Ther. 6(2), 141.

    Article  PubMed  CAS  Google Scholar 

  20. Lieberman, J. R. (2000) Orthopaedic gene therapy. Fracture healing and other nongenetic problems of bone. Clin. Orthop. 379(Suppl), S156–S158.

    PubMed  Google Scholar 

  21. Makarov, S. S., et al. (1996) Suppression of experimental arthritis by gene transfer of interleukin 1 receptor antagonist cDNA. Proc. Natl. Acad. Sci. USA 93(1), 402–406.

    Article  PubMed  CAS  Google Scholar 

  22. Baltzer, A. W. A. and Lieberman, J. (2004) Regional gene therapy to enhance bone repair. Gene Ther. 11, 344–350.

    Article  PubMed  CAS  Google Scholar 

  23. Marshall, E. (2003) Gene therapy. Second child in French trial is found to have leukemia. Science 299(5605), 320.

    Article  PubMed  CAS  Google Scholar 

  24. Evans, C. H., et al. (2004) Orthopaedic gene therapy. Clin. Orthop. Rel. Res. (in press).

    Google Scholar 

  25. Evans, C. H. and Robbins, P. D. (1999) Genetically augmented tissue engineering of the musculoskeletal system. Clin. Orthop. 367(Suppl), S410–S418.

    PubMed  Google Scholar 

  26. Evans, C. H. and Robbins, P. D. (1995) Possible orthopaedic applications of gene therapy. J. Bone Joint Surg. 77A(7), 1103–1114.

    Google Scholar 

  27. Evans, C. H., et al. (2004) Gene therapy for the treatment of musculoskeletal diseases. J. Am. Acad. Orthop. Surg. (in press).

    Google Scholar 

  28. Oligino, T. J., et al. (2000) Vector systems for gene transfer to joints. Clin. Orthop. 379(Suppl), S17–S30.

    PubMed  Google Scholar 

  29. Lieberman, J. R., et al. (1998) Regional gene therapy with a BMP-2-producing murine stromal cell line induces heterotopic and orthotopic bone formation in rodents. J. Orthop. Res. 16(3), 330–339.

    Article  PubMed  CAS  Google Scholar 

  30. Lieberman, J. R., et al. (1999) The effect of regional gene therapy with bone morphogenetic protein-2-producing bonemarrow cells on the repair of segmental femoral defects in rats. J. Bone Joint Surg. 81A(7), 905–917.

    Google Scholar 

  31. Lee, J. Y., et al. (2002) Enhancement of bone healing based on ex vivo gene therapy using human musclederived cells expressing bone morphogenetic protein 2. Hum. Gene Ther. 13(10), 1201–1211.

    Article  PubMed  CAS  Google Scholar 

  32. Gysin, R., et al. (2002) Ex vivo gene therapy with stromal cells transduced with a retroviral vector containing the BMP4 gene completely heals critical size calvarial defect in rats. Gene Ther. 9(15), 991–999.

    Article  PubMed  CAS  Google Scholar 

  33. Alden, T. D., et al. (2000) The use of bone morphogenetic protein gene therapy in craniofacial bone repair. J. Craniofac. Surg. 11(1), 24–30.

    Article  PubMed  CAS  Google Scholar 

  34. Dragoo, J. L., et al. (2003) Bone induction by BMP-2 transduced stem cells derived from human fat. J. Orthop. Res. 21(4), 622–629.

    Article  PubMed  CAS  Google Scholar 

  35. Franceschi, R. T., et al. (2000) Gene therapy for bone formation:in vitro and in vivo osteogenic activity of an adenovirus expressing BMP7. J. Cell Biochem. 78(3), 476–486.

    Article  PubMed  CAS  Google Scholar 

  36. Viggeswarapu, M., et al. (2001) Adenoviral delivery of LIM mineralization protein-1 induces new-bone formation in vitro and in vivo. J. Bone Joint Surg. 83A(3), 364–376.

    Google Scholar 

  37. Krebsbach, P. H., et al. (2000) Gene therapy-directed osteogenesis:BMP-7-transduced human fibroblasts form bone in vivo. Hum. Gene Ther. 11(8), 1201–1210.

    Article  PubMed  CAS  Google Scholar 

  38. Gugala, Z., et al. (2003) Osteoinduction by ex vivo adenovirus-mediated BMP2 delivery is independent of cell type. Gene Ther. 10(16), 1289–1296.

    Article  PubMed  CAS  Google Scholar 

  39. Tsuda, H., et al. (2003) Efficient BMP2 gene transfer and bone formation of mesenchymal stem cells by a fiber-mutant adenoviral vector. Mol. Ther. 7(3), 354–365.

    Article  PubMed  CAS  Google Scholar 

  40. Olmsted-Davis, E. A., et al. (2002) Use of a chimeric adenovirus vector enhances BMP2 production and bone formation. Hum. Gene Ther. 13(11), 1337–1347.

    Article  PubMed  CAS  Google Scholar 

  41. Abe, N., et al. (2002) Enhancement of bone repair with a helper-dependent adenoviral transfer of bone morphogenetic protein-2. Biochem. Biophys. Res. Commun. 297(3), 523–527.

    Article  PubMed  CAS  Google Scholar 

  42. Gysin, R., et al. (2002) Ex vivo gene therapy with stromal cells transduced with a retroviral vector containing the BMP4 gene completely heals critical size calvarial defect in rats. Gene Ther. 9(15), 991–999.

    Article  PubMed  CAS  Google Scholar 

  43. Chen, Y., et al. (2003) Gene therapy for new bone formation using adeno-associated viral bone morphogenetic protein-2 vectors. Gene Ther. 10(16), 1345–1353.

    Article  PubMed  CAS  Google Scholar 

  44. Luk, K. D., et al. (2003) Adeno-associated virus-mediated bone morphogenetic protein-4 gene therapy for in vivo bone formation. Biochem. Biophys. Res. Commun. 308(3), 636–645.

    Article  PubMed  CAS  Google Scholar 

  45. Park, J., et al. (2003) Bone regeneration in critical size defects by cell-mediated BMP-2 gene transfer:a comparison of adenoviral vectors and liposomes. Gene Ther. 10(13), 1089–1098.

    Article  PubMed  CAS  Google Scholar 

  46. Tsuchida, H., et al. (2003) Engineered allogeneic mesenchymal stem cells repair femoral segmental defect in rats. J. Orthop. Res. 21(1), 44–53.

    Article  PubMed  Google Scholar 

  47. Okubo, Y., et al. (2001) In vitro and in vivo studies of a bone morphogenetic protein-2 expressing adenoviral vector. J. Bone Joint Surg. 83A(Suppl 1, pt 2), S99–S104.

    Google Scholar 

  48. Okubo, Y., et al. (2000) Osteoinduction by bone morphogenetic protein-2 via adenoviral vector under transient immunosuppression. Biochem. Biophys. Res. Commun. 267(1), 382–387.

    Article  PubMed  CAS  Google Scholar 

  49. Fang, J., et al. (1996) Stimulation of new bone formation by direct transfer of osteogenic plasmid genes. Proc. Natl. Acad. Sci. USA 93(12), 5753–5758.

    Article  PubMed  CAS  Google Scholar 

  50. Bonadio, J., et al. (1999) Localized, direct plasmid gene delivery in vivo:prolonged therapy results in reproducible tissue regeneration. Nat. Med. 5(7), 753–759.

    Article  PubMed  CAS  Google Scholar 

  51. Musgrave, D. S., et al. (1999) Adenovirus-mediated direct gene therapy with bone morphogenetic protein-2 produces bone. Bone 24(6), 541–547.

    Article  PubMed  CAS  Google Scholar 

  52. Baltzer, A. W., et al. (1999) A gene therapy approach to accelerating bone healing. Evaluation of gene expression in a New Zealand white rabbit model. Knee Surg. Sports Traumatol. Arthrosc. 7(3), 197–202.

    Article  PubMed  CAS  Google Scholar 

  53. Baltzer, A. W., et al. (2000) Genetic enhancement of fracture repair:healing of an experimental segmental defect by adenoviral transfer of the BMP-2 gene. Gene Ther. 7(9), 734–739.

    Article  PubMed  CAS  Google Scholar 

  54. Sonobe, J., et al. (2004) Osteoinduction by bone morphogenetic protein-2 expressing adenoviral vector:application of biomaterial to mask the host immune response. Hum. Gene Ther. 15, 659–668.

    Article  PubMed  CAS  Google Scholar 

  55. Ito, T., et al. (2003) Coxsackievirus and adenovirus receptor (CAR)-positive immature osteoblasts as targets of adenovirus-mediated gene transfer for fracture healing. Gene Ther. 10(18), 1623–1628.

    Article  PubMed  CAS  Google Scholar 

  56. Kawai, M., et al. (2004) Ectopic bone formation by human bone morphogenetic protein-2 gene transfer to skeletal muscle using transcutaneous electroporation. Hum. Gene Ther. 14, 1547–1556.

    Article  CAS  Google Scholar 

  57. Li, J. Z., et al. (2004) Osteogenic potential of five different recombinant human bone morphogenetic protein (BMP) adenoviral vectors in the rat. Gene Ther. (in press).

    Google Scholar 

  58. Boden, S. D., et al. (1998) LMP-1, a LIM-domain protein, mediates BMP-6 effects on bone formation. Endocrinology 139(12), 5125–5134.

    Article  PubMed  CAS  Google Scholar 

  59. Minamide, A., et al. (2003) Mechanism of bone formation with gene transfer of the cDNA encoding for the intracellular protein LMP-1. J. Bone Joint Surg. 85A(6), 1030–1039.

    Google Scholar 

  60. Peng, H., et al. (2002) Synergistic enhancement of bone formation and healing by stem cell-expressed VEGF and bone morphogenetic protein-4. J. Clin. Invest. 110(6), 751–759.

    Article  PubMed  CAS  Google Scholar 

  61. Wang, J. C., et al. (2003) Effect of regional gene therapy with bone morphogenetic protein-2-producing bone marrow cells on spinal fusion in rats. J. Bone Joint Surg. 85A(5), 905–911.

    Google Scholar 

  62. Alden, T. D., et al. (1999) Percutaneous spinal fusion using bone morphogenetic protein-2 gene therapy. J. Neurosurg. 90(1 Suppl), 109–114.

    PubMed  CAS  Google Scholar 

  63. Helm, G. A., et al. (2000) Use of bone morphogenetic protein-9 gene therapy to induce spinal arthrodesis in the rodent. J. Neurosurg. 92(2 Suppl), 191–196.

    PubMed  CAS  Google Scholar 

  64. Chang, S. C., et al. (2003) Ex vivo gene therapy in autologous bone marrow stromal stem cells for tissue-engineered maxillofacial bone regeneration. Gene Ther. 10(24), 2013–2019.

    Article  PubMed  CAS  Google Scholar 

  65. Carmody, E. E., et al. (2002) Viral interleukin-10 gene inhibition of inflammation, osteoclastogenesis, and bone resorption in response to titanium particles. Arthritis Rheum. 46(5), 1298–1308.

    Article  PubMed  CAS  Google Scholar 

  66. Childs, L. M., et al. (2001) Effect of anti-tumor necrosis factor-alpha gene therapy on wear debris-induced osteolysis. J. Bone Joint Surg. 83A(12), 1789–1797.

    Google Scholar 

  67. Sud, S., et al. (2001) Effects of cytokine gene therapy on particulate-induced inflammation in the murine air pouch. Inflammation 25(6), 361–372.

    Article  PubMed  CAS  Google Scholar 

  68. Yang, S., et al. (2002) IL-1Ra and vIL-10 gene transfer using retroviral vectors ameliorates particle-associated inflam-mation in the murine air pouch model. Inflamm. Res. 51(7), 342–350.

    Article  PubMed  CAS  Google Scholar 

  69. Robbins, P. D., Evans, C. H., and Chernajovsky, Y. (2003) Gene therapy for arthritis. Gene Ther. 10(10), 902–911.

    Article  PubMed  CAS  Google Scholar 

  70. Gouze, E., et al. (2001) Gene therapy for rheumatoid arthritis. Curr. Rheumatol. Rep. 3(1), 79–85.

    Article  PubMed  CAS  Google Scholar 

  71. Evans, C. H. and Robbins, P. D. (1999) Gene therapy of arthritis. Intern. Med. 38(3), 233–239.

    PubMed  CAS  Google Scholar 

  72. Evans, C. H., et al. (1999) Gene therapy for rheumatic diseases. Arthritis Rheum. 42(1), 1–16.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Center for Molecular Orthopaedics, Harvard Medical School, Boston, MA

    Oliver Betz PhD, Mark Vrahas MD & Christopher H. Evans PhD

  2. Praxis und Klink für Orthopaedie, Dusseldorf, Germany

    Axel Baltzer MD

  3. Department of Orthopaedic Surgery, David Geffen School of Medicine, University of California, Los Angeles, CA

    Jay R. Lieberman MD

  4. Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, PA

    Paul D. Robbins PhD

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  1. Oliver Betz PhD
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  4. Jay R. Lieberman MD
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Editors and Affiliations

  1. Department of Orthopaedic Surgery David Geffen School of Medicine, University of California, Los Angeles, CA

    Jay R. Lieberman MD

  2. Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT

    Gary E. Friedlaender MD

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© 2005 Humana Press Inc., Totowa, NJ

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Betz, O., Vrahas, M., Baltzer, A., Lieberman, J.R., Robbins, P.D., Evans, C.H. (2005). Gene Transfer Approaches to Enhancing Bone Healing. In: Lieberman, J.R., Friedlaender, G.E. (eds) Bone Regeneration and Repair. Humana Press. https://doi.org/10.1385/1-59259-863-3:157

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  • DOI: https://doi.org/10.1385/1-59259-863-3:157

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