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Journal of Biomedicine and Biotechnology
Volume 2012 (2012), Article ID 601549, 14 pages
http://dx.doi.org/10.1155/2012/601549
Review Article

Bone Morphogenetic Proteins in Craniofacial Surgery: Current Techniques, Clinical Experiences, and the Future of Personalized Stem Cell Therapy

1Laboratory of Craniofacial Biology and Development, Section of Plastic and Reconstructive Surgery, University of Chicago Medical Center, 5841 South Maryland Avenue, MC 3079, Chicago, IL 60637, USA
2Molecular Oncology Laboratory, Department of Surgery, University of Chicago Medical Center, 5841 South Maryland Avenue, MC 3079, Chicago, IL 60637, USA

Received 16 June 2012; Accepted 16 October 2012

Academic Editor: Ji Wu

Copyright © 2012 Kristofer E. Chenard et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. D. J. Verret, Y. Ducic, L. Oxford, and J. Smith, “Hydroxyapatite cement in craniofacial reconstruction,” Otolaryngology, vol. 133, no. 6, pp. 897–899, 2005. View at Publisher · View at Google Scholar · View at Scopus
  2. S. Touzet, J. Ferri, T. Wojcik, and G. Raoul, “Complications of calvarial bone harvesting for maxillofacial reconstructions,” Journal of Craniofacial Surgery, vol. 22, no. 1, pp. 178–181, 2011. View at Publisher · View at Google Scholar · View at Scopus
  3. L. A. Whitaker, I. R. Munro, and K. E. Salyer, “Combined report of problems and complications in 793 craniofacial operations,” Plastic and Reconstructive Surgery, vol. 64, no. 2, pp. 198–203, 1979. View at Scopus
  4. C. M. L. Clokie and G. K. B. Sándor, “Reconstruction of 10 major mandibular defects using bioimplants containing BMP-7,” Journal of the Canadian Dental Association, vol. 74, no. 1, pp. 67–72, 2008. View at Scopus
  5. J. G. Seiler 3rd and J. Johnson, “Iliac crest autogenous bone grafting: donor site complications,” Journal of the Southern Orthopaedic Association, vol. 9, no. 2, pp. 91–97, 2000. View at Scopus
  6. M. A. Hoard, T. J. Bill, and R. L. Campbell, “Reduction in morbidity after iliac crest bone harvesting: the concept of preemptive analgesia,” Journal of Craniofacial Surgery, vol. 9, no. 5, pp. 448–451, 1998. View at Scopus
  7. P. Tessier, H. Kawamoto, D. Matthews et al., “Autogenous bone grafts and bone substitutes—tools and techniques: I. A 20,000-case experience in maxillofacial and craniofacial surgery,” Plastic and Reconstructive Surgery, vol. 116, no. 5, supplement, pp. 6S–24S, 2005. View at Publisher · View at Google Scholar · View at Scopus
  8. P. Tessier, H. Kawamoto, D. Matthews et al., “Taking bone grafts from the anterior and posterior ilium—tools and techniques: II. A 6800-case experience in maxillofacial and craniofacial surgery,” Plastic and Reconstructive Surgery, vol. 116, no. 5, supplement, pp. 25S–37S, 2005. View at Publisher · View at Google Scholar · View at Scopus
  9. P. Tessier, H. Kawamoto, D. Matthews et al., “Taking long rib grafts for facial reconstruction—tools and techniques: III. A 2900-case experience in maxillofacial and craniofacial surgery,” Plastic and Reconstructive Surgery, vol. 116, no. 5, supplement, pp. 38S–46S, 2005. View at Publisher · View at Google Scholar · View at Scopus
  10. P. Tessier, H. Kawamoto, D. Matthews et al., “Taking tibial grafts in the diaphysis and upper epiphysis—Tools and techniques: IV. A 650-case experience in maxillofacial and craniofacial surgery,” Plastic and Reconstructive Surgery, vol. 116, no. 5, supplement, pp. 47S–53S, 2005. View at Publisher · View at Google Scholar · View at Scopus
  11. P. Tessier, H. Kawamoto, J. Posnick, Y. Raulo, J. F. Tulasne, and S. A. Wolfe, “Taking calvarial grafts, either split in situ or splitting of the parietal bone flap ex vivo—tools and techniques: V. A 9650-case experience in craniofacial and maxillofacial surgery,” Plastic and Reconstructive Surgery, vol. 116, no. 5, supplement, pp. 54S–71S, 2005. View at Publisher · View at Google Scholar · View at Scopus
  12. P. Tessier, H. Kawamoto, J. Posnick, Y. Raulo, J. F. Tulasne, and S. A. Wolfe, “Complications of harvesting autogenous bone grafts: a group experience of 20,000 cases,” Plastic and Reconstructive Surgery, vol. 116, no. 5, supplement, pp. 72S–73S, 2005. View at Publisher · View at Google Scholar · View at Scopus
  13. P. Tessier, H. Kawamoto, J. Posnick, Y. Raulo, J. F. Tulasne, and S. A. Wolfe, “Taking calvarial grafts—tools and techniques: VI. The splitting of a parietal bone “flap”,” Plastic and Reconstructive Surgery, vol. 116, no. 5, supplement, pp. 74S–88S, 2005. View at Publisher · View at Google Scholar · View at Scopus
  14. M. J. Citardi and C. D. Friedman, “Nonvascularized autogenous bone grafts for craniofacial skeletal augmentation and replacement,” Otolaryngologic Clinics of North America, vol. 27, no. 5, pp. 891–910, 1994. View at Scopus
  15. D. M. Smith, A. M. Afifi, G. M. Cooper, M. P. Mooney, K. G. Marra, and J. E. Losee, “BMP-2YBased repair of large-scale calvarial defects in an experimental model: regenerative surgery in cranioplasty,” Journal of Craniofacial Surgery, vol. 19, no. 5, pp. 1315–1322, 2008. View at Publisher · View at Google Scholar · View at Scopus
  16. D. M. Smith, G. M. Cooper, A. M. Afifi et al., “Regenerative surgery in cranioplasty revisited: the role of adipose-derived stem cells and BMP-2,” Plastic and Reconstructive Surgery, vol. 128, no. 5, pp. 1053–1060, 2011. View at Publisher · View at Google Scholar · View at Scopus
  17. D. C. Wan, O. O. Aalami, Z. Wang et al., “Differential gene expression between juvenile and adult dura mater: a window into what genes play a role in the regeneration of membranous bone,” Plastic and Reconstructive Surgery, vol. 118, no. 4, pp. 851–861, 2006. View at Publisher · View at Google Scholar · View at Scopus
  18. D. M. Smith, G. M. Cooper, M. P. Mooney, K. G. Marra, and J. E. Losee, “Bone morphogenetic protein 2 therapy for craniofacial surgery,” Journal of Craniofacial Surgery, vol. 19, no. 5, pp. 1244–1259, 2008. View at Publisher · View at Google Scholar · View at Scopus
  19. S. D. Moss, E. Joganic, K. H. Manwaring, and S. P. Beals, “Transplanted demineralized bone graft in cranial reconstructive surgery,” Pediatric Neurosurgery, vol. 23, no. 4, pp. 199–205, 1995. View at Scopus
  20. M. Chin, T. Ng, W. K. Tom, and M. Carstens, “Repair of alveolar clefts with recombinant human bone morphogenetic protein (rhBMP-2) in patients with clefts,” Journal of Craniofacial Surgery, vol. 16, no. 5, pp. 778–789, 2005. View at Publisher · View at Google Scholar · View at Scopus
  21. M. H. Carstens, M. Chin, T. Ng, and W. K. Tom, “Reconstruction of #7 facial cleft with distraction-assisted in situ osteogenesis (DISO): role of recombinant human bone morphogenetic protein-2 with helistat-activated collagen implant,” Journal of Craniofacial Surgery, vol. 16, no. 6, pp. 1023–1032, 2005. View at Publisher · View at Google Scholar · View at Scopus
  22. A. S. Herford, P. J. Boyne, R. Rawson, and R. P. Williams, “Bone morphogenetic protein-induced repair of the premaxillary cleft,” Journal of Oral and Maxillofacial Surgery, vol. 65, no. 11, pp. 2136–2141, 2007. View at Publisher · View at Google Scholar · View at Scopus
  23. B. P. Dickinson, R. K. Ashley, K. L. Wasson et al., “Reduced morbidity and improved healing with bone morphogenic protein-2 in older patients with alveolar cleft defects,” Plastic and Reconstructive Surgery, vol. 121, no. 1, pp. 209–217, 2008. View at Publisher · View at Google Scholar · View at Scopus
  24. M. A. Fallucco and M. H. Carstens, “Primary reconstruction of alveolar clefts using recombinant human bone morphogenic protein-2: clinical and radiographic outcomes,” Journal of Craniofacial Surgery, vol. 20, no. 8, supplement, pp. 1759–1764, 2009. View at Publisher · View at Google Scholar · View at Scopus
  25. N. Alonso, D. Y. S. Tanikawa, R. D. S. Freitas, L. Canan, T. O. Ozawa, and D. L. Rocha, “Evaluation of maxillary alveolar reconstruction using a resorbable collagen sponge with recombinant human bone morphogenetic protein-2 in cleft lip and palate patients,” Tissue Engineering C, vol. 16, no. 5, pp. 1183–1189, 2010. View at Publisher · View at Google Scholar · View at Scopus
  26. H. G. Moghadam, M. R. Urist, G. K. B. Sandor, and C. M. L. Clokie, “Successful mandibular reconstruction using a BMP bioimplant,” Journal of Craniofacial Surgery, vol. 12, no. 2, pp. 119–127, 2001. View at Scopus
  27. C. Ferretti and U. Ripamonti, “Human segmental mandibular defects treated with naturally derived bone morphogenetic proteins,” Journal of Craniofacial Surgery, vol. 13, no. 3, pp. 434–444, 2002. View at Scopus
  28. P. H. Warnke, J. Wiltfang, I. Springer et al., “Man as living bioreactor: fate of an exogenously prepared customized tissue-engineered mandible,” Biomaterials, vol. 27, no. 17, pp. 3163–3167, 2006. View at Publisher · View at Google Scholar · View at Scopus
  29. T. G. Carter, P. S. Brar, A. Tolas, and O. R. Beirne, “Off-label use of recombinant human bone morphogenetic protein-2 (rhBMP-2) for reconstruction of mandibular bone defects in humans,” Journal of Oral and Maxillofacial Surgery, vol. 66, no. 7, pp. 1417–1425, 2008. View at Publisher · View at Google Scholar · View at Scopus
  30. R. Tieghi, G. Consorti, and L. C. Clauser, “Contouring of the forehead irregularities (washboard effect) with bone biomaterial,” Journal of Craniofacial Surgery, vol. 23, no. 3, pp. 932–934, 2012. View at Publisher · View at Google Scholar · View at Scopus
  31. S. Ehrmantraut, A. Naumann, V. Willnecker et al., “Vitalization of porous polyethylene (Medpor) with chondrocytes promotes early implant vascularization and incorporation into the host tissue,” Tissue Engineering A, vol. 18, no. 15-16, pp. 1562–1572, 2012. View at Publisher · View at Google Scholar · View at Scopus
  32. M. P. Bostrom and D. A. Seigerman, “The clinical use of allografts, demineralized bone matrices, synthetic bone graft substitutes and osteoinductive growth factors: a survey study,” HSS Journal, vol. 1, no. 1, pp. 9–18, 2005.
  33. A. Kolk, J. Handschel, W. Drescher, et al., “Current trends and future perspectives of bone substitute materials—from space holders to innovative biomaterials,” Journal of Cranio-Maxillofacial Surgery. In press.
  34. R. K. Wong, B. M. Gandolfi, H. St-Hilaire, M. W. Wise, and M. Moses, “Complications of hydroxyapatite bone cement in secondary pediatric craniofacial reconstruction,” Journal of Craniofacial Surgery, vol. 22, no. 1, pp. 247–251, 2011. View at Publisher · View at Google Scholar · View at Scopus
  35. L. Chen, W. Jiang, J. Huang et al., “Insulin-like growth factor 2 (IGF-2) potentiates BMP-9-induced osteogenic differentiation and bone formation,” Journal of Bone and Mineral Research, vol. 25, no. 11, pp. 2447–2459, 2010. View at Publisher · View at Google Scholar · View at Scopus
  36. J. Luo, M. Tang, J. Huang et al., “TGFβ/BMP type I receptors ALK1 and ALK2 are essential for BMP9-induced osteogenic signaling in mesenchymal stem cells,” Journal of Biological Chemistry, vol. 285, no. 38, pp. 29588–29598, 2010. View at Publisher · View at Google Scholar · View at Scopus
  37. Q. Kang, W. X. Song, Q. Luo et al., “A Comprehensive analysis of the dual roles of BMPs in regulating adipogenic and osteogenic differentiation of mesenchymal progenitor cells,” Stem Cells and Development, vol. 18, no. 4, pp. 545–558, 2009. View at Publisher · View at Google Scholar · View at Scopus
  38. K. A. Sharff, W. X. Song, X. Luo et al., “Hey1 basic helix-loop-helix protein plays an important role in mediating BMP9-induced osteogenic differentiation of mesenchymal progenitor cells,” Journal of Biological Chemistry, vol. 284, no. 1, pp. 649–659, 2009. View at Publisher · View at Google Scholar · View at Scopus
  39. N. Tang, W. X. Song, J. Luo et al., “BMP-9-induced osteogenic differentiation of mesenchymal progenitors requires functional canonical Wnt/β-catenin signalling,” Journal of Cellular and Molecular Medicine, vol. 13, no. 8 B, pp. 2448–2464, 2009. View at Publisher · View at Google Scholar · View at Scopus
  40. Q. Kang, M. H. Sun, H. Cheng et al., “Characterization of the distinct orthotopic bone-forming activity of 14 BMPs using recombinant adenovirus-mediated gene delivery,” Gene Therapy, vol. 11, no. 17, pp. 1312–1320, 2004. View at Publisher · View at Google Scholar · View at Scopus
  41. H. Cheng, W. Jiang, F. M. Phillips et al., “Osteogenic activity of the fourteen types of human bone morphogenetic proteins (BMPs),” Journal of Bone and Joint Surgery A, vol. 85, no. 8, pp. 1544–1552, 2003. View at Scopus
  42. Y. Peng, Q. Kang, H. Cheng et al., “Transcriptional characterization of bone morphogenetic proteins (BMPs)-mediated osteogenic signaling,” Journal of Cellular Biochemistry, vol. 90, no. 6, pp. 1149–1165, 2003. View at Publisher · View at Google Scholar · View at Scopus
  43. T. C. He, “Distinct osteogenic activity of BMPs and their orthopaedic applications,” Journal of Musculoskeletal Neuronal Interactions, vol. 5, no. 4, pp. 363–366, 2005. View at Scopus
  44. A. N. Glied and R. A. Kraut, “Off-label use of rhBMP-2 for reconstruction of critical-sized mandibular defects,” The New York State Dental Journal, vol. 76, no. 4, pp. 32–35, 2010. View at Scopus
  45. A. S. Herford, E. Stoffella, and R. Tandon, “Reconstruction of mandibular defects using bone morphogenic protein: can growth factors replace the need for autologous bone grafts? A systematic review of the literature,” Plastic Surgery International, vol. 2011, Article ID 165824, 7 pages, 2011. View at Publisher · View at Google Scholar
  46. K. B. Lee, S. S. Murray, C. E. Taghavi et al., “Bone morphogenetic protein-binding peptide reduces the inflammatory response to recombinant human bone morphogenetic protein-2 and recombinant human bone morphogenetic protein-7 in a rodent model of soft-tissue inflammation,” Spine Journal, vol. 11, no. 6, pp. 568–576, 2011. View at Publisher · View at Google Scholar · View at Scopus
  47. K.-B. Lee, C. E. Taghavi, S. S. Murray, K.-J. Song, G. Keorochana, and J. C. Wang, “BMP induced inflammation: a comparison of rhBMP-7 and rhBMP-2,” Journal of Orthopaedic Research, vol. 30, no. 12, pp. 1985–1994, 2012. View at Publisher · View at Google Scholar · View at Scopus
  48. M. M. Shah, M. D. Smyth, and A. S. Woo, “Adverse facial edema associated with off-label use of recombinant human bone morphogenetic protein-2 in cranial reconstruction for craniosynostosis: case report,” Journal of Neurosurgery, vol. 1, no. 3, pp. 255–257, 2008. View at Publisher · View at Google Scholar · View at Scopus
  49. B. Perri, M. Cooper, C. Lauryssen, and N. Anand, “Adverse swelling associated with use of rh-BMP-2 in anterior cervical discectomy and fusion: a case study,” Spine Journal, vol. 7, no. 2, pp. 235–239, 2007. View at Publisher · View at Google Scholar · View at Scopus
  50. L. M. Tumialan and G. E. Rodts, “Adverse swelling associated with use of rh-BMP-2 in anterior cervical discectomy and fusion,” Spine Journal, vol. 7, no. 4, pp. 509–510, 2007.
  51. M. Laursen, K. Høy, E. S. Hansen, J. Gelineck, F. B. Christensen, and C. E. Bünger, “Recombinant bone morphogenetic protein-7 as an intracorporal bone growth stimulator in unstable thoracolumbar burst fractures in humans: preliminary results,” European Spine Journal, vol. 8, no. 6, pp. 485–490, 1999. View at Publisher · View at Google Scholar · View at Scopus
  52. C. Jeppsson and P. Aspenberg, “BMP-2 can inhibit bone healing: bone-chamber study in rabbits,” Acta Orthopaedica, vol. 67, no. 6, pp. 589–592, 1996. View at Publisher · View at Google Scholar · View at Scopus
  53. L. Attisano and J. L. Wrana, “Signal transduction by the TGF-β superfamily,” Science, vol. 296, no. 5573, pp. 1646–1647, 2002. View at Publisher · View at Google Scholar · View at Scopus
  54. G. C. Blobe, W. P. Schiemann, and H. F. Lodish, “Role of transforming growth factor β in human disease,” New England Journal of Medicine, vol. 342, no. 18, pp. 1350–1358, 2000. View at Publisher · View at Google Scholar · View at Scopus
  55. R. Derynck and X. H. Feng, “TGF-beta receptor signaling,” Biochimica et Biophysica Acta, vol. 1333, no. 2, pp. F105–F150, 1997.
  56. J. Massagué and Y.-G. Chen, “Controlling TGF-β signaling,” Genes and Development, vol. 14, no. 6, pp. 627–644, 2000. View at Scopus
  57. J. Massague, “The transforming growth factor-β family,” Annual Review of Cell Biology, vol. 6, pp. 597–641, 1990. View at Scopus
  58. S. Ross and C. S. Hill, “How the Smads regulate transcription,” International Journal of Biochemistry and Cell Biology, vol. 40, no. 3, pp. 383–408, 2008. View at Publisher · View at Google Scholar · View at Scopus
  59. B. R. Olsen, A. M. Reginato, and W. Wang, “Bone development,” Annual Review of Cell and Developmental Biology, vol. 16, pp. 191–220, 2000. View at Publisher · View at Google Scholar · View at Scopus
  60. T. R. S. Amand, Y. Zhang, E. V. Semina et al., “Antagonistic signals between BMP4 and FGF8 define the expression of Pitx1 and Pitx2 in mouse tooth-forming anlage,” Developmental Biology, vol. 217, no. 2, pp. 323–332, 2000. View at Publisher · View at Google Scholar · View at Scopus
  61. E. Ozkaynak, P. N. J. Schnegelsberg, D. F. Jin et al., “Osteogenic protein-2. A new member of the transforming growth factor-β superfamily expressed early in embryogenesis,” Journal of Biological Chemistry, vol. 267, no. 35, pp. 25220–25227, 1992. View at Scopus
  62. J. M. Wozney, V. Rosen, A. J. Celeste et al., “Novel regulators of bone formation: molecular clones and activities,” Science, vol. 242, no. 4885, pp. 1528–1534, 1988. View at Scopus
  63. J. O. Hollinger, J. M. Schmitt, D. C. Buck et al., “Recombinant human bone morphogenetic protein-2 and collagen for bone regeneration,” Journal of Biomedical Materials Research, vol. 43, no. 4, pp. 356–364, 1998. View at Publisher · View at Google Scholar · View at Scopus
  64. R. G. Hammonds, R. Schwall, A. Dudley et al., “Bone-inducing activity of mature BMP-2b produced from a hybrid BMP-2a/2b precursor,” Molecular Endocrinology, vol. 5, no. 1, pp. 149–155, 1991. View at Scopus
  65. E. A. Wang, V. Rosen, J. S. D'Alessandro et al., “Recombinant human bone morphogenetic protein induces bone formation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 87, no. 6, pp. 2220–2224, 1990. View at Scopus
  66. M. R. Urist, “Bone: formation by autoinduction,” Science, vol. 150, no. 3698, pp. 893–899, 1965. View at Scopus
  67. B. L. M. Hogan, “Bone morphogenetic proteins: multifunctional regulators of vertebrate development,” Genes and Development, vol. 10, no. 13, pp. 1580–1594, 1996. View at Scopus
  68. C. H. Heldin, K. Miyazono, and P. Ten Dijke, “TGF-β signalling from cell membrane to nucleus through SMAD proteins,” Nature, vol. 390, no. 6659, pp. 465–471, 1997. View at Publisher · View at Google Scholar · View at Scopus
  69. J. Massague, “TGF-beta signal transduction,” Annual Review of Biochemistry, vol. 67, pp. 753–791, 1998.
  70. J. Massagué and F. Weis-Garcia, “Serine/threonine kinase receptors: mediators of transforming growth factor beta family signals,” Cancer Surveys, vol. 27, pp. 41–64, 1996. View at Scopus
  71. Y. Shi and J. Massagué, “Mechanisms of TGF-β signaling from cell membrane to the nucleus,” Cell, vol. 113, no. 6, pp. 685–700, 2003. View at Publisher · View at Google Scholar · View at Scopus
  72. H. Yamashita, P. Ten Dijke, C. H. Heldin, and K. Miyazono, “Bone morphogenetic protein receptors,” Bone, vol. 19, no. 6, pp. 569–574, 1996. View at Publisher · View at Google Scholar · View at Scopus
  73. D. Chen, M. Zhao, and G. R. Mundy, “Bone morphogenetic proteins,” Growth Factors, vol. 22, no. 4, pp. 233–241, 2004. View at Publisher · View at Google Scholar · View at Scopus
  74. S. Itoh, F. Itoh, M. J. Goumans, and P. T. Dijke, “Signaling of transforming growth factor-β family members through Smad proteins,” European Journal of Biochemistry, vol. 267, no. 24, pp. 6954–6967, 2000. View at Publisher · View at Google Scholar · View at Scopus
  75. L. Attisano and J. L. Wrana, “Smads as transcriptional co-modulators,” Current Opinion in Cell Biology, vol. 12, no. 2, pp. 235–243, 2000. View at Publisher · View at Google Scholar · View at Scopus
  76. A. Javed, F. Afzal, J. S. Bae et al., “Specific residues of RUNX2 are obligatory for formation of BMP2-induced RUNX2-SMAD complex to promote osteoblast differentiation,” Cells Tissues Organs, vol. 189, no. 1–4, pp. 133–137, 2008. View at Publisher · View at Google Scholar · View at Scopus
  77. K. S. Lee, H. J. Kim, Q. L. Li et al., “Runx2 is a common target of transforming growth factor β1 and bone morphogenetic protein 2, and cooperation between Runx2 and Smad5 induces osteoblast-specific gene expression in the pluripotent mesenchymal precursor cell line C2C12,” Molecular and Cellular Biology, vol. 20, no. 23, pp. 8783–8792, 2000. View at Publisher · View at Google Scholar · View at Scopus
  78. M. Phimphilai, Z. Zhao, H. Boules, H. Roca, and R. T. Franceschi, “BMP signaling is required for RUNX2-dependent induction of the osteoblast phenotype,” Journal of Bone and Mineral Research, vol. 21, no. 4, pp. 637–646, 2006. View at Publisher · View at Google Scholar · View at Scopus
  79. Y. W. Zhang, N. Yasui, K. Ito et al., “A RUNX2/PEBP2αA/CBFA1 mutation displaying impaired transactivation and Smad interaction in cleidocranial dysplasia,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 19, pp. 10549–10554, 2000. View at Scopus
  80. K. Miyazono, P. Ten Dijke, and C. H. Heldin, “TGF-β signaling by smad proteins,” Advances in Immunology, vol. 75, pp. 115–157, 2000. View at Scopus
  81. P. T. Dijke, M. J. Goumans, F. Itoh, and S. Itoh, “Regulation of cell proliferation by Smad proteins,” Journal of Cellular Physiology, vol. 191, no. 1, pp. 1–16, 2002. View at Publisher · View at Google Scholar · View at Scopus
  82. K. Miyazono, P. Ten Dijke, and C. H. Heldin, “TGF-β signaling by Smad proteins,” Advances in Immunology, vol. 75, pp. 115–157, 2000. View at Scopus
  83. J. L. Wrana, “Regulation of Smad activity,” Cell, vol. 100, no. 2, pp. 189–192, 2000. View at Scopus
  84. G. Chen, C. Deng, and Y.-P. Li, “TGF-β and BMP signaling in osteoblast differentiation and bone formation,” International Journal of Biological Sciences, vol. 8, no. 2, pp. 272–288, 2012. View at Publisher · View at Google Scholar · View at Scopus
  85. K. S. Lee, S. H. Hong, and S. C. Bae, “Both the Smad and p38 MAPK pathways play a crucial role in Runx2 expression following induction by transforming growth factor-β and bone morphogenetic protein,” Oncogene, vol. 21, no. 47, pp. 7156–7163, 2002. View at Publisher · View at Google Scholar · View at Scopus
  86. R. Nishimura, K. Hata, T. Matsubara, M. Wakabayashi, and T. Yoneda, “Regulation of bone and cartilage development by network between BMP signalling and transcription factors,” Journal of Biochemistry, vol. 151, no. 3, pp. 247–254, 2012. View at Publisher · View at Google Scholar · View at Scopus
  87. G. Luther, E. R. Wagner, G. Zhu et al., “BMP-9 induced osteogenic differentiation of mesenchymal stem cells: molecular mechanism and therapeutic potential,” Current Gene Therapy, vol. 11, no. 3, pp. 229–240, 2011. View at Scopus
  88. J. Luo, M. H. Sun, Q. Kang et al., “Gene therapy for bone regeneration,” Current Gene Therapy, vol. 5, no. 2, pp. 167–179, 2005. View at Publisher · View at Google Scholar · View at Scopus
  89. H. H. Luu, W. X. Song, X. Luo et al., “Distinct roles of bone morphogenetic proteins in osteogenic differentiation of mesenchymal stem cells,” Journal of Orthopaedic Research, vol. 25, no. 5, pp. 665–677, 2007. View at Publisher · View at Google Scholar · View at Scopus
  90. T. Reya and H. Clevers, “Wnt signalling in stem cells and cancer,” Nature, vol. 434, no. 7035, pp. 843–850, 2005. View at Publisher · View at Google Scholar · View at Scopus
  91. J. H. Jonason, G. Xiao, M. Zhang, L. Xing, and D. Chen, “Post-translational regulation of Runx2 in bone and cartilage,” Journal of Dental Research, vol. 88, no. 8, pp. 693–703, 2009. View at Publisher · View at Google Scholar · View at Scopus
  92. T. Komori, H. Yagi, S. Nomura et al., “Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts,” Cell, vol. 89, no. 5, pp. 755–764, 1997. View at Scopus
  93. F. Otto, A. P. Thornell, T. Crompton et al., “Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development,” Cell, vol. 89, no. 5, pp. 765–771, 1997. View at Scopus
  94. H. Kobayashi, Y. H. Gao, C. Ueta, A. Yamaguchi, and T. Komori, “Multilineage differentiation of Cbfa1-deficient calvarial cells in vitro,” Biochemical and Biophysical Research Communications, vol. 273, no. 2, pp. 630–636, 2000. View at Publisher · View at Google Scholar · View at Scopus
  95. C. F. Lai and S. L. Cheng, “Signal transductions induced by bone morphogenetic protein-2 and transforming growth factor-β in normal human osteoblastic cells,” Journal of Biological Chemistry, vol. 277, no. 18, pp. 15514–15522, 2002. View at Publisher · View at Google Scholar · View at Scopus
  96. N. Takahashi, K. Maeda, A. Ishihara, S. Uehara, and Y. Kobayashi, “Regulatory mechanism of osteoclastogenesis by RANKL and Wnt signals,” Frontiers in Bioscience, vol. 16, no. 1, pp. 21–30, 2011. View at Publisher · View at Google Scholar · View at Scopus
  97. F. Kugimiya, H. Kawaguchi, S. Kamekura et al., “Involvement of endogenous bone morphogenetic protein (BMP) 2 and BMP6 in bone formation,” Journal of Biological Chemistry, vol. 280, no. 42, pp. 35704–35712, 2005. View at Publisher · View at Google Scholar · View at Scopus
  98. X. B. Wu, Y. Li, A. Schneider et al., “Impaired osteoblastic differentiation, reduced bone formation, and severe osteoporosis in noggin-overexpressing mice,” Journal of Clinical Investigation, vol. 112, no. 6, pp. 924–934, 2003. View at Publisher · View at Google Scholar · View at Scopus
  99. E. Gazzerro, R. C. Pereira, V. Jorgetti, S. Olson, A. N. Economides, and E. Canalis, “Skeletal overexpression of gremlin impairs bone formation and causes osteopenia,” Endocrinology, vol. 146, no. 2, pp. 655–665, 2005. View at Publisher · View at Google Scholar · View at Scopus
  100. R. D. Devlin, Z. Du, R. C. Pereira et al., “Skeletal overexpression of noggin results in osteopenia and reduced bone formation,” Endocrinology, vol. 144, no. 5, pp. 1972–1978, 2003. View at Publisher · View at Google Scholar · View at Scopus
  101. K. Tsuji, A. Bandyopadhyay, B. D. Harfe et al., “BMP2 activity, although dispensable for bone formation, is required for the initiation of fracture healing,” Nature Genetics, vol. 38, no. 12, pp. 1424–1429, 2006. View at Publisher · View at Google Scholar · View at Scopus
  102. R. D. Farhadieh, R. Dickinson, Y. Yu, M. P. Gianoutsos, and W. R. Walsh, “The role of transforming growth factor-beta, insulin-like growth factor I, and basic fibroblast growth factor in distraction osteogenesis of the mandible,” Journal of Craniofacial Surgery, vol. 10, no. 1, pp. 80–86, 1999. View at Scopus
  103. R. D. Farhadieh, M. P. Gianoutsos, Y. Yu, and W. R. Walsh, “The role of bone morphogenetic proteins BMP-2 and BMP-4 and their related postreceptor signaling system (Smads) in distraction osteogenesis of the mandible,” The Journal of Craniofacial Surgery, vol. 15, no. 5, pp. 714–718, 2004. View at Scopus
  104. A. Khanal, I. Yoshioka, K. Tominaga, N. Furuta, M. Habu, and J. Fukuda, “The BMP signaling and its Smads in mandibular distraction osteogenesis,” Oral Diseases, vol. 14, no. 4, pp. 347–355, 2008. View at Publisher · View at Google Scholar · View at Scopus
  105. T. C. He, S. Zhou, L. T. Da Costa, J. Yu, K. W. Kinzler, and B. Vogelstein, “A simplified system for generating recombinant adenoviruses,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 5, pp. 2509–2514, 1998. View at Publisher · View at Google Scholar · View at Scopus
  106. M. E. Bahamonde and K. M. Lyons, “BMP3: to be or not to be a BMP,” Journal of Bone and Joint Surgery A, vol. 83, no. 1, pp. S56–S62, 2001. View at Scopus
  107. Y. Peng, Q. Kang, Q. Luo et al., “Inhibitor of DNA binding/differentiation helix-loop-helix proteins mediate bone morphogenetic protein-induced osteoblast differentiation of mesenchymal stem cells,” Journal of Biological Chemistry, vol. 279, no. 31, pp. 32941–32949, 2004. View at Publisher · View at Google Scholar · View at Scopus
  108. J. Nickel, M. K. Dreyer, T. Kirsch, and W. Sebald, “The crystal structure of the BMP-2:BMPR-IA complex and the generation of BMP-2 antagonists,” Journal of Bone and Joint Surgery A, vol. 83, supplement 1, pp. S7–S14, 2001. View at Scopus
  109. M. A. Brown, Q. Zhao, K. A. Baker et al., “Crystal structure of BMP-9 and functional interactions with pro-region and receptors,” Journal of Biological Chemistry, vol. 280, no. 26, pp. 25111–25118, 2005. View at Publisher · View at Google Scholar · View at Scopus
  110. A. H. Hassanein, R. A. Couto, K. C. Kurek, G. F. Rogers, J. B. Mulliken, and A. K. Greene, “Experimental comparison of cranial particulate bone graft, rhBMP-2, and split cranial bone graft for inlay cranioplasty,” The Cleft Palate-Craniofacial Journal. In press.
  111. C. R. Kinsella, J. J. Cray, D. M. Smith et al., “Novel model of calvarial defect in an infected unfavorable wound: reconstruction with rhBMP-2. part II,” Journal of Craniofacial Surgery, vol. 23, no. 2, pp. 410–414, 2012. View at Publisher · View at Google Scholar · View at Scopus
  112. G. E. Decesare, G. M. Cooper, D. M. Smith et al., “Novel animal model of calvarial defect in an infected unfavorable wound: reconstruction with rhBMP-2,” Plastic and Reconstructive Surgery, vol. 127, no. 2, pp. 588–594, 2011. View at Publisher · View at Google Scholar · View at Scopus
  113. J. Li, J. Hong, Q. Zheng et al., “Repair of rat cranial bone defects with nHAC/PLLA and BMP-2-related peptide or rhBMP-2,” Journal of Orthopaedic Research, vol. 29, no. 11, pp. 1745–1752, 2011. View at Publisher · View at Google Scholar · View at Scopus
  114. T. Aghaloo, C. M. Cowan, X. Zhang et al., “The effect of NELL1 and bone morphogenetic protein-2 on calvarial bone regeneration,” Journal of Oral and Maxillofacial Surgery, vol. 68, no. 2, pp. 300–308, 2010. View at Publisher · View at Google Scholar · View at Scopus
  115. J. H. Lee, C. S. Kim, K. H. Choi et al., “The induction of bone formation in rat calvarial defects and subcutaneous tissues by recombinant human BMP-2, produced in Escherichia coli,” Biomaterials, vol. 31, no. 13, pp. 3512–3519, 2010. View at Publisher · View at Google Scholar · View at Scopus
  116. A. A. Sawyer, S. J. Song, E. Susanto et al., “The stimulation of healing within a rat calvarial defect by mPCL-TCP/collagen scaffolds loaded with rhBMP-2,” Biomaterials, vol. 30, no. 13, pp. 2479–2488, 2009. View at Publisher · View at Google Scholar · View at Scopus
  117. S. J. Hong, C. S. Kim, D. K. Han et al., “The effect of a fibrin-fibronectin/β-tricalcium phosphate/recombinant human bone morphogenetic protein-2 system on bone formation in rat calvarial defects,” Biomaterials, vol. 27, no. 20, pp. 3810–3816, 2006. View at Publisher · View at Google Scholar · View at Scopus
  118. I. N. G. Springer, Y. Açil, S. Kuchenbecker et al., “Bone graft versus BMP-7 in a critical size defect—cranioplasty in a growing infant model,” Bone, vol. 37, no. 4, pp. 563–569, 2005. View at Publisher · View at Google Scholar · View at Scopus
  119. J. P. Sheehan, J. M. Sheehan, H. Seeherman, M. Quigg, and G. A. Helm, “The safety and utility of recombinant human bone morphogenetic protein-2 for cranial procedures in a nonhuman primate model,” Journal of Neurosurgery, vol. 98, no. 1, pp. 125–130, 2003. View at Scopus
  120. Y. Sawada, A. Hokugo, A. Nishiura et al., “A trial of alveolar cleft bone regeneration by controlled release of bone morphogenetic protein: an experimental study in rabbits,” Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology and Endodontology, vol. 108, no. 6, pp. 812–820, 2009. View at Publisher · View at Google Scholar · View at Scopus
  121. Y. Takahashi, M. Yamamoto, K. Yamada, O. Kawakami, and Y. Tabata, “Skull bone regeneration in nonhuman primates by controlled release of bone morphogenetic protein-2 from a biodegradable hydrogel,” Tissue Engineering, vol. 13, no. 2, pp. 293–300, 2007. View at Publisher · View at Google Scholar · View at Scopus
  122. S. Schultze-Mosgau, B. Lehner, F. Rödel et al., “Expression of bone morphogenic protein 2/4, transforming growth factor-β1, and bone matrix protein expression in healing area between vascular tibia grafts and irradiated bone—experimental model of osteonecrosis,” International Journal of Radiation Oncology Biology Physics, vol. 61, no. 4, pp. 1189–1196, 2005. View at Publisher · View at Google Scholar · View at Scopus
  123. I. N. G. Springer, P. Niehoff, Y. Açil et al., “BMP-2 and bFGF in an irradiated bone model,” Journal of Cranio-Maxillofacial Surgery, vol. 36, no. 4, pp. 210–217, 2008. View at Publisher · View at Google Scholar · View at Scopus
  124. H. F. Sailer and E. Kolb, “Application of purified hone morphogenetic protein (BMP) preparations in cranio-maxillo-facial surgery. Reconstruction in craniofacial malformations and post-traumatic or operative defects of the skull with lyophilized cartilage and BMP,” Journal of Cranio-Maxillo-Facial Surgery, vol. 22, no. 4, pp. 191–199, 1994. View at Scopus
  125. H. F. Sailer and E. Kolb, “Application of purified bone morphogenetic protein (BMP) in cranio- maxillo-facial surgery. BMP in compromised surgical reconstructions using titanium implants,” Journal of Cranio-Maxillo-Facial Surgery, vol. 22, no. 1, pp. 2–11, 1994. View at Scopus
  126. M. Chao, T. Donovan, C. Sotelo, and M. H. Carstens, “In situ osteogenesis of hemimandible with rhBMP-2 in a 9-year-old boy: osteoinduction via stem cell concentration,” Journal of Craniofacial Surgery, vol. 17, no. 3, pp. 405–412, 2006. View at Scopus
  127. A. S. Herford and P. J. Boyne, “Reconstruction of mandibular continuity defects with bone morphogenetic protein-2 (rhBMP-2),” Journal of Oral and Maxillofacial Surgery, vol. 66, no. 4, pp. 616–624, 2008. View at Publisher · View at Google Scholar · View at Scopus
  128. W. M. M. T. van Hout, A. B. M. van der Molen, C. C. Breugem, R. Koole, and E. M. van Cann, “Reconstruction of the alveolar cleft: can growth factor-aided tissue engineering replace autologous bone grafting? A literature review and systematic review of results obtained with bone morphogenetic protein-2,” Clinical Oral Investigations, vol. 15, no. 3, pp. 297–303, 2011. View at Publisher · View at Google Scholar · View at Scopus
  129. A. S. Herford, “rhBMP-2 as an option for reconstructing mandibular continuity defects,” Journal of Oral and Maxillofacial Surgery, vol. 67, no. 12, pp. 2679–2684, 2009. View at Publisher · View at Google Scholar · View at Scopus
  130. A. S. Herford and P. J. Boyne, “Reconstruction of mandibular continuity defects with bone morphogenetic protein-2 (rhBMP-2),” Journal of Oral and Maxillofacial Surgery, vol. 66, no. 4, pp. 616–624, 2008. View at Publisher · View at Google Scholar · View at Scopus
  131. A. S. Herford and M. Cicciù, “Recombinant human bone morphogenetic protein type 2 jaw reconstruction in patients affected by giant cell tumor,” Journal of Craniofacial Surgery, vol. 21, no. 6, pp. 1970–1975, 2010. View at Publisher · View at Google Scholar · View at Scopus
  132. A. S. Herford, P. J. Boyne, and R. P. Williams, “Clinical applications of rhBMP-2 in maxillofacial surgery,” Journal of the California Dental Association, vol. 35, no. 5, pp. 335–341, 2007. View at Scopus
  133. S. P. Bruder, N. Jaiswal, and S. E. Haynesworth, “Growth kinetics, self-renewal, and the osteogenic potential of purified human mesenchymal stem cells during extensive subcultivation and following cryopreservation,” Journal of Cellular Biochemistry, vol. 64, no. 2, pp. 278–294, 1997. View at Publisher · View at Google Scholar · View at Scopus
  134. S. E. Haynesworth, M. A. Baber, and A. I. Caplan, “Cell surface antigens on human marrow-derived mesenchymal cells are detected by monoclonal antibodies,” Bone, vol. 13, no. 1, pp. 69–80, 1992. View at Scopus
  135. S. E. Haynesworth, J. Goshima, V. M. Goldberg, and A. I. Caplan, “Characterization of cells with osteogenic potential from human marrow,” Bone, vol. 13, no. 1, pp. 81–88, 1992. View at Scopus
  136. M. Soleimani and S. Nadri, “A protocol for isolation and culture of mesenchymal stem cells from mouse bone marrow,” Nature Protocols, vol. 4, no. 1, pp. 102–106, 2009. View at Publisher · View at Google Scholar · View at Scopus
  137. N. Jaiswal, S. E. Haynesworth, A. I. Caplan, and S. P. Bruder, “Osteogenic differentiation of purified, culture-expanded human mesenchymal stem cells in vitro,” Journal of Cellular Biochemistry, vol. 64, no. 2, pp. 295–312, 1997. View at Publisher · View at Google Scholar · View at Scopus
  138. D. Baksh, L. Song, and R. S. Tuan, “Adult mesenchymal stem cells: characterization, differentiation, and application in cell and gene therapy,” Journal of Cellular and Molecular Medicine, vol. 8, no. 3, pp. 301–316, 2004. View at Scopus
  139. P. Bianco, M. Riminucci, S. Gronthos, and P. G. Robey, “Bone marrow stromal stem cells: nature, biology, and potential applications,” Stem Cells, vol. 19, no. 3, pp. 180–192, 2001. View at Scopus
  140. M. F. Pittenger, A. M. Mackay, S. C. Beck et al., “Multilineage potential of adult human mesenchymal stem cells,” Science, vol. 284, no. 5411, pp. 143–147, 1999. View at Publisher · View at Google Scholar · View at Scopus
  141. J. N. Beresford, J. H. Bennett, C. Devlin, P. S. Leboy, and M. E. Owen, “Evidence for an inverse relationship between the differentiation of adipocytic and osteogenic cells in rat marrow stromal cell cultures,” Journal of Cell Science, vol. 102, no. 2, pp. 341–351, 1992. View at Scopus
  142. J. H. Bennett, C. J. Joyner, J. T. Triffitt, and M. E. Owen, “Adipocytic cells cultured from marrow have osteogenic potential,” Journal of Cell Science, vol. 99, no. 1, pp. 131–139, 1991. View at Scopus
  143. Y. Zeng, X. Qu, H. Li et al., “MicroRNA-100 regulates osteogenic differentiation of human adipose-derived mesenchymal stem cells by targeting BMPR2,” FEBS Letters, vol. 586, no. 16, pp. 2375–2381, 2012. View at Publisher · View at Google Scholar · View at Scopus
  144. M. Locke, V. Feisst, and P. R. Dunbar, “Concise review: human adipose-derived stem cells: separating promise from clinical need,” Stem Cells, vol. 29, no. 3, pp. 404–411, 2011. View at Publisher · View at Google Scholar · View at Scopus
  145. S. Wang, X. Qu, and R. C. Zhao, “Mesenchymal stem cells hold promise for regenerative medicine,” Frontiers of Medicine in China, vol. 5, no. 4, pp. 372–378, 2011. View at Publisher · View at Google Scholar · View at Scopus
  146. C. M. Cowan, Y. Y. Shi, O. O. Aalami et al., “Adipose-derived adult stromal cells heal critical-size mouse calvarial defects,” Nature Biotechnology, vol. 22, no. 5, pp. 560–567, 2004. View at Publisher · View at Google Scholar · View at Scopus
  147. C. Szpalski, J. Barr, M. Wetterau, P. B. Saadeh, and S. M. Warren, “Cranial bone defects: current and future strategies,” Neurosurgical Focus, vol. 29, no. 6, pp. 1–11, 2010. View at Publisher · View at Google Scholar · View at Scopus
  148. H. Nakahara, H. Misawa, T. Hayashi et al., “Bone repair by transplantation of hTERT-immortalized human mesenchymal stem cells in mice,” Transplantation, vol. 88, no. 3, pp. 346–353, 2009. View at Publisher · View at Google Scholar · View at Scopus
  149. S. P. Bruder, A. A. Kurth, M. Shea, W. C. Hayes, N. Jaiswal, and S. Kadiyala, “Bone regeneration by implantation of purified, culture-expanded human mesenchymal stem cells,” Journal of Orthopaedic Research, vol. 16, no. 2, pp. 155–162, 1998. View at Publisher · View at Google Scholar · View at Scopus
  150. D. M. Steinert, L. J. Blakely, J. Salganick, and J. C. Trent, “Molecular targets in therapy for human soft-tissue and bone sarcomas,” Current Oncology Reports, vol. 5, no. 4, pp. 295–303, 2003. View at Scopus
  151. E. R. Wagner, G. Luther, G. Zhu et al., “Defective osteogenic differentiation in the development of osteosarcoma,” Sarcoma, vol. 2011, Article ID 325238, 2011. View at Publisher · View at Google Scholar · View at Scopus