Runx2 overexpression in bone marrow stromal cells accelerates bone formation in critical-sized femoral defects

Tissue Engineering - Part A

Volumn 16, Issue 9, 2010, Pages 2795-2808

  Wojtowicz, Abigail M ^a,b   Templeman, Kellie L ^b,c   Hutmacher, Dietmar W ^d   Guldberg, Robert E ^b,c   García, Andrés J ^b,c  

^a Emory University   (United States)

^b GEORGIA INSTITUTE OF TECHNOLOGY   (United States)

^c GEORGIA INSTITUTE OF TECHNOLOGY   (United States)

^d QUEENSLAND UNIVERSITY OF TECHNOLOGY   (Australia)

Author keywords

[No Author keywords available]

Indexed keywords

BONE; GENETIC ENGINEERING; REPAIR; SCAFFOLDS; TRANSCRIPTION FACTORS;

ACCELERATED METHOD; BONE DEFECT; BONE FORMATION; BONE MARROW STROMAL CELLS; CELL TYPES; CELL-BASED; CELL-FREE; CLINICAL PROBLEMS; DEFECT SITES; EX VIVO EXPANSION; EXTERNAL FIXATION; FAILURE RATE; LONG BONE; OSTEOGENIC CAPACITY; POLYCAPROLACTONE SCAFFOLDS; RECOVERY TIME; RUNX2 OVEREXPRESSION; TYPE I COLLAGEN;

DEFECTS;

RATTUS;

POLYCAPROLACTONE; POLYESTER; RUNX2 PROTEIN, RAT; TISSUE SCAFFOLD; TRANSCRIPTION FACTOR RUNX2;

ANIMAL; ARTICLE; BONE DEVELOPMENT; BONE MARROW CELL; CELL CULTURE; CELL SURVIVAL; CHEMISTRY; CYTOLOGY; FEMALE; FEMUR; FLOW CYTOMETRY; GENETIC ENGINEERING; GENETICS; INFRARED SPECTROSCOPY; MALE; METABOLISM; METHODOLOGY; MICRO-COMPUTED TOMOGRAPHY; PATHOLOGY; PHYSIOLOGY; RAT; STROMA CELL;

ANIMALS; BONE MARROW CELLS; CELL SURVIVAL; CELLS, CULTURED; CORE BINDING FACTOR ALPHA 1 SUBUNIT; FEMALE; FEMUR; FLOW CYTOMETRY; GENETIC ENGINEERING; MALE; OSTEOGENESIS; POLYESTERS; RATS; SPECTROSCOPY, FOURIER TRANSFORM INFRARED; STROMAL CELLS; TISSUE SCAFFOLDS; X-RAY MICROTOMOGRAPHY;

EID: 77956071511     PISSN: 19373341     EISSN: 1937335X     Source Type: Journal    
DOI: 10.1089/ten.tea.2010.0025     Document Type: Article

References (84)

1. Bucholz, R.W. Nonallograft osteoconductive bone graft substitutes. Clin Orthop Relat Res 395, 44, 2002.
2. Kretlow, J.D., and Mikos, A.G. Review: mineralization of synthetic polymer scaffolds for bone tissue engineering. Tissue Eng 13, 927, 2007.
3. Rawashdeh, M.A., and Telfah, H. Secondary alveolar bone grafting: the dilemma of donor site selection and morbidity. Br J Oral Maxillofac Surg 46, 665, 2008.
4. Gottfried, O.N., and Dailey, A.T. Mesenchymal stem cell and gene therapies for spinal fusion. Neurosurgery 63, 380, 2008.
5. Mankin, H.J., Hornicek, F.J., and Raskin, K.A. Infection in massive bone allografts. Clin Orthop Relat Res 432, 210, 2005.
6. Sorger, J.I., Hornicek, F.J., Zavatta, M., Menzner, J.P., Geb-hardt, M.C., Tomford, W.W., and Mankin, H.J. Allograft fractures revisited. Clin Orthop Relat Res 382, 66, 2001.
7. Ito, H., Koefoed, M., Tiyapatanaputi, P., Gromov, K., Goater, J.J., Carmouche, J., Zhang, X., Rubery, P.T., Rabinowitz, J., Samulski, R.J., Nakamura, T., Soballe, K., O'Keefe, R.J., Boyce, B.F., and Schwarz, E.M. Remodeling of cortical bone allografts mediated by adherent rAAV-RANKL and VEGF gene therapy. Nat Med 11, 291, 2005.
8. Cancedda, R., Giannoni, P., and Mastrogiacomo, M. A tissue engineering approach to bone repair in large animal models and in clinical practice. Biomaterials 28, 4240, 2007.
9. Awad, H.A., Zhang, X., Reynolds, D.G., Guldberg, R.E., O'Keefe, R.J., and Schwarz, E.M. Recent advances in gene delivery for structural bone allografts. Tissue Eng 13, 1973, 2007.
10. Kimelman, N., Pelled, G., Helm, G.A., Huard, J., Schwarz, E.M., and Gazit, D. Review: gene-and stem cell-based therapeutics for bone regeneration and repair. Tissue Eng 13, 1135, 2007.
11. Hutmacher, D.W., and García, A.J. Scaffold-based bone engineering by using genetically modified cells. Gene 347, 1, 2005.
12. Einhorn, T.A. The cell and molecular biology of fracture healing. Clin Orthop Relat Res (355 Suppl), S7, 1998.
13. Smiler, D., and Soltan, M. Bone marrow aspiration: technique, grafts, and reports. Implant Dent 15, 229, 2006.
14. Muschler, G.F., Boehm, C., and Easley, K. Aspiration to obtain osteoblast progenitor cells from human bone marrow: the influence of aspiration volume. J Bone Joint Surg Am 79, 1699, 1997.
15. Ishaug, S.L., Crane, G.M., Miller, M.J., Yasko, A.W., Yas-zemski, M.J., and Mikos, A.G. Bone formation by three-dimensional stromal osteoblast culture in biodegradable polymer scaffolds. J Biomed Mater Res 36, 17, 1997.
16. Cartmell, S., Huynh, K., Lin, A., Nagaraja, S., and Guldberg, R. Quantitative microcomputed tomography analysis of mineralization within three-dimensional scaffolds in vitro. J Biomed Mater Res A 69, 97, 2004.
17. Goshima, J., Goldberg, V.M., and Caplan, A.I. Osteogenic potential of culture-expanded rat marrow cells as assayed in vivo with porous calcium phosphate ceramic. Biomaterials 12, 253, 1991.
18. Krebsbach, P.H., Kuznetsov, S.A., Satomura, K., Emmons, R.V., Rowe, D.W., and Robey, P.G. Bone formation in vivo: comparison of osteogenesis by transplanted mouse and human marrow stromal fibroblasts. Transplantation 63, 1059, 1997.
19. Pittenger, M.F., Mackay, A.M., Beck, S.C., Jaiswal, R.K., Douglas, R., Mosca, J.D., Moorman, M.A., Simonetti, D.W., Craig, S., and Marshak, D.R. Multilineage potential of adult human mesenchymal stem cells. Science 284, 143, 1999.
20. Bruder, S.P., Kraus, K.H., Goldberg, V.M., and Kadiyala, S. The effect of implants loaded with autologous mesenchymal stem cells on the healing of canine segmental bone defects. J Bone Joint Surg Am 80, 985, 1998.
21. Kon, E., Muraglia, A., Corsi, A., Bianco, P., Marcacci, M., Martin, I., Boyde, A., Ruspantini, I., Chistolini, P., Rocca, M., Giardino, R., Cancedda, R., and Quarto, R. Autologous bone marrow stromal cells loaded onto porous hydroxyapatite ceramic accelerate bone repair in critical-size defects of sheep long bones. J Biomed Mater Res 49, 328, 2000.
22. Petite, H., Viateau, V., Bensaid, W., Meunier, A., de Pollak, C., Bourguignon, M., Oudina, K., Sedel, L., and Guillemin, G. Tissue-engineered bone regeneration. Nat Biotechnol 18, 959, 2000.
23. Werntz, J.R., Lane, J.M., Burstein, A.H., Justin, R., Klein, R., and Tomin, E. Qualitative and quantitative analysis of or-thotopic bone regeneration by marrow. J Orthop Res 14, 85, 1996.
24. Marcacci, M., Kon, E., Moukhachev, V., Lavroukov, A., Kutepov, S., Quarto, R., Mastrogiacomo, M., and Cancedda, R. Stem cells associated with macroporous bioceramics for long bone repair: 6-to 7-year outcome of a pilot clinical study. Tissue Eng 13, 947, 2007.
25. Quarto, R., Mastrogiacomo, M., Cancedda, R., Kutepov, S., Mukhachev, V., Lavroukov, A., Kon, E., and Marcacci, M. Repair of large bone defects with the use of autologous bone marrow stromal cells. N Engl J Med 344, 385, 2001.
26. Banfi, A., Muraglia, A., Dozin, B., Mastrogiacomo, M., Cancedda, R., and Quarto, R. Proliferation kinetics and differentiation potential of ex vivo expanded human bone marrow stromal cells: implications for their use in cell therapy. Exp Hematol 28, 707, 2000.
27. Derubeis, A.R., and Cancedda, R. Bone marrow stromal cells (BMSCs) in bone engineering: limitations and recent advances. Ann Biomed Eng 32, 160, 2004.
28. Yeon Lim, J., Jeun, S.S., Lee, K.J., Oh, J.H., Kim, S.M., Park, S.I., Jeong, C.H., and Kang, S.G. Multiple stem cell traits of expanded rat bone marrow stromal cells. Exp Neurol 199, 416, 2006.
29. Mendes, S.C., Tibbe, J.M., Veenhof, M., Bakker, K., Both, S., Platenburg, P.P., Oner, F.C., de Bruijn, J.D., and van Blit-terswijk, C.A. Bone tissue-engineered implants using human bone marrow stromal cells: effect of culture conditions and donor age. Tissue Eng 8, 911, 2002.
30. Phinney, D.G., Kopen, G., Righter, W., Webster, S., Tremain, N., and Prockop, D.J. Donor variation in the growth properties and osteogenic potential of human marrow stromal cells. J Cell Biochem 75, 424, 1999.
31. Kretlow, J.D., Jin, Y.Q., Liu, W., Zhang, W.J., Hong, T.H., Zhou, G., Baggett, L.S., Mikos, A.G., and Cao, Y. Donor age and cell passage affects differentiation potential of murine bone marrow-derived stem cells. BMC Cell Biol 9, 60, 2008.
32. Hanada, K., Dennis, J.E., and Caplan, A.I. Stimulatory effects of basic fibroblast growth factor and bone morphogenetic protein-2 on osteogenic differentiation of rat bone marrow-derived mesenchymal stem cells. J Bone Miner Res 12, 1606, 1997.
33. Huang, Y.C., Kaigler, D., Rice, K.G., Krebsbach, P.H., and Mooney, D.J. Combined angiogenic and osteogenic factor delivery enhances bone marrow stromal cell-driven bone regeneration. J Bone Miner Res 20, 848, 2005.
34. Gazit, D., Turgeman, G., Kelley, P., Wang, E., Jalenak, M., Zilberman, Y., and Moutsatsos, I. Engineered pluripotent mesenchymal cells integrate and differentiate in regenerating bone: a novel cell-mediated gene therapy. J Gene Med 1, 121, 1999.
35. Edgar, C.M., Chakravarthy, V., Barnes, G., Kakar, S., Ger-stenfeld, L.C., and Einhorn, T.A. Autogenous regulation of a network of bone morphogenetic proteins (BMPs) mediates the osteogenic differentiation in murine marrow stromal cells. Bone 40, 1389, 2007.
36. Hsu, W.K., Sugiyama, O., Park, S.H., Conduah, A., Feeley, B.T., Liu, N.Q., Krenek, L., Virk, M.S., An, D.S., Chen, I.S., and Lieberman, J.R. Lentiviral-mediated BMP-2 gene transfer enhances healing of segmental femoral defects in rats. Bone 40, 931, 2007.
37. Bishop, G.B., and Einhorn, T.A. Current and future clinical applications of bone morphogenetic proteins in orthopaedic trauma surgery. Int Orthop 31, 721, 2007.
38. Uludag, H., D'Augusta, D., Golden, J., Li, J., Timony, G., Riedel, R., and Wozney, J.M. Implantation of recombinant human bone morphogenetic proteins with biomaterial carriers: a correlation between protein pharmacokinetics and osteoinduction in the rat ectopic model. J Biomed Mater Res 50, 227, 2000.
39. Cahill, K.S., Chi, J.H., Day, A., and Claus, E.B. Prevalence, complications, and hospital charges associated with use of bone-morphogenetic proteins in spinal fusion procedures. JAMA 302, 58, 2009.
40. Byers, B.A., Guldberg, R.E., Hutmacher, D.W., and García, A.J. Effects of Runx2 genetic engineering and in vitro maturation of tissue-engineered constructs on the repair of critical size bone defects. J Biomed Mater Res A 76, 646, 2006.
41. Gersbach, C.A., Le Doux, J.M., Guldberg, R.E., and Garcia, A.J. Inducible regulation of Runx2-stimulated osteogenesis. Gene Ther 13, 873, 2006.
42. Phillips, J.E., Guldberg, R.E., and García, A.J. Dermal fibro-blasts genetically modified to express Runx2/Cbfa1 as a mineralizing cell source for bone tissue engineering. Tissue Eng 13, 2029, 2007.
43. Ducy, P. Cbfa1: a molecular switch in osteoblast biology. Dev Dyn 219, 461, 2000.
44. Ducy, P., Starbuck, M., Priemel, M., Shen, J., Pinero, G., Geoffroy, V., Amling, M., and Karsenty, G. A Cbfa1-dependent genetic pathway controls bone formation beyond embryonic development. Genes Dev 13, 1025, 1999.
45. Komori, T., Yagi, H., Nomura, S., Yamaguchi, A., Sasaki, K., Deguchi, K., Shimizu, Y., Bronson, R.T., Gao, Y.H., Inada, M., Sato, M., Okamoto, R., Kitamura, Y., Yoshiki, S., and Kishimoto, T. Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 89, 755, 1997.
46. Otto, F., Thornell, A.P., Crompton, T., Denzel, A., Gilmour, K.C., Rosewell, I.R., Stamp, G.W., Beddington, R.S., Mun-dlos, S., Olsen, B.R., Selby, P.B., and Owen, M.J. Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell 89, 765, 1997.
47. Mundlos, S., Otto, F., Mundlos, C., Mulliken, J.B., Aylsworth, A.S., Albright, S., Lindhout, D., Cole, W.G., Henn, W., Knoll, J.H., Owen, M.J., Mertelsmann, R., Zabel, B.U., and Olsen, B.R. Mutations involving the transcription factor CBFA1 cause cleidocranial dysplasia. Cell 89, 773, 1997.
48. Zhang, Y.W., Yasui, N., Kakazu, N., Abe, T., Takada, K., Imai, S., Sato, M., Nomura, S., Ochi, T., Okuzumi, S., Nogami, H., Nagai, T., Ohashi, H., and Ito, Y. PEBP2alphaA/CBFA1 mutations in Japanese cleidocranial dysplasia patients. Gene 244, 21, 2000.
49. Lee, B., Thirunavukkarasu, K., Zhou, L., Pastore, L., Baldini, A., Hecht, J., Geoffroy, V., Ducy, P., and Karsenty, G. Mis-sense mutations abolishing DNA binding of the osteoblast-specific transcription factor OSF2/CBFA1 in cleidocranial dysplasia. Nat Genet 16, 307, 1997.
50. Shui, C., Spelsberg, T.C., Riggs, B.L., and Khosla, S. Changes in Runx2/Cbfa1 expression and activity during osteoblastic differentiation of human bone marrow stromal cells. J Bone Miner Res 18, 213, 2003.
51. Xiao, Z.S., Hinson, T.K., and Quarles, L.D. Cbfa1 isoform overexpression upregulates osteocalcin gene expression in non-osteoblastic and pre-osteoblastic cells. J Cell Biochem 74, 596, 1999.
52. Byers, B.A., Pavlath, G.K., Murphy, T.J., Karsenty, G., and García, A.J. Cell-type-dependent up-regulation of in vitro mineralization after overexpression of the osteoblast-specific transcription factor Runx2/Cbfal. J Bone Miner Res 17, 1931, 2002.
53. Gersbach, C.A., Byers, B.A., Pavlath, G.K., and García, A.J. Runx2/Cbfa1 stimulates transdifferentiation of primary skeletal myoblasts into a mineralizing osteoblastic pheno-type. Exp Cell Res 300, 406, 2004.
54. Byers, B., Guldberg, R., and García, A. Synergy between genetic and tissue engineering: Runx2 overexpression and in vitro construct development enhance in vivo mineralization. Tissue Eng 10, 1757, 2004.
55. Zhao, Z., Zhao, M., Xiao, G., and Franceschi, R.T. Gene transfer of the Runx2 transcription factor enhances osteo-genic activity of bone marrow stromal cells in vitro and in vivo. Mol Ther 12, 247, 2005.
56. Zheng, H., Guo, Z., Ma, Q., Jia, H., and Dang, G. Cbfa1/osf2 transduced bone marrow stromal cells facilitate bone formation in vitro and in vivo. Calcif Tissue Int 74, 194, 2004.
57. Zhao, Z., Wang, Z., Ge, C., Krebsbach, P., and Franceschi, R.T. Healing cranial defects with AdRunx2-transduced marrow stromal cells. J Dent Res 86, 1207, 2007.
58. Aalami, O.O., Nacamuli, R.P., and Longaker, M.T. Roles of periosteum, dura, and adjacent bone on healing of cranial osteonecrosis\discussion. J Craniofac Surg 14, 380, 2003.
59. Javazon, E.H., Colter, D.C., Schwarz, E.J., and Prockop, D.J. Rat marrow stromal cells are more sensitive to plating density and expand more rapidly from single-cell-derived colonies than human marrow stromal cells. Stem Cells 19, 219, 2001.
60. Byers, B.A., and Garća, A.J. Exogenous Runx2 expression enhances in vitro osteoblastic differentiation and mineralization in primary bone marrow stromal cells. Tissue Eng 10, 1623, 2004.
61. Porter, B.D., Lin, A.S., Peister, A., Hutmacher, D., and Guldberg, R.E. Noninvasive image analysis of 3D construct mineralization in a perfusion bioreactor. Biomaterials 28, 2525, 2007.
62. Phillips, J.E., Hutmacher, D.W., Guldberg, R.E., and García, A.J. Mineralization capacity of Runx2/Cbfa1-genetically engineered fibroblasts is scaffold dependent. Biomaterials 27, 5535, 2006.
63. Gersbach, C.A., Byers, B.A., Pavlath, G.K., Guldberg, R.E., and García, A.J. Runx2/Cbfa1-genetically engineered skeletal myoblasts mineralize collagen scaffolds in vitro. Bio-technol Bioeng 88, 369, 2004.
64. Oest, M.E., Dupont, K.M., Kong, H.J., Mooney, D.J., and Guldberg, R.E. Quantitative assessment of scaffold and growth factor-mediated repair of critically sized bone defects. J Orthop Res 25, 941, 2007.
65. Wojtowicz, A.M., Shekaran, A., Oest, M.E., Dupont, K.M., Templeman, K.L., Hutmacher, D.W., Guldberg, R.E., and Garcia, A.J. Coating of biomaterial scaffolds with the collagen-mimetic peptide GFOGER for bone defect repair. Biomaterials 31, 2574, 2010.
66. Reyes, C.D., Petrie, T.A., Burns, K.L., Schwartz, Z., and García, A.J. Biomolecular surface coating to enhance orthopaedic tissue healing and integration. Biomaterials 28, 3228, 2007.
67. Hoerl, A., and Kennard, R. Ridge regression: applications to nonorthogonal problems. Technometrics 12, 69, 1970.
68. Hoerl, A., and Kennard, R. Ridge regression: biased estimation for nonorthogonal problems. Technometrics 12, 55, 1970.
69. Overton, W.R. Modified histogram subtraction technique for analysis of flow cytometry data. Cytometry 9, 619, 1988.
70. Sanderson, C., and Bachus, K.N. Staining technique to differentiate mineralized and demineralized bone in ground sections. J Histotechnol 20, 119, 1997.
71. Paschalis, E.P., Betts, F., DiCarlo, E., Mendelsohn, R., and Boskey, A.L. FTIR microspectroscopic analysis of normal human cortical and trabecular bone. Calcif Tissue Int 61, 480, 1997.
72. Bonewald, L.F., Harris, S.E., Rosser, J., Dallas, M.R., Dallas, S.L., Camacho, N.P., Boyan, B., and Boskey, A. von Kossa staining alone is not sufficient to confirm that mineralization in vitro represents bone formation. Calcif Tissue Int 72, 537, 2003.
73. Ozerdem, O.R., Anlatici, R., Bahar, T., Kayaselcuk, F., Bar-utcu, O., Tuncer, I., and Sen, O. Roles of periosteum, dura, and adjacent bone on healing of cranial osteonecrosis. J Craniofac Surg 14, 371, 2003.
74. LeGeros, R.Z. Properties of osteoconductive biomaterials: calcium phosphates. Clin Orthop Relat Res 395, 81, 2002.
75. Meyer, S., Floerkemeier, T., and Windhagen, H. Histological osseointegration of a calciumphosphate bone substitute material in patients. Biomed Mater Eng 17, 347, 2007.
76. Fialkov, J.A., Holy, C.E., Shoichet, M.S., and Davies, J.E. In vivo bone engineering in a rabbit femur. J Craniofac Surg 14, 324, 2003.
77. Turgeman, G., Pittman, D.D., Muller, R., Kurkalli, B.G., Zhou, S., Pelled, G., Peyser, A., Zilberman, Y., Moutsatsos, I.K., and Gazit, D. Engineered human mesenchymal stem cells: a novel platform for skeletal cell mediated gene therapy. J Gene Med 3, 240, 2001.
78. Wutticharoenmongkol, P., Pavasant, P., and Supaphol, P. Osteoblastic phenotype expression of MC3T3-E1 cultured on electrospun polycaprolactone fiber mats filled with hydroxy-apatite nanoparticles. Biomacromolecules 8, 2602, 2007.
79. Hutmacher, D.W., Schantz, J.T., Lam, C.X., Tan, K.C., and Lim, T.C. State of the art and future directions of scaffold-based bone engineering from a biomaterials perspective. J Tissue Eng Regen Med 1, 245, 2007.
80. Liebschner, M.A. Biomechanical considerations of animal models used in tissue engineering of bone. Biomaterials 25, 1697, 2004.
81. Cook, S.D., Baffes, G.C., Wolfe, M.W., Sampath, T.K., and Rueger, D.C. Recombinant human bone morphogenetic protein-7 induces healing in a canine long-bone segmental defect model. Clin Orthop Relat Res 301, 302, 1994.
82. Cook, S.D., Baffes, G.C., Wolfe, M.W., Sampath, T.K., Rueger, D.C., and Whitecloud, T.S., 3rd. The effect of re-combinant human osteogenic protein-1 on healing of large segmental bone defects. J Bone Joint Surg Am 76, 827, 1994.
83. Cook, S.D., Wolfe, M.W., Salkeld, S.L., and Rueger, D.C. Effect of recombinant human osteogenic protein-1 on healing of segmental defects in non-human primates. J Bone Joint Surg Am 77, 734, 1995.
84. Rai, B., Oest, M.E., Dupont, K.M., Ho, K.H., Teoh, S.H., and Guldberg, R.E. Combination of platelet-rich plasma with polycaprolactone-tricalcium phosphate scaffolds for seg-mental bone defect repair. J Biomed Mater Res A 81, 888, 2007.