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Synergistic Effect of Bone Morphogenetic Proteins 2 and 7 by ex Vivo Gene Therapy in a Rat Spinal Fusion Model

Kaito, Takashi, MD, PhD1; Johnson, Jared, MD2; Ellerman, Jessica, MD2; Tian, Haijun, MD2; Aydogan, Mehmet, MD2; Chatsrinopkun, Mongkol, MD2; Ngo, Stephanie, MPH2; Choi, Christine, BS2; Wang, Jeffrey C., MD2

doi: 10.2106/JBJS.L.01396
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Background: Previous studies have suggested that the co-expression of two different bone morphogenetic protein (BMP) genes can result in the production of heterodimeric BMPs that may be more potent than homodimers. In this study, combined BMP-2 and BMP-7 gene transfer was performed ex vivo to compare the resulting new bone formation with that of single-BMP gene transfer in a rat spinal fusion model.

Methods: Forty-four athymic rats underwent posterolateral fusion at L4-L5 and were implanted with a collagen sponge containing human adipose-derived stem cells. Group A received untreated cells, and the remaining groups received cells transfected with various genes in a lentivirus vector. The transferred genes were GFP (green fluorescent protein) in Group B, BMP-2 in Group C, BMP-7 in Group D, and both BMP-2 and BMP-7 in Group E. In vitro production of BMP-2 and BMP−7 was quantified by means of an enzyme-linked immunosorbent assay (ELISA) specific to BMP-2 or BMP-7. Osseous fusion was quantified with use of radiography and microcomputed tomography.

Results: ELISA demonstrated that Group E, which was treated with both BMP-2 and BMP-7, produced less than one-fourth as much BMP as the groups treated with a single transfected BMP (Groups C and D). Radiographs showed that all of the spines in Groups C, D, and E appeared to be fused by eight weeks; the spines in Groups A and B showed minimal evidence of new bone formation. Measurements confirmed that the mean bone formation area was significantly greater in Groups C, D, and E compared with Groups A and B (p < 0.001). In addition, the bone formation area was significantly greater in Group E compared with Groups C and D (p < 0.001).

Conclusions: Combined BMP-2 and BMP-7 ex vivo gene transfer was found to be significantly more effective for inducing new bone formation compared with ex vivo gene transfer of an individual BMP in a rat spinal fusion model.

Clinical Relevance: Combined BMP-2 and BMP-7 therapy may lead to efficient bone regeneration.

1Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871 Japan. E-mail address: takashikaito@gmail.com

2Department of Orthopaedic Surgery, University of California at Los Angeles, Box 956902, Los Angeles, CA 90095-1570

Copyright © 2013 by The Journal of Bone and Joint Surgery, Incorporated
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