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Published in: Journal of Orthopaedic Surgery and Research 1/2015

Open Access 01-12-2015 | Research article

Two-stage therapeutic utility of ectopically formed bone tissue in skeletal muscle induced by adeno-associated virus containing bone morphogenetic protein-4 gene

Authors: Ke Tian, Min Qi, Limin Wang, Zhifu Li, Jianzhong Xu, Yi Li, Guanlei Liu, Bing Wang, Johnny Huard, Guangheng Li

Published in: Journal of Orthopaedic Surgery and Research | Issue 1/2015

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Abstract

Background

The major disadvantage of using a stem cell-based bone morphogenetic protein-4 (BMP4) gene therapy for skull defect is the overgrowth of generated bone tissue in situ. In the present study, to overcome bony overgrowth of stem cell based-gene therapy, a new strategy of two-stage bone tissue engineering by an adeno-associated virus containing BMP4 gene (AAV-BMP4) gene therapy was used.

Methods

AAV-BMP4 was purposely implanted in the skeletal muscle of mice to generate ectopic bone tissues during the first stage. Next, the newly formed ectopic bone tissues were harvested and then transplanted to repair the mouse skull defect during the second stage.

Results

The results showed that skeletal muscle implantation of AAV-BMP4 yielded a large amount of new bone tissues. The ectopic bone tissues can be harvested as a bone graft and can successfully repair the mouse skull defect without any bony overgrowth in situ.

Conclusion

The results indicate that the bone tissues purposely generated by AAV-BMP4 in the skeletal muscle may be a new alternative of bone grafting for clinical purposes.
Literature
1.
go back to reference Wright V, Peng H, Usas A, Young B, Gearhart B, Cummins J, et al. BMP4-expressing muscle-derived stem cells differentiate into osteogenic lineage and improve bone healing in immunocompetent mice. Mol Ther. 2002;6(2):169–78. doi:S1525001602906544.CrossRefPubMed Wright V, Peng H, Usas A, Young B, Gearhart B, Cummins J, et al. BMP4-expressing muscle-derived stem cells differentiate into osteogenic lineage and improve bone healing in immunocompetent mice. Mol Ther. 2002;6(2):169–78. doi:S1525001602906544.CrossRefPubMed
3.
go back to reference Shen HC, Peng H, Usas A, Gearhart B, Fu FH, Huard J. Structural and functional healing of critical-size segmental bone defects by transduced muscle-derived cells expressing BMP4. J Gene Med. 2004;6(9):984–91. doi:10.1002/jgm.588.CrossRefPubMed Shen HC, Peng H, Usas A, Gearhart B, Fu FH, Huard J. Structural and functional healing of critical-size segmental bone defects by transduced muscle-derived cells expressing BMP4. J Gene Med. 2004;6(9):984–91. doi:10.​1002/​jgm.​588.CrossRefPubMed
4.
go back to reference Hannallah D, Peng H, Young B, Usas A, Gearhart B, Huard J. Retroviral delivery of Noggin inhibits the formation of heterotopic ossification induced by BMP-4, demineralized bone matrix, and trauma in an animal model. J Bone Joint Surg Am. 2004;86-A(1):80–91.PubMed Hannallah D, Peng H, Young B, Usas A, Gearhart B, Huard J. Retroviral delivery of Noggin inhibits the formation of heterotopic ossification induced by BMP-4, demineralized bone matrix, and trauma in an animal model. J Bone Joint Surg Am. 2004;86-A(1):80–91.PubMed
6.
go back to reference Rose T, Peng H, Usas A, Josten C, Fu FH, Huard J. Ex-vivo gene therapy with BMP-4 for critically sized defects and enhancement of fracture healing in an osteoporotic animal model. Unfallchirurg. 2005;108(1):25–34. doi:10.1007/s00113-004-0888-6.CrossRefPubMed Rose T, Peng H, Usas A, Josten C, Fu FH, Huard J. Ex-vivo gene therapy with BMP-4 for critically sized defects and enhancement of fracture healing in an osteoporotic animal model. Unfallchirurg. 2005;108(1):25–34. doi:10.​1007/​s00113-004-0888-6.CrossRefPubMed
8.
go back to reference Deng Y, Bi X, Zhou H, You Z, Wang Y, Gu P, et al. Repair of critical-sized bone defects with anti-miR-31-expressing bone marrow stromal stem cells and poly(glycerol sebacate) scaffolds. Eur Cell Mater. 2014;27:13–24. discussion −5. vol027a02.PubMed Deng Y, Bi X, Zhou H, You Z, Wang Y, Gu P, et al. Repair of critical-sized bone defects with anti-miR-31-expressing bone marrow stromal stem cells and poly(glycerol sebacate) scaffolds. Eur Cell Mater. 2014;27:13–24. discussion −5. vol027a02.PubMed
10.
go back to reference Luk KD, Chen Y, Cheung KM, Kung HF, Lu WW, Leong JC. Adeno-associated virus-mediated bone morphogenetic protein-4 gene therapy for in vivo bone formation. Biochem Biophys Res Commun. 2003;308(3):636–45. S0006291X03014293.CrossRefPubMed Luk KD, Chen Y, Cheung KM, Kung HF, Lu WW, Leong JC. Adeno-associated virus-mediated bone morphogenetic protein-4 gene therapy for in vivo bone formation. Biochem Biophys Res Commun. 2003;308(3):636–45. S0006291X03014293.CrossRefPubMed
11.
go back to reference Wang B, Li J, Fu FH, Xiao X. Systemic human minidystrophin gene transfer improves functions and life span of dystrophin and dystrophin/utrophin-deficient mice. J Orthop Res. 2009;27(4):421–6. doi:10.1002/jor.20781.CrossRefPubMed Wang B, Li J, Fu FH, Xiao X. Systemic human minidystrophin gene transfer improves functions and life span of dystrophin and dystrophin/utrophin-deficient mice. J Orthop Res. 2009;27(4):421–6. doi:10.​1002/​jor.​20781.CrossRefPubMed
12.
go back to reference Li G, Peng H, Corsi K, Usas A, Olshanski A, Huard J. Differential effect of BMP4 on NIH/3T3 and C2C12 cells: implications for endochondral bone formation. J Bone Miner Res. 2005;20(9):1611–23. doi:10.1359/JBMR.050513.CrossRefPubMed Li G, Peng H, Corsi K, Usas A, Olshanski A, Huard J. Differential effect of BMP4 on NIH/3T3 and C2C12 cells: implications for endochondral bone formation. J Bone Miner Res. 2005;20(9):1611–23. doi:10.​1359/​JBMR.​050513.CrossRefPubMed
14.
go back to reference Malik A, Khan W. Stem cell therapy and tissue engineering applications for bone. Curr Stem Cell Res Ther. 2013;8(3):183–4. CSCRT-EPUB-20130107-2.CrossRefPubMed Malik A, Khan W. Stem cell therapy and tissue engineering applications for bone. Curr Stem Cell Res Ther. 2013;8(3):183–4. CSCRT-EPUB-20130107-2.CrossRefPubMed
17.
go back to reference Yazici C, Takahata M, Reynolds DG, Xie C, Samulski RJ, Samulski J, et al. Self-complementary AAV2.5-BMP2-coated femoral allografts mediated superior bone healing versus live autografts in mice with equivalent biomechanics to unfractured femur. Mol Ther. 2011;19(8):1416–25. doi:10.1038/mt.2010.294.CrossRefPubMedCentralPubMed Yazici C, Takahata M, Reynolds DG, Xie C, Samulski RJ, Samulski J, et al. Self-complementary AAV2.5-BMP2-coated femoral allografts mediated superior bone healing versus live autografts in mice with equivalent biomechanics to unfractured femur. Mol Ther. 2011;19(8):1416–25. doi:10.​1038/​mt.​2010.​294.CrossRefPubMedCentralPubMed
18.
Metadata
Title
Two-stage therapeutic utility of ectopically formed bone tissue in skeletal muscle induced by adeno-associated virus containing bone morphogenetic protein-4 gene
Authors
Ke Tian
Min Qi
Limin Wang
Zhifu Li
Jianzhong Xu
Yi Li
Guanlei Liu
Bing Wang
Johnny Huard
Guangheng Li
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Journal of Orthopaedic Surgery and Research / Issue 1/2015
Electronic ISSN: 1749-799X
DOI
https://doi.org/10.1186/s13018-015-0229-1

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