Thymidine Kinase-Mediated Shut Down of Bone Morphogenetic Protein-4 Expression Allows Regulated Bone Production(411 views) Lombardo B, Rocco T, Esposito MT, Cantilena B, Gargiulo S, Greco A, Montanaro D, Brunetti A, Pastore L
Current Gene Therapy (ISSN: 1566-5232, 1875-5631), 2013 Jun 1; 13(3): 202-210.
Keywords: Bone Production Regulation, Fg-B4, Adenovirus Vector, Bone Morphogenetic Protein 4, Ganciclovir, Thymidine Kinase, Animal Experiment, Animal Tissue, Apoptosis, Article, Bone Densitometry, Cell Death, Cell Differentiation, Cell Infiltration, Controlled Study, Dual Energy X Ray Absorptiometry, Exostosis, Fibrosis, Histology, Human, Human Cell, Inflammation, Micro-Computed Tomography, Mouse, Nick End Labeling, Nonhuman, Ossification, Protein Expression, Upregulation, Bone And Bones, Bone Development, Gene Expression Regulation, Gene Transfer Techniques, Genetic Vectors, Nude, Osteogenesis, Quadriceps Muscle, Simplexvirus, Transgenes, Mus Musculus, Oryctolagus Cuniculus,
Affiliations: *** IBB - CNR ***
Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Via S. Pansini 5, 80131 Napoli, Italy
CEINGE-Biotecnologie Avanzate, Via Gaetano Salvatore 486, 80145 Napoli, Italy
Dipartimento di Scienze Biomorfologiche e Funzionali, Università degli Studi di Napoli Federico II, Via S. Pansini 5, 80131 Napoli, Italy
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Rider, C. C., Mulloy, B., Bone morphogenetic protein and growth differentiation factor cytokine families and their protein antagonists (2010) Biochem J, 429 (1), pp. 1-12
Spiro, A. S., Beil, F. T., Schinke, T., Short-term application of dexamethasone enhances bone morphogenetic protein-7-induced ectopic bone formation in vivo (2011) J Trauma, 69 (6), pp. 1473-1480
El Tamer, M. K., Reis, R. L., Progenitor and stem cells for bone and cartilage regeneration (2009) J Tissue Eng Regen Med, 3 (5), pp. 327-337
Koh, J. T., Zhao, Z., Wang, Z., Lewis, I. S., Krebsbach, P. H., Franceschi, R. T., Combinatorial gene therapy with BMP2/7 enhances cranial bone regeneration (2008) J Dent Res, 87 (9), pp. 845-849
Heldin, C. H., Miyazono, K., ten Dijke, P., TGF-beta signalling from cell membrane to nucleus through SMAD proteins (1997) Nature, 390 (6659), pp. 465-471
Desai, P. P., Bell, A. J., Suk, M., Treatment of recalcitrant, multiply operated tibial nonunions with the RIA graft and rh-BMP2 using intramedullary nails (2010) Injury, 41 (SUPPL. 2), pp. S69-S71
Papanna, M. C., Al-Hadithy, N., Somanchi, B. V., The use of bone morphogenic protein-7 (OP-1) in the management of resistant nonunions in the upper and lower limb (2012) Injury, 43 (7), pp. 1135-1140
Zara, J. N., Siu, R. K., Zhang, X., High doses of bone morphogenetic protein 2 induce structurally abnormal bone and inflammation in vivo (2011) Tissue Eng Part A, 17 (9-10), pp. 1389-1399
Koh, J. T., Ge, C., Zhao, M., Use of a stringent dimerizerregulated gene expression system for controlled BMP2 delivery (2006) Mol Ther, 14 (5), pp. 684-691
Jiang, Y. X., Lu, Y., Liu, T. J., Yang, J., Chen, Y., Fang, Y. W., Using HSVTK/ GCV suicide gene therapy to inhibit lens epithelial cell proliferation for treatment of posterior capsular opacification (2011) Mol Vis, 17, pp. 291-299
Shen, H. C., Peng, H., Usas, A., Ex vivo gene therapy-induced endochondral bone formation: Comparison of muscle-derived stem cells and different subpopulations of primary muscle-derived cells (2004) Bone, 34 (6), pp. 982-992
Usas, A., Ho, A. M., Cooper, G. M., Olshanski, A., Peng, H., Huard, J., Bone regeneration mediated by BMP4-expressing muscle-derived stem cells is affected by delivery system (2009) Tissue Eng Part A, 15 (2), pp. 285-293
Graham, F. L., Growth of 293 cells in suspension culture (1987) J Gen Virol, 68 (Pt 3), pp. 937-940
Becker, T. C., Noel, R. J., Coats, W. S., Use of recombinant adenovirus for metabolic engineering of mammalian cells (1994) Methods Cell Biol, (43 PART A), pp. 161-189
Kempen, D. H., Lu, L., Hefferan, T. E., Enhanced bone morphogenetic protein-2-induced ectopic and orthotopic bone formation by intermittent parathyroid hormone (1-34) administration (2010) Tissue Eng Part A, 16 (12), pp. 3769-3777
Jung, M. R., Shim, I. K., Chung, H. J., Local BMP-7 release from a PLGA scaffolding-matrix for the repair of osteochondral defects in rabbits (2012) J Control Release, 162 (3), pp. 485-491
Li, B. C., Zhang, J. J., Xu, C., Zhang, L. C., Kang, J. Y., Zhao, H., Treatment of rabbit femoral defect by firearm with BMP-4 gene combined with TGF-beta1 (2009) J Trauma, 66 (2), pp. 450-456
Cook, S. D., Baffes, G. C., Wolfe, M. W., Sampath, T. K., Rueger, D. C., Recombinant human bone morphogenetic protein-7 induces healing in a canine long-bone segmental defect model (1994) Clin Orthop Relat Res, (301), pp. 302-312
Gerhart, T. N., Kirker-Head, C. A., Kriz, M. J., Healing segmental femoral defects in sheep using recombinant human bone morphogenetic protein (1993) Clin Orthop Relat Res, (293), pp. 317-326
Cook, S. D., Wolfe, M. W., Salkeld, S. L., Rueger, D. C., Effect of recombinant human osteogenic protein-1 on healing of segmental defects in non-human primates (1995) J Bone Joint Surg Am, 77 (5), pp. 734-750
Miljkovic, N. D., Cooper, G. M., Marra, K. G., Chondrogenesis, bone morphogenetic protein-4 and mesenchymal stem cells (2008) Osteoarthritis Cartilage, 16 (10), pp. 1121-1130
Kim, I. S., Cho, T. H., Lee, Z. H., Hwang, S. J., Bone Regeneration by Transplantation of Human Mesenchymal Stromal Cells in a Rabbit Mandibular Distraction Osteogenesis Model (2012) Tissue Eng Part A, 19 (1-2), pp. 66-78
Bruder, S. P., Jaiswal, N., Haynesworth, S. E., Growth kinetics, selfrenewal, and the osteogenic potential of purified human mesenchymal stem cells during extensive subcultivation and following cryopreservation (1997) J Cell Biochem, 64 (2), pp. 278-294
Esposito, M. T., Di Noto, R., Mirabelli, P., Culture conditions allow selection of different mesenchymal progenitors from adult mouse bone marrow (2009) Tissue Eng Part A, 15 (9), pp. 2525-2536
Payumo, F. C., Kim, H. D., Sherling, M. A., Tissue engineering skeletal muscle for orthopaedic applications (2002) Clin Orthop Relat Res, (403 SUPPL.), pp. S228-S242
Liu, B., Wang, N. N., Wang, Z. L., Improved nude mouse models for green fluorescence human endometriosis (2010) J Obstet Gynaecol Res, 36 (6), pp. 1214-1221
Chang, P. C., Cirelli, J. A., Jin, Q., Adenovirus encoding human platelet-derived growth factor-B delivered to alveolar bone defects exhibits safety and biodistribution profiles favorable for clinical use (2009) Hum Gene Ther, 20 (5), pp. 486-496
Hu, W. W., Ward, B. B., Wang, Z., Krebsbach, P. H., Bone regeneration in defects compromised by radiotherapy (2010) J Dent Res, 89 (1), pp. 77-81
Thymidine Kinase-Mediated Shut Down of Bone Morphogenetic Protein-4 Expression Allows Regulated Bone Production
Bone morphogenetic Proteins (BMPs) are growth factors also involved in ossification and chondrogenesis that have generated interest for their efficiency in inducing bone neo-synthesis. BMPs expression in engineered cells has been successful in stimulating osteoblastic differentiation and ectopic and orthotopic bone formation in vivo. We have previously shown that an adenoviral vector expressing bone morphogenetic protein type-4 (BMP-4) is able to efficiently drive bone formation in a rabbit model of discontinuous bone lesions. However, unregulated secretion of BMPs has also been implicated in bone overproduction and exostosis. We have constructed a replication-defective first generation adenoviral (FG-Ad) vector containing a cassette for the expression of BMP-4 associated with the Herpes Simplex virus thymidine kinase (TK) gene (FG-B4TK) in order to shut down BMP-4 expression and, therefore, regulate bone production. TK expression does not interfere with BMP-4 ability to induce ectopic bone formation in athymic nude mice. Administration of ganciclovir blocks ectopic bone production in quadriceps muscle transduced with the FG-B4TK with no effect on the contralateral muscle transduced with a vector expressing only BMP-4. Histological findings confirmed the pro-apoptotic activity of TK and the reduction of mineralized areas in the quadriceps transduced with FG-B4TK in mice treated with ganciclovir. We have generated a system to block BMP-4 secretion by inducing apoptosis in transduced cells therefore blocking unwanted bone formation. This system is an additional tool to generate regulated amount of bone in discontinuous bone lesions and can be easily coupled with biomaterials capable of recruiting cells and generating a local bioreactor.
Thymidine Kinase-Mediated Shut Down of Bone Morphogenetic Protein-4 Expression Allows Regulated Bone Production
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Thymidine Kinase-Mediated Shut Down of Bone Morphogenetic Protein-4 Expression Allows Regulated Bone Production