Thymidine Kinase-Mediated Shut Down of Bone Morphogenetic Protein-4 Expression Allows Regulated Bone Production
| Autor: | Adelaide Greco, Arturo Brunetti, Sara Gargiulo, Maria Teresa Esposito, Teresa Rocco, Donatella Montanaro, Lucio Pastore, Barbara Lombardo, Bruno Cantilena |
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| Přispěvatelé: | Lombardo, Barbara, Rocco, T, Esposito, Mt, Cantilena, B, Gargiulo, Sara, Greco, Adelaide, Montanaro, D, Brunetti, Arturo, Pastore, Lucio |
| Rok vydání: | 2013 |
| Předmět: |
Male
Genetic Vectors Mice Nude Apoptosis Bone Morphogenetic Protein 4 FG-B4TK Bone morphogenetic protein Thymidine Kinase Bone and Bones Quadriceps Muscle Mice Osteogenesis Drug Discovery Genetics medicine Animals Humans Simplexvirus Transgenes Ganciclovir Molecular Biology Genetics (clinical) Bone Development bone production regulation Chemistry Ossification Gene Transfer Techniques Chondrogenesis Cell biology Bone morphogenetic protein 7 Bone morphogenetic protein 6 Bone morphogenetic protein 5 Gene Expression Regulation Bone morphogenetic protein 4 Thymidine kinase Immunology Molecular Medicine medicine.symptom FG-B4 |
| Zdroj: | Current gene therapy 13 (2013): 202–210. info:cnr-pdr/source/autori:Lombardo, Barbara; Rocco, Teresa; Esposito, Maria T.; Cantilena, Bruno; Gargiulo, Sara; Greco, Adelaide; Montanaro, Donatella; Brunetti, Arturo; Pastore, Lucio/titolo:Thymidine Kinase-Mediated Shut Down of Bone Morphogenetic Protein-4 Expression Allows Regulated Bone Production/doi:/rivista:Current gene therapy (Print)/anno:2013/pagina_da:202/pagina_a:210/intervallo_pagine:202–210/volume:13 |
| ISSN: | 1566-5232 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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