Use of a chimeric adenovirus vector enhances BMP2 production and bone formation.
Recombinant adenoviral vectors have potential for the treatment of a variety of musculoskeletal defects and such gene therapy systems have been a recent research focus in orthopedic surgery. In studies reported here, two different adenovirus vectors have been compared for their ability to transduce human bone marrow mesenchymal stem cells (hBM-MSCs) and elicit bone formation in vivo. Vectors consisted either of standard adenovirus type 5 (Ad5) vector or a chimeric adenovirus type 5 vector that contains an adenovirus type 35 fiber (Ad5F35), which has been recently demonstrated to bestow a different cellular tropism, and a complete cDNA encoding human bone morphogenetic 2 (BMP2). Studies were also conducted to compare the transduction efficiency of these vectors using enhanced green fluorescent protein (GFP). hBM-MSCs transduced with Ad5F35 vectors had higher levels of transgene expression than those transduced with Ad5 vectors. The results also demonstrate that hBM-MSCs lack the coxsackie-adenovirus receptor (CAR), which is responsible for cellular adsorption of Ad5. Therefore, the data suggest that Ad5 virus adsorption to hBM-MSCs is inefficient. Ad5BMP2- or Ad5F35BMP2-transduced hBM-MSCs were also compared in an in vivo heterotopic bone formation assay. Mineralized bone was radiologically identified only in muscle that received the Ad5F35BMP2 transduced hBM-MSCs. In summary, Ad5F35BMP2 can efficiently transduce hBM-MSCs leading to enhanced bone formation in vivo.
Olmsted-Davis
Elizabeth A
EA
Center for Cell and Gene Therapy, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Gugala
Zbigniew
Z
Gannon
Francis H
FH
Yotnda
Patricia
P
McAlhany
Robert E
RE
Lindsey
Ronald W
RW
Davis
Alan R
AR
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000096:biosynthesis / Q000235:genetics*; D002113:Calcification, Physiologic; D002277:Carcinoma / Q000473:pathology; D002460:Cell Line; D002472:Cell Transformation, Viral; D002478:Cells, Cultured; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D004274:DNA, Recombinant / Q000235:genetics; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000008:administration & dosage; D049452:Green Fluorescent Proteins; D006801:Humans; D007273:Injections, Intramuscular; D008164:Luminescent Proteins / Q000378:metabolism; D008175:Lung Neoplasms / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010012:Osteogenesis; D011991:Receptors, Virus / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D011994:Recombinant Proteins / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017154:Stromal Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D014161:Transduction, Genetic; D016212:Transforming Growth Factor beta; D019076:Transgenes; D014407:Tumor Cells, Cultured
C525718:BMP2 protein, human; C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; C568771:CLMP protein, human; C568772:CLMP protein, mouse; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D004274:DNA, Recombinant; D008164:Luminescent Proteins; D011991:Receptors, Virus; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; C499469:recombinant human bone morphogenetic protein-2; D049452:Green Fluorescent Proteins