Combinatorial gene therapy with BMP2/7 enhances cranial bone regeneration.
BMP2/7 heterodimer expression by adenovirus can stimulate bone formation at subcutaneous sites. In the present study, we evaluate whether this approach will also promote healing of cranial defects. Adenovirus expressing BMP2 or BMP7 (AdBMP2, AdBMP7) was titrated to yield equivalent BMP protein levels after transduction into murine BLK cells. Analysis of conditioned medium showed that BMP2/7 heterodimers have enhanced ability to stimulate alkaline phosphatase and Smad 1,5,8 phosphorylation relative to equivalent amounts of BMP2 or BMP7 homodimers. To measure bone regeneration, we implanted virally transduced BLK cells into critical-sized calvarial defects generated in C57BL6 mice. AdBMP2/7-transduced cells were more effective in healing cranial defects than were cells individually transduced with AdBMP2 or BMP7. Dramatic increases in bone volume fraction, as measured by microCT, as well as fusion of regenerated bone with the defect margins were noted. Thus, the use of gene therapy to express heterodimeric BMPs is a promising potential therapy for healing craniofacial bones.
Koh
J T
JT
Department of Periodontics and Oral Medicine, University of Michigan, Ann Arbor, MI 48109-1078, USA.
Zhao
Z
Z
Wang
Z
Z
Lewis
I S
IS
Krebsbach
P H
PH
Franceschi
R T
RT
D020341:Absorbable Implants; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D055396:Bone Morphogenetic Protein 2; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D001861:Bone Regeneration / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D003399:Craniotomy; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005781:Gelatin Sponge, Absorbable / Q000378:metabolism; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D048091:Guided Tissue Regeneration / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism; D010012:Osteogenesis / Q000235:genetics / Q000502:physiology; D054457:Tissue Scaffolds; D016212:Transforming Growth Factor beta / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D019076:Transgenes; D014945:Wound Healing / Q000235:genetics / Q000502:physiology*
C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D016212:Transforming Growth Factor beta