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Combinatorial Gene Therapy with BMP2/7 Enhances Cranial Bone Regeneration

¹ Department of Periodontics and Oral Medicine and
³ Department of Biologic and Materials Sciences, School of Dentistry, and Center for Craniofacial Regeneration, University of Michigan, 1011 North University Ave., Ann Arbor, MI 48109-1078, USA;
² BK21 Project for School of Dentistry and Dental Science Research Institution, Chonnam National University, Gwangju, 500-757, South Korea; and
⁴ Department of Biological Chemistry, School of Medicine, University of Michigan, Ann Arbor, MI 48109, USA

Correspondence: ^* corresponding author, rennyf{at}umich.edu

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.

Key Words: gene therapy • bone regeneration • adenovirus • bone morphogenetic proteins • heterodimer • cranial defect

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