Remodeling of cortical bone allografts mediated by adherent rAAV-RANKL and VEGF gene therapy

Hiromu Ito, Mette Koefoed, Prarop Tiyapatanaputi, Kirill Gromov, J Jeffrey Goater, Jonathan Carmouche, Xinping Zhang, Paul T Rubery, Joseph Rabinowitz, R Jude Samulski, Takashi Nakamura, Kjeld Soballe, Regis J O'Keefe, Brendan F Boyce, Edward M Schwarz

249 Citations (Scopus)

Abstract

Structural allograft healing is limited because of a lack of vascularization and remodeling. To study this we developed a mouse model that recapitulates the clinical aspects of live autograft and processed allograft healing. Gene expression analyses showed that there is a substantial decrease in the genes encoding RANKL and VEGF during allograft healing. Loss-of-function studies showed that both factors are required for autograft healing. To determine whether addition of these signals could stimulate allograft vascularization and remodeling, we developed a new approach in which rAAV can be freeze-dried onto the cortical surface without losing infectivity. We show that combination rAAV-RANKL- and rAAV-VEGF-coated allografts show marked remodeling and vascularization, which leads to a new bone collar around the graft. In conclusion, we find that RANKL and VEGF are necessary and sufficient for efficient autograft remodeling and can be transferred using rAAV to revitalize structural allografts.
Original languageEnglish
JournalNature Medicine
Volume11
Issue number3
Pages (from-to)291-7
Number of pages7
ISSN1078-8956
DOIs
Publication statusPublished - 2005

Keywords

  • Animals
  • Bone Remodeling
  • Bone Transplantation
  • Carrier Proteins
  • Dependovirus
  • Femur
  • Freeze Drying
  • Genetic Therapy
  • Genetic Vectors
  • Membrane Glycoproteins
  • Mice
  • Mice, Inbred C57BL
  • Molecular Sequence Data
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • Transduction, Genetic
  • Transplantation, Homologous
  • Vascular Endothelial Growth Factor A
  • Wound Healing

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