Remodeling of cortical bone allografts mediated by adherent rAAV-RANKL and VEGF gene therapy.
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.
Ito
Hiromu
H
The Center for Musculoskeletal Research, University of Rochester, 601 Elmwood Avenue, Box 665, Rochester, New York 14642, USA.
Koefoed
Mette
M
Tiyapatanaputi
Prarop
P
Gromov
Kirill
K
Goater
J Jeffrey
JJ
Carmouche
Jonathan
J
Zhang
Xinping
X
Rubery
Paul T
PT
Rabinowitz
Joseph
J
Samulski
R Jude
RJ
Nakamura
Takashi
T
Soballe
Kjeld
K
O'Keefe
Regis J
RJ
Boyce
Brendan F
BF
Schwarz
Edward M
EM
D000818:Animals; D016723:Bone Remodeling / Q000502:physiology*; D016025:Bone Transplantation; D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology; D000229:Dependovirus / Q000235:genetics; D005269:Femur; D005612:Freeze Drying; D015316:Genetic Therapy; D005822:Genetic Vectors; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D014161:Transduction, Genetic; D014184:Transplantation, Homologous; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000502:physiology; D014945:Wound Healing
D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D042461:Vascular Endothelial Growth Factor A