Efficient and rapid osteoinduction in an immune-competent host.
Osteoinductive systems to induce targeted rapid bone formation hold clinical promise, but development of technologies for clinical use that must be tested in animal models is often a difficult challenge. We previously demonstrated that implantation of human cells transduced with Ad5F35BMP2 to express high levels of bone morphogenetic protein-2 (BMP2) resulted in rapid bone formation at targeted sites. Inclusion of human cells in this model precluded us from testing this system in an immune-competent animal model, thus limiting information about the efficacy of this approach. Here, for the first time we demonstrate the similarity between BMP2-induced endochondral bone formation in a system using human cells in an immune-incompetent mouse and a murine cell-based BMP2 gene therapy system in immune-competent animals. In both cases the delivery cells are rapidly cleared, within 5 days, and in neither case do they appear to contribute to any of the structures forming in the tissues. Endochondral bone formation progressed through a highly ordered series of stages that were both morphologically and temporally indistinguishable between the two models. Even longterm analysis of the heterotopic bone demonstrated similar bone volumes and the eventual remodeling to form similar structures. The results suggest that the ability of BMP2 to rapidly induce bone formation overrides contributions from either immune status or the nature of delivery cells.
Fouletier-Dilling
Christine M
CM
Center for Cell and Gene Therapy, Department of Orthopedic Surgery, Baylor College of Medicine, Houston, TX 77030, USA.
Gannon
Francis H
FH
Olmsted-Davis
Elizabeth A
EA
Lazard
Zawaunyka
Z
Heggeness
Michael H
MH
Shafer
Jessica A
JA
Hipp
John A
JA
Davis
Alan R
AR
D016475:3T3 Cells; D000818:Animals; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000627:therapeutic use; D015316:Genetic Therapy; D006801:Humans; D007121:Immunocompetence / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D010012:Osteogenesis / Q000276:immunology / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics* / Q000627:therapeutic use
C525718:BMP2 protein, human; C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D016212:Transforming Growth Factor beta