Induction of Bone Formation Using a Recombinant Adenoviral Vector Carrying the Human BMP-2 Gene in a Rabbit Spinal Fusion Model

Abstract

Bone marrow-derived mesenchymal stem cells are pluripotential cells that have the capacity to differentiate into an osteoprogenitor line. It has been demonstrated that BMP-2 can enhance this differentiation process. In an attempt to prolong the transforming effect of BMP-2, we used an adenoviral vector carrying the human BMP-2 gene to transduce marrow-derived mesenchymal stem cells of New Zealand white rabbits. Assays on tissue culture demonstrated that these cells indeed produced the BMP-2 protein. These transduced stem cells were then autologously reimplanted into the donor rabbits. The cells were placed in the intertransverse process area of five rabbits. In one out of the five rabbits, this resulted in the production of new bone which was demonstrable on both radiographic and histologic examination. We conclude that it is possible to successfully transduce mesenchymal stem cells with the gene for BMP-2 such that these cells will produce the BMP-2 protein in vitro. Further, the transduction results in transformation of these cells into an osteoprogenitor line capable of producing bone in vivo. These data suggest the feasibility of employing gene therapy using recombinant adenoviral vectors as a tool for enhancing spine fusion. Further work to improve the fidelity and longevity of the gene transfer is warranted.

Osteoinduction by ex vivo adenovirus-mediated BMP2 delivery is independent of cell type

“…[1][2][3][4][5][6][7][8] Localized delivery of cells transduced ex vivo with adenoviral vectors encoding bone morphogenetic proteins (BMPs) has proven successful in induction of new bone formation in hetero-and orthotopic locations. Although safe and efficacious gene-based bone induction systems have yet to be developed, the adenoviral delivery of BMP offers the potential of rapidly achieving local effective concentrations of the protein to induce bone formation.…”

Ex vivo gene therapy with stromal cells transduced with a retroviral vector containing the BMP4 gene completely heals critical size calvarial defect in rats

“…[9][10][11][12][13][14] Accordingly, it has been shown that adenoviral transfer of BMP2 can stimulate bone formation at ectopic sites 16 and promote healing of a segmental defect in long bones. 9,14 In as much as the results of previous work using adenoviral vectors are promising and adenoviral vector systems have the advantage of high levels of gene expression acutely, adenoviral vector systems also have two important disadvantages: (1) these vectors, even with the use of 'gutted' adenoviral vectors, frequently elicit strong immune response, which is highly undesirable.…”

Transplanted xenogenic bone marrow stem cells survive and generate new bone formation in the posterolateral lumbar spine of non-immunosuppressed rabbits

“…However, harvesting autogenous bone graft is inevitably associated with donor site morbidities and increased surgical time [27]. Therefore, extensive basic and clinical researches have been directed at developing alternatives to autogenous bone graft [11,15,17,18,21,26].…”

“…Recently, several studies have reported that BMSCs may be immune-privileged cells that do not elicit immune responses due to an absence of their immunologically relevant cell surface markers. BMSCs also are known to inhibit proliferation of T lymphocytes, B lymphocytes, dendritic cells, and natural killer cells [3,14,24,26,31]. This poses the intriguing possibility of utilizing allogenic or xenogenic BMSCs as an alternative in patients who have limited availability of autologous BMSCs.…”