Regional gene therapy with a BMP‐2‐producing murine stromal cell line induces heterotopic and orthotopic bone formation in rodents

Abstract

The ability to continuously deliver osteoinductive proteins to a specific anatomic site would facilitate the treatment of fracture nonunions and other clinical problems associated with bone loss. We have developed a murine model of regional gene therapy. A bone-marrow stromal cell line infected with an adenovirus expressing recombinant bone morphogenetic protein-2 cDNA secreted biologically active bone morphogenetic protein-2. These bone morphogenetic protein-2-producing cells were able to induce abundant heterotopic bone formation when implanted into the quadriceps muscle of severe combined immune deficient mice and also successfully healed large segmental femoral defects in nude rats. These studies demonstrate that regional gene therapy with continuous delivery of osteoinductive factors to a specific anatomic site can enhance the formation and repair of bone.

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

“…Although there are several studies which have shown evidence for skeletal regeneration in vivo using ex vivo modified stromal cells, myoblasts, or fibroblasts, 10,15,16,22,24,25 our study is unique in that it provides quantitative data on the extent of healing by valid bone density measurements. Furthermore, our data demonstrate that the healing of a critical calvarial defect is dependent on the time of exposure, as well as the number of BMP4-expressing stromal cells implanted.…”

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.…”

Genetically Engineered Mesenchymal Stem Cells: The Ongoing Research for Bone Tissue Engineering

“…BMP-2, approved by Food and Drug Administration (FDA) for clinical practice, is the most potent member in promoting bone and cartilage development and therefore wins a popular choice for MSCs-based BTE (Lieberman et al, 1998;Lieberman et al, 1999;Lou et al, 1999;Turgeman et al, 2001;Olmsted-Davis et al, 2002;Blum et al, 2003;Gugala et al, 2003;Park et al, 2003;Riew et al, 2003;Tsuda et al, 2003;Kumar et al, 2004;Hasharoni et al, 2005;Egermann et al, 2006;Feeley et al, 2006). The BMP-2-modified MSCs are proven to increase the alkaline phosphatase (ALP) activity, mineralization, and cell proliferation in vitro and induce ectopic bone formation, heal critical size bone defect, repair fracture, and trigger spinal fusion in vivo (Lou et al, 1999;Moutsatsos et al, 2001;Turgeman et al, 2001;Blum et al, 2003;Park et al, 2003;Riew et al, 2003;Tsuda et al, 2003;Hasharoni et al, 2005;Egermann et al, 2006;Feeley et al, 2006).…”