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  • Title: Local ex vivo gene therapy with bone marrow stromal cells expressing human BMP4 promotes endosteal bone formation in mice.
    Author: Zhang XS, Linkhart TA, Chen ST, Peng H, Wergedal JE, Guttierez GG, Sheng MH, Lau KH, Baylink DJ.
    Journal: J Gene Med; 2004 Jan; 6(1):4-15. PubMed ID: 14716672.
    Abstract:
    BACKGROUND: Bone loss in osteoporosis is caused by an imbalance between resorption and formation on endosteal surfaces of trabecular and cortical bone. We investigated the feasibility of increasing endosteal bone formation in mice by ex vivo gene therapy with bone marrow stromal cells (MSCs) transduced with a MLV-based retroviral vector to express human bone morphogenetic protein 4 (BMP4). METHODS: We assessed two approaches for administering transduced MSCs. beta-Galactosidase (beta-Gal) transduced C57BL/6J mouse MSCs were injected intravenously via tail vein or directly injected into the femoral bone marrow cavity of non-marrow-ablated syngenic recipient mice and bone marrow cavity engraftment was assessed. BMP4- or beta-Gal-transduced cells were injected into the femoral bone marrow cavity and effects on bone were evaluated by X-ray, peripheral quantitative computed tomography (pQCT), and histology. RESULTS: After tail-vein injection less than 20% of recipient mice contained beta-Gal-positive donor cells in femur, humerus or vertebra marrow cavities combined, and in these mice only 0.02-0.29% of injected cells were present in the bone marrow. In contrast, direct intramedullary injection was always successful and an average of 2% of injected cells were present in the injected femur marrow cavity 24 hours after injection. Numbers of donor cells decreased over the next 14 days. Intramedullary injection of BMP4-transduced MSCs induced bone formation. Trabecular bone mineral density (BMD) determined by pQCT increased 20.5% at 14 days and total BMD increased 6.5% at 14 days and 10.4% at 56 days. CONCLUSIONS: The present findings support the feasibility of using ex vivo MSC-based retroviral gene therapy to induce relatively sustained new bone formation, with normal histological appearance, at endosteal bone sites.
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