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Cited by 22Virus-based gene therapy researchMultiple Myeloma Research and TreatmentsBone Metabolism and Diseases

Native osteoprotegerin gene transfer inhibits the development of murine osteolytic bone disease induced by tumor xenografts.

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Doran, Patrick M., Turner, Russell T., Chen, David, Facteau, Suzanne M., Ludvigson, Jill M., Khosla, Sundeep, Riggs, B.Lawrence, Russell, Stephen J.·2004·Experimental Hematology
DOI 10.1016/j.exphem.2004.01.006
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Abstract

Objective Multiple myeloma is a plasma cell malignancy characterized by the development of osteolytic lesions leading to bone pain, pathologic fractures, and hypercalcemia. Osteoprotegerin (OPG) is a potent inhibitor of osteoclast differentiation and activation, but is limited as a therapeutic agent due to its short circulating half-life. In order to overcome these limitations, the therapeutic effects of native OPG gene transfer are examined.Materials and methods We used replication-incompetent lentiviral vectors to transfer the unmodified, native human OPG gene ex vivo into human ARH-77 cells injected into severe combined immunodeficient (SCID) mice, to determine gene transfer efficiency as well as the impact on disease progression in this in vivo model.Results We can efficiently transfer and express either the LacZ marker gene or the native human OPG gene into human ARH-77 cells. Moreover, transfer of the OPG gene into ARH-77 cells reduces the development of osteolytic bony lesions when these cells are injected into SCID mice, compared to mice injected with either unmodified ARH-77 cells or ARH-77 cells transduced with the OPG gene in the antisense orientation. This therapeutic effect was manifested as a reduction in vertebral compression deformities and in the number and size of long-bone osteolytic lesions on skeletal radiographs, as well as a decrease in osteoclast surface on histologic analysis.Conclusions A lentiviral vector can efficiently transfer the native human OPG gene to myeloma cells ex vivo and inhibit myeloma-induced bone destruction, thereby suggesting a therapeutic potential for unmodified, native OPG gene transfer for osteoclast-dependent skeletal disorders.

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  • Lentiviral transfer of the human OPG gene into human myeloma cells caused secretion of therapeutic OPG levels and prevented bone destruction in immunodeficient mice without altering in vitro growth.

    “Direct lentiviral transfer of the human OPG gene into human myeloma cells led to their secretion of therapeutic levels of OPG, which was shown to prevent bone destruction in immunodeficient mice without altering their in vitro growth properties (359).”

    From Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease (2008) · cites this paper as [359]

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Authors
Doran, P. M., Turner, R. T., Chen, D., Facteau, S. M., Ludvigson, J. M., Khosla, S., Riggs, B. L., & Russell, S. J.
Affiliations
Amgen (United States) (US)
Corresponding author
Russell, Stephen J.
ORCID
Venue
Experimental Hematology
Publisher
Elsevier BV
Published
2004-04
Volume
32
Issue
4
Pages
351-359
ISSN
0301-472X (ISSN-L)
DOI
10.1016/j.exphem.2004.01.006
OpenAlex
W1995616953
Cited by
22
References
59
Citations by year
2026: 1 · 2019: 1 · 2018: 1 · 2015: 1 · 2012: 2
FWCI
2.14
Type
journal article
Language
en
Open access
Licence
Locations
  • Experimental Hematology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Mayo Foundation for Medical Education and Research
  • National Institutes of Health (5r01ar045233-04)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK07352-22, T32DK007352)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR 45233)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
  • Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
Keywords
osteoprotegerin, gene transfer, multiple myeloma, osteolytic bone disease, lentiviral vectors, osteoclasts, bone destruction, ex vivo gene therapy, SCID mice, vertebral compression fractures, bone metastasis
MeSH terms
Animals, DNA, Recombinant, Genetic Vectors, Glycoproteins, Lac Operon, Multiple Myeloma, Neoplasm Transplantation, Osteoclasts, Osteolysis, Pilot Projects, Radiography, Transduction, Genetic, Genetic Therapy, Bone Density, Lentivirus, DNA, Antisense, Receptors, Tumor Necrosis Factor, Receptors, Cytoplasmic and Nuclear, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice, Osteoprotegerin

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