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


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.
Doran
Patrick M
PM
Molecular Medicine Program, Endocrine Research Unit, Mayo Clinic and Mayo Foundation, Rochester, Minn. 55905, USA.
Turner
Russell T
RT
Chen
David
D
Facteau
Suzanne M
SM
Ludvigson
Jill M
JM
Khosla
Sundeep
S
Riggs
B Lawrence
BL
Russell
Stephen J
SJ
D000818:Animals; D015519:Bone Density; D045744:Cell Line, Tumor / Q000637:transplantation; D016373:DNA, Antisense / Q000235:genetics; D004274:DNA, Recombinant / Q000235:genetics; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics / Q000627:therapeutic use*; D006023:Glycoproteins / Q000235:genetics*; D007763:Lac Operon; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D009101:Multiple Myeloma / Q000150:complications*; D009368:Neoplasm Transplantation; D010010:Osteoclasts / Q000473:pathology; D010014:Osteolysis / Q000000981:diagnostic imaging / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D053244:Osteoprotegerin; D010865:Pilot Projects; D011859:Radiography; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D018124:Receptors, Tumor Necrosis Factor; D014161:Transduction, Genetic; D023041:Xenograft Model Antitumor Assays
D016373:DNA, Antisense; D004274:DNA, Recombinant; D006023:Glycoproteins; D053244:Osteoprotegerin; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C506030:TNFRSF11B protein, human; C506031:Tnfrsf11b protein, mouse