Adenoviral delivery of osteoprotegerin ameliorates bone resorption in a mouse ovariectomy model of osteoporosis.
Osteoprotegerin (OPG) regulates bone resorption by inhibiting osteoclast formation, function, and survival. The current studies employed a mouse ovariectomy (OVX) model of estrogen deficiency to investigate gene therapy with OPG as a means of preventing osteoporosis. Young adult females injected with a recombinant adenoviral (Ad) vector carrying cDNA of either full-length OPG or a fusion protein combining the hOPG ligand-binding domain with the human immunoglobulin constant domain (Ad-hOPG-Fc) developed serum OPG concentrations exceeding the threshold needed for efficacy. However, elevated circulating OPG levels were sustained for up to 18 months only in mice given Ad-hOPG-Fc. Administration of Ad-hOPG-Fc titers between 10(7) and 10(9) pfu yielded dose-dependent increases in serum OPG. Mice subjected to OVX or sham surgery followed by immediate treatment with Ad-hOPG-Fc had significantly more bone volume with reduced osteoclast numbers in axial and appendicular bones after 4 weeks. In contrast, animals given OVX and either a control vector or vehicle had significantly less bone than did comparably treated sham-operated mice. This study demonstrates that a single adenoviral gene transfer can produce persistent high-level OPG expression and shows that gene therapy to provide sustained delivery of OPG may prove useful in treating osteoporosis.
Department of Pharmacology and Pathology, Amgen, Thousand Oaks, California, 91320-1789, USA.
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Bolon
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Carter
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Daris
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Morony
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Capparelli
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Hsieh
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Mao
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Kostenuik
C R
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Dunstan
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Lacey
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Sheng
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001681:Biological Assay; D015139:Blotting, Southern; D015153:Blotting, Western; D015519:Bone Density / Q000187:drug effects; D001862:Bone Resorption; D018076:DNA, Complementary / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006023:Glycoproteins / Q000235:genetics*; D006801:Humans; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D010024:Osteoporosis / Q000628:therapy*; D053244:Osteoprotegerin; D010052:Ovariectomy; D010053:Ovary / Q000502:physiology; D010388:Pelvis / Q000000981:diagnostic imaging; D011859:Radiography; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013997:Time Factors
D018076:DNA, Complementary; D006023:Glycoproteins; D008024:Ligands; D053244:Osteoprotegerin; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; C506030:TNFRSF11B protein, human; C506031:Tnfrsf11b protein, mouse