Adenoviral delivery of osteoprotegerin ameliorates bone resorption in a mouse ovariectomy model of osteoporosis

Osteoprotegerin (OPG) regulates bone resorption by inhibiting osteoclast fo rmation, function, and survival. The current studies employed a mouse ovari ectomy (OVX) model of estrogen deficiency to investigate gene therapy with OPG as a means of preventing osteoporosis. Young adult females injected wit h a recombinant adenoviral (Ad) vector carrying cDNA of either full-length OPG or a fusion protein combining the hOPG ligand-binding domain with the h uman immunoglobulin constant domain (Ad-hOPG-Fc) developed serum OPG concen trations exceeding the threshold needed for efficacy. However, elevated cir culating OPG levels were sustained for up to 18 months only in mice given A d-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 sha m 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 v ector or vehicle had significantly less bone than did comparably treated sh am-operated mice. This study demonstrates that a single adenoviral gene tra nsfer can produce persistent high-level OPG expression and shows that gene therapy to provide sustained delivery of OPG may prove useful in treating o steoporosis.