Osteoprotegerin (OPG) gene therapy in animal models of osteoarticular disease

Abstract

The soluble decoy receptor osteoprotegerin (OPG) regulates bone resorption by inhibiting osteoclast formation, function and survival. We investigated OPG gene therapy as a means of ameliorating chronic osteoarticular disease using a mouse ovariectomy (OVX) model of estrogen deficiency-induced osteoporosis (Mol Ther 2001, 3:1–9). Young adult female mice injected once with an adenoviral (Ad) vector carrying a human fusion protein combining the OPG ligand-binding and immunoglobulin constant domains (hOPG-Fc) developed serum OPG levels that exceeded the threshold needed for efficacy (as assessed by a marked increase in bone density) for over 12 months. The extent of OPG production and skeletal enhancement was titer-dependent. Mice subjected to OVX or sham surgery and then treated with Ad-hOPG-Fc had significantly more bone volume and fewer osteoclasts in axial and appendicular bones after 4 weeks. In contrast, animals given OVX and either a control vector expressing β-galactosidase or vehicle had significantly less bone than did comparably treated, sham-operated mice. This study confirms that a single Ad gene transfer can produce persistent high-level OPG expression and shows that OPG gene therapy may prove useful in treating osteoporosis. We anticipate that OPG gene therapy will offer similar promise as a bone-sparing agent in chronic arthritis since we have shown previously that injected OPG significantly inhibits skeletal erosion in the Lewis rat model of mycobacterial-induced adjuvant arthritis (Nature 1999, 402:304–309).