Adenoviral Delivery of Osteoprotegerin Ameliorates Bone Resorption in a Mouse Ovariectomy Model of Osteoporosis

Abstract

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.

Gene therapy for osteoporosis: evaluation in a murine ovariectomy model

“…Here we report an impressive reduction in bone loss following the intramedullary transfer of IL1Ra genes to ovariectomized mice. While this manuscript was in preparation, similar results were reported by Bolon et al 32 using adenovirus to deliver a gene encoding osteoprotegerin.…”

“…Impressive protection from post-ovariectomy bone loss has also been reported after delivery of an osteoprotegerin gene. 32 Intramedullary injections of adenoviruses led to sustained transgene expression by cells associated with bone, and a more temporary appearance of secretable transgene products within the serum. Our data do not discern whether the circulating IL-1Ra or the IL-1Ra produced locally within the bone was more important in preventing osteoporosis.…”

Association between Increased Serum Osteoprotegerin Levels and Improvement in Bone Mineral Density after Parathyroidectomy in Hemodialysis Patients

“…OPG blocks the interaction between nuclear factor-kB (RANK) and its ligand (RANKL), thus inhibiting osteoclast differentiation and activity, and consequently preventing bone resorption (Bolon et al 2001). Calciotropic hormones and cytokines, including PTH, apparently act through a dual mode to inhibit OPG production and stimulate RANKL production (Vega et al 2007).…”

Opg/Rankl

“…Ce concept a été validé dans plusieurs modèles expérimentaux. Ainsi, l'administration d'OPG permet d'inhiber la différenciation, la fonction et la survie des ostéoclastes et donc la résorption osseuse, permettant d'améliorer la résistance osseuse chez la rate ovariectomisée, un modèle établi de perte osseuse par déficience oestrogénique [24]. Par ailleurs, l'administration d'OPG chez des femmes ostéoporotiques ménopausées induit bien une diminution de la résorption osseuse, évaluée par les marqueurs biochimiques [25].…”