RESUMO
OBJECTIVE: Adenovirus expressing small interfering RNA (siRNA)-targeting BMPR-IB was locally administered into the air pouch of mice to improve bone resorption induced by ultra-high molecular weight polyethylene (UHMWPE) particles. METHOD: Air pouches were established on the back of BALB/c mice, followed by the surgical introduction of a section of calvaria from a syngeneic mouse donor. The bone-implanted pouches were stimulated with the UHMWPE suspension. UHMWPE-containing mice were divided into three study groups to receive injections of adenovirus expressing BMPR-IB siRNA (BMPR-IB group), adenovirus expressing missense siRNA, and virus-free culture medium (control group) into the pouches, respectively. The tissues were harvested at 14 days after the treatment for molecular and histological analyses. RESULTS: Adenovirus-mediated BMPR-IB siRNA treatment significantly improved UHMWPE particle-induced bone resorption, reduced TRAP and RANK gene and protein expression levels, and diminished the number of TRAP-positive cells. Furthermore, the BMPR-IB siRNA inhibited osteoclast differentiation by targeting osteoblast for the induction of osteoprotegerin formation and downregulation of receptor for activation of nuclear factor-κB ligand production. CONCLUSIONS: This study suggested that loss of bone morphogenetic protein signaling by BMPR-IB siRNA directs osteoblasts to decrease bone destruction in part by downregulating osteoclastogenesis through the receptor for activation of nuclear factor-κB ligand-osteoprotegerin pathway. Local administration of adenovirus expressing siRNA-targeting BMPR-IB may be a feasible and effective therapeutic candidate to treat or prevent wear debris-associated osteolysis.
Assuntos
Adenoviridae , Receptores de Proteínas Morfogenéticas Ósseas Tipo I/biossíntese , Reabsorção Óssea/metabolismo , Vetores Genéticos , Polietileno/efeitos adversos , RNA Interferente Pequeno , Animais , Receptores de Proteínas Morfogenéticas Ósseas Tipo I/genética , Reabsorção Óssea/induzido quimicamente , Reabsorção Óssea/genética , Reabsorção Óssea/patologia , Transplante Ósseo , Modelos Animais de Doenças , Inativação Gênica , Camundongos , Camundongos Endogâmicos BALB C , Osteoprotegerina/genética , Osteoprotegerina/metabolismo , Polietileno/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transplante IsogênicoRESUMO
Aseptic loosening (AL) is the single most common complication of total joint arthroplasty. The critical factor may contribute to loosening is the adverse tissue response to wear debris. A growing body of literature suggests that BMPs influence the formation and activity of osteoclasts, and BMP signaling plays an important role in the osteoclast formation. In this study, we have employed an RNA interference approach by transfecting a small interfering RNA (siRNA) specific for BMPR-II, to determine the possible importance of this receptor as a target for UHMWPE (Ultra high molecular weight polyethylene) induced osteoclastogenesis in the air pouch model in vivo. Meanwhile, in order to further elucidation of the mechanism of BMPR-II signaling pathway in osteoclast formation, we investigated the effects of siBMPR-II toward RANKL induced osteoclast differentiation in vitro. The present study showed that locally injection of adenovirus-mediated siRNA targeting BMPR-II appears to be a feasible and effective candidate to treat or prevent wear debris-associated osteolysis. Furthermore, we revealed that the effects of BMPR-II signaling on osteoclast formation are mediated directly by osteoclast itself, as well as indirectly by altered expression of RANKL and OPG in osteoblast.