Effects of RANKL Knockdown by Virus-like Particle-Mediated RNAi in a Rat Model of Osteoporosis

Abstract

Rebalancing of the RANKL/OPG system seems to be an effective treatment strategy in postmenopausal osteoporosis. Here, we evaluate the knockdown of RANKL by in-vivo-delivered siRNA in a rat model of osteoporosis. Virus-like-particles (VLPs) derived from polyoma JC virus were used for delivering RANKL siRNA in ovariectomized (OVX) rats. 48 rats were ovariectomized and treated with either 17β-estradiol (E2), VLPs containing RANKL siRNA (siRANKL), or VLPs containing non-cognate siRNA (siCtrl). All OVX groups were subdivided into the prophylaxis group (PG) and the therapy group (TG). The PG received treatment directly after being OVX for 10 weeks. The TG received treatment 5 weeks after being OVX for 5 weeks. Rats were sacrificed 10 weeks after being OVX. Bone and blood samples were analyzed. E2 and siRANKL showed a significant knockdown of RANKL mRNA. A protein knockdown was observed with E2 and siRANKL in the TG but not in the PG. No distinct improvements in biomechanical and morphological properties of the bones were observed after siRANKL treatment. In the PG, E2 protected the bone structure. We demonstrated successful mRNA and protein knockdown by VLP-mediated RNAi in vivo. Knockdown of membranous RANKL did not result in significant improvements of bone properties in this model of early-stage postmenopausal osteoporosis.

A novel modified RANKL variant can prevent osteoporosis by acting as a vaccine and an inhibitor

“…The therapeutic vaccine also has been reported in previous studies, such as active immunization of OVX mice with RANKL covalently linked to human RANKL-TNF-like core fusion protein (RTFP-2), virus-like particles (VLP), Dickkopf-1-derived peptides, and interspecies RANKL mutation. 15,[32][33][34][35][36] However, vaccines introducing small particles or peptides may induce undesired immune responses. Interestingly in the present study, Th2 dependent cytokine production in spleen cells from immunized mice increased, although the level of inflammation did not alter significantly.…”

Resveratrol promotes osteogenesis and alleviates osteoporosis by inhibiting p53

“…Although osteoporosis is a widespread disease [ 13 ] that has become a major challenge for public health systems worldwide [ 3 ], there is currently no gold standard treatment. While resveratrol can reverse both osteoporosis-associated BMD reduction and microarchitectural deterioration [ 8 ], the mechanisms responsible for these effects remain unknown.…”

The shared KEGG pathways between icariin-targeted genes and osteoporosis

“…Osteoporosis is a metabolic bone disease caused by an imbalance in bone turnover, resulting in an increased risk of bone fractures. The treatment of osteoporosis is still a challenge [15]. Icariin is an herbal substance extracted from the plant Epimedium, which has antiosteoporotic and anti-osteoarthritic effects [3][4][5][6][7], and promotes bone healing [16].…”