title: Adenovirus-mediated small interfering RNA targeting tumor necrosis factor-α inhibits titanium particle-induced osteoclastogenesis and bone resorption.
abstract: Wear particles are phagocytosed by macrophages, resulting in cellular activation and the release of pro-inflammatory factors, which cause periprosthetic osteolysis and subsequent aseptic loosening, the most common causes of total joint arthroplasty (TJA) failure. During this pathological process, tumor necrosis factor (TNF)-α plays an important role in wear particle-induced osteolysis. Therefore, in this study, we used adenovirus-mediated small interfering RNA (siRNA) targeting TNF-α to suppress the TNF-α release from activated macrophages in response to titanium particles. Our results showed that recombinant adenovirus (Ad-TNF-α-siRNA) suppressed the TNF-α release from activated macrophages in response to titanium particles, and reduced titanium particle-induced osteoclastogenesis and bone resorption in the presence of receptor activator of nuclear factor-κB ligand (RANKL). In addition, the conditioned medium of macrophages challenged with titanium particles (Ti CM) stimulated osteoprogenitor RANKL expression. The conditioned medium of macrophages challenged with titanium particles and Ad-TNF-α-siRNA (Ti-Ad CM) reduced the mRNA expression in MC3T3-E1 cells compared to Ti CM. Based on these data, TNF-α strongly synergizes with RANKL to promote osteoclast differentiation. Furthermore, TNF-α promoted osteoclast differentiation by stimulating osteoprogenitor RANKL expression. Ad-TNF-α-siRNA effectively suppressed osteoclast differentiation and bone resorption following exposure to titanium particles in the presence of RANKL. In addition, recombinant adenovirus (Ad-TNF-α-siRNA) does not have a toxic effect on the murine macrophage cell line, RAW264.7. Consequently, it can be concluded that recombinant adenovirus-mediated siRNA targeting TNF-α (Ad-TNF-α-siRNA) may provide a novel therapeutic approach for the treatment of periprosthetic osteolysis.
authors.affiliation: Department of Orthopedic Surgery, Ningxia Medical University Affiliated Hospital, Yinchuan, Ningxia Hui Autonomous Region, P.R. China.
authors.forename: Haohui
authors.initials: H
authors.lastname: Guo
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Shaowen
authors.initials: S
authors.lastname: Hao
authors.forename: Qunhua
authors.initials: Q
authors.lastname: Jin
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001862:Bone Resorption / Q000209:etiology*; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005822:Genetic Vectors / Q000235:genetics*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D053245:RANK Ligand / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics* / Q000378:metabolism; D014025:Titanium / Q000009:adverse effects*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism
chemical_list: D017077:Culture Media, Conditioned; D053245:RANK Ligand; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D014025:Titanium