title: Suppression of titanium particle-induced TNF-alpha expression and apoptosis in human U937 macrophages by siRNA silencing.
abstract: Aseptic loosening of joint prosthetics is one of the most frequent reasons for the failure of total joint replacement surgeries. A major cause of the aseptic loosening is osteolysis caused by a periprosthetic inflammatory response to wear particles released from implanted prosthetics. Tumor necrosis factor (TNF)-α is thought to play a dominant role in wear-induced inflammation. It was shown previously by our group, as well as by other researchers, that macrophages produce abundant TNF-α when exposed to particulate titanium (Ti), which is widely used as a biomaterial in arthroplastic surgery. In the present study, we have tested the feasibility of using siRNA as a therapeutic intervention against wear-induced TNF-α production. Our data show that transfection of U937 macrophage cells with TNF-α siRNA inhibits Ti particle-induced expression of TNF-α mRNA and protein by >65%. Moreover, U937 cells transfected with TNF-α siRNA were significantly more resistant to Ti particle-induced apoptosis (>60%, p<0.05) and caspase-3 activation (>50%, p<0.05) compared with normal U937 cells. Collectively, our data show that siRNA can be an effective way to inhibit Ti particle-induced TNF-α expression and the activation of downstream pathways such as apoptosis in macrophages. These data provide a foundation for future studies to investigate the use of siRNA targeting inflammatory cytokines as a therapeutic modality for the treatment of aseptic loosening of prosthetic materials used in arthroplastic surgery.
authors: Department of Orthopedics, General Hospital of Ningxia Medical University, Yinchuan, China.
authors: Kening
authors: K
authors: Sun
authors: Yaping
authors: Y
authors: Li
authors: Zhidong
authors: Z
authors: Lu
authors: Liang
authors: L
authors: Zhang
authors: Zhihui
authors: Z
authors: Gao
authors: Qunhua
authors: Q
authors: Jin
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D007595:Joint Prosthesis; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D053768:Metal Nanoparticles; D011474:Prosthesis Design; D011475:Prosthesis Failure; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism*; D013997:Time Factors; D014025:Titanium / Q000633:toxicity*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D020298:U937 Cells
chemical_list: D018836:Inflammation Mediators; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D014025:Titanium; C505407:CASP3 protein, human; D053148:Caspase 3