stilbenes and Osteolysis

Aseptic loosening is the most common cause of total hip arthroplasty (THA) failure, and osteolysis induced by wear particles plays a major role in aseptic loosening. Various pathways in multiple cell types contribute to the pathogenesis of osteolysis, but the role of Sirtuin 1 (SIRT1), which can regulate inflammatory responses through its deacetylation, has never been investigated. We hypothesized that the downregulation of SIRT1 in macrophages induced by metal nanoparticles was one of the reasons for osteolysis in THA failure. In this study, the expression of SIRT1 was examined in macrophages stimulated with metal nanoparticles from materials used in prosthetics and in specimens from patients suffering from aseptic loosening. To address whether SIRT1 downregulation triggers these inflammatory responses, the effects of the SIRT1 activator resveratrol on the expression of inflammatory cytokines in metal nanoparticle-stimulated macrophages were tested. The results demonstrated that SIRT1 expression was significantly downregulated in metal nanoparticle-stimulated macrophages and clinical specimens of prosthesis loosening. Pharmacological activation of SIRT1 dramatically reduced the particle-induced expression of inflammatory cytokines in vitro and osteolysis in vivo. Furthermore, SIRT1 regulated particle-induced inflammatory responses through nuclear factor kappa B (NF-κB) acetylation. Thus, the results of this study suggest that SIRT1 plays a key role in metal nanoparticle-induced inflammatory responses and that targeting the SIRT1 pathway may lead to novel therapeutic approaches for the treatment of aseptic prosthesis loosening.

Topics: Acetylation; Aged, 80 and over; Animals; Arthroplasty, Replacement, Hip; Cytokines; Female; Humans; Inflammation; Macrophages; Male; Metal Nanoparticles; Mice, Inbred C57BL; Middle Aged; NF-kappa B; Osteolysis; Prostheses and Implants; Prosthesis Failure; Resveratrol; Sirtuin 1; Stilbenes

Aseptic implant loosening is closely associated with chronic inflammation induced by implant wear debris, and reactive oxygen species (ROS) play an important role in this process. Resveratrol, a plant compound, has been reported to act as an antioxidant in many inflammatory conditions; however, its protective effect and mechanism against wear particle-induced oxidative stress remain unknown. In this study, we evaluated resveratrol's protective effects against wear particle-induced oxidative stress in RAW 264.7 macrophages. At non-toxic concentrations, resveratrol showed dose-dependent inhibition of nitric oxide (NO) production, ROS generation, and lipid peroxidation. It also downregulated the gene expression of oxidative enzymes, including inducible nitric oxide synthase (iNOS) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX)-1 and NOX-2, and promoted the gene expression and activities of antioxidant enzymes, including catalase (CAT), superoxide dismutase (SOD), glutathione reductase (GR), and glutathione peroxidase (GPx). This protective effect against wear particle-induced oxidative stress was accompanied by a reduction of gene expression and release of tumor necrosis factor-α (TNF-α), and decreased gene expression and phosphorylation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). These findings demonstrate that resveratrol can inhibit wear particle-induced oxidative stress in macrophages, and may exert its antioxidant effect and protect against aseptic implant loosening.

Topics: Animals; Antioxidants; Catalase; Cell Line; Female; Glutathione Peroxidase; Glutathione Reductase; Lipid Peroxidation; Macrophages; Membrane Glycoproteins; Mice; Mice, Inbred C57BL; NADH, NADPH Oxidoreductases; NADPH Oxidase 1; NADPH Oxidase 2; NADPH Oxidases; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type II; Osteolysis; Oxidative Stress; Prostheses and Implants; RAW 264.7 Cells; Reactive Oxygen Species; Resveratrol; Stilbenes; Superoxide Dismutase; Titanium; Tumor Necrosis Factor-alpha