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Aseptic loosening due to wear particles is a serious challenge for orthopedic surgeons, sabotaging the long-term success of total joint arthroplasty. The existing treatments for aseptic loosening are still far from satisfactory, necessitating more aggressive drug exploration. Here, we examined the effect of emodin on titanium particle-induced osteolysis and further investigated its underlying mechanism in vivo and in vitro. Thirty-two C57BL/6 mice were randomly assigned into four groups: the Sham group (sham operation with vehicle injection), Vehicle group (titanium particle treatment with vehicle injections), Low group (titanium particle treatment with injections of 10 mg/kg/day emodin) and High group (titanium particle treatment with injections of 50 mg/kg/day emodin). Micro-CT scanning and histological analysis revealed that after emodin injections, the inflammatory response and bone destruction were markedly ameliorated. TRAP staining showed that osteoclast numbers were also dramatically reduced. Throughout the in vitro culture period, emodin significantly decreased the bone resorption area, number of osteoclasts and formation of F-actin rings. Mechanistic studies suggested that reduced NF-κB signaling might be mediating the inhibitory effects of emodin. Collectively, our findings suggest that emodin, a natural product extracted from Rheum palmatum, may be developed as a promising candidate for the treatment of wear particle-induced osteolysis and subsequent aseptic loosening.Titanium particles lead to inflammation and subsequent osteolysis in murine calvarial model.Emodin attenuated titanium particle-induced osteolysis and RANKL-induced osteoclastogenesis.Emodin impaired osteoclast-mediated bone resorption and F-actin ring formation.Emodin prevented from RANKL-induced osteoclastogenesis via the suppression of IKKα/β phosphorylation.Emodin could be a potential therapeutic candidate for peri-prosthetic osteolysis and aseptic loosening.