Effects And Mechanism Of Fraxetin For Periprosthetic Osteolysis

Background and PurposeAseptic loosening is the leading cause of prosthetic failure after total hip arthroplasty,which has become a gold standard for the treatment of severe hip diseases.The main cause of aseptic loosening is due to the increased bone resorption of osteoclasts induced by wear particles,accompanied by the release of inflammatory factors,leading to osteolysis around the prosthesis.Previous studies found that fraxetin,a small molecule of flavonoids,has bone formation and anti-inflammatory effect.This study focuses on the effect and mechanism of fraxetin for Periprosthetic osteolysis.Content and methods1.The mice model of calvaria osteolysis induced by Titanium(Ti)particle were used to investigate the effects of fraxetin on periprosthesis osteolysis in vivo;2.The CCK-8 methods was used to evaluate the cytotoxicity of fraxetin;Osteoclast culture-tartaric acid phosphatase(TRAP)staining and bone resorption experience were used to study the differentiation and function of osteoclast in vitro.3.RT-QPCR and Western blot were used to discover the molecular mechanism of the treatment of fraxetin on periprosthesis osteolysis targeting osteoclasts.Result1.In vivo,fraxetin had inhibitory effects on Ti particle-induced osteolysis through the blockade of osteoclast2.In vitro,fraxetin could block the differentiation process of osteoclast and bone resorption in a dose-dependent manner without cytotoxic effects.3.Fraxetin could inhibit osteoclast differentiation and function via(1)suppressing the expression of osteoclast-specific genes c-fos、NFATcl、TRAP、CTR and CtsK,and(2)blocking the RANKL-mediated p38-MAPK signaling pathway,but not NF-kB signaling pathway.ConclusionCollectively,we demonstreate that fraxetin has a good therapeutic effect on periprosthesis osteolysis in animal models,and dentify the molecular mechanism of fraxetin on osteolysis in vitro.Fraxetin may be potential agents for the treatment of periprosthetic osteolysis.