The Mechanism,therapy And Prevention Of Aseptic Loosening After Joint Arthroplasty

Background and PurposeJoint replacement has become an essential tool for serious joint disease.However,this surgery is associated with a risk of aseptic loosening,leading to prosthetic failure.Therefore,it is of great clinical significance and application value to study the molecular mechanism of aseptic loosening and to develop effective therapy measures,which will be a key point to improve the joint implant life.The leading cause of aseptic loosening is considered to be periprosthesis osteolysis,characterized with enhanced osteoclastic bone resorption activity induced by wear particles,accompanied by the release of inflammatory factors.Bicarbonate/chloride exchanger,solute carrier family 4,anion exchanger,member 2(SLC4A2),located in the contralateral basement membrane of osteoclast ruffled border(for bone resorption),is a key factor to promote osteoclast differentiation and ruffled border formation,maintain osteoclast bone resorption,which may play an important role in the pathology process of wear particles induced-periprosthesis osteolytic.This study mainly investigated the role and mechanism of SLC4A2 in wear particles induced-osteoclasts differentiation and function.4,4'-Diisothiocyano-2,2'-stilbenedisulfonic acid(DIDs)is an anion exchange inhibitor that blocks HCO3~-/Cl~-anion exchange in osteoclasts.We further assessed the inhibition effect of DIDS on wear particle-induced periprosthesis osteolysis in vivo.At the same time,based on the regulation of systemic bone metabolism,we explored the bone protective effect of plant extract myricetin,a Chinese medicinal agent,on wear particle-induced periprosthesis osteolysis.At last,we evaluated the patient-related risk factors for aseptic loosening after total hip/knee replacement,which may provide some guidelines for disease prevention.Content and method1.We studied the effect of SLC4A2 on wear particles induced-osteoclast differentiation,and bone resorption in vitro;the role of SLC4A2 in actin cytoskeleton formation and specific genes expression were studied to discover the mechanism.2.The model of mouse calvaria osteolysis induced by wear particles was used to investigate the effects of DIDS on periprosthesis osteolysis in vivo;we explored the potent inhibitory effects of myricetin on Ti particle-induced osteolysis by a mouse calvarial model in vivo,osteoclast formation and function in vitro,and mechanism in detail.3.Hospital-based case-control study was used to evaluate the patient-related risk factors for aseptic loosening after total hip arthroplasty(THA)and total knee arthroplasty(TKA).Conditional logistic regression was used to compute odds ratios(ORs)and 95%confidence intervals(CIs).Result1.The data indicated that SLC4A2 is up-regulated during Titanium(Ti)and polymymethyl methacrylate(PMMA)particles induced-osteoclastogenesis in an NFATc1-dependent manner.Suppression of SLC4A2 expression through RNAi technique effectively inhibited wear debris-induced osteoclast differentiation,bone resorption,and the expression of osteoclast-specific gene markers(TRAP,NFATc1,CTR and CTSK),caused by the role of SLC4A2 on acitin cytoskeleton formation.2.We indicated that inhibition of SLC4A2 mediated anion exchange activity by DIDS significantly suppressed particle-induced osteolysis.Myricetin had inhibitory effects on Ti particle-induced osteolysis in vivo.Further,myricetin functioned through the suppression of the MAPK(p38,JNK1/2,ERK1/2)and NF-?B signaling pathways and inhibition of TNF-?and IL-1?secretion.3.The demographic factors and comorbid conditions associated with a risk-adjusted increase in aseptic loosening(in decreasing order of significance)were a rural place of residence(OR=2.28;95%CI:1.21–4.30;p=0.011),body mass index(BMI)?28kg/m~2(vs.18.5-28 kg/m~2)(OR=2.29;95%CI:1.19–4.41;p=0.013),developmental dysplasia of the hip(DDH)(OR=2.91;95%CI:1.11–7.66;p=0.030),tobacco abuse(OR=2.88;95%CI:1.05–7.89;p=0.039),and age<45 years(vs.45–65 years)(OR=2.63;95%CI:1.01–6.80;p=0.047).Conclusion1.SLC4A2 plays an important role in the differentiation and function of osteoclasts induced by wear particles,and suppression of SLC4A2 expression may provide new targets and ideas for the treatment of periprosthesis osteolysis.2.DIDS and myricetin have a good therapeutic effect on periprosthesis osteolysis in animal models,which may be potential agents for the treatment of aseptic loosening and other osteoclast-related osteolytic diseases.3.Patients aged<45 years and those with a BMI of?28 kg/m~2,a preoperative diagnosis of DDH,history of tobacco abuse,or living in rural areas are at increased risk for aseptic loosening after THA and TKA in Chinese population.