{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T02:39:33Z","timestamp":1789180773169,"version":"build-2803163510"},"reference-count":37,"publisher":"Portland Press Ltd.","issue":"4","license":[{"start":{"date-parts":[[2019,7,25]],"date-time":"2019-07-25T00:00:00Z","timestamp":1564012800000},"content-version":"vor","delay-in-days":710,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2017,8,31]]},"abstract":"<jats:p>Wear particle induced periprosthetic osteolysis is the main cause of aseptic loosening of orthopedic implants. The aim of the present study is to determine the protective effect of quercetin (QUE) against titanium (Ti) particle induced endoplasmic reticulum stress (ERS) related apoptosis and osteolysis. In the present study, RAW264.7 cells were pretreated with different concentrations (40, 80, and 160 \u03bcmol\/l) of QUE for 30 min and then treated with Ti particle (5 mg\/ml) for 24 h. Cell viability and apoptosis were determined using MTT assay and Annexin V-FITC Apoptosis Detection Kit, respectively. Protein and mRNA expressions of ERS-related genes were examined by Western blot and real-time PCR, respectively. The release of inflammatory cytokines was detected by ELISA. Then, a mouse calvarial osteolysis model was established. Histological sections of calvaria were stained with Hematoxylin-Eosin (H&amp;E) or tartrate-resistant acid phosphatase (TRAP). The results showed that Ti particle reduced cell viability and induced apoptosis in RAW264.7 macrophages. The cytotoxic effects of Ti particle were dramatically inhibited by QUE pretreatment. Interestingly, we found that QUE also significantly reduced Ti particle induced up-regulation of the expression levels of protein kinase RNA-like ER kinase (PERK), inositol-requiring enzyme-1 (IRE1), glucose-regulated protein (GRP78), CCAAT\/enhancer-binding protein homologous protein (CHOP), caspase-12, and caspase-3 and enhanced the down-regulation of Bcl-2. In addition, QUE decreased Ti particle-induced inflammatory cytokines release from RAW264.7 cells. Moreover, treatment with QUE markedly decreased osteoclast number. In a mouse calvarial osteolysis model, QUE inhibited Ti particle induced osteolysis in vivo by inhibiting osteoclast formation and expressions of ERS-related genes. In conclusion, QUE can protect RAW264.7 cells from Ti particle induced ERS-related apoptosis and suppress calvarial osteolysis in vivo.<\/jats:p>","DOI":"10.1042\/bsr20170961","type":"journal-article","created":{"date-parts":[[2017,8,1]],"date-time":"2017-08-01T00:30:21Z","timestamp":1501547421000},"update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Inhibitory effect of quercetin on titanium particle induced endoplasmic reticulum stress related apoptosis and <i>in vivo<\/i> osteolysis"],"prefix":"10.1042","volume":"37","author":[{"given":"Laibo","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Bone and Joint, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhoubin","family":"Tian","sequence":"additional","affiliation":[{"name":"Department of Bone and Joint, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Bone and Joint, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianquan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Bone and Joint, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhentao","family":"Man","sequence":"additional","affiliation":[{"name":"Department of Bone and Joint, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shui","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Bone and Joint, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2017,8,14]]},"reference":[{"key":"2021111618524257800_B1","doi-asserted-by":"crossref","first-page":"1496","DOI":"10.1002\/acr.22326","article-title":"Total hip replacement due to primary osteoarthritis in relation to cumulative occupational exposures and lifestyle factors: a nationwide nested case-control study","volume":"66","author":"Rubak","year":"2014","journal-title":"Arthritis Care Res."},{"key":"2021111618524257800_B2","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1590\/1414-431X20133092","article-title":"Adenovirus-mediated siRNA targeting TNF-\u03b1 andoverexpression of bone morphogenetic protein-2 promotes early osteoblastdifferentiation on a cell model of Ti particle-induced inflammatory response in vitro","volume":"46","author":"Guo","year":"2013","journal-title":"Braz. J. Med. Biol. Res."},{"key":"2021111618524257800_B3","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1503\/cjs.003711","article-title":"Periprosthetic osteolysis: genetics, mechanisms and potential therapeutic interventions","volume":"55","author":"Noordin","year":"2012","journal-title":"Can. J. Surg."},{"key":"2021111618524257800_B4","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1002\/jor.21554","article-title":"Review of periprosthetic osteolysis in total joint arthroplasty: an emphasis on host factors and future directions","volume":"30","author":"Beck","year":"2012","journal-title":"J. Orthop. Res."},{"key":"2021111618524257800_B5","doi-asserted-by":"crossref","first-page":"983","DOI":"10.4314\/tjpr.v14i6.7","article-title":"Etanercept inhibits pro-inflammatory cytokines expression in titanium particle-stimulated peritoneal macrophages","volume":"14","author":"Chen","year":"2015","journal-title":"Trop. J. Pharm. Res."},{"key":"2021111618524257800_B6","doi-asserted-by":"crossref","first-page":"1756","DOI":"10.1016\/j.biomaterials.2008.12.018","article-title":"Inhibition of titanium particle-induced osteoclastogenesis through inactivation of NFATc1 by VIVIT peptide","volume":"30","author":"Liu","year":"2009","journal-title":"Biomaterials"},{"key":"2021111618524257800_B7","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1007\/s00776-007-1180-8","article-title":"Effect of etidronate on COX-2 expression and PGE 2 production in macrophage-like RAW 264.7 cells stimulated by titanium particles","volume":"12","author":"Suzuki","year":"2007","journal-title":"J. Orthop. Sci."},{"key":"2021111618524257800_B8","doi-asserted-by":"crossref","first-page":"8981650","DOI":"10.1155\/2016\/8981650","article-title":"The function of naringin in inducing secretion of osteoprotegerin and inhibiting formation of osteoclasts","volume":"2016","author":"Xu","year":"2016","journal-title":"Evid. Based Complement. Alternat. Med."},{"key":"2021111618524257800_B9","doi-asserted-by":"crossref","first-page":"127","DOI":"10.2302\/kjm.54.127","article-title":"TNF-alpha and pathologic bone resorption","volume":"54","author":"Boyce","year":"2005","journal-title":"Keio J. Med."},{"key":"2021111618524257800_B10","doi-asserted-by":"crossref","first-page":"1332","DOI":"10.1007\/s10495-013-0884-9","article-title":"Treadmill exercise represses neuronal cell death and inflammation during A\u03b2-induced ER stress by regulating unfolded protein response in aged presenilin 2 mutant mice","volume":"18","author":"Kang","year":"2013","journal-title":"Apoptosis"},{"key":"2021111618524257800_B11","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1016\/j.bbrc.2013.10.056","article-title":"Unfolding protein response signaling is involved in development, maintenance, and regression of the corpus luteum during the bovine estrous cycle","volume":"441","author":"Park","year":"2013","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2021111618524257800_B12","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/j.ymeth.2004.10.010","article-title":"The ER chaperone and signaling regulator GRP78\/BiP as a monitor of endoplasmic reticulum stress","volume":"35","author":"Lee","year":"2005","journal-title":"Methods"},{"key":"2021111618524257800_B13","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1038\/nrd2755","article-title":"Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities","volume":"7","author":"Kim","year":"2008","journal-title":"Nat. Rev. Drug Discov."},{"key":"2021111618524257800_B14","doi-asserted-by":"crossref","first-page":"1440","DOI":"10.1017\/S0007114508102434","article-title":"Effect of apoE genotype and dietary quercetin on blood lipids and TNF-\u03b1 levels in apoE3 and apoE4 targeted gene replacement mice","volume":"101","author":"Boeschsaadatmandi","year":"2009","journal-title":"Br. J. Nutr."},{"key":"2021111618524257800_B15","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1097\/MCO.0b013e32831394b8","article-title":"Quercetin: potentials in the prevention and therapy of disease","volume":"11","author":"Bischoff","year":"2008","journal-title":"Curr. Opin. Clin. Nutr. Metab. Care"},{"key":"2021111618524257800_B16","doi-asserted-by":"crossref","first-page":"8696587","DOI":"10.1155\/2016\/8696587","article-title":"Hepatoprotective effect of quercetin on endoplasmic reticulum stress and inflammation after intense exercise in mice through phosphoinositide 3-kinase and nuclear factor-kappa B","volume":"2016","author":"Tang","year":"2016","journal-title":"Oxid. Med. Cell Longev."},{"key":"2021111618524257800_B17","first-page":"788","article-title":"Wear debris inhibition of anti-osteoclastogenic signaling by interleukin-6 and interferon-gamma. Mechanistic insights and implications for periprosthetic osteolysis","volume":"88","author":"Rakshit","year":"2006","journal-title":"J. Bone Joint Surg. Am."},{"key":"2021111618524257800_B18","doi-asserted-by":"crossref","first-page":"5721","DOI":"10.1016\/j.biomaterials.2014.04.006","article-title":"The effect of enoxacin on osteoclastogenesis and reduction of titanium particle-induced osteolysis via suppression of JNK signaling pathway","volume":"35","author":"Liu","year":"2014","journal-title":"Biomaterials"},{"key":"2021111618524257800_B19","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.bone.2014.12.058","article-title":"CCN2 enhances RANKL-induced osteoclast differentiation via direct binding to RANK and OPG","volume":"73","author":"Aoyama","year":"2015","journal-title":"Bone"},{"key":"2021111618524257800_B20","doi-asserted-by":"crossref","first-page":"2354","DOI":"10.1016\/j.actbio.2014.02.003","article-title":"Contributions of human tissue analysis to understanding the mechanisms of loosening and osteolysis in total hip replacement","volume":"10","author":"Gallo","year":"2014","journal-title":"Acta Biomater."},{"key":"2021111618524257800_B21","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.1016\/S0142-9612(00)00041-7","article-title":"Apoptosis in peri-implant tissue","volume":"21","author":"Stea","year":"2000","journal-title":"Biomaterials"},{"key":"2021111618524257800_B22","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1007\/s10495-008-0297-3","article-title":"Pan-caspase inhibition suppresses polyethylene particle-induced osteolysis","volume":"14","author":"Landgraeber","year":"2009","journal-title":"Apoptosis"},{"key":"2021111618524257800_B23","doi-asserted-by":"crossref","first-page":"9159","DOI":"10.1016\/j.biomaterials.2011.08.039","article-title":"Pathways of macrophage apoptosis within the interface membrane in aseptic loosening of prostheses","volume":"32","author":"Yang","year":"2011","journal-title":"Biomaterials"},{"key":"2021111618524257800_B24","doi-asserted-by":"crossref","first-page":"705431","DOI":"10.1155\/2010\/705431","article-title":"Endoplasmic reticulum stress-mediated apoptosis involved in indirect recognition pathway blockade induces long-term heart allograft survival","volume":"2010","author":"Xiang","year":"2010","journal-title":"J. Biomed. Biotechnol."},{"key":"2021111618524257800_B25","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1083\/jcb.200310015","article-title":"Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and A\u03b2-induced cell death","volume":"165","author":"Hitomi","year":"2004","journal-title":"J. Cell Biol."},{"key":"2021111618524257800_B26","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1007\/s00125-006-0590-z","article-title":"Endoplasmic reticulum stress contributes to beta cell apoptosis in type 2 diabetes","volume":"50","author":"Laybutt","year":"2007","journal-title":"Diabetologia"},{"key":"2021111618524257800_B27","doi-asserted-by":"crossref","first-page":"11658","DOI":"10.1158\/0008-5472.CAN-05-2370","article-title":"Bortezomib sensitizes pancreatic cancer cells to endoplasmic reticulum stress-mediated apoptosis","volume":"65","author":"Nawrocki","year":"2006","journal-title":"Cancer Res."},{"key":"2021111618524257800_B28","doi-asserted-by":"crossref","first-page":"31156","DOI":"10.1074\/jbc.M501069200","article-title":"Multiple signals induce endoplasmic reticulum stress in both primary and immortalized chondrocytes resulting in loss of differentiation, impaired cell growth, and apoptosis","volume":"280","author":"Yang","year":"2005","journal-title":"J. Biol. Chem."},{"key":"2021111618524257800_B29","doi-asserted-by":"crossref","first-page":"1775","DOI":"10.1111\/j.1462-5822.2008.01164.x","article-title":"Subtilase cytotoxin activates PERK, IRE1 and ATF6 endoplasmic reticulum stress-signalling pathways","volume":"10","author":"Wolfson","year":"2008","journal-title":"Cell. Microbiol."},{"key":"2021111618524257800_B30","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1016\/S1097-2765(00)00108-8","article-title":"Regulated translation initiation controls stress-induced gene expression in mammalian cells","volume":"6","author":"Harding","year":"2000","journal-title":"Mol. Cell."},{"key":"2021111618524257800_B31","doi-asserted-by":"crossref","first-page":"e0159171","DOI":"10.1371\/journal.pone.0159171","article-title":"miRNA-1283 regulates the PERK\/ATF4 pathway in vascular injury by targeting ATF4","volume":"11","author":"Ling","year":"2016","journal-title":"PLoS ONE"},{"key":"2021111618524257800_B32","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1016\/j.actbio.2013.08.031","article-title":"Adiponectin attenuates osteolysis in aseptic loosening of total hip replacements","volume":"10","author":"Landgraeber","year":"2014","journal-title":"Acta Biomater."},{"key":"2021111618524257800_B33","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.1097\/WNR.0000000000000667","article-title":"Protective effects of quercetin on dieldrin-induced endoplasmic reticulum stress and apoptosis in dopaminergic neuronal cells","volume":"27","author":"Park","year":"2016","journal-title":"Neuroreport"},{"key":"2021111618524257800_B34","doi-asserted-by":"crossref","first-page":"403","DOI":"10.3892\/ijmm.2013.1392","article-title":"Adenovirus-mediated expression of bone morphogenetic protein-2 activates titanium particle-induced osteoclastogenesis and this effect occurs in spite of the suppression of TNF-\u03b1 expression by siRNA","volume":"32","author":"Sun","year":"2013","journal-title":"Int. J. Mol. Med."},{"key":"2021111618524257800_B35","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1034\/j.1601-0825.2003.02904.x","article-title":"Inhibitory effect of titanium particles on osteoclast formation generated by treatment of mouse bone marrow cells with PGE 2","volume":"9","author":"Nakano","year":"2003","journal-title":"Oral Dis."},{"key":"2021111618524257800_B36","doi-asserted-by":"crossref","first-page":"1170","DOI":"10.1002\/jbm.b.33415","article-title":"Polycan suppresses osteoclast differentiation and titanium particle-induced osteolysis in mice","volume":"104","author":"Lee","year":"2015","journal-title":"J. Biomed. Mater. Res. B Appl. Biomater."},{"key":"2021111618524257800_B37","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/j.jss.2014.05.038","article-title":"Inhibitory effect of icariin on Ti-induced inflammatory osteoclastogenesis","volume":"192","author":"Cui","year":"2014","journal-title":"J. Surg. Res."}],"container-title":["Bioscience Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/bioscirep\/article-pdf\/doi\/10.1042\/BSR20170961\/480669\/bsr-2017-0961.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/bioscirep\/article-pdf\/doi\/10.1042\/BSR20170961\/480669\/bsr-2017-0961.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,16]],"date-time":"2021-11-16T19:31:28Z","timestamp":1637091088000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/bioscirep\/article\/37\/4\/BSR20170961\/57347\/Inhibitory-effect-of-quercetin-on-titanium"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,8,14]]},"references-count":37,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2017,8,31]]}},"URL":"https:\/\/doi.org\/10.1042\/bsr20170961","relation":{},"ISSN":["0144-8463","1573-4935"],"issn-type":[{"value":"0144-8463","type":"print"},{"value":"1573-4935","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,8,14]]},"article-number":"BSR20170961"}}