{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,15]],"date-time":"2025-08-15T00:17:46Z","timestamp":1755217066137,"version":"3.43.0"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,8,5]],"date-time":"2025-08-05T00:00:00Z","timestamp":1754352000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Aseptic loosening (AL) of hip prostheses is one of the main reasons for revision total hip arthroplasty (rTHA). However, the transcriptomic characteristics of AL are scarcely understood. This study aimed to discover candidate biomarkers for the diagnosis of AL.<\/jats:p><\/jats:sec><jats:sec><jats:title>Patients and methods<\/jats:title><jats:p>The interface membrane from four patients with AL of hip prostheses and the synovium samples from four patients with a periprosthetic femoral fracture (PFF) after total hip arthroplasty (THA) were analyzed via RNA sequencing. Integrated bioinformatics analysis was employed to identify immune-related hub genes in AL. Immune cell infiltration analysis and correlation analysis were performed. Connectivity map analysis was utilized to predict the potential small-molecule compounds for AL treatment. Western blotting and histological staining were used to verify the expression of hub genes in AL.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A total of 2,184 differentially expressed genes (DEGs) were identified in the AL samples, including 2,050 upregulated genes and 134 downregulated genes, and these DEGs were mainly enriched in immune cell-related signaling pathways and immune-related processes. Immune cell infiltration analysis showed that the proportion of M1 macrophages increased in AL. Three genes closely related to M1 macrophages were screened, namely, <jats:italic>CD68<\/jats:italic>, <jats:italic>CD163<\/jats:italic>, and <jats:italic>SPP1<\/jats:italic>, according to the results of correlation analysis. Hematoxylin\u2013eosin staining showed that the synovitis score of AL samples was significantly higher than that of controls (average, 6.2 vs. 3.8). Western blotting and immunohistochemical analysis showed that the expression of <jats:italic>CD68<\/jats:italic>, <jats:italic>CD163<\/jats:italic>, and <jats:italic>SPP1<\/jats:italic> in the AL group was significantly higher than that in the control group. The top 10 compounds with the highest negative scores were predicted to be potential therapeutic drugs for the treatment of AL.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Preliminary transcriptomic signatures suggested that <jats:italic>CD68<\/jats:italic>, <jats:italic>CD163<\/jats:italic>, and <jats:italic>SPP1<\/jats:italic> may serve as potential biomarkers for AL, offering a novel research perspective for future diagnosis and therapeutic intervention of AL.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fgene.2025.1597219","type":"journal-article","created":{"date-parts":[[2025,8,5]],"date-time":"2025-08-05T05:24:55Z","timestamp":1754371495000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Identification of immune-related diagnostic genes and immune cell infiltration in aseptic loosening of prostheses after total hip arthroplasty by integrated bioinformatics analysis and experimental confirmation"],"prefix":"10.3389","volume":"16","author":[{"given":"Yunke","family":"Liu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaming","family":"Liang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuo","family":"Qiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yonghui","family":"Dong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lichao","family":"Ma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhihua","family":"Yan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Songkai","family":"Yue","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yifan","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jia","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,8,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"S6","DOI":"10.1186\/ar2170","article-title":"Aseptic loosening of total joint replacements: mechanisms underlying osteolysis and potential therapies","volume":"9","author":"Abu-Amer","year":"2007","journal-title":"Arthritis Res. Ther."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1494","DOI":"10.1016\/j.arth.2022.02.060","article-title":"Diagnosis and detection of subtle aseptic loosening in total hip arthroplasty","volume":"37","author":"Anil","year":"2022","journal-title":"J. Arthroplasty"},{"key":"B3","doi-asserted-by":"publisher","first-page":"S34","DOI":"10.1016\/j.arth.2023.03.088","article-title":"Trends in revision total hip arthroplasty cost, revenue, and contribution margin 2011 to 2021","volume":"38","author":"Ashkenazi","year":"2023","journal-title":"J. Arthroplasty"},{"key":"B4","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1302\/2046-3758.55.BJR-2016-0086","article-title":"The pathobiology and pathology of aseptic implant failure","volume":"5","author":"Athanasou","year":"2016","journal-title":"Bone Jt. Res."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1954","DOI":"10.1016\/j.arth.2017.01.037","article-title":"Complications after revision total hip arthroplasty in the medicare population","volume":"32","author":"Badarudeen","year":"2017","journal-title":"J. Arthroplasty"},{"key":"B6","doi-asserted-by":"publisher","first-page":"2700","DOI":"10.1007\/s11999-015-4220-2","article-title":"What host factors affect aseptic loosening after THA and TKA?","volume":"473","author":"Cherian","year":"2015","journal-title":"Clin. Orthop. Relat. Res."},{"key":"B7","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1038\/labinvest.2016.116","article-title":"CD68\/macrosialin: not just a histochemical marker","volume":"97","author":"Chistiakov","year":"2017","journal-title":"Lab. Invest."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1122057","DOI":"10.3389\/fimmu.2023.1122057","article-title":"Macrophages in aseptic loosening: characteristics, functions, and mechanisms","volume":"14","author":"Cong","year":"2023","journal-title":"Front. Immunol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"2663","DOI":"10.1016\/j.arth.2017.03.066","article-title":"Current epidemiology of revision total knee arthroplasty in the United States","volume":"32","author":"Delanois","year":"2017","journal-title":"J. Arthroplasty"},{"key":"B10","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1302\/0301-620X.96B6.34040","article-title":"The unified classification system (UCS): improving our understanding of periprosthetic fractures","author":"Duncan","year":"2014","journal-title":"Bone Jt. J."},{"key":"B11","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1172\/JCI19190","article-title":"Osteopontin: a bridge between bone and the immune system","volume":"112","author":"Gravallese","year":"2003","journal-title":"J. Clin. Invest."},{"key":"B12","doi-asserted-by":"publisher","first-page":"834","DOI":"10.1136\/ard.2004.029751","article-title":"Synovial tissue macrophages: a sensitive biomarker for response to treatment in patients with rheumatoid arthritis","volume":"64","author":"Haringman","year":"2005","journal-title":"Ann. Rheum. Dis."},{"key":"B13","doi-asserted-by":"publisher","first-page":"92","DOI":"10.3390\/ijms19010092","article-title":"The phagocytic function of macrophage-enforcing innate immunity and tissue homeostasis","volume":"19","author":"Hirayama","year":"2017","journal-title":"Int. J. Mol. Sci."},{"key":"B14","doi-asserted-by":"publisher","first-page":"121127","DOI":"10.1016\/j.biomaterials.2021.121127","article-title":"Aseptic and septic prosthetic joint loosening: impact of biomaterial wear on immune cell function, inflammation, and infection","volume":"278","author":"Hodges","year":"2021","journal-title":"Biomaterials"},{"key":"B15","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.clinbiochem.2018.07.003","article-title":"The multiple functions and mechanisms of osteopontin","volume":"59","author":"Icer","year":"2018","journal-title":"Clin. Biochem."},{"key":"B16","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1016\/j.intimp.2017.02.003","article-title":"4-Methoxylonchocarpin attenuates inflammation by inhibiting lipopolysaccharide binding to toll-like receptor of macrophages and M1 macrophage polarization","volume":"45","author":"Jang","year":"2017","journal-title":"Int. Immunopharmacol."},{"key":"B17","first-page":"1","article-title":"Current research in the pathogenesis of aseptic implant loosening associated with particulate wear debris","volume":"79","author":"Jiang","year":"2013","journal-title":"Acta Orthop. Belg"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1046","DOI":"10.1016\/j.bbrc.2007.04.042","article-title":"Human CD4+CD25+ regulatory T cells inhibit the differentiation of osteoclasts from peripheral blood mononuclear cells","volume":"357","author":"Kim","year":"2007","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B19","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1111\/j.1365-2559.2006.02508.x","article-title":"Synovitis score: discrimination between chronic low-grade and high-grade synovitis","volume":"49","author":"Krenn","year":"2006","journal-title":"Histopathology"},{"key":"B20","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1038\/35051594","article-title":"Identification of the haemoglobin scavenger receptor","volume":"409","author":"Kristiansen","year":"2001","journal-title":"Nature"},{"key":"B21","doi-asserted-by":"publisher","first-page":"780","DOI":"10.2106\/JBJS.F.00222","article-title":"Projections of primary and revision hip and knee arthroplasty in the United States from 2005 to 2030","volume":"89","author":"Kurtz","year":"2007","journal-title":"J. Bone Jt. Surg. Am."},{"key":"B22","doi-asserted-by":"publisher","first-page":"13832","DOI":"10.1002\/jcp.28063","article-title":"Vaccarin prevents titanium particle-induced osteolysis and inhibits RANKL-induced osteoclastogenesis by blocking NF-\u03baB and MAPK signaling pathways","volume":"234","author":"Liu","year":"2019","journal-title":"J. Cell Physiol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"158654","DOI":"10.1016\/j.bbalip.2020.158654","article-title":"Contribution of FP receptors in M1 macrophage polarization via IL-10-regulated nuclear translocation of NF-\u03baB p65","volume":"1865","author":"Maehara","year":"2020","journal-title":"Biochim. Biophys. Acta Mol. Cell Biol. Lipids"},{"key":"B24","doi-asserted-by":"publisher","first-page":"27","DOI":"10.2106\/00004623-200301000-00005","article-title":"Rates and outcomes of primary and revision total hip replacement in the United States medicare population","volume":"85","author":"Mahomed","year":"2003","journal-title":"J. Bone Jt. Surg. Am."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1285","DOI":"10.1016\/j.arth.2013.12.024","article-title":"Early failures in total hip arthroplasty -- a changing paradigm","volume":"29","author":"Melvin","year":"2014","journal-title":"J. Arthroplasty"},{"key":"B26","doi-asserted-by":"publisher","first-page":"2999","DOI":"10.3390\/nu12102999","article-title":"Macrophage polarization and osteoporosis: a review","volume":"12","author":"Mu\u00f1oz","year":"2020","journal-title":"Nutrients"},{"key":"B27","doi-asserted-by":"publisher","first-page":"S367","DOI":"10.1016\/j.arth.2024.04.032","article-title":"Inpatient hospital costs, emergency department visits, and readmissions for revision hip and knee arthroplasty","volume":"39","author":"Murphy","year":"2024","journal-title":"J. Arthroplasty"},{"key":"B28","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1002\/jbm.a.35581","article-title":"Lipoteichoic acid modulates inflammatory response in macrophages after phagocytosis of titanium particles through toll-like receptor 2 cascade and inflammasomes","volume":"104","author":"Naganuma","year":"2016","journal-title":"J. Biomed. Mater Res. A"},{"key":"B29","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1038\/nmeth.3337","article-title":"Robust enumeration of cell subsets from tissue expression profiles","volume":"12","author":"Newman","year":"2015","journal-title":"Nat. Methods"},{"key":"B30","doi-asserted-by":"publisher","first-page":"768","DOI":"10.7150\/ijms.48014","article-title":"circRNA expression pattern and ceRNA network in the pathogenesis of aseptic loosening after total hip arthroplasty","volume":"18","author":"Ni","year":"2021","journal-title":"Int. J. Med. Sci."},{"key":"B31","doi-asserted-by":"publisher","first-page":"3033","DOI":"10.1002\/jbm.a.34599","article-title":"Macrophages-key cells in the response to wear debris from joint replacements","volume":"101","author":"Nich","year":"2013","journal-title":"J. Biomed. Mater Res. A"},{"key":"B32","doi-asserted-by":"publisher","first-page":"1019","DOI":"10.1016\/j.biomaterials.2004.03.038","article-title":"Screening for symptomatic metal sensitivity: a prospective study of 92 patients undergoing total knee arthroplasty","volume":"26","author":"Niki","year":"2005","journal-title":"Biomaterials"},{"key":"B33","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1016\/j.bioactmat.2023.02.028","article-title":"Macrophage-derived exosomes modulate wear particle-induced osteolysis via miR-3470b targeting TAB3\/NF-\u03baB signaling","volume":"26","author":"Pan","year":"2023","journal-title":"Bioact. Mater"},{"key":"B34","doi-asserted-by":"publisher","first-page":"1310262","DOI":"10.3389\/fimmu.2023.1310262","article-title":"Roles of inflammatory cell infiltrate in periprosthetic osteolysis","volume":"14","author":"Panez-Toro","year":"2023","journal-title":"Front. Immunol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"S31","DOI":"10.1038\/ng1570","article-title":"Integrative analysis of the cancer transcriptome","volume":"37","author":"Rhodes","year":"2005","journal-title":"Nat. Genet."},{"key":"B36","doi-asserted-by":"publisher","first-page":"e15","DOI":"10.1017\/S1462399411001839","article-title":"Osteopontin in macrophage function","volume":"13","author":"Rittling","year":"2011","journal-title":"Expert Rev. Mol. Med."},{"key":"B37","doi-asserted-by":"publisher","first-page":"e36","DOI":"10.1002\/imt2.36","article-title":"Sangerbox: a comprehensive, interaction-friendly clinical bioinformatics analysis platform","volume":"1","author":"Shen","year":"2022","journal-title":"Imeta"},{"key":"B38","doi-asserted-by":"publisher","first-page":"1329","DOI":"10.1002\/art.27400","article-title":"Osteopontin deficiency impairs wear debris-induced osteolysis via regulation of cytokine secretion from murine macrophages","volume":"62","author":"Shimizu","year":"2010","journal-title":"Arthritis Rheum."},{"key":"B39","doi-asserted-by":"publisher","first-page":"e919159","DOI":"10.12659\/MSM.919159","article-title":"Osteopontin in bone metabolism and bone diseases","volume":"26","author":"Si","year":"2020","journal-title":"Med. Sci. Monit."},{"key":"B40","doi-asserted-by":"publisher","first-page":"1285951","DOI":"10.3389\/fimmu.2023.1285951","article-title":"OPN promotes pro-inflammatory cytokine expression via ERK\/JNK pathway and M1 macrophage polarization in Rosacea","volume":"14","author":"Tang","year":"2023","journal-title":"Front. Immunol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"1396","DOI":"10.1055\/s-0041-1735282","article-title":"The epidemiology of revision total knee arthroplasty","volume":"34","author":"Tarazi","year":"2021","journal-title":"J. Knee Surg."},{"key":"B42","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1186\/s12967-016-0950-5","article-title":"Immune response and innervation signatures in aseptic hip implant loosening","volume":"14","author":"Vasconcelos","year":"2016","journal-title":"J. Transl. Med."},{"key":"B43","doi-asserted-by":"publisher","first-page":"805978","DOI":"10.3389\/fonc.2022.805978","article-title":"Recent advances in nanoplatforms for the treatment of osteosarcoma","volume":"12","author":"Wu","year":"2022","journal-title":"Front. Oncol."}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2025.1597219\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,5]],"date-time":"2025-08-05T05:24:56Z","timestamp":1754371496000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2025.1597219\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,5]]},"references-count":43,"alternative-id":["10.3389\/fgene.2025.1597219"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2025.1597219","relation":{},"ISSN":["1664-8021"],"issn-type":[{"type":"electronic","value":"1664-8021"}],"subject":[],"published":{"date-parts":[[2025,8,5]]},"article-number":"1597219"}}