{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T23:11:40Z","timestamp":1787785900601,"version":"build-2784847793"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,8,29]],"date-time":"2022-08-29T00:00:00Z","timestamp":1661731200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Postmenopausal osteoporosis (PMOP) is one of the most commonly occurring conditions worldwide and is characterized by estrogen deficiency as well as persistent calcium loss with age. The aim of our study was to identify significant ferroptosis-associated biomarkers for PMOP.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and materials<\/jats:title>\n                    <jats:p>We obtained our training dataset from the Gene Expression Omnibus (GEO) database using GSE56815 expression profiling data. Meanwhile, we extracted ferroptosis-associated genes for further analysis. Differentially expressed ferroptosis-associated genes (DEFAGs) between OP patients and normal controls were selected using the \u201climma\u201d package. We established a ferroptosis-associated gene signature using training models, specifically, random forest (RF) and support vector machine (SVM) models. It was further validated in another dataset (GSE56814) which also showed a high AUC: 0.98, indicating high diagnostic value. Using consensus clustering, the OP patient subtypes were identified. A ferroptosis associated gene (FAG)-Scoring scheme was developed by PCA. The important candidate genes associated with OP were also compared between different ferrclusters and geneclusters.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>There were significant DEFAGs acquired, of which five (HMOX1, HAMP, LPIN1, MAP3K5, FLT3) were selected for establishing a ferroptosis-associated gene signature. Analyzed from the ROC curve, our established RF model had a higher AUC value than the SVM model (RF model AUC:1.00). Considering these results, the established RF model was chosen to be the most appropriate training model. Later, based on the expression levels of the five DEFAGs, a clinical application nomogram was established. The OP patients were divided into two subtypes (ferrcluster A, B and genecluster A, B, respectively) according to the consensus clustering method based on DEFAGs and differentially expressed genes (DEGs). Ferrcluster B and genecluster B had higher ferroptosis score than ferrcluster A and genecluster A, respectively. The expression of COL1A1 gene was significantly higher in ferrcluster B and gencluster B compared with ferrcluster A and gencluster A, respectively, while there is no statistical difference in term of VDR gene, COL1A2 genes, and PTH gene expressions between ferrcluster A and B, together with gencluster A and B.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>On the basis of five explanatory variables (HMOX1, HAMP, LPIN1, MAP3K5 and FLT3), we developed a diagnostic ferroptosis-associated gene signature and identified two differently categorized OP subtypes that may potentially be applied for the early diagnosis and individualized treatment of PMOP. The ER gene, VDR gene, IL-6 gene, COL1A1 and COL1A2 genes, and PTH gene are important candidate gene of OP, however, more studies are still anticipated to further elucidate the relationship between these genes and ferroptosis in OP.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fendo.2022.986384","type":"journal-article","created":{"date-parts":[[2022,8,29]],"date-time":"2022-08-29T01:08:46Z","timestamp":1661735326000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":57,"title":["Identification of ferroptosis-associated biomarkers for the potential diagnosis and treatment of postmenopausal osteoporosis"],"prefix":"10.3389","volume":"13","author":[{"given":"Yunxiang","family":"Hu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengqiang","family":"Ding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanmao","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,8,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcna.2021.05.016","article-title":"Update on osteoporosis screening and management","volume":"105","author":"Anam","year":"2021","journal-title":"Med Clin North Am"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1007\/s12020-021-02806-x","article-title":"DXA parameters, trabecular bone score (tbs) and bone mineral density (bmd), in fracture risk prediction in endocrine-mediated secondary osteoporosis","volume":"74","author":"Shevroja","year":"2021","journal-title":"Endocrine"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1097\/GME.0000000000001831","article-title":"Management of Osteoporosis in Postmenopausal Women: The 2021 Position Statement of The North American Menopause Society\u2019\u2019 Editorial Panel. Management of osteoporosis in postmenopausal women: the 2021 position statement of The North American Menopause Society","volume":"28","year":"2021","journal-title":"Menopause"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.tjog.2016.04.038","article-title":"Bioinformatics analysis of gene expression profiles in b cells of postmenopausal osteoporosis patients","volume":"56","author":"Ma","year":"2017","journal-title":"Taiwan J Obstet Gynecol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3892\/mmr.2015.4283","article-title":"In silico analysis of the molecular mechanism of postmenopausal osteoporosis","volume":"12","author":"Liu","year":"2015","journal-title":"Mol Med Rep"},{"key":"B6","doi-asserted-by":"publisher","first-page":"100380","DOI":"10.1016\/j.jbo.2021.100380","article-title":"Targeting ferroptosis in osteosarcoma","volume":"30","author":"Zhao","year":"2021","journal-title":"J Bone Oncol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.701163","article-title":"Ferroptosis: A trigger of proinflammatory state progression to immunogenicity in necroinflammatory disease","volume":"12","author":"Li","year":"2021","journal-title":"Front Immunol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2021.710963","article-title":"The link between ferroptosis and cardiovascular diseases: A novel target for treatment","volume":"8","author":"Hu","year":"2021","journal-title":"Front Cardiovasc Med"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.exger.2022.111836","article-title":"Ferroptosis - a new target of osteoporosis","volume":"111836","author":"Gao","year":"2022","journal-title":"Exp Gerontol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.7150\/ijms.27333","article-title":"Influence of DNA methylation on the expression of OPG\/RANKL in primary osteoporosis","volume":"15","author":"Wang","year":"2018","journal-title":"Int J Med Sci"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202101610R","article-title":"Activation of osteoblast ferroptosis via the METTL3\/ASK1-p38 signaling pathway in high glucose and high fat (HGHF)-induced diabetic bone loss","volume":"36","author":"Lin","year":"2022","journal-title":"FASEB J"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.7717\/peerj.12510","article-title":"Zoledronic acid promotes osteoclasts ferroptosis by inhibiting FBXO9-mediated p53 ubiquitination and degradation","volume":"9","author":"Qu","year":"2021","journal-title":"PeerJ"},{"key":"B13","doi-asserted-by":"publisher","first-page":"baaa021","DOI":"10.1093\/database\/baaa021","article-title":"FerrDb: a manually curated resource for regulators and markers of ferroptosis and ferroptosis-disease associations","volume":"2020","author":"Zhou","year":"2020","journal-title":"Database (Oxford)"},{"key":"B14","doi-asserted-by":"publisher","first-page":"474","DOI":"10.12688\/f1000research.14451.3","article-title":"Predicting lithium treatment response in bipolar patients using gender-specific gene expression biomarkers and machine learning","volume":"7","author":"Eugene","year":"2018","journal-title":"F1000Res"},{"key":"B15","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1186\/s12943-020-01170-0","article-title":"m(6)A regulator-mediated methylation modification patterns and tumor microenvironment infiltration characterization in gastric cancer","volume":"19","author":"Zhang","year":"2020","journal-title":"Mol Cancer"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-18-0436","article-title":"Tumor microenvironment characterization in gastric cancer identifies prognostic and immunotherapeutically relevant gene signatures","volume":"7","author":"Zeng","year":"2019","journal-title":"Cancer Immunol Res"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2021.717065","article-title":"Recent progresses in the treatment of osteoporosis","volume":"12","author":"Li","year":"2021","journal-title":"Front Pharmacol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.2174\/1574888X16666210512020103","article-title":"The anti-osteoporosis effects of vitamin K in postmenopausal women","volume":"17","author":"Liu","year":"2022","journal-title":"Curr Stem Cell Res Ther"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2021.06.074","article-title":"Effects of advanced glycation end products on osteocytes mechanosensitivity","volume":"568","author":"Yang","year":"2021","journal-title":"Biochem Biophys Res Commun"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2021.04.027","article-title":"Hypoxia inhibits RANKL-induced ferritinophagy and protects osteoclasts from ferroptosis","volume":"169","author":"Ni","year":"2021","journal-title":"Free Radic Biol Med"},{"key":"B21","doi-asserted-by":"publisher","first-page":"2634431","DOI":"10.1155\/2022\/2634431","article-title":"Ferroptosis: A new regulatory mechanism in osteoporosis","author":"Liu","year":"2022","journal-title":"Oxid Med Cell Longev"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.csbj.2021.09.001","article-title":"Machine learning and deep learning methods that use omics data for metastasis prediction","volume":"19","author":"Albaradei","year":"2021","journal-title":"Comput Struct Biotechnol J"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2021.809560","article-title":"Lessons learnt from using the machine learning random forest algorithm to predict virulence in streptococcus pyogenes","volume":"11","author":"Buckley","year":"2021","journal-title":"Front Cell Infect Microbiol"},{"key":"B24","doi-asserted-by":"publisher","first-page":"1684017","DOI":"10.1155\/2022\/1684017","article-title":"A novel diabetes healthcare disease prediction framework using machine learning techniques","volume":"2022","author":"Krishnamoorthi","year":"2022","journal-title":"J Healthc Eng"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1159\/000518572","article-title":"Impact of machine learning-associated research strategies on the identification of peptide-receptor interactions in the post-omics era","author":"Satake","year":"2021","journal-title":"Neuroendocrinology"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2021.815245","article-title":"Analysis and validation of hub genes in blood monocytes of postmenopausal osteoporosis patients","volume":"12","author":"Deng","year":"2021","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2020.00798","article-title":"Identification and analysis of genes underlying bone mineral density by integrating microarray data of osteoporosis","volume":"8","author":"Zhang","year":"2020","journal-title":"Front Cell Dev Biol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"668","DOI":"10.1038\/s41598-018-19196-2","article-title":"A novel approach for correction of crosstalk effects in pathway analysis and its application in osteoporosis research","volume":"8","author":"Zhou","year":"2018","journal-title":"Sci Rep"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1007\/BF03324331","article-title":"Prevention and treatment of osteoporosis","volume":"7","author":"Chapuy","year":"1995","journal-title":"Aging (Milano)"},{"key":"B30","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/j.tig.2018.10.004","article-title":"Dissecting the genetics of osteoporosis using systems approaches","volume":"35","author":"Al-Barghouthi","year":"2019","journal-title":"Trends Genet"},{"key":"B31","doi-asserted-by":"publisher","first-page":"108168","DOI":"10.1016\/j.pharmthera.2022.108168","article-title":"Advances in pathogenesis and therapeutic strategies for osteoporosis","volume":"237","author":"Song","year":"2022","journal-title":"Pharmacol Ther"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1111\/eci.13534","article-title":"The role of statins in the differentiation and function of bone cells","volume":"51","author":"Chamani","year":"2021","journal-title":"Eur J Clin Invest"},{"key":"B33","doi-asserted-by":"publisher","first-page":"155655","DOI":"10.1016\/j.cyto.2021.155655","article-title":"Influences of the IL-6 cytokine family on bone structure and function","volume":"146","author":"Sims","year":"2021","journal-title":"Cytokine"},{"key":"B34","doi-asserted-by":"publisher","first-page":"e210494","DOI":"10.1530\/EC-21-0494","article-title":"The role of menin in bone pathology","volume":"11","author":"Gorbacheva","year":"2022","journal-title":"Endocr Connect"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.beem.2015.04.008","article-title":"Estrogen receptor alpha and beta in health and disease","volume":"29","author":"Jia","year":"2015","journal-title":"Best Pract Res Clin Endocrinol Metab"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2019.05.060","article-title":"Estrogen receptor \u03b1 and \u03b2 gene polymorphism in relation to bone mineral density and lipid profile in northeast Indian women","volume":"710","author":"Saoji","year":"2019","journal-title":"Gene"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1007\/s12291-017-0706-x","article-title":"Association of vitamin d receptor (foki and bsmi) gene polymorphism with bone mineral density and their effect on 25-hydroxyvitamin d level in north indian postmenopausal women with osteoporosis","volume":"33","author":"Ahmad","year":"2018","journal-title":"Indian J Clin Biochem"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1185\/03007995.2014.890927","article-title":"Current challenges in the treatment of osteoporosis: an opportunity for bazedoxifene","volume":"30","author":"Reginster","year":"2014","journal-title":"Curr Med Res Opin"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2015.08.005","article-title":"Glycoprotein130 (Gp130)\/interleukin-6 (IL-6) signalling in osteoclasts promotes bone formation in periosteal and trabecular bone","volume":"81","author":"Johnson","year":"2015","journal-title":"Bone"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/ng1096-203","article-title":"Reduced bone density and osteoporosis associated with a polymorphic Sp1 binding site in the collagen type I alpha 1 gene","volume":"14","author":"Grant","year":"1996","journal-title":"Nat Genet"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2004.01.006","article-title":"Parathyroid hormone: a double-edged sword for bone metabolism","volume":"15","author":"Qin","year":"2004","journal-title":"Trends Endocrinol Metab"},{"key":"B42","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.bonr.2016.01.002","article-title":"Short-term intermittent administration of parathyroid hormone facilitates osteogenesis by different mechanisms in cancellous and cortical bone","volume":"5","author":"Ogura","year":"2016","journal-title":"Bone Rep"},{"key":"B43","doi-asserted-by":"publisher","first-page":"318","DOI":"10.3390\/antiox11020318","article-title":"Bone regeneration and oxidative stress: an updated overview","volume":"11","author":"B\u0103dil\u0103","year":"2022","journal-title":"Antioxidants (Basel)"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2019.09.023","article-title":"Artesunate activates the ATF4-CHOP-CHAC1 pathway and affects ferroptosis in burkitt\u2019s lymphoma","volume":"519","author":"Wang","year":"2019","journal-title":"Biochem Biophys Res Commun"},{"key":"B45","doi-asserted-by":"publisher","first-page":"205","DOI":"10.3390\/antiox9030205","article-title":"Inhibitory effect and mechanism of action of quercetin and quercetin diels-alder anti-dimer on erastin-induced ferroptosis in bone marrow-derived mesenchymal stem cells","volume":"9","author":"Li","year":"2020","journal-title":"Antioxidants (Basel)"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2022.986384\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,8,29]],"date-time":"2022-08-29T01:08:51Z","timestamp":1661735331000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2022.986384\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,29]]},"references-count":45,"alternative-id":["10.3389\/fendo.2022.986384"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2022.986384","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,29]]},"article-number":"986384"}}