{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T20:14:50Z","timestamp":1790626490681,"version":"4.1.0"},"reference-count":66,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T00:00:00Z","timestamp":1763596800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Jiangxi Provincial Natural Science Foundation project","award":["20232BAB206154"],"award-info":[{"award-number":["20232BAB206154"]}]},{"DOI":"10.13039\/501100012175","name":"Zhejiang Traditional Chinese Medicine Administration","doi-asserted-by":"publisher","award":["2022FSYYZQ21"],"award-info":[{"award-number":["2022FSYYZQ21"]}],"id":[{"id":"10.13039\/501100012175","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The association between inflammatory bowel disease (IBD) and reduced bone mineral density (BMD) or osteoporosis is still a subject of ongoing debate, underscoring the need for further exploration, particularly from a genetic perspective.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Utilizing data from genome-wide association studies on 59,957 IBD, 40,266 CD, 45,975 UC, 31,492 BMD, and 399,054 osteoporosis, comprehensive analyses were performed focusing on two main aspects: genetic correlations (Rg) and shared genetic loci. Initially, the overall Rg between these traits was assessed via genetic covariance analyzers and high-definition likelihood approaches. Following this, local genetic patterns were examined using local variant association analysis. Mendelian randomization (MR) analysis was performed to infer potential causal relationships. The genetic overlap was then explored using conditional\/conjunctional false discovery rate (cond\/conjFDR) statistical methods, leading to the identification of several biologically significant shared genetic loci.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>A notable genetic correlation was found between IBD, its subtypes, and BMD\/osteoporosis at the genome-wide level. Additionally, significant local genetic associations were identified across various chromosomal regions. The conjFDR analysis further supported the genetic overlap and pinpointed several critical shared loci. Furthermore, significant enrichment of the Wnt signaling pathway was detected for both conditions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec004\">\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This investigation offers robust genetic evidence supporting the comorbidity of IBD with BMD\/osteoporosis, highlights possible underlying mechanisms, and provides new insights into clinical research and practice.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0336775","type":"journal-article","created":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T18:38:33Z","timestamp":1763663913000},"page":"e0336775","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["A multilayered genetic structure analysis between inflammatory bowel disease and bone density\/osteoporosis"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-0573-9103","authenticated-orcid":true,"given":"Mengting","family":"Qin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinhong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinghua","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruyun","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,11,20]]},"reference":[{"issue":"12","key":"pone.0336775.ref001","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1038\/nrgastro.2015.150","article-title":"The global burden of IBD: from 2015 to 2025","volume":"12","author":"GG Kaplan","year":"2015","journal-title":"Nat Rev Gastroenterol Hepatol"},{"issue":"4","key":"pone.0336775.ref002","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1053\/j.gastro.2021.07.042","article-title":"Extraintestinal Manifestations of Inflammatory Bowel Disease: Current Concepts, Treatment, and Implications for Disease Management","volume":"161","author":"G Rogler","year":"2021","journal-title":"Gastroenterology"},{"issue":"1","key":"pone.0336775.ref003","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s40168-018-0604-3","article-title":"Host immunoglobulin G selectively identifies pathobionts in pediatric inflammatory bowel diseases","volume":"7","author":"H Armstrong","year":"2019","journal-title":"Microbiome"},{"issue":"10","key":"pone.0336775.ref004","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1038\/s41575-025-01097-1","article-title":"The global burden of inflammatory bowel disease: from 2025 to 2045","volume":"22","author":"GG Kaplan","year":"2025","journal-title":"Nat Rev Gastroenterol Hepatol"},{"issue":"4","key":"pone.0336775.ref005","doi-asserted-by":"crossref","first-page":"241","DOI":"10.4103\/1319-3767.98428","article-title":"Bone density and bone metabolism in patients with inflammatory bowel disease","volume":"18","author":"KM Shirazi","year":"2012","journal-title":"Saudi J Gastroenterol"},{"issue":"1","key":"pone.0336775.ref006","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1186\/s40169-020-00270-0","article-title":"Bone mineral density is negatively correlated with ulcerative colitis: a systematic review and meta-analysis","volume":"9","author":"T Zhou","year":"2020","journal-title":"Clin Transl Med"},{"issue":"2","key":"pone.0336775.ref007","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1007\/s10620-020-06220-7","article-title":"Low Bone Mineral Density in Young Patients Newly Diagnosed with Inflammatory Bowel Disease","volume":"66","author":"JS Lee","year":"2021","journal-title":"Dig Dis Sci"},{"key":"pone.0336775.ref008","doi-asserted-by":"crossref","first-page":"1425610","DOI":"10.3389\/fimmu.2024.1425610","article-title":"Association between inflammatory bowel disease and osteoporosis in European and East Asian populations: exploring causality, mediation by nutritional status, and shared genetic architecture","volume":"15","author":"J Kang","year":"2024","journal-title":"Front Immunol"},{"key":"pone.0336775.ref009","doi-asserted-by":"crossref","first-page":"1151837","DOI":"10.3389\/fpubh.2023.1151837","article-title":"Two-sample Mendelian randomization analysis evaluates causal associations between inflammatory bowel disease and osteoporosis","volume":"11","author":"Z Dai","year":"2023","journal-title":"Front Public Health"},{"key":"pone.0336775.ref010","doi-asserted-by":"crossref","first-page":"1148107","DOI":"10.3389\/fimmu.2023.1148107","article-title":"The genetically predicted causal relationship of inflammatory bowel disease with bone mineral density and osteoporosis: evidence from two-sample Mendelian randomization","volume":"14","author":"D Xu","year":"2023","journal-title":"Front Immunol"},{"issue":"6","key":"pone.0336775.ref011","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1038\/nmat1911","article-title":"Nanoscale heterogeneity promotes energy dissipation in bone","volume":"6","author":"K Tai","year":"2007","journal-title":"Nat Mater"},{"key":"pone.0336775.ref012","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1097\/01.blo.0000132404.30139.f2","article-title":"Osteoporosis","volume":"425","author":"JT Lin","year":"2004","journal-title":"Clinical Orthopaedics and Related Research"},{"issue":"9","key":"pone.0336775.ref013","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1007\/s12603-023-1971-4","article-title":"Sex Specific Global Burden of Osteoporosis in 204 Countries and Territories, from 1990 to 2030: An Age-Period-Cohort Modeling Study","volume":"27","author":"Z Zhu","year":"2023","journal-title":"J Nutr Health Aging"},{"issue":"6","key":"pone.0336775.ref014","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1016\/j.ajhg.2017.11.001","article-title":"A Powerful Approach to Estimating Annotation-Stratified Genetic Covariance via GWAS Summary Statistics","volume":"101","author":"Q Lu","year":"2017","journal-title":"Am J Hum Genet"},{"issue":"8","key":"pone.0336775.ref015","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1038\/s41588-020-0653-y","article-title":"High-definition likelihood inference of genetic correlations across human complex traits","volume":"52","author":"Z Ning","year":"2020","journal-title":"Nat Genet"},{"issue":"3","key":"pone.0336775.ref016","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1038\/s41588-022-01017-y","article-title":"An integrated framework for local genetic correlation analysis","volume":"54","author":"J Werme","year":"2022","journal-title":"Nat Genet"},{"key":"pone.0336775.ref017","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1016\/j.jad.2024.08.149","article-title":"The shared genetic etiology of antisocial behavior and psychiatric disorders: Insights from pleiotropy and causality analysis","volume":"365","author":"S Wang","year":"2024","journal-title":"J Affect Disord"},{"issue":"1","key":"pone.0336775.ref018","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1038\/s41537-024-00533-6","article-title":"Unraveling the heart-brain axis: shared genetic mechanisms in cardiovascular diseases and Schizophrenia","volume":"10","author":"J Shen","year":"2024","journal-title":"Schizophrenia (Heidelb)"},{"issue":"1","key":"pone.0336775.ref019","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1007\/s00439-019-02060-2","article-title":"Discovery of shared genomic loci using the conditional false discovery rate approach","volume":"139","author":"OB Smeland","year":"2020","journal-title":"Hum Genet"},{"issue":"1","key":"pone.0336775.ref020","doi-asserted-by":"crossref","first-page":"868","DOI":"10.1186\/s12864-024-10787-0","article-title":"Investigating the shared genetic basis of inflammatory bowel disease and systemic lupus erythematosus using genetic overlap analysis","volume":"25","author":"W Yuan","year":"2024","journal-title":"BMC Genomics"},{"issue":"19","key":"pone.0336775.ref021","doi-asserted-by":"crossref","first-page":"1925","DOI":"10.1001\/jama.2017.17219","article-title":"Mendelian Randomization","volume":"318","author":"CA Emdin","year":"2017","journal-title":"JAMA"},{"issue":"2","key":"pone.0336775.ref022","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1038\/ng.3760","article-title":"Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease","volume":"49","author":"KM de Lange","year":"2017","journal-title":"Nat Genet"},{"issue":"1","key":"pone.0336775.ref023","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.ajhg.2017.12.005","article-title":"Life-Course Genome-wide Association Study Meta-analysis of Total Body BMD and Assessment of Age-Specific Effects","volume":"102","author":"C Medina-Gomez","year":"2018","journal-title":"Am J Hum Genet"},{"issue":"7944","key":"pone.0336775.ref024","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1038\/s41586-022-05473-8","article-title":"FinnGen provides genetic insights from a well-phenotyped isolated population","volume":"613","author":"MI Kurki","year":"2023","journal-title":"Nature"},{"key":"pone.0336775.ref025","doi-asserted-by":"crossref","first-page":"1468457","DOI":"10.3389\/fnut.2025.1468457","article-title":"Exploring genetic structures and shared sites between alcohol, cheese intake, and inflammatory bowel disease","volume":"12","author":"Z Huang","year":"2025","journal-title":"Front Nutr"},{"issue":"1","key":"pone.0336775.ref026","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1186\/s12888-025-07096-5","article-title":"Exploring the shared genetic architecture between testosterone traits and major depressive disorder","volume":"25","author":"W Lu","year":"2025","journal-title":"BMC Psychiatry"},{"issue":"3","key":"pone.0336775.ref027","doi-asserted-by":"crossref","DOI":"10.1212\/NXG.0000000000200143","article-title":"Dissecting the Shared Genetic Architecture of Common Epilepsies With Cortical Brain Morphology","volume":"10","author":"N Karadag","year":"2024","journal-title":"Neurol Genet"},{"issue":"1","key":"pone.0336775.ref028","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1038\/s41398-023-02387-5","article-title":"The genetic architecture of human amygdala volumes and their overlap with common brain disorders","volume":"13","author":"Y-N Ou","year":"2023","journal-title":"Transl Psychiatry"},{"issue":"5","key":"pone.0336775.ref029","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1007\/s10654-017-0255-x","article-title":"Interpreting findings from Mendelian randomization using the MR-Egger method","volume":"32","author":"S Burgess","year":"2017","journal-title":"Eur J Epidemiol"},{"issue":"5","key":"pone.0336775.ref030","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1038\/s41588-018-0099-7","article-title":"Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases","volume":"50","author":"M Verbanck","year":"2018","journal-title":"Nat Genet"},{"key":"pone.0336775.ref031","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.hrtlng.2023.05.016","article-title":"The gut-lung axis: Mendelian randomization identifies a causal association between inflammatory bowel disease and interstitial lung disease","volume":"61","author":"Q Luo","year":"2023","journal-title":"Heart Lung"},{"issue":"1","key":"pone.0336775.ref032","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1097\/EDE.0000000000000559","article-title":"Sensitivity Analyses for Robust Causal Inference from Mendelian Randomization Analyses with Multiple Genetic Variants","volume":"28","author":"S Burgess","year":"2017","journal-title":"Epidemiology"},{"issue":"1","key":"pone.0336775.ref033","doi-asserted-by":"crossref","first-page":"2417","DOI":"10.1038\/s41467-019-10310-0","article-title":"Bivariate causal mixture model quantifies polygenic overlap between complex traits beyond genetic correlation","volume":"10","author":"O Frei","year":"2019","journal-title":"Nat Commun"},{"issue":"7","key":"pone.0336775.ref034","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1001\/jamaneurol.2017.0469","article-title":"Genome-wide Pleiotropy Between Parkinson Disease and Autoimmune Diseases","volume":"74","author":"A Witoelar","year":"2017","journal-title":"JAMA Neurol"},{"issue":"1","key":"pone.0336775.ref035","doi-asserted-by":"crossref","first-page":"1826","DOI":"10.1038\/s41467-017-01261-5","article-title":"Functional mapping and annotation of genetic associations with FUMA","volume":"8","author":"K Watanabe","year":"2017","journal-title":"Nat Commun"},{"issue":"3","key":"pone.0336775.ref036","doi-asserted-by":"crossref","DOI":"10.1002\/imt2.36","article-title":"Sangerbox: A comprehensive, interaction-friendly clinical bioinformatics analysis platform","volume":"1","author":"W Shen","year":"2022","journal-title":"Imeta"},{"issue":"6","key":"pone.0336775.ref037","doi-asserted-by":"crossref","first-page":"1863","DOI":"10.3390\/nu13061863","article-title":"Associations of Lifestyle Factors with Osteopenia and Osteoporosis in Polish Patients with Inflammatory Bowel Disease","volume":"13","author":"AM Rychter","year":"2021","journal-title":"Nutrients"},{"issue":"6","key":"pone.0336775.ref038","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1016\/j.cgh.2007.02.024","article-title":"Vertebral fractures and role of low bone mineral density in Crohn\u2019s disease","volume":"5","author":"JS Siffledeen","year":"2007","journal-title":"Clin Gastroenterol Hepatol"},{"issue":"5","key":"pone.0336775.ref039","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1136\/gut.51.5.654","article-title":"High prevalence of osteoporotic vertebral fractures in patients with Crohn\u2019s disease","volume":"51","author":"J Klaus","year":"2002","journal-title":"Gut"},{"issue":"9","key":"pone.0336775.ref040","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1111\/j.1365-2036.2004.01876.x","article-title":"Review article: Osteoporosis and inflammatory bowel disease","volume":"19","author":"CN Bernstein","year":"2004","journal-title":"Aliment Pharmacol Ther"},{"issue":"7","key":"pone.0336775.ref041","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1111\/j.1365-2036.2008.03599.x","article-title":"Low body mass not vitamin D receptor polymorphisms predict osteoporosis in patients with inflammatory bowel disease","volume":"27","author":"CL Noble","year":"2008","journal-title":"Aliment Pharmacol Ther"},{"issue":"28","key":"pone.0336775.ref042","doi-asserted-by":"crossref","first-page":"3528","DOI":"10.3748\/wjg.15.3528","article-title":"Osteoporosis in adult Sri Lankan inflammatory bowel disease patients","volume":"15","author":"AP de Silva","year":"2009","journal-title":"World J Gastroenterol"},{"issue":"3","key":"pone.0336775.ref043","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1016\/j.cgh.2012.10.022","article-title":"Inflammatory bowel disease has a small effect on bone mineral density and risk for osteoporosis","volume":"11","author":"LE Targownik","year":"2013","journal-title":"Clin Gastroenterol Hepatol"},{"issue":"5","key":"pone.0336775.ref044","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.1053\/gast.2000.19280","article-title":"Bone mineral density in patients with recently diagnosed inflammatory bowel disease","volume":"119","author":"EJ Schoon","year":"2000","journal-title":"Gastroenterology"},{"issue":"5","key":"pone.0336775.ref045","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1038\/ng.2249","article-title":"Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture","volume":"44","author":"K Estrada","year":"2012","journal-title":"Nat Genet"},{"issue":"22","key":"pone.0336775.ref046","doi-asserted-by":"crossref","first-page":"2355","DOI":"10.1056\/NEJMoa0801197","article-title":"Multiple genetic loci for bone mineral density and fractures","volume":"358","author":"U Styrkarsdottir","year":"2008","journal-title":"N Engl J Med"},{"issue":"9623","key":"pone.0336775.ref047","doi-asserted-by":"crossref","first-page":"1505","DOI":"10.1016\/S0140-6736(08)60599-1","article-title":"Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study","volume":"371","author":"JB Richards","year":"2008","journal-title":"Lancet"},{"issue":"9","key":"pone.0336775.ref048","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1038\/ng.3359","article-title":"Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations","volume":"47","author":"JZ Liu","year":"2015","journal-title":"Nat Genet"},{"issue":"5","key":"pone.0336775.ref049","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1038\/ng2032","article-title":"Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis","volume":"39","author":"JD Rioux","year":"2007","journal-title":"Nat Genet"},{"issue":"7","key":"pone.0336775.ref050","doi-asserted-by":"crossref","first-page":"1923","DOI":"10.1093\/hmg\/ddt575","article-title":"Multistage genome-wide association meta-analyses identified two new loci for bone mineral density","volume":"23","author":"L Zhang","year":"2014","journal-title":"Hum Mol Genet"},{"issue":"11","key":"pone.0336775.ref051","doi-asserted-by":"crossref","first-page":"2874","DOI":"10.1158\/1055-9965.EPI-09-0544","article-title":"Genetic variants in the vitamin d receptor are associated with advanced prostate cancer at diagnosis: findings from the prostate testing for cancer and treatment study and a systematic review","volume":"18","author":"L Chen","year":"2009","journal-title":"Cancer Epidemiol Biomarkers Prev"},{"issue":"4","key":"pone.0336775.ref052","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pgen.1001372","article-title":"Genome-wide association study using extreme truncate selection identifies novel genes affecting bone mineral density and fracture risk","volume":"7","author":"EL Duncan","year":"2011","journal-title":"PLoS Genet"},{"issue":"5","key":"pone.0336775.ref053","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1038\/s41375-019-0404-1","article-title":"Aberrant Wnt signaling in multiple myeloma: molecular mechanisms and targeting options","volume":"33","author":"H van Andel","year":"2019","journal-title":"Leukemia"},{"issue":"7330","key":"pone.0336775.ref054","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1038\/nature09637","article-title":"Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts","volume":"469","author":"T Sato","year":"2011","journal-title":"Nature"},{"issue":"1","key":"pone.0336775.ref055","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1038\/s41577-018-0084-5","article-title":"The immunological anatomy of the skin","volume":"19","author":"K Kabashima","year":"2019","journal-title":"Nat Rev Immunol"},{"issue":"2","key":"pone.0336775.ref056","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/j.semarthrit.2013.01.004","article-title":"The role of extracellular modulators of canonical Wnt signaling in bone metabolism and diseases","volume":"43","author":"E Boudin","year":"2013","journal-title":"Semin Arthritis Rheum"},{"key":"pone.0336775.ref057","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1038\/s41413-018-0026-7","article-title":"R-spondin-2 is a Wnt agonist that regulates osteoblast activity and bone mass","volume":"6","author":"MN Knight","year":"2018","journal-title":"Bone Res"},{"issue":"5","key":"pone.0336775.ref058","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1007\/s00109-014-1123-8","article-title":"CXC chemokine ligand 12 (CXCL12) and its receptor CXCR4","volume":"92","author":"T Nagasawa","year":"2014","journal-title":"J Mol Med (Berl)"},{"issue":"2","key":"pone.0336775.ref059","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1038\/nm.3074","article-title":"WNT signaling in bone homeostasis and disease: from human mutations to treatments","volume":"19","author":"R Baron","year":"2013","journal-title":"Nat Med"},{"key":"pone.0336775.ref060","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1146\/annurev-immunol-030409-101225","article-title":"Inflammatory bowel disease","volume":"28","author":"A Kaser","year":"2010","journal-title":"Annu Rev Immunol"},{"issue":"7360","key":"pone.0336775.ref061","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1038\/nature10337","article-title":"Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling","volume":"476","author":"W de Lau","year":"2011","journal-title":"Nature"},{"issue":"2","key":"pone.0336775.ref062","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1038\/nm1538","article-title":"Dickkopf-1 is a master regulator of joint remodeling","volume":"13","author":"D Diarra","year":"2007","journal-title":"Nat Med"},{"issue":"5","key":"pone.0336775.ref063","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1016\/j.devcel.2005.02.017","article-title":"Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation","volume":"8","author":"DA Glass","year":"2005","journal-title":"Dev Cell"},{"key":"pone.0336775.ref064","doi-asserted-by":"crossref","first-page":"116587","DOI":"10.1016\/j.bcp.2024.116587","article-title":"Therapeutic targeting of Wnt antagonists by small molecules for treatment of osteoporosis","volume":"230","author":"A Abhishek Shah","year":"2024","journal-title":"Biochem Pharmacol"},{"issue":"6","key":"pone.0336775.ref065","doi-asserted-by":"crossref","first-page":"1192","DOI":"10.1016\/j.cell.2012.05.012","article-title":"Wnt\/\u03b2-catenin signaling and disease","volume":"149","author":"H Clevers","year":"2012","journal-title":"Cell"},{"issue":"2","key":"pone.0336775.ref066","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1093\/jb\/mvae082","article-title":"GPLD1+ cancer stem cells contribute to chemotherapy resistance and tumour relapse in intestinal cancer","volume":"177","author":"T Mizoo","year":"2025","journal-title":"J Biochem"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0336775","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T18:38:43Z","timestamp":1763663923000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0336775"}},"subtitle":[],"editor":[{"given":"Emmanuel O","family":"Adewuyi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2025,11,20]]},"references-count":66,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,11,20]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0336775","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,20]]}}}