{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T02:35:31Z","timestamp":1776479731334,"version":"3.51.2"},"reference-count":114,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,9,2]],"date-time":"2024-09-02T00:00:00Z","timestamp":1725235200000},"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. Med."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>While several risk factors for knee osteoarthritis (KOA) have been recognized, the pathogenesis of KOA and the causal relationship between modifiable risk factors and KOA in genetic epidemiology remain unclear. This study aimed to determine the causal relationship between KOA and its risk factors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Data were obtained from published Genome-Wide Association study (GWAS) databases. A two-sample Mendelian randomization (MR) analysis was performed with genetic variants associated with risk factors as instrumental variables and KOA as outcome. First, inverse variance weighting was used as the main MR analysis method, and then a series of sensitivity analyses were conducted to comprehensively evaluate the causal relationship between them.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Univariate forward MR analysis revealed that genetically predicted hypothyroidism, hyperthyroidism\/thyrotoxicosis, educational level, income level, metabolic syndrome (MS), essential hypertension, height, hot drink temperature, diet (abstaining from sugar-sweetened or wheat products), and psychological and psychiatric disorders (stress, depression, and anxiety) were causally associated with KOA. Reverse MR exhibits a causal association between KOA and educational attainment. Multivariate MR analysis adjusted for the inclusion of potential mediators, such as body mass index (BMI), smoking, alcohol consumption, and sex, exhibited some variation in causal effects. However, hyperthyroidism\/thyrotoxicosis had a significant causal effect on KOA, and there was good evidence that height, hypothyroidism, educational level, psychological and psychiatric disorders (stress, depression, and anxiety), and abstaining from wheat products had an independent causal relationship. The mediating effect of BMI as a mediator was also identified.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study used MR to validate the causal relationship between KOA and its risk factors, providing new insights for preventing and treating KOA in clinical practice and for developing public health policies.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fmed.2024.1405188","type":"journal-article","created":{"date-parts":[[2024,9,2]],"date-time":"2024-09-02T04:20:11Z","timestamp":1725250811000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Causal relationship between modifiable risk factors and knee osteoarthritis: a Mendelian randomization study"],"prefix":"10.3389","volume":"11","author":[{"given":"Zhihao","family":"Diao","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Danyang","family":"Guo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingzhi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruiyu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chunjing","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hao","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuxia","family":"Ma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2024,9,2]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1097","DOI":"10.1016\/j.autrev.2018.06.002","article-title":"Osteoarthritis and its management - epidemiology, nutritional aspects and environmental factors","volume":"17","author":"Bortoluzzi","year":"2018","journal-title":"Autoimmun Rev"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1016\/S0140-6736(14)60802-3","article-title":"Osteoarthritis","volume":"386","author":"Glyn-Jones","year":"2015","journal-title":"Lancet"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"100587","DOI":"10.1016\/j.eclinm.2020.100587","article-title":"Global, regional prevalence, incidence and risk factors of knee osteoarthritis in population-based studies","author":"Cui","year":"2020","journal-title":"EClinicalMedicine"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"e001938","DOI":"10.1136\/rmdopen-2021-001938","article-title":"Impact of pain sensitisation on the quality of life of patients with knee osteoarthritis","volume":"8","author":"Aw","year":"2022","journal-title":"RMD Open"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"2163","DOI":"10.1016\/S0140-6736(12)61729-2","article-title":"Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: a systematic analysis for the global burden of disease study 2010","volume":"380","author":"Vos","year":"2012","journal-title":"Lancet"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1097\/BOR.0000000000000479","article-title":"Epidemiology of osteoarthritis: literature update","volume":"30","author":"Vina","year":"2018","journal-title":"Curr Opin Rheumatol"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"819","DOI":"10.1136\/annrheumdis-2019-216515","article-title":"Global, regional and national burden of osteoarthritis 1990-2017: a systematic analysis of the global burden of disease study 2017","volume":"79","author":"Safiri","year":"2020","journal-title":"Ann Rheum Dis"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"641","DOI":"10.1002\/art.24464","article-title":"The high prevalence of knee osteoarthritis in a rural Chinese population: the Wuchuan osteoarthritis study","volume":"61","author":"Kang","year":"2009","journal-title":"Arthritis Rheum"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"R169","DOI":"10.1186\/ar3492","article-title":"Associations of educational attainment, occupation and community poverty with knee osteoarthritis in the Johnston County (North Carolina) osteoarthritis project","volume":"13","author":"Callahan","year":"2011","journal-title":"Arthritis Res Ther"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"711","DOI":"10.1007\/s10067-020-05216-y","article-title":"Metabolic syndrome, hypertension, and hyperglycemia were positively associated with knee osteoarthritis, while dyslipidemia showed no association with knee osteoarthritis","volume":"40","author":"Xie","year":"2021","journal-title":"Clin Rheumatol"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"7701","DOI":"10.1177\/0300060519897701","article-title":"Assessment of the relationship between knee ultrasound and clinical symptoms in patients with thyroid dysfunction","volume":"48","author":"Kim","year":"2020","journal-title":"J Int Med Res"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"5919686","DOI":"10.1155\/2022\/5919686","article-title":"Healthcare and scientific treatment of knee osteoarthritis","volume":"2022","author":"Wang","year":"2022","journal-title":"J Healthc Eng"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"1348","DOI":"10.1093\/ajcn\/nqaa219","article-title":"Morning diurnal preference and food intake: a Mendelian randomization study","volume":"112","author":"Dashti","year":"2020","journal-title":"Am J Clin Nutr"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"1418","DOI":"10.1002\/art.21017","article-title":"Knee height, knee pain, and knee osteoarthritis: the Beijing osteoarthritis study","volume":"52","author":"Hunter","year":"2005","journal-title":"Arthritis Rheum"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"1926","DOI":"10.1016\/j.joca.2017.08.009","article-title":"Knee osteoarthritis phenotypes and their relevance for outcomes: a systematic review","volume":"25","author":"Deveza","year":"2017","journal-title":"Osteoarthr Cartil"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"k601","DOI":"10.1136\/bmj.k601","article-title":"Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians","volume":"362","author":"Davies","year":"2018","journal-title":"BMJ"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1002\/jrsm.1346","article-title":"Meta-analysis and Mendelian randomization: a review","volume":"10","author":"Bowden","year":"2019","journal-title":"Res Synth Methods"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"1925","DOI":"10.1001\/jama.2017.17219","article-title":"Mendelian randomization","volume":"318","author":"Emdin","year":"2017","journal-title":"JAMA"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"a038984","DOI":"10.1101\/cshperspect.a038984","article-title":"Multivariable Mendelian randomization and mediation","volume":"11","author":"Sanderson","year":"2021","journal-title":"Cold Spring Harb Perspect Med"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1007\/s10654-021-00757-1","article-title":"Mendelian randomisation for mediation analysis: current methods and challenges for implementation","volume":"36","author":"Carter","year":"2021","journal-title":"Eur J Epidemiol"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1093\/ije\/dyy262","article-title":"An examination of multivariable Mendelian randomization in the single-sample and two-sample summary data settings","volume":"48","author":"Sanderson","year":"2019","journal-title":"Int J Epidemiol"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"n2233","DOI":"10.1136\/bmj.n2233","article-title":"Strengthening the reporting of observational studies in epidemiology using Mendelian randomisation (STROBE-MR): explanation and elaboration","volume":"375","author":"Skrivankova","year":"2021","journal-title":"BMJ"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"1614","DOI":"10.1001\/jama.2021.18236","article-title":"Strengthening the reporting of observational studies in epidemiology using Mendelian randomization: the STROBE-MR statement","volume":"326","author":"Skrivankova","year":"2021","journal-title":"JAMA"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"230","DOI":"10.1038\/s41588-018-0327-1","article-title":"Identification of new therapeutic targets for osteoarthritis through genome-wide analyses of UK biobank data","volume":"51","author":"Tachmazidou","year":"2019","journal-title":"Nat Genet"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"1254","DOI":"10.1093\/ije\/dyab251","article-title":"Using multivariable Mendelian randomization to estimate the causal effect of bone mineral density on osteoarthritis risk, independently of body mass index","volume":"51","author":"Hartley","year":"2022","journal-title":"Int J Epidemiol"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"104154","DOI":"10.1016\/j.ebiom.2022.104154","article-title":"Appraising the causal role of smoking in multiple diseases: a systematic review and meta-analysis of Mendelian randomization studies","volume":"82","author":"Larsson","year":"2022","journal-title":"EBioMedicine"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1016\/j.joca.2020.12.015","article-title":"Cardiometabolic traits mediating the effect of education on osteoarthritis risk: a Mendelian randomization study","volume":"29","author":"Gill","year":"2021","journal-title":"Osteoarthr Cartil"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"663","DOI":"10.1038\/s41588-021-00846-7","article-title":"Genetic analyses identify widespread sex-differential participation bias","volume":"53","author":"Pirastu","year":"2021","journal-title":"Nat Genet"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"e34408","DOI":"10.7554\/eLife.34408","article-title":"The MR-base platform supports systematic causal inference across the human phenome","volume":"7","author":"Hemani","year":"2018","journal-title":"eLife"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"1177","DOI":"10.1001\/jama.2022.2505","article-title":"Instrumental variables and heterogeneous treatment effects","volume":"327","author":"Maciejewski","year":"2022","journal-title":"JAMA"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1186\/s12916-023-02761-6","article-title":"Causal relationship between gut microbiota and cancers: a two-sample Mendelian randomisation study","volume":"21","author":"Long","year":"2023","journal-title":"BMC Med"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"2333","DOI":"10.1177\/0962280215597579","article-title":"A review of instrumental variable estimators for Mendelian randomization","volume":"26","author":"Burgess","year":"2017","journal-title":"Stat Methods Med Res"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"256","DOI":"10.1186\/s12885-023-10737-1","article-title":"Association of smoking, alcohol, and coffee consumption with the risk of ovarian cancer and prognosis: a Mendelian randomization study","volume":"23","author":"Liu","year":"2023","journal-title":"BMC Cancer"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"2681","DOI":"10.1093\/aje\/kwy185","article-title":"Invited commentary: detecting individual and global horizontal pleiotropy in mendelian randomization-a job for the humble heterogeneity statistic","volume":"187","author":"Bowden","year":"2018","journal-title":"Am J Epidemiol"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"1783","DOI":"10.1002\/sim.7221","article-title":"A framework for the investigation of pleiotropy in two-sample summary data Mendelian randomization","volume":"36","author":"Bowden","year":"2017","journal-title":"Stat Med"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"214","DOI":"10.1007\/s40471-018-0152-1","article-title":"Understanding the assumptions underlying instrumental variable analyses: a brief review of falsification strategies and related tools","volume":"5","author":"Labrecque","year":"2018","journal-title":"Curr Epidemiol Rep"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1093\/ije\/dyv080","article-title":"Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression","volume":"44","author":"Bowden","year":"2015","journal-title":"Int J Epidemiol"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1002\/gepi.21965","article-title":"Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator","volume":"40","author":"Bowden","year":"2016","journal-title":"Genet Epidemiol"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"1985","DOI":"10.1093\/ije\/dyx102","article-title":"Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption","volume":"46","author":"Hartwig","year":"2017","journal-title":"Int J Epidemiol"},{"key":"ref40","doi-asserted-by":"publisher","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":"Burgess","year":"2017","journal-title":"Epidemiology"},{"key":"ref41","doi-asserted-by":"publisher","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":"Verbanck","year":"2018","journal-title":"Nat Genet"},{"key":"ref42","first-page":"711","article-title":"Lack of association between thyroid status and chondrocalcinosis or osteoarthritis: the Framingham osteoarthritis study","volume":"23","author":"Chaisson","year":"1996","journal-title":"J Rheumatol"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1186\/s12891-017-1565-6","article-title":"Incidence of total hip or knee replacement due to osteoarthritis in relation to thyroid function: a prospective cohort study (the Nord-Tr\u00f8ndelag health study)","volume":"18","author":"Hellevik","year":"2017","journal-title":"BMC Musculoskelet Disord"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/0049-0172(79)90002-7","article-title":"Rheumatic syndromes in endocrine disease","volume":"9","author":"Bland","year":"1979","journal-title":"Semin Arthritis Rheum"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1016\/0006-291X(72)90363-4","article-title":"Activation of human synovial membrane adenylate cyclase by thyroid stimulating hormone (TSH)","volume":"48","author":"Newcombe","year":"1972","journal-title":"Biochem Biophys Res Commun"},{"key":"ref46","doi-asserted-by":"publisher","first-page":"5199","DOI":"10.1177\/1759720X211035199","article-title":"Association of anti-thyroid antibodies with radiographic knee osteoarthritis and chondrocalcinosis: a NHANES III study","volume":"13","author":"Tagoe","year":"2021","journal-title":"Ther Adv Musculoskelet Dis"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"567","DOI":"10.1038\/hr.2016.35","article-title":"Hypertension as an autoimmune and inflammatory disease","volume":"39","author":"Solak","year":"2016","journal-title":"Hypertens Res"},{"key":"ref48","doi-asserted-by":"publisher","first-page":"e7584","DOI":"10.1097\/MD.0000000000007584","article-title":"Association between hypertension and risk of knee osteoarthritis: a meta-analysis of observational studies","volume":"96","author":"Zhang","year":"2017","journal-title":"Medicine (Baltimore)"},{"key":"ref49","doi-asserted-by":"publisher","first-page":"133","DOI":"10.21037\/atm.2016.03.48","article-title":"Metabolic syndrome and components exacerbate osteoarthritis symptoms of pain, depression and reduced knee function","volume":"4","author":"Li","year":"2016","journal-title":"Ann Transl Med"},{"key":"ref50","doi-asserted-by":"publisher","first-page":"729","DOI":"10.1038\/nrrheum.2012.135","article-title":"Metabolic syndrome meets osteoarthritis","volume":"8","author":"Zhuo","year":"2012","journal-title":"Nat Rev Rheumatol"},{"key":"ref51","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.jot.2021.05.003","article-title":"Association between hypertension and osteoarthritis: a systematic review and meta-analysis of observational studies","volume":"32","author":"Lo","year":"2022","journal-title":"J Orthop Translat"},{"key":"ref52","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1016\/j.mehy.2017.09.027","article-title":"Is subchondral bone cyst formation in non-load-bearing region of osteoarthritic knee a vascular problem","volume":"109","author":"Chan","year":"2017","journal-title":"Med Hypotheses"},{"key":"ref53","doi-asserted-by":"publisher","first-page":"704","DOI":"10.1038\/nm.3143","article-title":"Inhibition of TGF-\u03b2 signaling in mesenchymal stem cells of subchondral bone attenuates osteoarthritis","volume":"19","author":"Zhen","year":"2013","journal-title":"Nat Med"},{"key":"ref54","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1089\/met.2009.0110","article-title":"Osteoarthritis: another component of metabolic syndrome","volume":"8","author":"Velasquez","year":"2010","journal-title":"Metab Syndr Relat Disord"},{"key":"ref55","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1016\/j.pmn.2021.08.002","article-title":"Association of hypertension with knee pain severity among people with knee osteoarthritis","volume":"23","author":"Shi","year":"2022","journal-title":"Pain Manag Nurs"},{"key":"ref56","doi-asserted-by":"publisher","first-page":"640","DOI":"10.3390\/nu15030640","article-title":"New advances in metabolic syndrome, from prevention to treatment: the role of diet and food","volume":"15","author":"Ambroselli","year":"2023","journal-title":"Nutrients"},{"key":"ref57","doi-asserted-by":"publisher","first-page":"155043","DOI":"10.1016\/j.cyto.2020.155043","article-title":"An update on the association between metabolic syndrome and osteoarthritis and on the potential role of leptin in osteoarthritis","volume":"129","author":"Gao","year":"2020","journal-title":"Cytokine"},{"key":"ref58","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1189\/jlb.1012519","article-title":"RAGE regulation and signaling in inflammation and beyond","volume":"94","author":"Kierdorf","year":"2013","journal-title":"J Leukoc Biol"},{"key":"ref59","doi-asserted-by":"publisher","first-page":"432","DOI":"10.3390\/nu10040432","article-title":"Obesity, inflammation, toll-like receptor 4 and fatty acids","volume":"10","author":"Rogero","year":"2018","journal-title":"Nutrients"},{"key":"ref60","doi-asserted-by":"publisher","first-page":"703","DOI":"10.1002\/JLB.MR1218-478R","article-title":"Leptin in the regulation of the immunometabolism of adipose tissue-macrophages","volume":"106","author":"Monteiro","year":"2019","journal-title":"J Leukoc Biol"},{"key":"ref61","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1186\/s12964-018-0268-4","article-title":"Activation of the JAK\/STAT3 and PI3K\/AKT pathways are crucial for IL-6 trans-signaling-mediated pro-inflammatory response in human vascular endothelial cells","volume":"16","author":"Zegeye","year":"2018","journal-title":"Cell Commun Signal"},{"key":"ref62","doi-asserted-by":"publisher","first-page":"43245","DOI":"10.1038\/srep43245","article-title":"AMPK deficiency in chondrocytes accelerated the progression of instability-induced and ageing-associated osteoarthritis in adult mice","volume":"7","author":"Zhou","year":"2017","journal-title":"Sci Rep"},{"key":"ref63","doi-asserted-by":"publisher","first-page":"1928","DOI":"10.1002\/art.30333","article-title":"Chondrocyte AMP-activated protein kinase activity suppresses matrix degradation responses to proinflammatory cytokines interleukin-1\u03b2 and tumor necrosis factor \u03b1","volume":"63","author":"Terkeltaub","year":"2011","journal-title":"Arthritis Rheum"},{"key":"ref64","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1186\/s13075-019-2081-x","article-title":"The burden of metabolic syndrome on osteoarthritic joints","volume":"21","author":"Dickson","year":"2019","journal-title":"Arthritis Res Ther"},{"key":"ref65","doi-asserted-by":"publisher","first-page":"13983","DOI":"10.1038\/s41598-021-93394-3","article-title":"Effects of education, income, and occupation on prevalence and symptoms of knee osteoarthritis","volume":"11","author":"Lee","year":"2021","journal-title":"Sci Rep"},{"key":"ref66","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1186\/s12889-016-2782-x","article-title":"Prevalence and associated factors of knee osteoarthritis in a rural Chinese adult population: an epidemiological survey","volume":"16","author":"Liu","year":"2016","journal-title":"BMC Public Health"},{"key":"ref67","doi-asserted-by":"publisher","first-page":"1323","DOI":"10.1186\/s12889-020-09451-5","article-title":"Associations between social determinants and the presence of chronic diseases: data from the osteoarthritis initiative","volume":"20","author":"Vennu","year":"2020","journal-title":"BMC Public Health"},{"key":"ref68","doi-asserted-by":"publisher","first-page":"1176","DOI":"10.1016\/j.joca.2011.07.009","article-title":"Socio-demographic factors, reproductive history and risk of osteoarthritis in a cohort of 4.6 million Danish women and men","volume":"19","author":"J\u00f8rgensen","year":"2011","journal-title":"Osteoarthr Cartil"},{"key":"ref69","doi-asserted-by":"publisher","first-page":"983","DOI":"10.1097\/AJP.0000000000000761","article-title":"Psychosocial factors and knee pain among older people in Japan: the JAGES Cross-sectional study","volume":"35","author":"Ikeda","year":"2019","journal-title":"Clin J Pain"},{"key":"ref70","doi-asserted-by":"publisher","first-page":"2361","DOI":"10.1007\/s10067-020-05518-1","article-title":"Lower education is an associated factor with the combination of pain catastrophizing and kinesiophobia in patients with knee osteoarthritis","volume":"40","author":"Aily","year":"2021","journal-title":"Clin Rheumatol"},{"key":"ref71","doi-asserted-by":"publisher","first-page":"4327","DOI":"10.1093\/rheumatology\/keab067","article-title":"Temporal relationship between osteoarthritis and comorbidities: a combined case control and cohort study in the UK primary care setting","volume":"60","author":"Swain","year":"2021","journal-title":"Rheumatology (Oxford)"},{"key":"ref72","doi-asserted-by":"publisher","first-page":"444","DOI":"10.4103\/psychiatry.IndianJPsychiatry_241_18","article-title":"Depressive symptoms and the risk of arthritis: a survival analysis using data from the osteoarthritis initiative","volume":"61","author":"Vennu","year":"2019","journal-title":"Indian J Psychiatry"},{"key":"ref73","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1186\/s12891-022-05137-8","article-title":"Bidirectional association between knee osteoarthritis and depressive symptoms: evidence from a nationwide population-based cohort","volume":"23","author":"Lu","year":"2022","journal-title":"BMC Musculoskelet Disord"},{"key":"ref74","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1186\/s13075-017-1229-9","article-title":"Synovitis in osteoarthritis: current understanding with therapeutic implications","volume":"19","author":"Mathiessen","year":"2017","journal-title":"Arthritis Res Ther"},{"key":"ref75","doi-asserted-by":"publisher","first-page":"394","DOI":"10.1186\/s12891-017-1755-2","article-title":"Neuroimmune expression in hip osteoarthritis: a systematic review","volume":"18","author":"Da Silva","year":"2017","journal-title":"BMC Musculoskelet Disord"},{"key":"ref76","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1016\/j.brainresbull.2021.10.009","article-title":"Inspiration for the prevention and treatment of neuropsychiatric disorders: new insight from the bone-brain-axis","volume":"177","author":"Zhao","year":"2021","journal-title":"Brain Res Bull"},{"key":"ref77","doi-asserted-by":"publisher","first-page":"1337","DOI":"10.1016\/j.joca.2022.07.004","article-title":"Alkylresorcinol, a biomarker for whole grain intake, and its association with osteoarthritis: the MOST study","volume":"30","author":"Zertuche","year":"2022","journal-title":"Osteoarthr Cartil"},{"key":"ref78","doi-asserted-by":"publisher","first-page":"459S","DOI":"10.1093\/ajcn\/70.3.459s","article-title":"Plausible mechanisms for the protectiveness of whole grains","volume":"70","author":"Slavin","year":"1999","journal-title":"Am J Clin Nutr"},{"key":"ref79","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1080\/07315724.2002.10719227","article-title":"Intake of refined carbohydrates and whole grain foods in relation to risk of type 2 diabetes mellitus and coronary heart disease","volume":"21","author":"Liu","year":"2002","journal-title":"J Am Coll Nutr"},{"key":"ref80","doi-asserted-by":"publisher","first-page":"1411","DOI":"10.1136\/annrheumdis-2016-210810","article-title":"Dietary intake of fibre and risk of knee osteoarthritis in two US prospective cohorts","volume":"76","author":"Dai","year":"2017","journal-title":"Ann Rheum Dis"},{"key":"ref81","doi-asserted-by":"publisher","first-page":"2735","DOI":"10.1016\/j.clnu.2018.11.032","article-title":"Mediterranean diet and knee osteoarthritis outcomes: a longitudinal cohort study","volume":"38","author":"Veronese","year":"2019","journal-title":"Clin Nutr"},{"key":"ref82","doi-asserted-by":"publisher","first-page":"e12995","DOI":"10.1097\/MD.0000000000012995","article-title":"Whole grain diet reduces systemic inflammation: a meta-analysis of 9 randomized trials","volume":"97","author":"Xu","year":"2018","journal-title":"Medicine (Baltimore)"},{"key":"ref83","doi-asserted-by":"publisher","first-page":"715","DOI":"10.1002\/mnfr.201600715","article-title":"Whole grain oats, more than just a fiber: role of unique phytochemicals","volume":"61","author":"Sang","year":"2017","journal-title":"Mol Nutr Food Res"},{"key":"ref84","doi-asserted-by":"publisher","first-page":"e53414","DOI":"10.7554\/eLife.53414","article-title":"Adult chondrogenesis and spontaneous cartilage repair in the skate, Leucoraja erinacea","volume":"9","author":"Marconi","year":"2020","journal-title":"Elife"},{"key":"ref85","doi-asserted-by":"publisher","first-page":"17799","DOI":"10.1074\/jbc.RA119.009556","article-title":"Chondroprotective effects of 4-methylumbelliferone and hyaluronan synthase-2 overexpression involve changes in chondrocyte energy metabolism","volume":"294","author":"Terabe","year":"2019","journal-title":"J Biol Chem"},{"key":"ref86","doi-asserted-by":"publisher","first-page":"15131","DOI":"10.1038\/s41598-021-94611-9","article-title":"Metabolic reprogramming in chondrocytes to promote mitochondrial respiration reduces downstream features of osteoarthritis","volume":"11","author":"Ohashi","year":"2021","journal-title":"Sci Rep"},{"key":"ref87","doi-asserted-by":"publisher","first-page":"1206","DOI":"10.26355\/eurrev_202102_24823","article-title":"HIF-1\u03b1 repairs degenerative chondrocyte glycolytic metabolism by the transcriptional regulation of Runx2","volume":"25","author":"Kong","year":"2021","journal-title":"Eur Rev Med Pharmacol Sci"},{"key":"ref88","doi-asserted-by":"publisher","first-page":"3780","DOI":"10.1021\/acs.jproteome.8b00455","article-title":"1H NMR metabolomics identifies underlying inflammatory pathology in osteoarthritis and rheumatoid arthritis synovial joints","volume":"17","author":"Anderson","year":"2018","journal-title":"J Proteome Res"},{"key":"ref89","doi-asserted-by":"publisher","first-page":"923","DOI":"10.12182\/20211160206","article-title":"Research progress in glucose metabolism of chondrocytes","volume":"52","author":"Wei","year":"2021","journal-title":"Sichuan Da Xue Xue Bao Yi Xue Ban"},{"key":"ref90","doi-asserted-by":"publisher","first-page":"109223","DOI":"10.1016\/j.jnutbio.2022.109223","article-title":"Excessive sucrose exacerbates high fat diet-induced hepatic inflammation and fibrosis promoting osteoarthritis in mice model","volume":"112","author":"Min","year":"2023","journal-title":"J Nutr Biochem"},{"key":"ref91","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1177\/0884533617700353","article-title":"Anti-inflammatory diet in clinical practice: a review","volume":"32","author":"Ricker","year":"2017","journal-title":"Nutr Clin Pract"},{"key":"ref92","doi-asserted-by":"publisher","first-page":"1095","DOI":"10.1111\/1756-185X.13059","article-title":"Association between height and osteoarthritis of the knee and hip: the northern Finland birth cohort 1966 study","volume":"20","author":"Welling","year":"2017","journal-title":"Int J Rheum Dis"},{"key":"ref93","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1002\/1529-0131(199901)42:1<17::AID-ANR2>3.0.CO;2-E","article-title":"Incidence and risk factors for radiographic knee osteoarthritis in middle-aged women: the Chingford study","volume":"42","author":"Hart","year":"1999","journal-title":"Arthritis Rheum"},{"key":"ref94","doi-asserted-by":"publisher","first-page":"e0279198","DOI":"10.1371\/journal.pone.0279198","article-title":"Causal associations of anthropometric measurements with osteoarthritis: a Mendelian randomization study","volume":"18","author":"Sun","year":"2023","journal-title":"PLoS One"},{"key":"ref95","doi-asserted-by":"publisher","first-page":"11707","DOI":"10.1038\/s41598-022-15585-w","article-title":"Cartilage thickness and bone shape variations as a function of sex, height, body mass, and age in young adult knees","volume":"12","author":"Schneider","year":"2022","journal-title":"Sci Rep"},{"key":"ref96","doi-asserted-by":"publisher","first-page":"955","DOI":"10.1007\/s00484-019-01785-z","article-title":"The effect of balneotherapy and peloid therapy on changes in the functional state of patients with knee joint osteoarthritis: a randomized, controlled, single-blind pilot study","volume":"64","author":"Varzaityte","year":"2020","journal-title":"Int J Biometeorol"},{"key":"ref97","doi-asserted-by":"publisher","first-page":"1807","DOI":"10.1007\/s00296-018-4081-6","article-title":"Effects of balneotherapy and spa therapy on quality of life of patients with knee osteoarthritis: a systematic review and meta-analysis","volume":"38","author":"Antonelli","year":"2018","journal-title":"Rheumatol Int"},{"key":"ref98","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1016\/j.eujim.2017.01.001","article-title":"Balneotherapy in osteoarthritis: facts, fiction and gaps in knowledge","volume":"9","author":"Fioravanti","year":"2017","journal-title":"Eur J Integr Med"},{"key":"ref99","doi-asserted-by":"publisher","first-page":"1839","DOI":"10.1007\/s10067-017-3592-y","article-title":"The effect of balneotherapy on pain relief, stiffness, and physical function in patients with osteoarthritis of the knee: a meta-analysis","volume":"36","author":"Matsumoto","year":"2017","journal-title":"Clin Rheumatol"},{"key":"ref100","doi-asserted-by":"publisher","first-page":"2063","DOI":"10.1007\/s10067-007-0618-x","article-title":"A 10-day course of SPA therapy is beneficial for people with severe knee osteoarthritis. A 24-week randomised, controlled pilot study","volume":"26","author":"Karag\u00fclle","year":"2007","journal-title":"Clin Rheumatol"},{"key":"ref101","doi-asserted-by":"publisher","first-page":"724","DOI":"10.1002\/art.1780380530","article-title":"Hypothalamic-pituitary-adrenal axis dysregulation in healthy subjects undergoing mud-bath applications","volume":"38","author":"Cozzi","year":"1995","journal-title":"Arthritis Rheum"},{"key":"ref102","doi-asserted-by":"publisher","first-page":"1777","DOI":"10.1007\/s00484-017-1361-x","article-title":"Anti-inflammatory effect as a mechanism of effectiveness underlying the clinical benefits of pelotherapy in osteoarthritis patients: regulation of the altered inflammatory and stress feedback response","volume":"61","author":"Ortega","year":"2017","journal-title":"Int J Biometeorol"},{"key":"ref103","doi-asserted-by":"publisher","first-page":"e19761","DOI":"10.1097\/MD.0000000000019761","article-title":"The short-term efficacy of mud therapy for knee osteoarthritis: a meta-analysis","volume":"99","author":"Hou","year":"2020","journal-title":"Medicine (Baltimore)"},{"key":"ref104","doi-asserted-by":"publisher","first-page":"518","DOI":"10.1016\/j.molmed.2011.11.005","article-title":"Do MicroRNAs have a key epigenetic role in osteoarthritis and in mechanotransduction","volume":"35","author":"De Palma","year":"2017","journal-title":"Clin Exp Rheumatol"},{"key":"ref105","doi-asserted-by":"publisher","first-page":"R86","DOI":"10.1186\/ar3013","article-title":"Plasma and synovial fluid microRNAs as potential biomarkers of rheumatoid arthritis and osteoarthritis","volume":"12","author":"Murata","year":"2010","journal-title":"Arthritis Res Ther"},{"key":"ref106","doi-asserted-by":"publisher","first-page":"e86820","DOI":"10.1172\/jci.insight.86820","article-title":"Identification of microRNA-181a-5p and microRNA-4454 as mediators of facet cartilage degeneration","volume":"1","author":"Nakamura","year":"2016","journal-title":"JCI Insight"},{"key":"ref107","doi-asserted-by":"publisher","first-page":"446","DOI":"10.3109\/s10165-011-0536-2","article-title":"Changes in microRNA expression in peripheral mononuclear cells according to the progression of osteoarthritis","volume":"22","author":"Okuhara","year":"2012","journal-title":"Mod Rheumatol"},{"key":"ref108","doi-asserted-by":"publisher","first-page":"2153","DOI":"10.1007\/s00484-017-1420-3","article-title":"Can balneotherapy modify microRNA expression levels in osteoarthritis? A comparative study in patients with knee osteoarthritis","volume":"61","author":"Giannitti","year":"2017","journal-title":"Int J Biometeorol"},{"key":"ref109","doi-asserted-by":"publisher","first-page":"1042576","DOI":"10.1155\/2018\/1042576","article-title":"Efficacy of spa therapy, mud-pack therapy, balneotherapy, and mud-bath therapy in the management of knee osteoarthritis. A systematic review","volume":"2018","author":"Fraioli","year":"2018","journal-title":"Biomed Res Int"},{"key":"ref110","doi-asserted-by":"publisher","first-page":"966","DOI":"10.1002\/acr.23116","article-title":"Mud-bath therapy in addition to usual care in bilateral knee osteoarthritis: An economic evaluation alongside a randomized controlled trial","volume":"69","author":"Ciani","year":"2017","journal-title":"Arthritis Care Res"},{"key":"ref111","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1002\/gepi.21998","article-title":"Bias due to participant overlap in two-sample Mendelian randomization","volume":"40","author":"Burgess","year":"2016","journal-title":"Genet Epidemiol"},{"key":"ref112","doi-asserted-by":"publisher","first-page":"2227","DOI":"10.2147\/IJGM.S314180","article-title":"The causal relationship between body mass index and the risk of osteoarthritis","volume":"14","author":"He","year":"2021","journal-title":"Int J Gen Med"},{"key":"ref113","doi-asserted-by":"publisher","first-page":"11906","DOI":"10.3390\/ijms231911906","article-title":"Mendelian randomization studies of lifestyle-related risk factors for osteoarthritis: a PRISMA review and Meta-analysis","volume":"23","author":"Ho","year":"2022","journal-title":"Int J Mol Sci"},{"key":"ref114","doi-asserted-by":"publisher","first-page":"3183","DOI":"10.1097\/j.pain.0000000000003183","article-title":"Causal associations of central and peripheral risk factors with knee osteoarthritis: a longitudinal and Mendelian randomisation study using UK biobank data","volume":"2024","author":"Thompson","year":"2024","journal-title":"Pain"}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2024.1405188\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,2]],"date-time":"2024-09-02T04:20:19Z","timestamp":1725250819000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2024.1405188\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,2]]},"references-count":114,"alternative-id":["10.3389\/fmed.2024.1405188"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2024.1405188","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,2]]},"article-number":"1405188"}}