{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T14:24:34Z","timestamp":1788531874290,"version":"build-2803163510"},"reference-count":127,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T00:00:00Z","timestamp":1788480000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Osteoarthritis (OA) and other rheumatic diseases are among the leading causes of chronic pain, disability, and reduced quality of life worldwide. Increasing evidence indicates that disturbances in metal homeostasis contribute to the pathogenesis of these disorders through their effects on oxidative stress, immune regulation, cartilage metabolism, bone remodeling, and extracellular matrix degradation. This review summarizes current knowledge regarding the role of essential metals and trace elements, including zinc, iron, copper, magnesium, selenium, and manganese, as well as toxic metals such as cadmium, lead, mercury, and arsenic, with primary emphasis on their involvement in the development and progression of osteoarthritis. Other rheumatic diseases are discussed briefly to provide a comparative perspective. Particular attention is given to the molecular mechanisms underlying metal-mediated pathology, including oxidative stress, ferroptosis, mitochondrial dysfunction, activation of intracellular signaling pathways, and inflammasome activation. The diagnostic and therapeutic potential of metal-related biomarkers, metalomics, and targeted interventions aimed at restoring metal homeostasis are also discussed. Furthermore, current limitations of available studies and emerging research directions, including single-cell technologies, spatial transcriptomics, multi-omics approaches, and personalized medicine, are highlighted. A better understanding of metal homeostasis may improve the identification of novel biomarkers and therapeutic targets, ultimately contributing to more precise diagnosis and individualized treatment strategies for osteoarthritis and other rheumatic diseases.<\/jats:p>","DOI":"10.3390\/ijms27177889","type":"journal-article","created":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T13:50:44Z","timestamp":1788529844000},"page":"7889","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Role of Metals and Trace Elements in the Pathogenesis of Osteoarthritis and Other Rheumatic Diseases"],"prefix":"10.3390","volume":"27","author":[{"given":"El\u017cbieta","family":"Krzemi\u0144ska","sequence":"first","affiliation":[{"name":"Faculty of Medicine, Collegium Medicum, Cardinal Stefan Wyszynski University, Dewajtis 5, 01-815 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9902-5969","authenticated-orcid":false,"given":"Beata","family":"Tarnacka","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation, Faculty of Medicine, Medical University of Warsaw, 02-091 Warsaw, Poland"},{"name":"National Institute of Geriatrics, Rheumatology and Rehabilitation, Sparta\u0144ska 1, 02-637 Warszawa, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1724-520X","authenticated-orcid":false,"given":"Agnieszka","family":"\u015acibior","sequence":"additional","affiliation":[{"name":"Department of Biomedicine and Environmental Research, Institute of Biological Sciences, Faculty of Medicine, The John Paul II Catholic University of Lublin, Konstantyn\u00f3w 1J, 20-708 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/s41392-023-01330-w","article-title":"Osteoarthritis: Pathogenic Signaling Pathways and Therapeutic Targets","volume":"8","author":"Yao","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Li, G., Cheng, T., and Yu, X. (2021). The Impact of Trace Elements on Osteoarthritis. Front. Med., 8.","DOI":"10.3389\/fmed.2021.771297"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Liu, L., Luo, P., Yang, M., Wang, J., Hou, W., and Xu, P. (2022). The Role of Oxidative Stress in the Development of Knee Osteoarthritis: A Comprehensive Research Review. Front. Mol. Biosci., 9.","DOI":"10.3389\/fmolb.2022.1001212"},{"key":"ref_4","first-page":"527","article-title":"Toxic Metals in Rheumatological Diseases: A Systematic Review","volume":"12","author":"Skare","year":"2025","journal-title":"North. Clin. Istanb."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.jtemb.2019.07.007","article-title":"Common Trace Metals in Rheumatoid Arthritis: A Systematic Review and Meta-Analysis","volume":"56","author":"Ma","year":"2019","journal-title":"J. Trace Elem. Med. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s12011-015-0325-4","article-title":"Serum Levels of Copper and Zinc in Patients with Rheumatoid Arthritis: A Meta-Analysis","volume":"168","author":"Xin","year":"2015","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2170","DOI":"10.1007\/s12011-022-03335-y","article-title":"Essential Trace Element Status in Systemic Lupus Erythematosus: A Meta-Analysis Based on Case-Control Studies","volume":"201","author":"Wang","year":"2023","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Bryli\u0144ski, \u0141., Bryli\u0144ska, K., Woli\u0144ski, F., Sado, J., Smyk, M., Komar, O., Karpi\u0144ski, R., Prz\u0105dka, M., and Baj, J. (2025). Trace Elements\u2014Role in Joint Function and Impact on Joint Diseases. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26157493"},{"key":"ref_9","first-page":"e23","article-title":"Oxidative Stress in Secondary Osteoarthritis: From Cartilage Destruction to Clinical Presentation","volume":"2","author":"Ziskoven","year":"2010","journal-title":"Orthop. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1007\/s12011-015-0501-6","article-title":"Serum Trace Element Concentrations in Rheumatoid Arthritis","volume":"171","author":"Sahebari","year":"2016","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Fan, W., Pi, Z., Kong, K., Qiao, H., Jin, M., Chang, Y., Zhang, J., and Li, H. (2024). Analyzing the Impact of Heavy Metal Exposure on Osteoarthritis and Rheumatoid Arthritis: An Approach Based on Interpretable Machine Learning. Front. Nutr., 11.","DOI":"10.3389\/fnut.2024.1422617"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Pamphlett, R., and Kum Jew, S. (2019). Mercury Is Taken Up Selectively by Cells Involved in Joint, Bone, and Connective Tissue Disorders. Front. Med., 6.","DOI":"10.3389\/fmed.2019.00168"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Nemeth, E., and Ganz, T. (2021). Hepcidin\u2013Ferroportin Interaction Controls Systemic Iron Homeostasis. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22126493"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"119770","DOI":"10.1016\/j.lfs.2021.119770","article-title":"Metal Ion Homeostasis with Emphasis on Zinc and Copper: Potential Crucial Link to Explain the Non-Classical Antioxidative Properties of Vitamin D and Melatonin","volume":"281","author":"Bergam","year":"2021","journal-title":"Life Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1016\/j.tem.2021.08.004","article-title":"The Impact of Metal Availability on Immune Function during Infection","volume":"32","author":"Monteith","year":"2021","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"118890","DOI":"10.1016\/j.bbamcr.2020.118890","article-title":"Iron and Manganese Transport in Mammalian Systems","volume":"1868","author":"Liu","year":"2021","journal-title":"Biochim. Biophys. Acta Mol. Cell Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3204","DOI":"10.1182\/blood-2006-06-027631","article-title":"Interleukin-6 Induces Hepcidin Expression through STAT3","volume":"108","author":"Wrighting","year":"2006","journal-title":"Blood"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Subramanian Vignesh, K., and Deepe, G.S. (2017). Metallothioneins: Emerging Modulators in Immunity and Infection. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18102197"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Dai, H., Wang, L., Li, L., Huang, Z., and Ye, L. (2021). Metallothionein 1: A New Spotlight on Inflammatory Diseases. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.739918"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1016\/S0891-5849(02)00842-0","article-title":"Ferritin, Iron Homeostasis, and Oxidative Damage","volume":"33","author":"Arosio","year":"2002","journal-title":"Free Radic. Biol. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.tvjl.2007.07.006","article-title":"Molecular, Physiological and Clinical Aspects of the Iron Storage Protein Ferritin","volume":"178","author":"Orino","year":"2008","journal-title":"Vet. J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2289","DOI":"10.3390\/nu5072289","article-title":"Multi-Copper Oxidases and Human Iron Metabolism","volume":"5","author":"Vashchenko","year":"2013","journal-title":"Nutrients"},{"key":"ref_23","first-page":"305","article-title":"IL-6\u2013STAT3\u2013Hepcidin: Linking Inflammation to Iron Metabolism","volume":"45","author":"Stoian","year":"2007","journal-title":"Rom. J. Intern. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1007\/s12011-022-03148-z","article-title":"Circulating Level of Blood Iron and Copper Associated with Inflammation and Disease Activity of Rheumatoid Arthritis","volume":"201","author":"Wang","year":"2023","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"D\u0105browski, M., Zio\u0142a-Frankowska, A., Frankowski, M., Kaczmarczyk, J., and Kubaszewski, \u0141. (2021). Comparison of Bone Tissue Trace Element Content in the Different Radiological Stages of Hip Osteoarthritis. Int. J. Environ. Res. Public Health, 18.","DOI":"10.3390\/ijerph18063260"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.2147\/CIA.S66354","article-title":"Comparison of Bone Tissue Trace-Element Concentrations and Mineral Density in Osteoporotic Femoral Neck Fractures and Osteoarthritis","volume":"9","author":"Karaaslan","year":"2014","journal-title":"Clin. Interv. Aging"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Jura-P\u00f3\u0142torak, A., Szeremeta, A., Olczyk, K., Zo\u0144-Giebel, A., and Komosi\u0144ska-Vassev, K. (2021). Bone Metabolism and RANKL\/OPG Ratio in Rheumatoid Arthritis Women Treated with TNF-\u03b1 Inhibitors. J. Clin. Med., 10.","DOI":"10.3390\/jcm10132905"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1385\/BTER:106:2:123","article-title":"Synovial Fluid and Plasma Selenium, Copper, Zinc, and Iron Concentrations in Patients with Rheumatoid Arthritis and Osteoarthritis","volume":"106","author":"Yazar","year":"2005","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_29","first-page":"584","article-title":"Relationship between Trace Elements in Synovial Fluid and Cartilage and Severity of Knee Osteoarthritis","volume":"37","author":"Li","year":"2023","journal-title":"Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1866","DOI":"10.1007\/s12011-023-03801-1","article-title":"Circulating Copper Is Associated with Inflammatory Biomarkers in Greek Older Adults with Osteoarthritis","volume":"202","author":"Amerikanou","year":"2024","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1016\/j.cell.2014.01.007","article-title":"Regulation of the Catabolic Cascade in Osteoarthritis by the Zinc\u2013ZIP8\u2013MTF1 Axis","volume":"156","author":"Kim","year":"2014","journal-title":"Cell"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Kim, J.R., Yoo, J.J., and Kim, H.A. (2018). Therapeutics in Osteoarthritis Based on an Understanding of Its Molecular Pathogenesis. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19030674"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"101539","DOI":"10.1016\/j.tjnut.2026.101539","article-title":"Serum Magnesium Concentrations in the United States\u2014An Updated Population Reference Interval in Children and Adults","volume":"156","author":"Jiao","year":"2026","journal-title":"J. Nutr."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1385\/BTER:75:1-3:253","article-title":"Concentrations of Trace Elements in Osteoarthritic Knee-Joint Effusions","volume":"75","author":"Krachler","year":"2000","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.clnesp.2025.09.031","article-title":"Serum Reference Intervals for Essential and Toxic Trace Elements in a Healthy Population: A Basis for Nutritional Monitoring and Clinical Intervention","volume":"70","author":"Rivas","year":"2025","journal-title":"Clin. Nutr. ESPEN"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"114796","DOI":"10.1016\/j.intimp.2025.114796","article-title":"OPTN Ameliorates Chondrocyte Apoptosis in Temporomandibular Joint Osteoarthritis by Modulating ER-Mitochondria Ca2+ Transfer","volume":"157","author":"Zhang","year":"2025","journal-title":"Int. Immunopharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.joca.2015.07.016","article-title":"Reciprocal Activation of Hypoxia-Inducible Factor (HIF)-2\u03b1 and the Zinc\u2013ZIP8\u2013MTF1 Axis Amplifies Catabolic Signaling in Osteoarthritis","volume":"24","author":"Lee","year":"2016","journal-title":"Osteoarthr. Cartil."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Yu, Q., Xiao, Y., Guan, M., Zhang, X., Yu, J., Han, M., and Li, Z. (2024). Copper Metabolism in Osteoarthritis and Its Relation to Oxidative Stress and Ferroptosis in Chondrocytes. Front. Mol. Biosci., 11.","DOI":"10.3389\/fmolb.2024.1472492"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"116570","DOI":"10.1016\/j.biopha.2024.116570","article-title":"Roles and Mechanisms of Copper Homeostasis and Cuproptosis in Osteoarticular Diseases","volume":"174","author":"Han","year":"2024","journal-title":"Biomed. Pharmacother."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1186\/s13018-024-05055-6","article-title":"Mechanisms of Chondrocyte Cell Death in Osteoarthritis: Implications for Disease Progression and Treatment","volume":"19","author":"Guan","year":"2024","journal-title":"J. Orthop. Surg. Res."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Lu, S., Liu, Z., Qi, M., Wang, Y., Chang, L., Bai, X., Jiao, Y., Chen, X., and Zhen, J. (2024). Ferroptosis and Its Role in Osteoarthritis: Mechanisms, Biomarkers, and Therapeutic Perspectives. Front. Cell Dev. Biol., 12.","DOI":"10.3389\/fcell.2024.1510390"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"21592","DOI":"10.1038\/s41598-023-49089-y","article-title":"Characteristics and Time Points to Inhibit Ferroptosis in Human Osteoarthritis","volume":"13","author":"Xu","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3406","DOI":"10.1038\/s41598-018-21783-2","article-title":"Magnesium Enhances the Chondrogenic Differentiation of Mesenchymal Stem Cells by Inhibiting Activated Macrophage-Induced Inflammation","volume":"8","author":"Hu","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1186\/s13018-022-03294-z","article-title":"Intra-Bone Marrow Injection of Magnesium Isoglycyrrhizinate Inhibits Inflammation and Delays Osteoarthritis Progression through the NF-\u03baB Pathway","volume":"17","author":"Chen","year":"2022","journal-title":"J. Orthop. Surg. Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1198","DOI":"10.1038\/s12276-020-0408-y","article-title":"The Role of Selenium Metabolism and Selenoproteins in Cartilage Homeostasis and Arthropathies","volume":"52","author":"Kang","year":"2020","journal-title":"Exp. Mol. Med."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Cheng, H.-L., Yen, C.-C., Huang, L.-W., Hu, Y.-C., Huang, T.-C., Hsieh, B.-S., and Chang, K.-L. (2024). Selenium Lessens Osteoarthritis by Protecting Articular Chondrocytes from Oxidative Damage through Nrf2 and NF-\u03baB Pathways. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25052511"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1007\/s12603-022-1739-2","article-title":"A Cross-Sectional Study of Association between Plasma Selenium Levels and the Prevalence of Osteoarthritis: Data from the Xiangya Osteoarthritis Study","volume":"26","author":"Wang","year":"2022","journal-title":"J. Nutr. Health Aging"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"119467","DOI":"10.1016\/j.biomaterials.2019.119467","article-title":"Manganese Dioxide Nanoparticles Protect Cartilage from Inflammation-Induced Oxidative Stress","volume":"224","author":"Kumar","year":"2019","journal-title":"Biomaterials"},{"key":"ref_49","first-page":"30","article-title":"The Impact of Mitochondrial Dysfunction on Osteoarthritis Pathogenesis","volume":"13","author":"Tan","year":"2025","journal-title":"Bone Res."},{"key":"ref_50","first-page":"133","article-title":"Heavy Metal Toxicity and the Environment","volume":"101","author":"Tchounwou","year":"2012","journal-title":"Exp. Suppl."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Qu, F., and Zheng, W. (2024). Cadmium Exposure: Mechanisms and Pathways of Toxicity and Implications for Human Health. Toxics, 12.","DOI":"10.3390\/toxics12060388"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Branca, J.J.V., Pacini, A., Gulisano, M., Taddei, N., Fiorillo, C., and Becatti, M. (2020). Cadmium-Induced Cytotoxicity: Effects on Mitochondrial Electron Transport Chain. Front. Cell Dev. Biol., 8.","DOI":"10.3389\/fcell.2020.604377"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Gu, J., Li, S., Wang, G., Zhang, X., Yuan, Y., Liu, X., Bian, J., Tong, X., and Liu, Z. (2021). Cadmium Toxicity on Chondrocytes and the Palliative Effects of 1\u03b1,25-Dihydroxy Vitamin D3 in White Leghorns Chicken Embryos. Front. Vet. Sci., 8.","DOI":"10.3389\/fvets.2021.637369"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1007\/s00441-022-03639-4","article-title":"Chondrocyte Death Involvement in Osteoarthritis","volume":"389","author":"Salucci","year":"2022","journal-title":"Cell Tissue Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1289\/ehp.919117","article-title":"Cellular and Molecular Toxicity of Lead in Bone","volume":"91","author":"Pounds","year":"1991","journal-title":"Environ. Health Perspect."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1289\/ehp.7596","article-title":"Lead Exposure Inhibits Fracture Healing and Is Associated with Increased Chondrogenesis, Delay in Cartilage Mineralization, and a Decrease in Osteoprogenitor Frequency","volume":"113","author":"Carmouche","year":"2005","journal-title":"Environ. Health Perspect."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1093\/toxsci\/kfv234","article-title":"Elevated Lifetime Lead Exposure Impedes Osteoclast Activity and Produces an Increase in Bone Mass in Adolescent Mice","volume":"149","author":"Beier","year":"2016","journal-title":"Toxicol. Sci."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1016\/j.bone.2010.07.013","article-title":"The Effect of Lead on Bone Mineral Properties from Female Adult C57\/BL6 Mice","volume":"47","author":"Monir","year":"2010","journal-title":"Bone"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"129299","DOI":"10.1016\/j.bbagen.2019.02.001","article-title":"Mercury-Induced Inflammation and Autoimmunity","volume":"1863","author":"Pollard","year":"2019","journal-title":"Biochim. Biophys. Acta Gen. Subj."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"108352","DOI":"10.1016\/j.clim.2020.108352","article-title":"Mercury-Induced Autoimmunity: Drifting from Micro to Macro Concerns on Autoimmune Disorders","volume":"213","author":"Peana","year":"2020","journal-title":"Clin. Immunol."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Lee, G.R. (2018). The Balance of Th17 versus Treg Cells in Autoimmunity. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19030730"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1002\/jat.3256","article-title":"Mitochondrial Oxidative Stress and Dysfunction in Arsenic Neurotoxicity: A Review","volume":"36","author":"Prakash","year":"2016","journal-title":"J. Appl. Toxicol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"14439","DOI":"10.1007\/s11356-025-36538-6","article-title":"Metal Mechanisms of Mitochondrial Toxicity: Recent Review of Arsenic, Cadmium, and Lead-Induced Nephrotoxicity","volume":"32","author":"Turkington","year":"2025","journal-title":"Environ. Sci. Pollut. Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"3395","DOI":"10.1007\/s12011-022-03421-1","article-title":"Arsenic Activates the NLRP3 Inflammasome and Disturbs the Th1\/Th2\/Th17\/Treg Balance in the Hippocampus in Mice","volume":"201","author":"Jing","year":"2023","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"13659","DOI":"10.1038\/s41598-018-31717-7","article-title":"Mercury and Arsenic Attenuate Canonical and Non-Canonical NLRP3 Inflammasome Activation","volume":"8","author":"Ahn","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2205","DOI":"10.1056\/NEJMra1004965","article-title":"The Pathogenesis of Rheumatoid Arthritis","volume":"365","author":"McInnes","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1038\/nri2094","article-title":"Cytokines in the Pathogenesis of Rheumatoid Arthritis","volume":"7","author":"McInnes","year":"2007","journal-title":"Nat. Rev. Immunol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"533","DOI":"10.12688\/f1000research.17296.1","article-title":"RANKL Is a Therapeutic Target of Bone Destruction in Rheumatoid Arthritis","volume":"8","author":"Tanaka","year":"2019","journal-title":"F1000Research"},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Wessels, I., Maywald, M., and Rink, L. (2017). Zinc as a Gatekeeper of Immune Function. Nutrients, 9.","DOI":"10.3390\/nu9121286"},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Turrubiates-Hern\u00e1ndez, F.J., M\u00e1rquez-Sandoval, Y.F., Gonz\u00e1lez-Estevez, G., Reyes-Castillo, Z., and Mu\u00f1oz-Valle, J.F. (2020). The Relevance of Selenium Status in Rheumatoid Arthritis. Nutrients, 12.","DOI":"10.3390\/nu12103007"},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Sim, T.M., Ong, S.J., and Mak, A. (2022). Type I Interferons in Systemic Lupus Erythematosus. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23052505"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"139","DOI":"10.4172\/2155-9899.1000139","article-title":"Neutrophil Extracellular Traps and Systemic Lupus Erythematosus","volume":"4","author":"Yu","year":"2013","journal-title":"J. Clin. Cell. Immunol."},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Chen, X., Gao, D., Wang, M., Wang, L., Hu, H., Wen, C., and Tang, Y. (2025). Neutrophil Extracellular Traps in Systemic Lupus Erythematosus: Pathogenic Mechanisms, Crosstalk with Oxidative Stress, and Antioxidant Therapeutic Potential. Antioxidants, 15.","DOI":"10.20944\/preprints202511.1028.v1"},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Lopalco, G., Cito, A., Iannone, F., Diekhoff, T., Poddubnyy, D., and Proft, F. (2025). Beyond Inflammation: The Molecular Basis of Bone Remodeling in Axial Spondyloarthritis and Psoriatic Arthritis. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1599995"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1186\/s43166-025-00363-z","article-title":"A Narrative Review of Bone Disease in Spondyloarthropathy: Molecular Mechanisms and Emerging Advances","volume":"52","author":"Yuliasih","year":"2025","journal-title":"Egypt. Rheumatol. Rehabil."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1111\/cei.12670","article-title":"The Interleukin (IL)-23\/IL-17 Axis in Ankylosing Spondylitis","volume":"183","author":"Jethwa","year":"2016","journal-title":"Clin. Exp. Immunol."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Tsukazaki, H., and Kaito, T. (2020). The Role of the IL-23\/IL-17 Pathway in the Pathogenesis of Spondyloarthritis. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21176401"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1038\/nature04516","article-title":"Gout-Associated Uric Acid Crystals Activate the NALP3 Inflammasome","volume":"440","author":"Martinon","year":"2006","journal-title":"Nature"},{"key":"ref_79","first-page":"39","article-title":"The Role of the NLRP3 Inflammasome in Gout","volume":"4","author":"Kingsbury","year":"2011","journal-title":"J. Inflamm. Res."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"140","DOI":"10.4078\/jrd.2022.29.3.140","article-title":"The Mechanism of the NLRP3 Inflammasome Activation and Pathogenic Implication in Inflammatory Diseases","volume":"29","author":"Kim","year":"2022","journal-title":"J. Rheum. Dis."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"110452","DOI":"10.1016\/j.biopha.2020.110452","article-title":"Oxidative Stress and Inflammation in Osteoarthritis Pathogenesis: Role of Polyphenols","volume":"129","author":"Ansari","year":"2020","journal-title":"Biomed. Pharmacother."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1186\/s12967-024-05799-z","article-title":"From Dysfunction to Healing: Advances in Mitochondrial Therapy for Osteoarthritis","volume":"22","author":"Zhang","year":"2024","journal-title":"J. Transl. Med."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1038\/nm.2153","article-title":"Hypoxia-Inducible Factor-2\u03b1 Is a Catabolic Regulator of Osteoarthritic Cartilage Destruction","volume":"16","author":"Yang","year":"2010","journal-title":"Nat. Med."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"6619","DOI":"10.2147\/JIR.S479186","article-title":"The Multifaceted Protective Role of Nuclear Factor Erythroid 2-Related Factor 2 in Osteoarthritis: Regulation of Oxidative Stress and Inflammation","volume":"17","author":"Sheng","year":"2024","journal-title":"J. Inflamm. Res."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Altahla, R., and Tao, X. (2024). Thioredoxin-Interacting Protein\u2019s Role in NLRP3 Activation and Osteoarthritis Pathogenesis by Pyroptosis Pathway: In Vivo Study. Metabolites, 14.","DOI":"10.3390\/metabo14090488"},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Hu, Q., and Ecker, M. (2021). Overview of MMP-13 as a Promising Target for the Treatment of Osteoarthritis. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22041742"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1007\/s00223-020-00739-7","article-title":"Targeting Dysregulation of Metalloproteinase Activity in Osteoarthritis","volume":"109","author":"Yamamoto","year":"2021","journal-title":"Calcif. Tissue Int."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1007\/s43657-025-00242-9","article-title":"Metabolomics for the Identification of Biomarkers in Rheumatoid Arthritis","volume":"5","author":"Pandey","year":"2025","journal-title":"Phenomics"},{"key":"ref_89","first-page":"295","article-title":"Clinical and Omics Biomarkers in Osteoarthritis Diagnosis and Treatment","volume":"50","author":"Deng","year":"2025","journal-title":"J. Orthop. Transl."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1038\/s41467-022-28385-7","article-title":"Selenophosphate Synthetase 1 Deficiency Exacerbates Osteoarthritis by Dysregulating Redox Homeostasis","volume":"13","author":"Kang","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1631\/jzus.B2300402","article-title":"Advances in the Study of Mitophagy in Osteoarthritis","volume":"25","author":"Cao","year":"2024","journal-title":"J. Zhejiang Univ. Sci. B"},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Bartikoski, B.J., de Oliveira, M.S., do Esp\u00edrito Santo, R.C., dos Santos, L.P., dos Santos, N.G., and Xavier, R.M. (2022). A Review of Metabolomic Profiling in Rheumatoid Arthritis: Bringing New Insights in Disease Pathogenesis, Treatment and Comorbidities. Metabolites, 12.","DOI":"10.3390\/metabo12050394"},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Xu, L., Chang, C., Jiang, P., Wei, K., Zhang, R., Jin, Y., Zhao, J., Xu, L., Shi, Y., and Guo, S. (2022). Metabolomics in Rheumatoid Arthritis: Advances and Review. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.961708"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1007\/s10753-021-01604-x","article-title":"Metabolomics of Synovial Fluid and Infrapatellar Fat Pad in Patients with Osteoarthritis or Rheumatoid Arthritis","volume":"45","author":"Nieminen","year":"2022","journal-title":"Inflammation"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"3792","DOI":"10.1002\/art.20720","article-title":"Use of Mass Spectrometry to Identify Protein Biomarkers of Disease Severity in the Synovial Fluid and Serum of Patients with Rheumatoid Arthritis","volume":"50","author":"Liao","year":"2004","journal-title":"Arthritis Rheum."},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Smolinska, V., Klimova, D., Danisovic, L., and Harsanyi, S. (2024). Synovial Fluid Markers and Extracellular Vesicles in Rheumatoid Arthritis. Medicina, 60.","DOI":"10.3390\/medicina60121945"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1186\/ar520","article-title":"Immunomic Analysis of Synovial Fluid Exosomes of Patients with Rheumatic Diseases","volume":"4","author":"Sternjak","year":"2002","journal-title":"Arthritis Res."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1038\/nrrheum.2016.1","article-title":"Metabolomics in Rheumatic Diseases: Desperately Seeking Biomarkers","volume":"12","author":"Guma","year":"2016","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Michalke, B. (2022). Review about Powerful Combinations of Advanced and Hyphenated Sample Introduction Techniques with Inductively Coupled Plasma-Mass Spectrometry (ICP-MS) for Elucidating Trace Element Species in Pathologic Conditions on a Molecular Level. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23116109"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1039\/C7MT00023E","article-title":"Metallomics: The History over the Last Decade and a Future Outlook","volume":"9","author":"Haraguchi","year":"2017","journal-title":"Metallomics"},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Becker, J.S. (2007). Inorganic Mass Spectrometry: Principles and Applications, John Wiley & Sons.","DOI":"10.1002\/9780470517222"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1016\/S0140-6736(76)91793-1","article-title":"Oral Zinc Sulphate in Rheumatoid Arthritis","volume":"2","author":"Simkin","year":"1976","journal-title":"Lancet"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"479","DOI":"10.31138\/mjr.270325.amr","article-title":"Zinc, Copper, and Manganese Supplementations in Rheumatic Disease: A Narrative Review","volume":"36","author":"Martinez","year":"2025","journal-title":"Mediterr. J. Rheumatol."},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Guo, Z., Lin, J., Sun, K., Guo, J., Yao, X., Wang, G., Hou, L., Xu, J., Guo, J., and Guo, F. (2022). Deferoxamine Alleviates Osteoarthritis by Inhibiting Chondrocyte Ferroptosis and Activating the Nrf2 Pathway. Front. Pharmacol., 13, Correction in Front. Pharmacol.\u00a02023, 14, 1199951.","DOI":"10.3389\/fphar.2022.791376"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1177\/0022034510388035","article-title":"N-Acetyl Cysteine Protects TMJ Chondrocytes from Oxidative Stress-Induced Cell Death","volume":"90","author":"Ueno","year":"2011","journal-title":"J. Dent. Res."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.freeradbiomed.2021.12.257","article-title":"Systemic Administration of a Pharmacologic Iron Chelator Reduces Cartilage Lesion Development in the Dunkin-Hartley Model of Primary Osteoarthritis","volume":"179","author":"Burton","year":"2022","journal-title":"Free Radic. Biol. Med."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"2786","DOI":"10.1002\/art.23799","article-title":"The Antioxidant Resveratrol Protects against Chondrocyte Apoptosis via Effects on Mitochondrial Polarization and ATP Production","volume":"58","author":"Dave","year":"2008","journal-title":"Arthritis Rheum."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"e12992","DOI":"10.1111\/jpi.12992","article-title":"Melatonin Alleviates Osteoarthritis by Regulating NADPH Oxidase 4-Induced Ferroptosis and Mitigating Mitochondrial Dysfunction","volume":"76","author":"Wang","year":"2024","journal-title":"J. Pineal Res."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1177\/19476035221142011","article-title":"Ferroptosis Plays a Role in Human Chondrocytes of Osteoarthritis Induced by IL-1\u03b2 In Vitro","volume":"14","author":"Xu","year":"2023","journal-title":"Cartilage"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.1002\/sim.7992","article-title":"Minimum Sample Size for Developing a Multivariable Prediction Model: Part II\u2014Binary and Time-to-Event Outcomes","volume":"38","author":"Riley","year":"2019","journal-title":"Stat. Med."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"55","DOI":"10.7326\/M14-0697","article-title":"Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis (TRIPOD): The TRIPOD Statement","volume":"162","author":"Collins","year":"2015","journal-title":"Ann. Intern. Med."},{"key":"ref_112","doi-asserted-by":"crossref","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":"ref_113","doi-asserted-by":"crossref","first-page":"e12105","DOI":"10.1002\/jeo2.12105","article-title":"Blood and Urine Biomarkers for the Diagnosis of Early Stages of Knee Osteoarthritis: A Systematic Review","volume":"11","author":"Ostojic","year":"2024","journal-title":"J. Exp. Orthop."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1039\/D2JA00402J","article-title":"A Systematic Study of High-Resolution Multielemental Quantitative Bioimaging of Animal Tissue Using LA-ICP-TOFMS","volume":"38","author":"Strekopytov","year":"2023","journal-title":"J. Anal. At. Spectrom."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"e13517","DOI":"10.1111\/cpr.13517","article-title":"Single-Cell RNA Sequencing in Osteoarthritis","volume":"56","author":"Gu","year":"2023","journal-title":"Cell Prolif."},{"key":"ref_116","doi-asserted-by":"crossref","unstructured":"Ho, J., Mak, C.C.H., Sharma, V., To, K., and Khan, W. (2022). Mendelian Randomization Studies of Lifestyle-Related Risk Factors for Osteoarthritis: A PRISMA Review and Meta-Analysis. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231911906"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1136\/annrheumdis-2017-212863","article-title":"Single-Cell RNA-Seq Analysis Reveals the Progression of Human Osteoarthritis","volume":"78","author":"Ji","year":"2019","journal-title":"Ann. Rheum. Dis."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1038\/s41413-023-00304-6","article-title":"Spatial Analysis of the Osteoarthritis Microenvironment: Techniques, Insights, and Applications","volume":"12","author":"Fan","year":"2024","journal-title":"Bone Res."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1038\/s41413-025-00429-w","article-title":"Advances in Spatial Transcriptomics and Its Application in the Musculoskeletal System","volume":"13","author":"Wang","year":"2025","journal-title":"Bone Res."},{"key":"ref_120","doi-asserted-by":"crossref","unstructured":"Gong, X., Su, L., Huang, J., Liu, J., Wang, Q., Luo, X., Yang, G., and Chi, H. (2024). An Overview of Multi-Omics Technologies in Rheumatoid Arthritis: Applications in Biomarker and Pathway Discovery. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1381272"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"2755","DOI":"10.1038\/s41467-018-05044-4","article-title":"Multi-Omics Monitoring of Drug Response in Rheumatoid Arthritis in Pursuit of Molecular Remission","volume":"9","author":"Tasaki","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/s12929-024-01110-w","article-title":"Unlocking Precision Medicine: Clinical Applications of Integrating Health Records, Genetics, and Immunology through Artificial Intelligence","volume":"32","author":"Chen","year":"2025","journal-title":"J. Biomed. Sci."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1038\/s41746-024-01073-0","article-title":"Digital Twins for Health: A Scoping Review","volume":"7","author":"Katsoulakis","year":"2024","journal-title":"npj Digit. Med."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"276","DOI":"10.20517\/evcna.2024.14","article-title":"Synovial Fluid Extracellular Vesicles as Arthritis Biomarkers: The Added Value of Lipid Profiling and Integrated Omics","volume":"5","author":"Varela","year":"2024","journal-title":"Extracell. Vesicles Circ. Nucleic Acids"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"144127","DOI":"10.1016\/j.ijbiomac.2025.144127","article-title":"MICU1 Is the Nexus for CaV3.3 Regulation of Mitochondrial Calcium, Redox Balance and Chondrocyte Viability","volume":"312","author":"Huang","year":"2025","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"127520","DOI":"10.1016\/j.jtemb.2024.127520","article-title":"Serum Trace Elements and Osteoarthritis: A Meta-Analysis and Mendelian Randomization Study","volume":"86","author":"Shi","year":"2024","journal-title":"J. Trace Elem. Med. Biol."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.coi.2020.10.014","article-title":"Type I Interferon in the Pathogenesis of Systemic Lupus Erythematosus","volume":"67","author":"Postal","year":"2020","journal-title":"Curr. Opin. Immunol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/17\/7889\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T13:52:29Z","timestamp":1788529949000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/17\/7889"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,4]]},"references-count":127,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["ijms27177889"],"URL":"https:\/\/doi.org\/10.3390\/ijms27177889","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,4]]}}}