{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T14:43:11Z","timestamp":1778769791512,"version":"3.51.4"},"reference-count":51,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T00:00:00Z","timestamp":1766448000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004281","name":"National Science Centre, Poland","doi-asserted-by":"publisher","award":["2023\/07\/X\/NZ9\/00439"],"award-info":[{"award-number":["2023\/07\/X\/NZ9\/00439"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>This study aimed to investigate the effects of dietary manganese deficiency and compare the impact of manganese macroparticles (MnCO3) and nanoparticles (Mn2O3NPs) on bone remodeling and metabolism. Twenty-seven male Wistar rats were divided into three groups (n = 9): control (standard MnCO3, 65 mg Mn\/kg), manganese-deficient, and Mn2O3NPs-supplemented (65 mg Mn\/kg). After a 12-week feeding period, bone-related markers and gene expression were analyzed in the femur and blood. Mn-deficient rats showed reduced plasma levels of bone-specific alkaline phosphatase (BALP), tartrate-resistant acid phosphatase 5b (TRAP5b), interferon-\u03b2 (IFN-\u03b2), RANKL glycoprotein, 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3), vitamin K2, and collagen turnover markers (PINP, CTX-1, NTX). Femur levels of BALP, TRAP5b, interferon-\u03b3 (IFN-\u03b3), osteonectin, calcitonin, PICP, PINP, and CTX-1 were also decreased. Replacing MnCO3 with Mn2O3NPs increased IFN-\u03b3 but lowered IFN-\u03b2 and 1,25-(OH)2D3 levels in plasma. This treatment also decreased the femur level of BALP and calcitonin, and the RANKL:OPG ratio, while increasing the expression level of Sp7 and Ctsk genes. To conclude, our results suggest that manganese deficiency is associated with suppressed bone turnover and altered mineral metabolism. Furthermore, replacing MnCO3 with Mn2O3 nanoparticles did not yield the anticipated benefits for bone remodeling, as evidenced by the observed imbalances in osteogenic and resorptive markers, indicating a need for cautious evaluation of nanoparticle-based supplementation.<\/jats:p>","DOI":"10.3390\/ijms27010153","type":"journal-article","created":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T10:57:18Z","timestamp":1766487438000},"page":"153","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Manganese Deficiency and Mn2O3 Nanoparticles Supplementation Disrupt Bone Remodeling and Mineral Matrix Maturation in Rats"],"prefix":"10.3390","volume":"27","author":[{"given":"Ewelina","family":"Cholewi\u0144ska","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Toxicology, Faculty of Animal Sciences and Bioeconomy, University of Life Sciences in Lublin, Akademicka 13, 20-950 Lublin, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0068-5970","authenticated-orcid":false,"given":"Jerzy","family":"Ju\u015bkiewicz","sequence":"additional","affiliation":[{"name":"InLife Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Tryli\u0144skiego 18, 10-683 Olsztyn, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9727-7481","authenticated-orcid":false,"given":"Bartosz","family":"Fotschki","sequence":"additional","affiliation":[{"name":"InLife Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Tryli\u0144skiego 18, 10-683 Olsztyn, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katarzyna","family":"Ognik","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Toxicology, Faculty of Animal Sciences and Bioeconomy, University of Life Sciences in Lublin, Akademicka 13, 20-950 Lublin, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Taskozhina, G., Batyrova, G., Umarova, G., Issanguzhina, Z., and Kereyeva, N. (2024). The manganese\u2013bone connection: Investigating the role of manganese in bone health. J. Clin. Med., 13.","DOI":"10.3390\/jcm13164679"},{"key":"ref_2","first-page":"1934578X211016649","article-title":"Essentiality of manganese for bone health: An overview and update","volume":"16","author":"Rondanelli","year":"2021","journal-title":"Nat. Prod. Commun."},{"key":"ref_3","first-page":"3839","article-title":"Mn-containing bioceramics inhibit osteoclastogenesis and promote osteoporotic bone regeneration via scavenging ROS","volume":"6","author":"Li","year":"2021","journal-title":"Bioact. Mater."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"520","DOI":"10.3945\/an.117.015305","article-title":"Manganese","volume":"8","author":"Aschner","year":"2017","journal-title":"Adv. Nutr."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1093\/jn\/116.1.135","article-title":"Effects of long-term dietary manganese and copper deficiency on rat skeleton","volume":"116","author":"Strause","year":"1986","journal-title":"J. Nutr."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"7580707","DOI":"10.1155\/2018\/7580707","article-title":"The essential element manganese, oxidative stress, and metabolic diseases: Links and interactions","volume":"2018","author":"Li","year":"2018","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.rvsc.2021.08.018","article-title":"Manganese deficiency induces avian tibial dyschondroplasia by inhibiting chondrocyte proliferation and differentiation","volume":"140","author":"Wang","year":"2021","journal-title":"Res. Vet. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"126554","DOI":"10.1016\/j.jtemb.2020.126554","article-title":"The impact of manganese on neurotransmitter systems","volume":"61","author":"Soares","year":"2020","journal-title":"J. Trace Elem. Med. Biol."},{"key":"ref_9","first-page":"253","article-title":"Manganese: Its Role in Disease and Health","volume":"19","author":"Erikson","year":"2019","journal-title":"Met. Ions Life Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/j.mam.2005.07.003","article-title":"Nutritional aspects of manganese homeostasis","volume":"26","author":"Aschner","year":"2005","journal-title":"Mol. Aspects Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"16405","DOI":"10.1039\/D1NR04964J","article-title":"Manganese-based advanced nanoparticles for biomedical applications: Future opportunity and challenges","volume":"13","author":"Haque","year":"2021","journal-title":"Nanoscale"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2305890","DOI":"10.1002\/advs.202305890","article-title":"Manganese enhances the osteogenic effect of silicon-hydroxyapatite nanowires by targeting T lymphocyte polarization","volume":"11","author":"Li","year":"2024","journal-title":"Adv. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1806","DOI":"10.1002\/jbm.a.36945","article-title":"Osteogenic properties of manganese-doped mesoporous bioactive glass nanoparticles","volume":"108","author":"Westhauser","year":"2020","journal-title":"J. Biomed. Mater. Res. A"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1093\/jn\/78.1.51","article-title":"Studies on the role of manganese in bone formation. I. Effect upon the mucopolysaccharide content of chick bone","volume":"78","author":"Leach","year":"1962","journal-title":"J. Nutr."},{"key":"ref_15","first-page":"69","article-title":"The adverse effects of manganese deficiency on reproduction and health: A literature review","volume":"11","author":"Tuormaa","year":"1996","journal-title":"J. Orthomol. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1373\/clinchem.2016.259085","article-title":"Bone turnover markers in the diagnosis and monitoring of metabolic bone disease","volume":"63","author":"Greenblatt","year":"2017","journal-title":"Clin. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/0092-8674(81)90037-4","article-title":"Osteonectin, a bone-specific protein linking mineral to collagen","volume":"26","author":"Termine","year":"1981","journal-title":"Cell"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Cholewi\u0144ska, E., So\u0142ek, P., Ju\u015bkiewicz, J., Fotschki, B., Dworza\u0144ski, W., and Ognik, K. (2024). Chromium nanoparticles improve bone turnover regulation in rats fed a high-fat, low-fibre diet. PLoS ONE, 19.","DOI":"10.1371\/journal.pone.0300292"},{"key":"ref_19","first-page":"1553","article-title":"The regulation of osteoclastogenesis by IFN","volume":"63","author":"Kim","year":"2005","journal-title":"Nihon Rinsho"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Cholewi\u0144ska, E., Dworza\u0144ski, W., Ju\u015bkiewicz, J., Listos, P., and Ognik, K. (2025). Consequences of dietary manganese deficiency or Mn2O3 nanoparticles supplementation on rat manganese biodistribution and femur morphology. Nutrients, 17.","DOI":"10.3390\/nu17193184"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.1038\/cdd.2015.168","article-title":"Fate decision of mesenchymal stem cells: Adipocytes or osteoblasts?","volume":"23","author":"Chen","year":"2016","journal-title":"Cell Death Differ."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.mce.2011.05.038","article-title":"Vitamin D and intestinal calcium absorption","volume":"347","author":"Christakos","year":"2011","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Fleet, J.C. (2022). Vitamin D-mediated regulation of intestinal calcium absorption. Nutrients, 14.","DOI":"10.3390\/nu14163351"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"15650","DOI":"10.1073\/pnas.1315006110","article-title":"CYP2R1 is a major, but not exclusive, contributor to 25-hydroxyvitamin D production in vivo","volume":"110","author":"Zhu","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1194\/jlr.R031534","article-title":"Cytochrome P450-mediated metabolism of vitamin D","volume":"55","author":"Jones","year":"2014","journal-title":"J. Lipid Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"19883","DOI":"10.1038\/s41598-021-99158-3","article-title":"Effect and mechanism of vitamin D activation disorder on liver fibrosis in biliary atresia","volume":"11","author":"Sun","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1002\/jat.2887","article-title":"Toxicity assessment of manganese oxide micro and nanoparticles in Wistar rats after 28 days of repeated oral exposure","volume":"33","author":"Singh","year":"2013","journal-title":"J. Appl. Toxicol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"115487","DOI":"10.1016\/j.fct.2025.115487","article-title":"Mn2O3 NPs-induced liver injury is potentially associated with gut microbiota dysbiosis in broiler chicken","volume":"202","author":"Li","year":"2025","journal-title":"Food Chem. Toxicol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1","DOI":"10.15586\/jrenhep.2020.66","article-title":"Manganese-induced nephrotoxicity is mediated through oxidative stress and mitochondrial impairment","volume":"4","author":"Niknahad","year":"2020","journal-title":"J. Ren. Hep. Disord."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/j.yrtph.2018.08.005","article-title":"Protection of manganese oxide nanoparticles\u2013induced liver and kidney damage by vitamin D","volume":"98","author":"Hafez","year":"2018","journal-title":"Regul. Toxicol. Pharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Cholewi\u0144ska, E., Ognik, K., Fotschki, B., Zdu\u0144czyk, Z., and Ju\u015bkiewicz, J. (2018). Comparison of the effect of dietary copper nanoparticles and one copper(II) salt on the copper biodistribution and gastrointestinal and hepatic morphology and function in a rat model. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0197083"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"175","DOI":"10.2478\/aoas-2024-0057","article-title":"Are the biodistribution and metabolic effects of copper nanoparticles dependent on differences in the physiological functions of dietary fibre?","volume":"25","author":"Marzec","year":"2025","journal-title":"Ann. Anim. Sci."},{"key":"ref_33","first-page":"2883","article-title":"Comparative toxicity and biodistribution of copper nanoparticles and cupric ions in rats","volume":"11","author":"Lee","year":"2016","journal-title":"Int. J. Nanomed."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1186\/s12989-016-0169-x","article-title":"Comparative toxicity and biodistribution assessments in rats following subchronic oral exposure to copper nanoparticles and microparticles","volume":"13","author":"Lee","year":"2016","journal-title":"Part. Fibre Toxicol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1038\/35046102","article-title":"T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-\u03b3","volume":"408","author":"Takayanagi","year":"2000","journal-title":"Nature"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1111\/j.1349-7006.2003.tb01455.x","article-title":"New aspects of IFN-\u03b1\/\u03b2 signalling in immunity, oncogenesis and bone metabolism","volume":"94","author":"Takaoka","year":"2003","journal-title":"Cancer Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.afos.2025.04.003","article-title":"Molecular crosstalk in SP7-mediated osteogenesis: Regulatory mechanisms and therapeutic potential","volume":"11","author":"Lang","year":"2025","journal-title":"Osteoporos. Sarcopenia"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3966","DOI":"10.1016\/j.febslet.2009.10.036","article-title":"Correlation of mRNA and protein in complex biological samples","volume":"583","author":"Maier","year":"2009","journal-title":"FEBS Lett."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"68","DOI":"10.3892\/ijmm.2024.5392","article-title":"Role of ubiquitination in the occurrence and development of osteoporosis (Review)","volume":"54","author":"Fan","year":"2024","journal-title":"Int. J. Mol. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1186\/ar3325","article-title":"MicroRNA biogenesis and regulation of bone remodeling","volume":"13","author":"Kapinas","year":"2011","journal-title":"Arthritis Res. Ther."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Sanit\u00e0, G., Carrese, B., and Lamberti, A. (2020). Nanoparticle Surface Functionalization: How to Improve Biocompatibility and Cellular Internalization. Front. Mol. Biosci., 7.","DOI":"10.3389\/fmolb.2020.587012"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"825","DOI":"10.3109\/17435390.2014.980450","article-title":"Effect of surface coating on the biocompatibility and in vivo MRI detection of iron oxide nanoparticles after intrapulmonary administration","volume":"9","author":"Shaik","year":"2015","journal-title":"Nanotoxicology"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2134","DOI":"10.1080\/13880209.2022.2136208","article-title":"Ameliorative effect of chitosan nanoparticles against carbon tetrachloride-induced nephrotoxicity in Wistar rats","volume":"60","author":"Nomier","year":"2022","journal-title":"Pharm. Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"19","DOI":"10.2147\/NSA.S494533","article-title":"Consequences of dietary manganese-based nanoparticles supplementation or deficiency on systemic health and gut metabolic dynamics in rats","volume":"18","author":"Fotschki","year":"2025","journal-title":"Nanotechnol. Sci. Appl."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"R\u00f3\u017caniecka-Zwoli\u0144ska, K., Cholewi\u0144ska, E., Fotschki, B., Ju\u015bkiewicz, J., and Ognik, K. (2025). Manganese deficiency or dietary manganese(III) oxide nanoparticle supplementation: Consequences for hematology, and intestinal and brain immunity in rats. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1528770"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1017\/S1751731118002653","article-title":"The effect of manganese nanoparticles on performance, redox reactions and epigenetic changes in turkey tissues","volume":"13","author":"Ognik","year":"2019","journal-title":"Animal"},{"key":"ref_47","unstructured":"(2010). Directive 2010\/63\/EU of the European Parliament and of the Council of 22 September 2010 on the protection of animals used for scientific purposes. Off. J. Eur. Union., L276, 33\u201379."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Percie du Sert, N., Hurst, V., Ahluwalia, A., Alam, S., Avey, M.T., Baker, M., Browne, W.J., Clark, A., Cuthill, I.C., and Dirnagl, U. (2020). The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research. PLoS Biol., 18.","DOI":"10.1371\/journal.pbio.3000410"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"838S","DOI":"10.1093\/jn\/127.5.838S","article-title":"Components of the AIN-93 diets as improvements in the AIN-76A diet","volume":"127","author":"Reeves","year":"1997","journal-title":"J. Nutr."},{"key":"ref_50","unstructured":"National Research Council (1995). Science and the Endangered Species Act, National Academies Press."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"311","DOI":"10.2144\/btn-2019-0153","article-title":"A method for isolating RNA from canine bone","volume":"68","author":"Nance","year":"2020","journal-title":"Biotechniques"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/1\/153\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,24]],"date-time":"2025-12-24T09:59:06Z","timestamp":1766570346000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/1\/153"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,23]]},"references-count":51,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["ijms27010153"],"URL":"https:\/\/doi.org\/10.3390\/ijms27010153","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,23]]}}}