{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T22:00:24Z","timestamp":1788127224274,"version":"build-2803163510"},"reference-count":41,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2022,1,16]],"date-time":"2022-01-16T00:00:00Z","timestamp":1642291200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007393","name":"French Muscular Dystrophy Association","doi-asserted-by":"publisher","award":["#20006"],"award-info":[{"award-number":["#20006"]}],"id":[{"id":"10.13039\/100007393","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Lipocalin 2 (Lcn2) is an adipokine involved in bone and energy metabolism. Its serum levels correlate with bone mechanical unloading and inflammation, two conditions representing hallmarks of Duchenne Muscular Dystrophy (DMD). Therefore, we investigated the role of Lcn2 in bone loss induced by muscle failure in the MDX mouse model of DMD. We found increased Lcn2 serum levels in MDX mice at 1, 3, 6, and 12 months of age. Consistently, Lcn2 mRNA was higher in MDX versus WT muscles. Immunohistochemistry showed Lcn2 expression in mononuclear cells between muscle fibres and in muscle fibres, thus confirming the gene expression results. We then ablated Lcn2 in MDX mice, breeding them with Lcn2\u2212\/\u2212 mice (MDXxLcn2\u2212\/\u2212), resulting in a higher percentage of trabecular volume\/total tissue volume compared to MDX mice, likely due to reduced bone resorption. Moreover, MDXxLcn2\u2212\/\u2212 mice presented with higher grip strength, increased intact muscle fibres, and reduced serum creatine kinase levels compared to MDX. Consistently, blocking Lcn2 by treating 2-month-old MDX mice with an anti-Lcn2 monoclonal antibody (Lcn2Ab) increased trabecular volume, while reducing osteoclast surface\/bone surface compared to MDX mice treated with irrelevant IgG. Grip force was also increased, and diaphragm fibrosis was reduced by the Lcn2Ab. These results suggest that Lcn2 could be a possible therapeutic target to treat DMD-induced bone loss.<\/jats:p>","DOI":"10.3390\/ijms23020958","type":"journal-article","created":{"date-parts":[[2022,1,16]],"date-time":"2022-01-16T20:44:00Z","timestamp":1642365840000},"page":"958","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Lipocalin 2 Influences Bone and Muscle Phenotype in the MDX Mouse Model of Duchenne Muscular Dystrophy"],"prefix":"10.3390","volume":"23","author":[{"given":"Marco","family":"Ponzetti","sequence":"first","affiliation":[{"name":"Department of Biotechnological and Applied Clinical Sciences, University of L\u2019Aquila, 67100 L\u2019Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5191-5337","authenticated-orcid":false,"given":"Argia","family":"Ucci","sequence":"additional","affiliation":[{"name":"Department of Biotechnological and Applied Clinical Sciences, University of L\u2019Aquila, 67100 L\u2019Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Maurizi","sequence":"additional","affiliation":[{"name":"Department of Biotechnological and Applied Clinical Sciences, University of L\u2019Aquila, 67100 L\u2019Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Giacchi","sequence":"additional","affiliation":[{"name":"Department of Biotechnological and Applied Clinical Sciences, University of L\u2019Aquila, 67100 L\u2019Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Teti","sequence":"additional","affiliation":[{"name":"Department of Biotechnological and Applied Clinical Sciences, University of L\u2019Aquila, 67100 L\u2019Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia","family":"Rucci","sequence":"additional","affiliation":[{"name":"Department of Biotechnological and Applied Clinical Sciences, University of L\u2019Aquila, 67100 L\u2019Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1016\/S0167-4838(00)00164-3","article-title":"Immunocalins: A lipocalin subfamily that modulates immune and inflammatory responses","volume":"1482","author":"Wester","year":"2000","journal-title":"Biochim. Biophys. Acta Protein Struct. Mol. Enzymol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2534","DOI":"10.1097\/01.ASN.0000088027.54400.C6","article-title":"Identification of neutrophil gelatinase-associated lipocalin as a novel early urinary biomarker for ischemic renal injury","volume":"14","author":"Mishra","year":"2003","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2210","DOI":"10.1002\/jcp.24391","article-title":"Altered bone development and turnover in transgenic mice over-expressing Lipocalin-2 in bone","volume":"228","author":"Costa","year":"2013","journal-title":"J. Cell. Physiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1002\/jbmr.2341","article-title":"Lipocalin 2: A new mechanoresponding gene regulating bone homeostasis","volume":"30","author":"Rucci","year":"2015","journal-title":"J. Bone Miner. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1038\/nature21697","article-title":"MC4R-dependent suppression of appetite by bone-derived lipocalin 2","volume":"543","author":"Mosialou","year":"2017","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1002\/jbmr.3406","article-title":"A Complex Role for Lipocalin 2 in Bone Metabolism: Global Ablation in Mice Induces Osteopenia Caused by an Altered Energy Metabolism","volume":"33","author":"Capulli","year":"2018","journal-title":"J. Bone Miner. Res."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Gambara, G., Salanova, M., Ciciliot, S., Furlan, S., Gutsmann, M., Schiffl, G., Ungethuem, U., Volpe, P., Gunga, H.C., and Blottner, D. (2017). Microgravity-induced transcriptome adaptation in mouse paraspinal longissimus dorsi muscle highlights insulin resistance-linked genes. Front. Physiol., 8.","DOI":"10.3389\/fphys.2017.00279"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"C714","DOI":"10.1152\/ajpcell.00195.2017","article-title":"Loss of the adipokine lipocalin-2 impairs satellite cell activation and skeletal muscle regeneration","volume":"315","author":"Rebalka","year":"2018","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Ponzetti, M., Aielli, F., Ucci, A., Cappariello, A., Lombardi, G., Teti, A., and Rucci, N. (2021). Lipocalin 2 increases after high-intensity exercise in humans and influences muscle gene expression and differentiation in mice. J. Cell. Physiol., jcp.30501.","DOI":"10.1002\/jcp.30501"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e005971","DOI":"10.1161\/JAHA.117.005971","article-title":"Experimental and Human Evidence for Lipocalin-2 (Neutrophil Gelatinase-Associated Lipocalin [NGAL]) in the Development of Cardiac Hypertrophy and heart failure","volume":"6","author":"Marques","year":"2017","journal-title":"J. Am. Heart Assoc."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2125","DOI":"10.1002\/jcp.25672","article-title":"Lipocalin-2 (NGAL) Attenuates Autophagy to Exacerbate Cardiac Apoptosis Induced by Myocardial Ischemia","volume":"232","author":"Sung","year":"2017","journal-title":"J. Cell. Physiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4808","DOI":"10.1074\/jbc.M111.275719","article-title":"Lipocalin-2 induces cardiomyocyte apoptosis by increasing intracellular iron accumulation","volume":"287","author":"Xu","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1253\/circj.CJ-09-0485","article-title":"Lipocalin-2\/neutrophil gelatinase-B associated lipocalin is strongly induced in hearts of rats with autoimmune myocarditis and in human myocarditis","volume":"74","author":"Ding","year":"2010","journal-title":"Circ. J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1007\/BF00275183","article-title":"Duchenne muscular dystrophy: Pathogenetic aspects and genetic prevention","volume":"66","author":"Moser","year":"1984","journal-title":"Hum. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3710","DOI":"10.1073\/pnas.90.8.3710","article-title":"Dystrophin protects the sarcolemma from stresses developed during muscle contraction","volume":"90","author":"Petrof","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"De Paepe, B., and De Bleecker, J.L. (2013). Cytokines and chemokines as regulators of skeletal muscle inflammation: Presenting the case of Duchenne muscular dystrophy. Mediat. Inflamm., 2013.","DOI":"10.1155\/2013\/540370"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/S1474-4422(18)30024-3","article-title":"Diagnosis and management of Duchenne muscular dystrophy, part 1: Diagnosis, and neuromuscular, rehabilitation, endocrine, and gastrointestinal and nutritional management","volume":"17","author":"Birnkrant","year":"2018","journal-title":"Lancet Neurol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1007\/s00198-003-1443-y","article-title":"Bone mineral density and bone metabolism in Duchenne muscular dystrophy","volume":"14","author":"Bianchi","year":"2003","journal-title":"Osteoporos. Int."},{"key":"ref_19","first-page":"147","article-title":"Disuse osteoporosis","volume":"48","author":"Takata","year":"2001","journal-title":"J. Med. Investig."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1016\/j.jbspin.2011.04.007","article-title":"Pathophysiology of bone loss in disuse osteoporosis","volume":"78","author":"Alexandre","year":"2011","journal-title":"Jt. Bone Spine."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Ginaldi, L., Di Benedetto, M.C., and De Martinis, M. (2005). Osteoporosis, inflammation and ageing. Immun. Ageing, 2.","DOI":"10.1186\/1742-4933-2-14"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Buckner, J.L., Bowden, S.A., and Mahan, J.D. (2015). Optimizing bone health in Duchenne muscular dystrophy. Int. J. Endocrinol., 2015:928385.","DOI":"10.1155\/2015\/928385"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1891","DOI":"10.1002\/jbmr.410","article-title":"Mechanisms inducing low bone density in Duchenne muscular dystrophy in mice and humans","volume":"26","author":"Rufo","year":"2011","journal-title":"J. Bone Miner. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/S1474-4422(18)30025-5","article-title":"Diagnosis and management of Duchenne muscular dystrophy, part 2: Respiratory, cardiac, bone health, and orthopaedic management","volume":"17","author":"Birnkrant","year":"2018","journal-title":"Lancet Neurol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"De Almeida Hermes, T., M\u00e2ncio, R.D., Macedo, A.B., Mizobuti, D.S., Da Rocha, G.L., Alves Cagnon, V.H., and Minatel, E. (2019). Tempol treatment shows phenotype improvement in mdx mice. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0215590"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3909","DOI":"10.1093\/hmg\/ddn293","article-title":"Cell-penetrating peptide-conjugated antisense oligonucleotides restore systemic muscle and cardiac dystrophin expression and function","volume":"17","author":"Yin","year":"2008","journal-title":"Hum. Mol. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1002\/jcb.22120","article-title":"Global transcriptome analysis in mouse calvarial osteoblasts highlights sets of genes regulated by modeled microgravity and identifies A \u201cmechanoresponsive osteoblast gene signature\u201d","volume":"107","author":"Capulli","year":"2009","journal-title":"J. Cell. Biochem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"565","DOI":"10.3109\/1354750X.2015.1123354","article-title":"The potential of lipocalin-2\/NGAL as biomarker for inflammatory and metabolic diseases","volume":"20","author":"Abella","year":"2015","journal-title":"Biomarkers"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1146\/annurev-nutr-071816-064559","article-title":"Lipocalin 2: An Emerging Player in Iron Homeostasis and Inflammation","volume":"37","author":"Xiao","year":"2017","journal-title":"Annu. Rev. Nutr."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1016\/j.tem.2017.01.003","article-title":"Lipocalin-2: A Master Mediator of Intestinal and Metabolic Inflammation","volume":"28","author":"Moschen","year":"2017","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Rosenberg, A.S., Puig, M., Nagaraju, K., Hoffman, E.P., Villalta, S.A., Rao, V.A., Wakefield, L.M., and Woodcock, J. (2015). Immune-mediated pathology in Duchenne muscular dystrophy. Sci. Transl. Med., 7.","DOI":"10.1126\/scitranslmed.aaa7322"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1172","DOI":"10.1016\/j.joca.2017.01.017","article-title":"Corticoids synergize with IL-1 in the induction of LCN2","volume":"25","author":"Conde","year":"2017","journal-title":"Osteoarthr. Cartil."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1834","DOI":"10.1073\/pnas.0510847103","article-title":"Lipocalin 2-deficient mice exhibit increased sensitivity to Escherichia coli infection but not to ischemia-reperfusion injury","volume":"103","author":"Berger","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1111\/sji.12245","article-title":"Lipocalin-2 promotes M1 macrophages polarization in a mouse cardiac ischaemia-reperfusion injury model","volume":"81","author":"Cheng","year":"2015","journal-title":"Scand. J. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/j.ebiom.2015.02.014","article-title":"Functional and Morphological Improvement of Dystrophic Muscle by Interleukin 6 Receptor Blockade","volume":"2","author":"Pelosi","year":"2015","journal-title":"EBioMedicine"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Gutpel, K.M., Hrinivich, W.T., and Hoffman, L.M. (2015). Skeletal muscle fibrosis in the mdx\/utrn+\/-mouse validates its suitability as a murine model of duchenne muscular dystrophy. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0117306"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1002\/jbmr.1805","article-title":"Standardized nomenclature, symbols, and units for bone histomorphometry: A 2012 update of the report of the ASBMR Histomorphometry Nomenclature Committee","volume":"28","author":"Dempster","year":"2013","journal-title":"J. Bone Miner. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1364\/JOSAA.1.000612","article-title":"Practical cone-beam algorithm","volume":"1","author":"Feldkamp","year":"1984","journal-title":"J. Opt. Soc. Am. A"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1145\/37402.37422","article-title":"Marching Cubes: A High Resolution 3D Surface Construction Algorithm","volume":"21","author":"Lorensen","year":"1987","journal-title":"Comput. Graph."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"085201","DOI":"10.1088\/1751-8113\/44\/8\/085201","article-title":"A \u201cmissing\u201d family of classical orthogonal polynomials","volume":"44","author":"Vinet","year":"2011","journal-title":"J. Phys. A Math. Theor."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1468","DOI":"10.1002\/jbmr.141","article-title":"Guidelines for assessment of bone microstructure in rodents using micro-computed tomography","volume":"25","author":"Bouxsein","year":"2010","journal-title":"J. Bone Miner. Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/2\/958\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T14:15:10Z","timestamp":1760364910000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/2\/958"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,16]]},"references-count":41,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2022,1]]}},"alternative-id":["ijms23020958"],"URL":"https:\/\/doi.org\/10.3390\/ijms23020958","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,16]]}}}