{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T10:18:50Z","timestamp":1792664330145,"version":"4.5.0"},"reference-count":127,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2023,3,22]],"date-time":"2023-03-22T00:00:00Z","timestamp":1679443200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Natural Science Foundation of China","award":["82130030"],"award-info":[{"award-number":["82130030"]}]},{"name":"National Natural Science Foundation of China","award":["81920108011"],"award-info":[{"award-number":["81920108011"]}]},{"name":"National Natural Science Foundation of China","award":["82171115"],"award-info":[{"award-number":["82171115"]}]},{"name":"National Natural Science Foundation of China","award":["81770982"],"award-info":[{"award-number":["81770982"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>The airway epithelium is exposed to numerous external irritants including infectious agents, environmental allergens, and atmospheric pollutants, releasing epithelial cytokines including thymic stromal lymphopoietin (TSLP), IL-33, and IL-25 and initiating downstream type 2 (IL-4, IL-13, and IL-5) and IgE-driven pathways. These pathways trigger the initiation and progression of allergic airway diseases, including chronic rhinosinusitis with nasal polyps (CRSwNP), allergic rhinitis (AR), and allergic asthma. However, the use of biological agents that target downstream cytokines, such as IL-5, IL-4, and IL-13 receptors and IgE, might not be sufficient to manage some patients successfully. Instead of blocking downstream cytokines, targeting upstream epithelial cytokines has been proposed to address the complex immunologic networks associated with allergic airway diseases. Osteopontin (OPN), an extracellular matrix glyco-phosphoprotein, is a key mediator involved in Th1-related diseases, including systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, and rheumatoid arthritis. Emerging evidence, including ours, indicates that epithelial-cell-derived OPN also plays an essential role in Th2-skewed airway diseases, including CRSwNP, AR, and allergic asthma involving the Th17 response. Therefore, we reviewed the current knowledge of epithelial-cell-derived OPN in the pathogenesis of three type-2-biased airway diseases and provided a direction for its future investigation and clinical relevance.<\/jats:p>","DOI":"10.3390\/jcm12062433","type":"journal-article","created":{"date-parts":[[2023,3,22]],"date-time":"2023-03-22T07:09:31Z","timestamp":1679468971000},"page":"2433","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["The Role and Clinical Relevance of Osteopontin in Allergic Airway Diseases"],"prefix":"10.3390","volume":"12","author":[{"given":"Yang","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China"},{"name":"Institute of Allergy and Clinical Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China"},{"name":"Hubei Clinical Research Center for Nasal Inflammatory Diseases, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2835-2107","authenticated-orcid":false,"given":"Li","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China"},{"name":"Institute of Allergy and Clinical Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China"},{"name":"Hubei Clinical Research Center for Nasal Inflammatory Diseases, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4168-6702","authenticated-orcid":false,"given":"Zheng","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China"},{"name":"Institute of Allergy and Clinical Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China"},{"name":"Hubei Clinical Research Center for Nasal Inflammatory Diseases, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S103","DOI":"10.1016\/j.jaci.2009.12.989","article-title":"Rhinitis and sinusitis","volume":"125","author":"Dykewicz","year":"2010","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1016\/S0140-6736(08)61452-X","article-title":"Endotyping asthma: New insights into key pathogenic mechanisms in a complex, heterogeneous disease","volume":"372","author":"Anderson","year":"2008","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1016\/S0140-6736(06)69288-X","article-title":"The mechanisms, diagnosis, and management of severe asthma in adults","volume":"368","author":"Holgate","year":"2006","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1454","DOI":"10.1016\/j.jaci.2015.10.011","article-title":"Drivers of chronic rhinosinusitis: Inflammation versus infection","volume":"136","author":"Hamilos","year":"2015","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1002\/alr.22083","article-title":"Distinct gene expression profiles and regulation networks of nasal polyps in eosinophilic and non-eosinophilic chronic rhinosinusitis","volume":"8","author":"Okada","year":"2018","journal-title":"Int. Forum. Allergy Rhinol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1038\/s41577-018-0006-6","article-title":"Targeting cytokines to treat asthma and chronic obstructive pulmonary disease","volume":"18","author":"Barnes","year":"2018","journal-title":"Nat. Rev. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"299","DOI":"10.4168\/aair.2017.9.4.299","article-title":"Emerging Endotypes of Chronic Rhinosinusitis and Its Application to Precision Medicine","volume":"9","author":"Kim","year":"2017","journal-title":"Allergy Asthma. Immunol. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.chest.2019.04.101","article-title":"Group 2 Innate Lymphoid Cells in Airway Diseases","volume":"156","author":"Kato","year":"2019","journal-title":"Chest"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1097\/ACI.0000000000000129","article-title":"The paradigm of cytokine networks in allergic airway inflammation","volume":"15","author":"Pawankar","year":"2015","journal-title":"Curr. Opin. Allergy Clin. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.cytogfr.2017.11.004","article-title":"Orchestration of epithelial-derived cytokines and innate immune cells in allergic airway inflammation","volume":"39","author":"Castillo","year":"2018","journal-title":"Cytokine. Growth. Factor. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1038\/ni805","article-title":"Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP","volume":"3","author":"Soumelis","year":"2002","journal-title":"Nat. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1080\/19420862.2017.1392425","article-title":"Personalized medicine with biologics for severe type 2 asthma: Current status and future prospects","volume":"10","author":"Godar","year":"2018","journal-title":"MAbs"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1016\/j.jaci.2004.11.053","article-title":"The anti-inflammatory effects of omalizumab confirm the central role of IgE in allergic inflammation","volume":"115","author":"Holgate","year":"2005","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.1016\/S2213-2600(21)00226-5","article-title":"Effect of tezepelumab on airway inflammatory cells, remodelling, and hyperresponsiveness in patients with moderate-to-severe uncontrolled asthma (CASCADE): A double-blind, randomised, placebo-controlled, phase 2 trial","volume":"9","author":"Diver","year":"2021","journal-title":"Lancet. Respir. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1016\/S0140-6736(12)60988-X","article-title":"Mepolizumab for severe eosinophilic asthma (DREAM): A multicentre, double-blind, placebo-controlled trial","volume":"380","author":"Pavord","year":"2012","journal-title":"Lancet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1198","DOI":"10.1056\/NEJMoa1403290","article-title":"Mepolizumab treatment in patients with severe eosinophilic asthma","volume":"371","author":"Ortega","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2447","DOI":"10.1016\/j.jaip.2019.03.023","article-title":"Dupilumab improves patient-reported outcomes in patients with chronic rhinosinusitis with nasal polyps and comorbid asthma","volume":"7","author":"Bachert","year":"2019","journal-title":"J. Allergy Clin. Immunol. Pract."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2102","DOI":"10.1056\/NEJMoa1402895","article-title":"Effects of an anti-TSLP antibody on allergen-induced asthmatic responses","volume":"370","author":"Gauvreau","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1656","DOI":"10.1056\/NEJMoa2024257","article-title":"Efficacy and Safety of Itepekimab in Patients with Moderate-to-Severe Asthma","volume":"385","author":"Wechsler","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_20","unstructured":"Corren, J., Garcia Gil, E., Parnes, J., Pham, T.-H., and Griffiths, J. (2019). B15. Immunotherapy for Lung Disease, American Thoracic Society."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.jneuroim.2011.12.004","article-title":"Increased levels of IL-23 and osteopontin in serum and cerebrospinal fluid of multiple sclerosis patients","volume":"244","author":"Wen","year":"2012","journal-title":"J. Neuroimmunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3355","DOI":"10.4049\/jimmunol.1403191","article-title":"Osteopontin Promotes Oncostatin M Production in Human Osteoblasts: Implication of Rheumatoid Arthritis Therapy","volume":"195","author":"Su","year":"2015","journal-title":"J. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"38","DOI":"10.9738\/INTSURG-D-13-00160.1","article-title":"Plasma osteopontin predicts inflammatory bowel disease activities","volume":"100","author":"Masuda","year":"2015","journal-title":"Int. Surg."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/j.jneuroim.2004.09.004","article-title":"Plasma osteopontin levels in multiple sclerosis","volume":"158","author":"Comabella","year":"2005","journal-title":"J. Neuroimmunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1111\/1756-185X.14308","article-title":"Association of Osteopontin gene single nucleotide polymorphism with lupus nephritis","volume":"25","author":"Metwally","year":"2022","journal-title":"Int. J. Rheum. Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1460","DOI":"10.1016\/j.intimp.2007.06.009","article-title":"Successful treatment of collagen-induced arthritis in non-human primates by chimeric anti-osteopontin antibody","volume":"7","author":"Yamamoto","year":"2007","journal-title":"Int. Immunopharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1172\/JCI17778","article-title":"Essential role of the cryptic epitope SLAYGLR within osteopontin in a murine model of rheumatoid arthritis","volume":"112","author":"Yamamoto","year":"2003","journal-title":"J. Clin. Investig."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"777928","DOI":"10.3389\/fimmu.2022.777928","article-title":"Eosinophil-Derived Osteopontin Induces the Expression of Pro-Inflammatory Mediators and Stimulates Extracellular Matrix Production in Nasal Fibroblasts: The Role of Osteopontin in Eosinophilic Chronic Rhinosinusitis","volume":"13","author":"Yang","year":"2022","journal-title":"Front. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1632","DOI":"10.1111\/j.1365-2222.2010.03549.x","article-title":"The expression of osteopontin and its association with Clara cell 10 kDa protein in allergic rhinitis","volume":"40","author":"Liu","year":"2010","journal-title":"Clin. Exp. Allergy"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"100659","DOI":"10.1016\/j.waojou.2022.100659","article-title":"Osteopontin mediated eosinophils activation by group II innate lymphoid cells","volume":"15","author":"Zeng","year":"2022","journal-title":"World Allergy Organ. J."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1111\/cea.12320","article-title":"Expression and regulation of osteopontin in chronic rhinosinusitis with nasal polyps","volume":"45","author":"Liu","year":"2015","journal-title":"Clin. Exp. Allergy"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1111\/j.1398-9995.2008.01829.x","article-title":"Expression of osteopontin in chronic rhinosinusitis with and without nasal polyps","volume":"64","author":"Lu","year":"2009","journal-title":"Allergy"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1111\/j.1440-1827.2011.02649.x","article-title":"Osteopontin, intrinsic tissue regulator of intractable inflammatory diseases","volume":"61","author":"Uede","year":"2011","journal-title":"Pathol. Int."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.clinbiochem.2018.07.003","article-title":"The multiple functions and mechanisms of osteopontin","volume":"59","author":"Icer","year":"2018","journal-title":"Clin. Biochem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/s00011-018-1200-5","article-title":"The role of osteopontin in kidney diseases","volume":"68","author":"Kaleta","year":"2019","journal-title":"Inflamm. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.canlet.2012.12.003","article-title":"Human osteopontin splicing isoforms: Known roles, potential clinical applications and activated signaling pathways","volume":"331","author":"Gimba","year":"2013","journal-title":"Cancer Lett."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Lamort, A.S., Giopanou, I., Psallidas, I., and Stathopoulos, G.T. (2019). Osteopontin as a Link between Inflammation and Cancer: The Thorax in the Spotlight. Cells, 8.","DOI":"10.3390\/cells8080815"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1638","DOI":"10.1177\/0022034515605270","article-title":"Osteopontin in Immune-mediated Diseases","volume":"94","author":"Rittling","year":"2015","journal-title":"J. Dent. Res."},{"key":"ref_39","first-page":"ZE10","article-title":"OPN-Revisited","volume":"9","author":"Subraman","year":"2015","journal-title":"J. Clin. Diagn. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"494","DOI":"10.2174\/138945010790980321","article-title":"Osteopontin; as a target molecule for the treatment of inflammatory diseases","volume":"11","author":"Morimoto","year":"2010","journal-title":"Curr. Drug. Targets."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1007\/s12026-010-8179-5","article-title":"Intracellular osteopontin (iOPN) and immunity","volume":"49","author":"Inoue","year":"2011","journal-title":"Immunol. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"4049098","DOI":"10.1155\/2017\/4049098","article-title":"Osteopontin at the Crossroads of Inflammation and Tumor Progression","volume":"2017","author":"Castello","year":"2017","journal-title":"Mediators. Inflamm."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"17101","DOI":"10.1073\/pnas.0508666102","article-title":"T-bet-dependent expression of osteopontin contributes to T cell polarization","volume":"102","author":"Shinohara","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1159\/000369685","article-title":"The OPN gene polymorphism confers the susceptibility and response to Ara-C based chemotherapy in Chinese AML patients","volume":"35","author":"Zhang","year":"2015","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1158\/0008-5472.CAN-14-0615","article-title":"Intracellular Osteopontin inhibits toll-like receptor signaling and impedes liver carcinogenesis","volume":"75","author":"Fan","year":"2015","journal-title":"Cancer Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"36328","DOI":"10.1074\/jbc.274.51.36328","article-title":"The integrin alpha(9)beta(1) binds to a novel recognition sequence (SVVYGLR) in the thrombin-cleaved amino-terminal fragment of osteopontin","volume":"274","author":"Yokosaki","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"13483","DOI":"10.1074\/jbc.M011392200","article-title":"Identification of dual alpha 4beta1 integrin binding sites within a 38 amino acid domain in the N-terminal thrombin fragment of human osteopontin","volume":"276","author":"Bayless","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"7929","DOI":"10.1074\/jbc.M109.075010","article-title":"Osteopontin is cleaved at multiple sites close to its integrin-binding motifs in milk and is a novel substrate for plasmin and cathepsin D","volume":"285","author":"Christensen","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1016\/j.immuni.2004.08.012","article-title":"Osteopontin as a mediator of NKT cell function in T cell-mediated liver diseases","volume":"21","author":"Diao","year":"2004","journal-title":"Immunity"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"e1083","DOI":"10.1212\/NXI.0000000000001083","article-title":"CSF Levels of CXCL12 and Osteopontin as Early Markers of Primary Progressive Multiple Sclerosis","volume":"8","author":"Marastoni","year":"2021","journal-title":"Neurol. Neuroimmunol. Neuroinflamm."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1731","DOI":"10.1126\/science.1062960","article-title":"The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease","volume":"294","author":"Chabas","year":"2001","journal-title":"Science"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"7480","DOI":"10.4049\/jimmunol.181.11.7480","article-title":"Increased osteopontin expression in dendritic cells amplifies IL-17 production by CD4+ T cells in experimental autoimmune encephalomyelitis and in multiple sclerosis","volume":"181","author":"Murugaiyan","year":"2008","journal-title":"J. Immunol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.cytogfr.2019.05.004","article-title":"Role of osteopontin in dendritic cell shaping of immune responses","volume":"50","author":"Scutera","year":"2019","journal-title":"Cytokine. Growth. Factor. Rev."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2734","DOI":"10.1128\/MCB.20.8.2734-2742.2000","article-title":"Coupling of osteopontin and its cell surface receptor CD44 to the cell survival response elicited by interleukin-3 or granulocyte-macrophage colony-stimulating factor","volume":"20","author":"Lin","year":"2000","journal-title":"Mol. Cell. Biol."},{"key":"ref_55","first-page":"293","article-title":"Stimulation of endothelial cell migration by vascular permeability factor\/vascular endothelial growth factor through cooperative mechanisms involving the alphavbeta3 integrin, osteopontin, and thrombin","volume":"149","author":"Senger","year":"1996","journal-title":"Am. J. Pathol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1172\/JCI12980","article-title":"Osteopontin as a means to cope with environmental insults: Regulation of inflammation, tissue remodeling, and cell survival","volume":"107","author":"Denhardt","year":"2001","journal-title":"J. Clin. Investig."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1002\/(SICI)1097-4652(200007)184:1<118::AID-JCP13>3.0.CO;2-Y","article-title":"Intracellular osteopontin is an integral component of the CD44-ERM complex involved in cell migration","volume":"184","author":"Zohar","year":"2000","journal-title":"J. Cell. Physiol."},{"key":"ref_58","first-page":"899","article-title":"The role of osteopontin as a candidate biomarker of renal involvement in systemic lupus erythematosus","volume":"37","author":"Spinelli","year":"2019","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.bbrc.2012.02.024","article-title":"Post-translational modification of osteopontin: Effects on in vitro hydroxyapatite formation and growth","volume":"419","author":"Boskey","year":"2012","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1042\/BJ20050341","article-title":"Post-translationally modified residues of native human osteopontin are located in clusters: Identification of 36 phosphorylation and five O-glycosylation sites and their biological implications","volume":"390","author":"Christensen","year":"2005","journal-title":"Biochem. J."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1007\/s10585-006-9007-0","article-title":"Enhanced cell surface CD44 variant (v6, v9) expression by osteopontin in breast cancer epithelial cells facilitates tumor cell migration: Novel post-transcriptional, post-translational regulation","volume":"22","author":"Khan","year":"2005","journal-title":"Clin. Exp. Metastasis"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"2040","DOI":"10.1002\/pro.5560041009","article-title":"Posttranslational modifications of bovine osteopontin: Identification of twenty-eight phosphorylation and three O-glycosylation sites","volume":"4","author":"Petersen","year":"1995","journal-title":"Protein. Sci."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1729","DOI":"10.1074\/jbc.274.3.1729","article-title":"Cross-linking of osteopontin by tissue transglutaminase increases its collagen binding properties","volume":"274","author":"Kaartinen","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1093\/oxfordjournals.jbchem.a124395","article-title":"Osteopontin: Its transglutaminase-catalyzed posttranslational modifications and cross-linking to fibronectin","volume":"115","author":"Beninati","year":"1994","journal-title":"J. Biochem."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"7675437","DOI":"10.1155\/2016\/7675437","article-title":"Osteopontin Bridging Innate and Adaptive Immunity in Autoimmune Diseases","volume":"2016","author":"Clemente","year":"2016","journal-title":"J. Immunol. Res"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1038\/ni.3814","article-title":"Myelopoiesis embraces its inner weakness","volume":"18","author":"Gerlic","year":"2017","journal-title":"Nat. Immunol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/cmi.2017.94","article-title":"Osteopontin and the immune system: Another brick in the wall","volume":"15","author":"Caputo","year":"2018","journal-title":"Cell. Mol. Immunol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"11170","DOI":"10.1074\/jbc.M110.189258","article-title":"Osteopontin undergoes polymerization in vivo and gains chemotactic activity for neutrophils mediated by integrin alpha9beta1","volume":"286","author":"Nishimichi","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1038\/ni.3791","article-title":"Skewing of the population balance of lymphoid and myeloid cells by secreted and intracellular osteopontin","volume":"18","author":"Kanayama","year":"2017","journal-title":"Nat. Immunol."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Stampanoni Bassi, M., Buttari, F., Gilio, L., Iezzi, E., Galifi, G., Carbone, F., Micillo, T., Dolcetti, E., Azzolini, F., and Bruno, A. (2023). Osteopontin Is Associated with Multiple Sclerosis Relapses. Biomedicines, 11.","DOI":"10.3390\/biomedicines11010178"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1093\/rheumatology\/keh558","article-title":"Elevation of plasma osteopontin concentration is correlated with disease activity in patients with systemic lupus erythematosus","volume":"44","author":"Wong","year":"2005","journal-title":"Rheumatology"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1177\/1352458513503052","article-title":"Evaluation of circulating osteopontin levels in an unselected cohort of patients with multiple sclerosis: Relevance for biomarker development","volume":"20","author":"Healy","year":"2014","journal-title":"Mult. Scler."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1007\/s10787-022-00932-0","article-title":"Osteopontin in autoimmune disorders: Current knowledge and future perspective","volume":"30","author":"Xu","year":"2022","journal-title":"Inflammopharmacology"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1007\/s00296-014-3122-z","article-title":"Role of osteopontin in rheumatoid arthritis","volume":"35","author":"Zhang","year":"2015","journal-title":"Rheumatol. Int."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1038\/ni1327","article-title":"Osteopontin expression is essential for interferon-alpha production by plasmacytoid dendritic cells","volume":"7","author":"Shinohara","year":"2006","journal-title":"Nat. Immunol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.immuni.2008.05.008","article-title":"Engagement of the type I interferon receptor on dendritic cells inhibits T helper 17 cell development: Role of intracellular osteopontin","volume":"29","author":"Shinohara","year":"2008","journal-title":"Immunity"},{"key":"ref_77","first-page":"1523","article-title":"Introduction of an osteopontin gene confers the increase in B1 cell population and the production of anti-DNA autoantibodies","volume":"78","author":"Iizuka","year":"1998","journal-title":"Lab. Investig."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1006\/clim.2001.5039","article-title":"Cytokine and chemokine dysregulation in hyper-IgE syndrome","volume":"100","author":"Chehimi","year":"2001","journal-title":"Clin. Immunol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"246","DOI":"10.2353\/ajpath.2010.090488","article-title":"Antigen-specific induction of osteopontin contributes to the chronification of allergic contact dermatitis","volume":"176","author":"Seier","year":"2010","journal-title":"Am. J. Pathol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1084\/jem.194.9.1219","article-title":"Osteopontin is involved in the initiation of cutaneous contact hypersensitivity by inducing Langerhans and dendritic cell migration to lymph nodes","volume":"194","author":"Weiss","year":"2001","journal-title":"J. Exp. Med."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1038\/nm1580","article-title":"Osteopontin has a crucial role in allergic airway disease through regulation of dendritic cell subsets","volume":"13","author":"Xanthou","year":"2007","journal-title":"Nat. Med."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1586\/eci.10.82","article-title":"Osteopontin and allergic disease: Pathophysiology and implications for diagnostics and therapy","volume":"7","author":"Frenzel","year":"2011","journal-title":"Expert. Rev. Clin. Immunol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1416","DOI":"10.1016\/j.jaci.2012.06.010","article-title":"Elevated serum osteopontin level is associated with blood eosinophilia and asthma comorbidity in patients with allergic rhinitis","volume":"130","author":"Liu","year":"2012","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1360","DOI":"10.1111\/j.1365-2222.2011.03775.x","article-title":"Role of osteopontin, a multifunctional protein, in allergy and asthma","volume":"41","author":"Konno","year":"2011","journal-title":"Clin. Exp. Allergy"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"35","DOI":"10.2500\/ajra.2017.31.4449","article-title":"Osteopontin induced vascular endothelial growth factor production in dispersed nasal polyp cells through the phosphatidylinositol 3-kinase-protein kinase B and the extracellular signal-regulated kinase 1\/2 pathways","volume":"31","author":"Du","year":"2017","journal-title":"Am. J. Rhinol. Allergy"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"9138904","DOI":"10.1155\/2018\/9138904","article-title":"Role of Leptin\/Osteopontin Axis in the Function of Eosinophils in Allergic Rhinitis with Obesity","volume":"2018","author":"Liu","year":"2018","journal-title":"Mediators. Inflamm."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.ebiom.2018.05.037","article-title":"Leptin\/Osteopontin Axis Regulated Type 2T Helper Cell Response in Allergic Rhinitis with Obesity","volume":"32","author":"Zeng","year":"2018","journal-title":"EBioMedicine"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1111\/pai.12926","article-title":"Leptin\/osteopontin axis contributes to enhanced T helper 17 type responses in allergic rhinitis","volume":"29","author":"Liu","year":"2018","journal-title":"Pediatr. Allergy Immunol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1186\/1710-1492-6-28","article-title":"Quantitative expression of osteopontin in nasal mucosa of patients with allergic rhinitis: Effects of pollen exposure and nasal glucocorticoid treatment","volume":"6","author":"Samitas","year":"2010","journal-title":"Allergy Asthma. Clin. Immunol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.ijporl.2015.12.001","article-title":"Decreased level of osteopontin in children with allergic rhinitis during sublingual immunotherapy","volume":"81","author":"Wang","year":"2016","journal-title":"Int. J. Pediatr. Otorhinolaryngol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1016\/j.jaci.2005.01.055","article-title":"Increased expression of osteopontin is associated with long-term bee venom immunotherapy","volume":"115","author":"Konno","year":"2005","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1016\/j.jaci.2015.08.046","article-title":"Short-term subcutaneous grass pollen immunotherapy under the umbrella of anti-IL-4: A randomized controlled trial","volume":"137","author":"Chaker","year":"2016","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Navas, A., Ruiz-Leon, B., Serrano, P., Mart\u00ed, M., Espinazo, M.L., Blanco, N., Molina, J., Alonso, C., Jurado, A., and Moreno-Aguilar, C. (2022). Natural and Induced Tolerance to Hymenoptera Venom: A Single Mechanism?. Toxins, 14.","DOI":"10.3390\/toxins14070426"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1017\/S002221511700175X","article-title":"MicroRNA let-7a up-regulates OPN expression in a mouse model of allergic rhinitis","volume":"131","author":"Yu","year":"2017","journal-title":"J. Laryngol. Otol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.jaci.2006.10.025","article-title":"Severe asthma: Lessons from the Severe Asthma Research Program","volume":"119","author":"Wenzel","year":"2007","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1002\/humu.9025","article-title":"An osteopontin (SPP1) polymorphism is associated with systemic lupus erythematosus","volume":"19","author":"Forton","year":"2002","journal-title":"Hum. Mutat."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/S0165-5728(03)00004-3","article-title":"Genetic polymorphisms of osteopontin in association with multiple sclerosis in Japanese patients","volume":"136","author":"Niino","year":"2003","journal-title":"J. Neuroimmunol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1016\/j.bbrc.2003.12.045","article-title":"Genetic polymorphims in promoter region of osteopontin gene may be a marker reflecting hepatitis activity in chronic hepatitis C patients","volume":"313","author":"Mochida","year":"2004","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1111\/j.1365-2222.2006.02414.x","article-title":"Sequence variants of the secreted phosphoprotein 1 gene are associated with total serum immunoglobulin E levels in a Japanese population","volume":"36","author":"Tanino","year":"2006","journal-title":"Clin. Exp. Allergy"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1183\/09031936.00017810","article-title":"Osteopontin expression and relation to disease severity in human asthma","volume":"37","author":"Samitas","year":"2011","journal-title":"Eur. Respir. J."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1016\/j.cyto.2012.12.028","article-title":"Osteopontin is increased in the bronchoalveolar lavage fluid and bronchial tissue of smoking asthmatics","volume":"61","author":"Samitas","year":"2013","journal-title":"Cytokine"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"3513","DOI":"10.1177\/0300060519860684","article-title":"Association between osteopontin expression and asthma: A meta-analysis","volume":"47","author":"Xu","year":"2019","journal-title":"J. Int. Med. Res."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1402","DOI":"10.1177\/147323001103900426","article-title":"Osteopontin levels are elevated in patients with asthma","volume":"39","author":"Zhao","year":"2011","journal-title":"J. Int. Med. Res."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/j.aller.2013.01.009","article-title":"Elevated level of serum osteopontin in school-age children with asthma","volume":"42","author":"Akelma","year":"2014","journal-title":"Allergol. Immunopathol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.immuni.2018.04.023","article-title":"Amphiregulin-Producing Pathogenic Memory T Helper 2 Cells Instruct Eosinophils to Secrete Osteopontin and Facilitate Airway Fibrosis","volume":"49","author":"Morimoto","year":"2018","journal-title":"Immunity"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1136\/thx.2010.138552","article-title":"Increased levels of osteopontin in sputum supernatant in severe refractory asthma","volume":"65","author":"Delimpoura","year":"2010","journal-title":"Thorax"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.cyto.2012.10.002","article-title":"Increased levels of osteopontin in sputum supernatant of smoking asthmatics","volume":"61","author":"Hillas","year":"2013","journal-title":"Cytokine"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1067\/mai.2000.107195","article-title":"Tissue remodeling as a feature of persistent asthma","volume":"105","author":"Vignola","year":"2000","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1067\/mai.2003.128","article-title":"Airway remodeling in asthma: New insights","volume":"111","author":"Davies","year":"2003","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1164\/rccm.201403-0562LE","article-title":"Osteopontin and periostin are associated with a 20-year decline of pulmonary function in patients with asthma","volume":"190","author":"Kanemitsu","year":"2014","journal-title":"Am. J. Respir. Crit. Care. Med."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1444","DOI":"10.1111\/j.1365-2222.2007.02801.x","article-title":"Enhanced osteopontin expression in a murine model of allergen-induced airway remodelling","volume":"37","author":"Kohan","year":"2007","journal-title":"Clin. Exp. Allergy"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1164\/rccm.200807-1081OC","article-title":"Osteopontin deficiency protects against airway remodeling and hyperresponsiveness in chronic asthma","volume":"179","author":"Simoes","year":"2009","journal-title":"Am. J. Respir. Crit. Care. Med."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1583","DOI":"10.1172\/JCI37662","article-title":"Osteopontin promotes fibrosis in dystrophic mouse muscle by modulating immune cell subsets and intramuscular TGF-beta","volume":"119","author":"Vetrone","year":"2009","journal-title":"J. Clin. Investig."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1165\/rcmb.2008-0307OC","article-title":"Osteopontin induces airway remodeling and lung fibroblast activation in a murine model of asthma","volume":"41","author":"Kohan","year":"2009","journal-title":"Am. J. Respir. Cell. Mol. Biol."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"S28","DOI":"10.1164\/ajrccm.164.supplement_2.2106061","article-title":"Remodeling in asthma and chronic obstructive lung disease","volume":"164","author":"Jeffery","year":"2001","journal-title":"Am. J. Respir. Crit. Care. Med."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1016\/j.coi.2007.07.021","article-title":"The role of eosinophils in airway tissue remodelling in asthma","volume":"19","author":"Kariyawasam","year":"2007","journal-title":"Curr. Opin. Immunol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1111\/j.1398-9995.2009.02148.x","article-title":"Osteopontin is expressed and functional in human eosinophils","volume":"65","author":"Puxeddu","year":"2010","journal-title":"Allergy"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"1152","DOI":"10.1111\/j.1365-2222.2009.03249.x","article-title":"Osteopontin is involved in migration of eosinophils in asthma","volume":"39","author":"Takahashi","year":"2009","journal-title":"Clin. Exp. Allergy"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1002\/eji.200737057","article-title":"Osteopontin is produced by mast cells and affects IgE-mediated degranulation and migration of mast cells","volume":"38","author":"Nagasaka","year":"2008","journal-title":"Eur. J. Immunol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1002\/eji.200738131","article-title":"Osteopontin as a new player in mast cell biology","volume":"38","author":"Paus","year":"2008","journal-title":"Eur. J. Immunol."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"1036423","DOI":"10.3389\/fphar.2022.1036423","article-title":"Osteopontin: An important protein in the formation of kidney stones","volume":"13","author":"Jia","year":"2022","journal-title":"Front. Pharmacol."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1084\/jem.20040035","article-title":"Essential role of lung plasmacytoid dendritic cells in preventing asthmatic reactions to harmless inhaled antigen","volume":"200","author":"Hammad","year":"2004","journal-title":"J. Exp. Med."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"1270","DOI":"10.4049\/jimmunol.1701345","article-title":"Osteopontin Promotes Protective Antigenic Tolerance against Experimental Allergic Airway Disease","volume":"200","author":"Alissafi","year":"2018","journal-title":"J. Immunol."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1159\/000210647","article-title":"Effects of corticosteroids on osteopontin expression in a murine model of allergic asthma","volume":"149","author":"Kurokawa","year":"2009","journal-title":"Int. Arch. Allergy Immunol."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"313","DOI":"10.3122\/jabfm.2011.03.100180","article-title":"Smoking and asthma","volume":"24","author":"Stapleton","year":"2011","journal-title":"J. Am. Board. Fam. Med."},{"key":"ref_126","doi-asserted-by":"crossref","unstructured":"Kumar, S., Lanckacker, E., Dentener, M., Bracke, K., Provoost, S., De Grove, K., Brusselle, G., Wouters, E., Maes, T., and Joos, G. (2016). Aggravation of Allergic Airway Inflammation by Cigarette Smoke in Mice Is CD44-Dependent. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0151113"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1038\/s12276-020-0376-2","article-title":"Osteopontin contributes to late-onset asthma phenotypes in adult asthma patients","volume":"52","author":"Trinh","year":"2020","journal-title":"Exp. Mol. Med."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/12\/6\/2433\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:00:37Z","timestamp":1760122837000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/12\/6\/2433"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,22]]},"references-count":127,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2023,3]]}},"alternative-id":["jcm12062433"],"URL":"https:\/\/doi.org\/10.3390\/jcm12062433","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,22]]}}}