{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T19:51:36Z","timestamp":1774554696660,"version":"3.50.1"},"reference-count":34,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2024,10,10]],"date-time":"2024-10-10T00:00:00Z","timestamp":1728518400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["22K16755"],"award-info":[{"award-number":["22K16755"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["C:20K09514"],"award-info":[{"award-number":["C:20K09514"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["C:KK230021"],"award-info":[{"award-number":["C:KK230021"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009666","name":"Salt Science Research Foundation","doi-asserted-by":"publisher","award":["22C1"],"award-info":[{"award-number":["22C1"]}],"id":[{"id":"10.13039\/100009666","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Chronic kidney disease (CKD) is a significant global health issue and often involves CKD-mineral and bone disorder (MBD) and sarcopenia. Plasminogen activator inhibitor-1 (PAI-1) is an inhibitor of fibrinolysis. PAI-1 has been implicated in the pathogenesis of osteoporosis and muscle wasting induced by inflammatory conditions. However, the roles of PAI-1 in CKD-MBD and sarcopenia remain unknown. Therefore, the present study investigated the roles of PAI-1 in bone loss and muscle wasting induced by adenine in PAI-1-deficient mice. CKD was induced in PAI-1<jats:sup>+\/+<\/jats:sup> and PAI-1<jats:sup>-\/-<\/jats:sup> mice by administration of adenine for ten weeks. Muscle wasting was assessed by grip strength test, quantitative computed tomography (CT) analysis and muscle weight measurement. Osteoporosis was assessed by micro-CT analysis of femoral microstructural parameters. PAI-1 deficiency did not affect adenine-induced decreases in body weight and food intake or renal dysfunction in male or female mice. PAI-1 deficiency also did not affect adenine-induced decreases in grip strength, muscle mass in the lower limbs, or the tissue weights of the gastrocnemius, soleus, and tibialis anterior muscles in male or female mice. PAI-1 deficiency aggravated trabecular bone loss in CKD-induced male mice, but significantly increased trabecular bone in CKD-induced female mice. On the other hand, PAI-1 deficiency did not affect cortical bone loss in CKD-induced mice. In conclusion, PAI-1 is not critical for the pathophysiology of CKD-MBD or CKD-induced sarcopenia in mice. However, PAI-1 may be partly related to bone metabolism in trabecular bone in the CKD state with sex differences.<\/jats:p>","DOI":"10.1371\/journal.pone.0311902","type":"journal-article","created":{"date-parts":[[2024,10,10]],"date-time":"2024-10-10T17:32:33Z","timestamp":1728581553000},"page":"e0311902","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["Effects of plasminogen activator inhibitor-1 deficiency on bone disorders and sarcopenia caused by adenine-induced renal dysfunction in mice"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3684-6396","authenticated-orcid":true,"given":"Yuya","family":"Mizukami","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naoyuki","family":"Kawao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takashi","family":"Ohira","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kiyotaka","family":"Okada","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hisatoshi","family":"Yamao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Osamu","family":"Matsuo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7433-5135","authenticated-orcid":true,"given":"Hiroshi","family":"Kaji","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2024,10,10]]},"reference":[{"issue":"7","key":"pone.0311902.ref001","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1038\/s41581-024-00820-6","article-title":"American Society of Nephrology; European Renal Association; International Society of Nephrology. Chronic kidney disease and the global public health agenda: an international consensus","volume":"20","author":"A Francis","year":"2024","journal-title":"Nat Rev Nephrol"},{"issue":"10225","key":"pone.0311902.ref002","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1016\/S0140-6736(20)30045-3","article-title":"Global, regional, and national burden of chronic kidney disease, 1990\u20132017: a systematic analysis for the Global Burden of Disease Study 2017","volume":"395","author":"GBD Chronic Kidney Disease Collaboration","year":"2020","journal-title":"Lancet"},{"issue":"3","key":"pone.0311902.ref003","first-page":"418","article-title":"Chronic Kidney Disease with Mineral Bone Disorder and Vascular Calcification: An Overview","volume":"14","author":"C Izzo","year":"2024","journal-title":"Life (Basel)"},{"issue":"4","key":"pone.0311902.ref004","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1007\/s40620-020-00840-y","article-title":"Sarcopenia in chronic kidney disease: what have we learned so far?","volume":"34","author":"A Sabatino","year":"2021","journal-title":"J Nephrol"},{"issue":"1","key":"pone.0311902.ref005","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1002\/jcsm.12892","article-title":"Renal failure suppresses muscle irisin expression, and irisin blunts cortical bone loss in mice","volume":"13","author":"N Kawao","year":"2022","journal-title":"J Cachexia Sarcopenia Muscle"},{"issue":"4","key":"pone.0311902.ref006","doi-asserted-by":"crossref","first-page":"1873","DOI":"10.1002\/cphy.c160004","article-title":"Adipose Tissue-Derived Plasminogen Activator Inhibitor-1 Function and Regulation","volume":"6","author":"H. Kaji","year":"2016","journal-title":"Compr Physiol"},{"key":"pone.0311902.ref007","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1186\/s41232-020-00128-5","article-title":"Roles of fibrinolytic factors in the alterations in bone marrow hematopoietic stem\/progenitor cells during bone repair","volume":"40","author":"K Okada","year":"2020","journal-title":"Inflamm Regen"},{"issue":"6","key":"pone.0311902.ref008","doi-asserted-by":"crossref","first-page":"2194","DOI":"10.2337\/db14-1192","article-title":"Role of plasminogen activator inhibitor-1 in glucocorticoid-induced diabetes and osteopenia in mice","volume":"64","author":"Y Tamura","year":"2015","journal-title":"Diabetes"},{"issue":"3","key":"pone.0311902.ref009","doi-asserted-by":"crossref","first-page":"e92686","DOI":"10.1371\/journal.pone.0092686","article-title":"Plasminogen activator inhibitor-1 is involved in impaired bone repair associated with diabetes in female mice","volume":"9","author":"L Mao","year":"2014","journal-title":"PLoS One"},{"key":"pone.0311902.ref010","doi-asserted-by":"crossref","first-page":"115310","DOI":"10.1016\/j.bone.2020.115310","article-title":"PAI-1 is involved in delayed bone repair induced by glucocorticoids in mice","volume":"134","author":"K Okada","year":"2020","journal-title":"Bone"},{"issue":"9","key":"pone.0311902.ref011","doi-asserted-by":"crossref","first-page":"3170","DOI":"10.2337\/db12-1552","article-title":"Plasminogen activator inhibitor-1 is involved in streptozotocin-induced bone loss in female mice","volume":"62","author":"Y Tamura","year":"2013","journal-title":"Diabetes"},{"issue":"6","key":"pone.0311902.ref012","doi-asserted-by":"crossref","first-page":"9687","DOI":"10.1002\/jcp.27655","article-title":"Plasminogen activator inhibitor-1 deficiency suppresses osteoblastic differentiation of mesenchymal stem cells in mice","volume":"234","author":"Y Takafuji","year":"2019","journal-title":"J Cell Physiol"},{"issue":"5","key":"pone.0311902.ref013","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1007\/s00223-024-01193-5","article-title":"Roles of Plasminogen Activator Inhibitor-1 in Heterotopic Ossification Induced by Achilles Tenotomy in Thermal Injured Mice","volume":"114","author":"Y Mizukami","year":"2024","journal-title":"Calcif Tissue Int"},{"issue":"12","key":"pone.0311902.ref014","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.1507\/endocrj.EJ21-0142","article-title":"Role of plasminogen activator inhibitor-1 in muscle wasting induced by a diabetic state in female mice","volume":"68","author":"H Ehara","year":"2021","journal-title":"Endocr J"},{"issue":"11","key":"pone.0311902.ref015","doi-asserted-by":"crossref","first-page":"2999","DOI":"10.1681\/ASN.2006050503","article-title":"Plasminogen activator inhibitor-1 in chronic kidney disease: evidence and mechanisms of action","volume":"17","author":"AA Eddy","year":"2006","journal-title":"J Am Soc Nephrol"},{"issue":"1","key":"pone.0311902.ref016","doi-asserted-by":"crossref","first-page":"e23","DOI":"10.1159\/000093673","article-title":"Plasminogen activator inhibitor-1 deficiency has renal benefits but some adverse systemic consequences in diabetic mice","volume":"104","author":"SJ Collins","year":"2006","journal-title":"Nephron Exp Nephrol"},{"issue":"2","key":"pone.0311902.ref017","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1046\/j.1523-1755.2001.030002587.x","article-title":"PAI-1 deficiency attenuates the fibrogenic response to ureteral obstruction","volume":"60","author":"T Oda","year":"2001","journal-title":"Kidney Int"},{"issue":"6","key":"pone.0311902.ref018","doi-asserted-by":"crossref","first-page":"e0157012","DOI":"10.1371\/journal.pone.0157012","article-title":"Novel Plasminogen Activator Inhibitor-1 Inhibitors Prevent Diabetic Kidney Injury in a Mouse Model","volume":"11","author":"BY Jeong","year":"2016","journal-title":"PLoS One"},{"key":"pone.0311902.ref019","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1186\/1471-2369-14-116","article-title":"A novel model of adenine-induced tubulointerstitial nephropathy in mice","volume":"14","author":"T Jia","year":"2013","journal-title":"BMC Nephrol"},{"issue":"6","key":"pone.0311902.ref020","doi-asserted-by":"crossref","first-page":"2746","DOI":"10.1172\/JCI116892","article-title":"Plasminogen activator inhibitor-1 gene-deficient mice. I. Generation by homologous recombination and characterization","volume":"92","author":"P Carmeliet","year":"1993","journal-title":"J Clin Invest"},{"issue":"8","key":"pone.0311902.ref021","doi-asserted-by":"crossref","first-page":"1811","DOI":"10.1002\/jbmr.1916","article-title":"Rapid cortical bone loss in patients with chronic kidney disease","volume":"28","author":"TL Nickolas","year":"2013","journal-title":"J Bone Miner Res"},{"issue":"4","key":"pone.0311902.ref022","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1007\/s00223-019-00642-w","article-title":"Elevations in Cortical Porosity Occur Prior to Significant Rise in Serum Parathyroid Hormone in Young Female Mice with Adenine-Induced CKD","volume":"106","author":"CE Metzger","year":"2020","journal-title":"Calcif Tissue Int"},{"key":"pone.0311902.ref023","doi-asserted-by":"crossref","first-page":"115963","DOI":"10.1016\/j.bone.2021.115963","article-title":"Strain-specific alterations in the skeletal response to adenine-induced chronic kidney disease are associated with differences in parathyroid hormone levels","volume":"148","author":"CE Metzger","year":"2021","journal-title":"Bone"},{"issue":"4","key":"pone.0311902.ref024","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1002\/jbmr.4503","article-title":"Sclerostin Protects Against Vascular Calcification Development in Mice","volume":"37","author":"A De Mar\u00e9","year":"2022","journal-title":"J Bone Miner Res"},{"key":"pone.0311902.ref025","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.bone.2015.07.015","article-title":"Altered material properties are responsible for bone fragility in rats with chronic kidney injury","volume":"81","author":"Y Iwasaki","year":"2015","journal-title":"Bone"},{"issue":"11","key":"pone.0311902.ref026","doi-asserted-by":"crossref","first-page":"F1169","DOI":"10.1152\/ajprenal.00676.2013","article-title":"Gender differences in adenine-induced chronic kidney disease and cardiovascular complications in rats","volume":"307","author":"V Diwan","year":"2014","journal-title":"Am J Physiol Renal Physiol"},{"issue":"3","key":"pone.0311902.ref027","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1038\/sj.ki.5002287","article-title":"Development and progression of secondary hyperparathyroidism in chronic kidney disease: lessons from molecular genetics","volume":"74","author":"WG Goodman","year":"2008","journal-title":"Kidney Int"},{"issue":"6","key":"pone.0311902.ref028","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1002\/jbmr.4272","article-title":"The HIF-PHI BAY 85\u20133934 (Molidustat) Improves Anemia and Is Associated With Reduced Levels of Circulating FGF23 in a CKD Mouse Model","volume":"36","author":"ML Noonan","year":"2021","journal-title":"J Bone Miner Res"},{"issue":"8","key":"pone.0311902.ref029","doi-asserted-by":"crossref","first-page":"1787","DOI":"10.1681\/ASN.2014060530","article-title":"Alteration of the Intestinal Environment by Lubiprostone Is Associated with Amelioration of Adenine-Induced CKD","volume":"26","author":"E Mishima","year":"2015","journal-title":"J Am Soc Nephrol"},{"issue":"4","key":"pone.0311902.ref030","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1016\/S0272-6386(96)90473-4","article-title":"Phosphorus accelerates the development of parathyroid hyperplasia and secondary hyperparathyroidism in rats with renal failure","volume":"28","author":"M Denda","year":"1996","journal-title":"Am J Kidney Dis"},{"issue":"1","key":"pone.0311902.ref031","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1681\/ASN.2009121311","article-title":"Klotho deficiency causes vascular calcification in chronic kidney disease","volume":"22","author":"MC Hu","year":"2011","journal-title":"J Am Soc Nephrol"},{"issue":"3","key":"pone.0311902.ref032","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1038\/s41581-022-00665-x","article-title":"Regulation of FGF23 production and phosphate metabolism by bone-kidney interactions","volume":"19","author":"R Agoro","year":"2023","journal-title":"Nat Rev Nephrol"},{"issue":"4","key":"pone.0311902.ref033","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1172\/JCI200419081","article-title":"Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism","volume":"113","author":"T Shimada","year":"2004","journal-title":"J Clin Invest"},{"issue":"9","key":"pone.0311902.ref034","doi-asserted-by":"crossref","first-page":"e1603259","DOI":"10.1126\/sciadv.1603259","article-title":"PAI-1 is a critical regulator of FGF23 homeostasis","volume":"3","author":"M Eren","year":"2017","journal-title":"Sci Adv"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0311902","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,10]],"date-time":"2024-10-10T17:32:46Z","timestamp":1728581566000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0311902"}},"subtitle":[],"editor":[{"given":"Toshio","family":"Matsumoto","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2024,10,10]]},"references-count":34,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2024,10,10]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0311902","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,10]]}}}