{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T09:00:04Z","timestamp":1781082004077,"version":"3.54.1"},"reference-count":41,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T00:00:00Z","timestamp":1779753600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T00:00:00Z","timestamp":1779753600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81972110"],"award-info":[{"award-number":["81972110"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2026,5,31]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Rapamycin (Rapa), an mTOR inhibitor, enhances autophagy to alleviate bone loss in senile and estrogen\u2010deficient osteoporosis by restoring the biological properties of bone marrow stromal cells (BMSCs). However, Rapa against bone loss induced by ketogenic diet (KD) and the underlying mechanism remain elusive. This study aims to evaluate Rapa's influence on KD\u2010induced osteoporosis and clarify its underlying mechanisms. Microarchitectures of bone, serum concentrations of bone alkaline phosphatase (ALP) and tartrate\u2010resistant acid phosphatase (TRAP), along with osteocalcin (OCN), microtubule\u2010associated protein light chain 3 (LC3), TRAP, and Sca\u20101 immunohistochemistry staining were evaluated in Sham, the OVX (ovariectomy), the OVX+ Rapa, the KD, and the KD+ Rapa groups. Expression of mTOR and the autophagy\u2010related proteins, including LC3\u2010II\/LC3\u2010I, Beclin1, ATG7, and P62 were also analyzed. Both KD and OVX induced significant bone loss in the cancellous bone of the distal femur and the L5 vertebra. Furthermore, KD effectively decreased serum ALP and increased TRAP in mice. In addition, KD and OVX downregulated OCN, ALP, RUNX2, the autophagy\u2010related proteins, upregulated TRAP, PPAR\u03b3, p\u2010mTOR, and P62, and decreased LC3 and Sca\u20101 expressions in mice. On the other hand, Rapa reduced significant bone loss in cancellous bone induced by KD or OVX. Additionally, Rapa effectively increased serum ALP and decreased TRAP in KD mice and decreased serum TRAP in OVX mice. It upregulated OCN, ALP, RUNX2, LC3\u2010II\/LC3\u2010I, Beclin1, and ATG7 and downregulated TRAP, PPAR\u03b3, p\u2010mTOR, and P62 in the KD and OVX cohorts. The findings demonstrated that autophagy downregulation might contribute to KD\u2010induced osteoporosis, which may be part of the pathogenic mechanism responsible for bone loss during KD.<\/jats:p>","DOI":"10.1096\/fj.202601131r","type":"journal-article","created":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T08:45:07Z","timestamp":1779785107000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Ketogenic Diet Might Regulate Autophagy of\n                    <scp>BMSCs<\/scp>\n                    via\n                    <scp>mTOR<\/scp>\n                    Signaling Contributing to Osteoporosis in Mice"],"prefix":"10.1096","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3066-9595","authenticated-orcid":false,"given":"Qi","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Orthopedics, The Second Affiliated Hospital Guangzhou Medical University  Guangzhou China"},{"name":"Division of Spinal Surgery, Department of Orthopaedics, Nanfang Hospital Southern Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhou","family":"Yang","sequence":"additional","affiliation":[{"name":"Division of Spinal Surgery, Department of Orthopaedics, Nanfang Hospital Southern Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongnong","family":"Ye","sequence":"additional","affiliation":[{"name":"Pharmacy Department Guangzhou Panyu Hospital of Traditional Chinese Medicine  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruo yao","family":"Li","sequence":"additional","affiliation":[{"name":"Division of Spinal Surgery, Department of Orthopaedics, Nanfang Hospital Southern Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinjun","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, The Second Affiliated Hospital Guangzhou Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoshan","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, The Second Affiliated Hospital Guangzhou Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutao","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, The Second Affiliated Hospital Guangzhou Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuhua","family":"Wu","sequence":"additional","affiliation":[{"name":"Division of Spinal Surgery, Department of Orthopaedics, Nanfang Hospital Southern Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingan","family":"Zhu","sequence":"additional","affiliation":[{"name":"Division of Spinal Surgery, Department of Orthopaedics, Nanfang Hospital Southern Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,26]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/jcbfm.2008.79"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00702-008-0050-7"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0078765"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2008.01853.x"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2023.1042744"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgaa759"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1538\/expanim.18-0084"},{"issue":"4","key":"e_1_2_12_9_1","first-page":"2503","article-title":"Bone Loss and Biomechanical Reduction of Appendicular and Axial Bones Under Ketogenic Diet in Rats","volume":"17","author":"Ding J.","year":"2019","journal-title":"Experimental and Therapeutic Medicine"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00223-017-0292-1"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00391-019-01659-4"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2016-015187"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.3892\/etm.2017.4712"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40199-017-0167-z"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2020.593820"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00223-018-0468-3"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13018-024-04529-x"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40520-022-02190-0"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00198-015-3325-5"},{"issue":"5","key":"e_1_2_12_20_1","first-page":"321","article-title":"Rapamycin Activates Autophagy by Inhibiting mTOR Pathway to Alleviate Early Osteoporosis in Rats With Skeletal Fluorosis","volume":"39","author":"Li X. N.","year":"2021","journal-title":"Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/jbmrpl\/ziae001"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12325-023-02676-x"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.12709"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.morpho.2008.10.003"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.7164\/antibiotics.28.721"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejim.2006.07.017"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2021.2017587"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.exger.2021.111516"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01352014"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00381-013-2185-6"},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpn.2013.03.002"},{"key":"e_1_2_12_32_1","doi-asserted-by":"publisher","DOI":"10.7150\/thno.17949"},{"key":"e_1_2_12_33_1","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2015.1038016"},{"key":"e_1_2_12_34_1","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2019.1590519"},{"key":"e_1_2_12_35_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.86.12.4634"},{"key":"e_1_2_12_36_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.2898810"},{"key":"e_1_2_12_37_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1036475100"},{"key":"e_1_2_12_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2010.09.012"},{"key":"e_1_2_12_39_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.222570"},{"key":"e_1_2_12_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41413-017-0004-5"},{"key":"e_1_2_12_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.exger.2022.111841"},{"key":"e_1_2_12_42_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.27335"}],"container-title":["The FASEB Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.202601131R","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/full-xml\/10.1096\/fj.202601131R","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.202601131R","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T08:21:13Z","timestamp":1781079673000},"score":1,"resource":{"primary":{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/10.1096\/fj.202601131R"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,26]]},"references-count":41,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2026,5,31]]}},"alternative-id":["10.1096\/fj.202601131R"],"URL":"https:\/\/doi.org\/10.1096\/fj.202601131r","archive":["Portico"],"relation":{},"ISSN":["0892-6638","1530-6860"],"issn-type":[{"value":"0892-6638","type":"print"},{"value":"1530-6860","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,26]]},"assertion":[{"value":"2026-03-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-28","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-26","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e71890"}}