{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T16:18:53Z","timestamp":1787674733707,"version":"build-2784847793"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000},"content-version":"vor","delay-in-days":12,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82172504"],"award-info":[{"award-number":["82172504"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82302935"],"award-info":[{"award-number":["82302935"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Osteoporosis is associated with reduced active vitamin D, but the molecular basis remains incompletely understood. This study investigated how active vitamin D preserves skeletal homeostasis and prevents bone loss.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Design<\/jats:title>\n                    <jats:p>Experimental mechanistic study using genetically modified mouse models and bone marrow mesenchymal stem cells (BMSCs).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Mice with reduced active vitamin D production were examined for bone mass, skeletal aging, and osteogenic capacity. Mouse and human BMSCs were used to assess proliferation, osteogenic differentiation, and molecular signaling. Gene expression, protein turnover, and pathway analyses determined how active vitamin D regulates cell-cycle control in skeletal progenitors. Genetic deletion studies tested the functional contribution of P27 to bone loss.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Active vitamin D protected against osteoporosis by activating a vitamin D receptor (VDR)-dependent pathway that increased cyclin-dependent kinase 2 (CDK2) expression and promoted P27 degradation in BMSCs. Loss of this signaling caused P27 accumulation, reduced stem-cell proliferation, impaired osteogenic differentiation, and enhanced skeletal senescence, leading to bone loss. Active vitamin D promoted P27 phosphorylation at threonine 187 and its degradation via the ubiquitin-proteasome pathway. Importantly, P27 deletion partially rescued the osteoporotic phenotype in mice with reduced active vitamin D production.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Active vitamin D maintains bone integrity through a VDR-dependent mechanism that enhances CDK2 expression and promotes P27 degradation in BMSCs. These findings identify a previously unrecognized mechanism linking vitamin D signaling to skeletal aging and suggest that targeting P27 turnover may offer a therapeutic strategy, provided tissue-specific approaches mitigate the oncogenic risks of P27 manipulation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/ejendo\/lvag152","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T11:46:17Z","timestamp":1786535177000},"page":"329-344","source":"Crossref","is-referenced-by-count":0,"title":["Active vitamin D protects against osteoporosis by promoting VDR-dependent CDK2 transcription and P27 degradation"],"prefix":"10.1093","volume":"195","author":[{"given":"Fangrong","family":"Xu","sequence":"first","affiliation":[{"name":"The Research Center for Bone and Stem Cells, Department of Anatomy, Histology and Embryology, Nanjing Medical University , Nanjing 211166 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Nanjing First Hospital, Nanjing Medical University , Nanjing 210006 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingxin","family":"Huang","sequence":"additional","affiliation":[{"name":"The Research Center for Bone and Stem Cells, Department of Anatomy, Histology and Embryology, Nanjing Medical University , Nanjing 211166 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Wang","sequence":"additional","affiliation":[{"name":"The Research Center for Bone and Stem Cells, Department of Anatomy, Histology and Embryology, Nanjing Medical University , Nanjing 211166 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3421-7147","authenticated-orcid":false,"given":"David","family":"Goltzman","sequence":"additional","affiliation":[{"name":"Calcium Research Laboratory, McGill University Health Centre and Department of Medicine, McGill University , Montreal, Quebec H4A 3J1 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingjie","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Nanjing First Hospital, Nanjing Medical University , Nanjing 210006 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2682-3502","authenticated-orcid":false,"given":"Dengshun","family":"Miao","sequence":"additional","affiliation":[{"name":"Department of Plastic Surgery, Affiliated Friendship Plastic Surgery Hospital of Nanjing Medical University , Nanjing 210029 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,8,13]]},"reference":[{"issue":"10","key":"2026082511213524500_lvag152-B1","doi-asserted-by":"publisher","first-page":"894","DOI":"10.1001\/jama.2025.6003","article-title":"Osteoporosis: a review","volume":"334","author":"Morin","year":"2025","journal-title":"JAMA"},{"issue":"4","key":"2026082511213524500_lvag152-B2","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1056\/NEJMoa2202106","article-title":"Supplemental vitamin D and incident fractures in midlife and older adults","volume":"387","author":"LeBoff","year":"2022","journal-title":"N Engl J Med"},{"issue":"3","key":"2026082511213524500_lvag152-B3","doi-asserted-by":"publisher","first-page":"266","DOI":"10.1056\/NEJMra070553","article-title":"Vitamin D deficiency","volume":"357","author":"Holick","year":"2007","journal-title":"N Engl J Med"},{"issue":"6","key":"2026082511213524500_lvag152-B4","doi-asserted-by":"publisher","first-page":"726","DOI":"10.1210\/er.2008-0004","article-title":"Vitamin D and human health: lessons from vitamin D receptor null mice","volume":"29","author":"Bouillon","year":"2008","journal-title":"Endocr Rev"},{"issue":"4","key":"2026082511213524500_lvag152-B5","doi-asserted-by":"publisher","first-page":"815","DOI":"10.1016\/j.ecl.2017.07.001","article-title":"Biology and mechanisms of action of the vitamin D hormone","volume":"46","author":"Pike","year":"2017","journal-title":"Endocrinol Metab Clin North Am"},{"issue":"6","key":"2026082511213524500_lvag152-B6","doi-asserted-by":"publisher","first-page":"1689S","DOI":"10.1093\/ajcn\/80.6.1689S","article-title":"Overview of general physiologic features and functions of vitamin D","volume":"80","author":"DeLuca","year":"2004","journal-title":"Am J Clin Nutr"},{"issue":"2","key":"2026082511213524500_lvag152-B7","doi-asserted-by":"publisher","first-page":"e13095","DOI":"10.1111\/acel.13095","article-title":"1,25-Dihydroxyvitamin D protects against age-related osteoporosis by a novel VDR-Ezh2-p16 signal axis","volume":"19","author":"Yang","year":"2020","journal-title":"Aging Cell"},{"key":"2026082511213524500_lvag152-B8","doi-asserted-by":"publisher","first-page":"246","DOI":"10.1016\/j.freeradbiomed.2021.12.010","article-title":"Inhibition of Nrf2 degradation alleviates age-related osteoporosis induced by 1,25-dihydroxyvitamin D deficiency","volume":"178","author":"Yang","year":"2022","journal-title":"Free Radic Biol Med"},{"key":"2026082511213524500_lvag152-B9","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1016\/j.jot.2024.10.011","article-title":"The vitamin D-sirt1\/PGC1alpha axis regulates bone metabolism and counteracts osteoporosis","volume":"50","author":"Yang","year":"2025","journal-title":"J Orthop Translat"},{"issue":"2","key":"2026082511213524500_lvag152-B10","first-page":"507","article-title":"1,25-Dihydroxyvitamin D insufficiency accelerates age-related bone loss by increasing oxidative stress and cell senescence","volume":"12","author":"Qiao","year":"2020","journal-title":"Am J Transl Res"},{"issue":"3","key":"2026082511213524500_lvag152-B11","doi-asserted-by":"publisher","first-page":"956","DOI":"10.7150\/ijbs.65954","article-title":"A sonic hedgehog-gli-bmi1 signaling pathway plays a critical role in p27 deficiency induced bone anabolism","volume":"18","author":"Wu","year":"2022","journal-title":"Int J Biol Sci"},{"key":"2026082511213524500_lvag152-B12","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1016\/j.jot.2024.08.012","article-title":"The senolytic agent ABT263 ameliorates osteoporosis caused by active vitamin D insufficiency through selective clearance of senescent skeletal cells","volume":"49","author":"Yang","year":"2024","journal-title":"J Orthop Translat"},{"issue":"6","key":"2026082511213524500_lvag152-B13","doi-asserted-by":"publisher","first-page":"1194","DOI":"10.1016\/j.cell.2013.05.039","article-title":"The hallmarks of aging","volume":"153","author":"Lopez-Otin","year":"2013","journal-title":"Cell"},{"issue":"9","key":"2026082511213524500_lvag152-B14","doi-asserted-by":"publisher","first-page":"1520","DOI":"10.1177\/0963689717721201","article-title":"Age-related changes in bone marrow mesenchymal stromal cells: a potential impact on osteoporosis and osteoarthritis development","volume":"26","author":"Ganguly","year":"2017","journal-title":"Cell Transplant"},{"key":"2026082511213524500_lvag152-B15","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1159\/000358899","article-title":"Cell senescence: role in aging and age-related diseases","volume":"39","author":"Campisi","year":"2014","journal-title":"Interdiscip Top Gerontol"},{"key":"2026082511213524500_lvag152-B16","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1016\/j.bone.2019.01.015","article-title":"Cellular senescence in bone","volume":"121","author":"Farr","year":"2019","journal-title":"Bone"},{"issue":"12","key":"2026082511213524500_lvag152-B17","doi-asserted-by":"publisher","first-page":"1501","DOI":"10.1101\/gad.13.12.1501","article-title":"CDK inhibitors: positive and negative regulators of G1-phase progression","volume":"13","author":"Sherr","year":"1999","journal-title":"Genes Dev"},{"key":"2026082511213524500_lvag152-B18","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.dnarep.2018.07.008","article-title":"Multiple functions of p27 in cell cycle, apoptosis, epigenetic modification and transcriptional regulation for the control of cell growth: a double-edged sword protein","volume":"69","author":"Abbastabar","year":"2018","journal-title":"DNA Repair (Amst)"},{"issue":"3","key":"2026082511213524500_lvag152-B19","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1016\/S0531-5565(00)00083-8","article-title":"Tumor suppressors and oncogenes in cellular senescence","volume":"35","author":"Bringold","year":"2000","journal-title":"Exp Gerontol"},{"issue":"5224","key":"2026082511213524500_lvag152-B20","doi-asserted-by":"publisher","first-page":"682","DOI":"10.1126\/science.7624798","article-title":"Role of the ubiquitin-proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27","volume":"269","author":"Pagano","year":"1995","journal-title":"Science"},{"issue":"20","key":"2026082511213524500_lvag152-B21","doi-asserted-by":"publisher","first-page":"3601","DOI":"10.1091\/mbc.e10-01-0054","article-title":"Phosphorylation of p27Kip1 at Thr187 by cyclin-dependent kinase 5 modulates neural stem cell differentiation","volume":"21","author":"Zheng","year":"2010","journal-title":"Mol Biol Cell"},{"issue":"9","key":"2026082511213524500_lvag152-B22","doi-asserted-by":"publisher","first-page":"1181","DOI":"10.1101\/gad.13.9.1181","article-title":"Ubiquitination of p27 is regulated by cdk-dependent phosphorylation and trimeric complex formation","volume":"13","author":"Montagnoli","year":"1999","journal-title":"Genes Dev"},{"issue":"3","key":"2026082511213524500_lvag152-B23","first-page":"787","article-title":"P27 deletion enhances hematopoiesis by paracrine action of IL22 secreted from bone marrow mesenchymal stem cells","volume":"12","author":"Lu","year":"2020","journal-title":"Am J Transl Res"},{"issue":"11","key":"2026082511213524500_lvag152-B24","doi-asserted-by":"publisher","first-page":"1969","DOI":"10.1002\/jbmr.2544","article-title":"The p27 pathway modulates the regulation of skeletal growth and osteoblastic bone formation by parathyroid hormone-related peptide","volume":"30","author":"Zhu","year":"2015","journal-title":"J Bone Miner Res"},{"issue":"17","key":"2026082511213524500_lvag152-B25","doi-asserted-by":"publisher","first-page":"3451","DOI":"10.1158\/0008-5472.CAN-19-3663","article-title":"P27 as a transcriptional regulator: new roles in development and cancer","volume":"80","author":"Razavipour","year":"2020","journal-title":"Cancer Res"},{"issue":"2","key":"2026082511213524500_lvag152-B26","doi-asserted-by":"publisher","first-page":"368","DOI":"10.1002\/ijc.31317","article-title":"1,25-Dihydroxy vitamin D prevents tumorigenesis by inhibiting oxidative stress and inducing tumor cellular senescence in mice","volume":"143","author":"Chen","year":"2018","journal-title":"Int J Cancer"},{"issue":"21","key":"2026082511213524500_lvag152-B27","doi-asserted-by":"publisher","first-page":"15462","DOI":"10.1074\/jbc.M610758200","article-title":"Substrate recognition and ubiquitination of SCFSkp2\/cks1 ubiquitin-protein isopeptide ligase","volume":"282","author":"Xu","year":"2007","journal-title":"J Biol Chem"},{"issue":"13","key":"2026082511213524500_lvag152-B28","doi-asserted-by":"publisher","first-page":"7498","DOI":"10.1073\/pnas.131029498","article-title":"Targeted ablation of the 25-hydroxyvitamin D 1alpha -hydroxylase enzyme: evidence for skeletal, reproductive, and immune dysfunction","volume":"98","author":"Panda","year":"2001","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"16","key":"2026082511213524500_lvag152-B29","doi-asserted-by":"publisher","first-page":"16754","DOI":"10.1074\/jbc.M310271200","article-title":"Inactivation of the 25-hydroxyvitamin D 1alpha-hydroxylase and vitamin D receptor demonstrates independent and interdependent effects of calcium and vitamin D on skeletal and mineral homeostasis","volume":"279","author":"Panda","year":"2004","journal-title":"J Biol ChemApr"},{"issue":"3","key":"2026082511213524500_lvag152-B30","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1002\/jbmr.3921","article-title":"The polycomb protein Bmi1 plays a crucial role in the prevention of 1,25(OH)(2) D deficiency-induced bone loss","volume":"35","author":"Sun","year":"2020","journal-title":"J Bone Miner Res"},{"issue":"4","key":"2026082511213524500_lvag152-B31","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1080\/14653240600855905","article-title":"Minimal criteria for defining multipotent mesenchymal stromal cells. The international society for cellular therapy position statement","volume":"8","author":"Dominici","year":"2006","journal-title":"Cytotherapy"},{"issue":"13","key":"2026082511213524500_lvag152-B32","doi-asserted-by":"publisher","first-page":"4291","DOI":"10.7150\/ijbs.81738","article-title":"LncRNA PTTG3P promotes tumorigenesis and metastasis of NSCLC by binding with ILF3 to maintain mRNA stability and form a positive feedback loop with E2F1","volume":"19","author":"Wang","year":"2023","journal-title":"Int J Biol Sci"},{"issue":"1","key":"2026082511213524500_lvag152-B33","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.molcel.2005.09.003","article-title":"Structural basis of the Cks1-dependent recognition of p27(Kip1) by the SCF(skp2) ubiquitin ligase","volume":"20","author":"Hao","year":"7 2005","journal-title":"Mol Cell"},{"issue":"1","key":"2026082511213524500_lvag152-B34","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1038\/s41368-024-00309-9","article-title":"Multiomics profiling reveals VDR as a central regulator of mesenchymal stem cell senescence with a known association with osteoporosis after high-fat diet exposure","volume":"16","author":"Chen","year":"2024","journal-title":"Int J Oral Sci"},{"issue":"4","key":"2026082511213524500_lvag152-B35","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1038\/nrc2347","article-title":"The Cdk inhibitor p27 in human cancer: prognostic potential and relevance to anticancer therapy","volume":"8","author":"Chu","year":"2008","journal-title":"Nat Rev Cancer"},{"issue":"12","key":"2026082511213524500_lvag152-B36","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1016\/S0960-9822(99)80290-5","article-title":"P27(Kip1) ubiquitination and degradation is regulated by the SCF(Skp2) complex through phosphorylated Thr187 in p27","volume":"9","author":"Tsvetkov","year":"1999","journal-title":"Curr Biol"},{"issue":"1","key":"2026082511213524500_lvag152-B37","doi-asserted-by":"publisher","first-page":"685","DOI":"10.1146\/annurev-physiol-030212-183653","article-title":"Aging, cellular senescence, and cancer","volume":"75","author":"Campisi","year":"2013","journal-title":"Annu Rev Physiol"},{"issue":"1","key":"2026082511213524500_lvag152-B38","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1146\/annurev-pathol-121808-102144","article-title":"The senescence-associated secretory phenotype: the dark side of tumor suppression","volume":"5","author":"Coppe","year":"2010","journal-title":"Annu Rev Pathol"},{"issue":"9","key":"2026082511213524500_lvag152-B39","doi-asserted-by":"publisher","first-page":"1316","DOI":"10.3390\/biom10091316","article-title":"Regulation of p27(kip1) and p57(Kip2) functions by natural polyphenols","volume":"10","author":"Russo","year":"2020","journal-title":"Biomolecules"},{"issue":"9","key":"2026082511213524500_lvag152-B40","doi-asserted-by":"publisher","first-page":"1072","DOI":"10.1038\/nm.4385","article-title":"Targeting cellular senescence prevents age-related bone loss in mice","volume":"23","author":"Farr","year":"2017","journal-title":"Nat Med"},{"issue":"5","key":"2026082511213524500_lvag152-B41","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1038\/s41574-020-0335-y","article-title":"The role of cellular senescence in ageing and endocrine disease","volume":"16","author":"Khosla","year":"2020","journal-title":"Nat Rev Endocrinol"},{"issue":"8","key":"2026082511213524500_lvag152-B42","doi-asserted-by":"publisher","first-page":"1176","DOI":"10.3390\/biom15081176","article-title":"The role of senolytics in osteoporosis","volume":"15","author":"Chen","year":"2025","journal-title":"Biomolecules"}],"container-title":["European Journal of Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ejendo\/advance-article-pdf\/doi\/10.1093\/ejendo\/lvag152\/70632578\/lvag152.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ejendo\/article-pdf\/195\/2\/329\/70632578\/lvag152.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ejendo\/article-pdf\/195\/2\/329\/70632578\/lvag152.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T15:21:46Z","timestamp":1787671306000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ejendo\/article\/195\/2\/329\/8760861"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8]]},"references-count":42,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2026,8,3]]}},"URL":"https:\/\/doi.org\/10.1093\/ejendo\/lvag152","relation":{},"ISSN":["0804-4643","1479-683X"],"issn-type":[{"value":"0804-4643","type":"print"},{"value":"1479-683X","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,8]]},"published":{"date-parts":[[2026,8]]}}}