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Here, it is found that Prx1 and Bmi\u20101 co\u2010localized in trabecular bone, bone marrow cavity, endosteum, and periosteum. <jats:italic>Prx1<\/jats:italic>\u2010driven <jats:italic>Bmi\u20101<\/jats:italic> knockout in bone\u2010marrow mesenchymal stem cells (BMSCs) reduced bone mass and increased bone marrow adiposity by inhibiting osteoblastic bone formation, promoting osteoclastic bone resorption, downregulating the proliferation and osteogenic differentiation of BMSCs, and upregulating the adipogenic differentiation of BMSCs. However, <jats:italic>Prx1<\/jats:italic>\u2010driven <jats:italic>Bmi\u20101<\/jats:italic> overexpression showed a contrasting phenotype to <jats:italic>Prx1<\/jats:italic>\u2010driven <jats:italic>Bmi\u20101<\/jats:italic> knockout in BMSCs. Regarding mechanism, Bmi\u20101\u2010RING1B bound to DNMT3A and promoted its ubiquitination and inhibited DNA methylation of <jats:italic>Runx2<\/jats:italic> at the region from 45047012 to 45047313\u00a0bp, thus promoting the osteogenic differentiation of BMSCs. Moreover, Bmi\u20101\u2010EZH2 repressed the transcription of <jats:italic>Cebpa<\/jats:italic> by promoting H3K27 trimethylation at the promoter region \u22121605 to \u22121596\u2009bp, thus inhibiting the adipogenic differentiation of BMSCs. It is also found that <jats:italic>Prx1<\/jats:italic>\u2010driven <jats:italic>Bmi\u20101<\/jats:italic> overexpression rescued the SOP induced by <jats:italic>Prx1<\/jats:italic>\u2010driven <jats:italic>Bmi\u20101<\/jats:italic> knockout in BMSCs. Thus, Bmi\u20101 functioned as a hub protein in the epigenetic regulation of BMSCs differentiation to delay bone aging. The <jats:italic>Prx1<\/jats:italic>\u2010driven <jats:italic>Bmi\u20101<\/jats:italic> overexpression in BMSCs can be used as an approach for the translational therapy of SOP.<\/jats:p>","DOI":"10.1002\/advs.202404518","type":"journal-article","created":{"date-parts":[[2024,9,3]],"date-time":"2024-09-03T07:41:37Z","timestamp":1725349297000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Bmi\u20101 Epigenetically Orchestrates Osteogenic and Adipogenic Differentiation of Bone Marrow Mesenchymal Stem Cells to Delay Bone Aging"],"prefix":"10.1002","volume":"11","author":[{"given":"Jingyu","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Human Anatomy Research Centre for Bone and Stem Cells School of Basic Medical Sciences Key Laboratory for Aging &amp; Disease School of Biomedical Engineering and Informatics Nanjing Medical University  Nanjing Jiangsu 211166 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