title: Suppression of EZH2 Prevents the Shift of Osteoporotic MSC Fate to Adipocyte and Enhances Bone Formation During Osteoporosis.
abstract: During osteoporosis, the shift of mesenchymal stem cell (MSC) lineage commitment to adipocyte leads to the imbalance between bone mass and fat, which increases the risk of fracture. The Enhancer of Zeste homology 2 (EZH2), which methylates histone H3 on lysine 27 (H3K27me3), controls MSC cell lineage commitment. However, whether EZH2 is related to osteoporosis remains elusive. In our study, we found EZH2 expression was significantly increased in osteoporotic MSCs. EZH2 directly increased H3K27me3 levels on promoters of Wnt1, Wnt6, and Wnt10a to silence Wnt gene transcription. The inhibition of Wnt/β-catenin signaling shifted MSC cell lineage commitment to adipocyte. Knockdown of EZH2 by lentivirus-expressing shRNA rescued the abnormal fate of osteoporotic MSC. By employing the H3K27me3 inhibitor DZNep, we effectively derepressed Wnt signaling and improved osteogenic differentiation of osteoporotic MSCs in vitro. Furthermore, in vivo administration of DZNep successfully increased bone formation and repressed excessive bone marrow fat formation in osteoporotic mice. Noteworthy, DZNep treatment persistently enhanced osteogenic differentiation of endogenous MSCs. In conclusion, our study demonstrated that redundant EZH2 shifted MSC cell lineage commitment to adipocyte, which contributed to the development of osteoporosis. We also provided EZH2 as a novel therapeutic target for improving bone formation during osteoporosis.
authors: State Key Laboratory of Military Stomatology, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, China; Research and Development Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, China; State Key Laboratory of Military Stomatology, Department of Oral Histology and Pathology, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors: Huan
authors: H
authors: Jing
authors: State Key Laboratory of Military Stomatology, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, China; Research and Development Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, China; State Key Laboratory of Military Stomatology, Department of Oral Histology and Pathology, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors: Li
authors: L
authors: Liao
authors: State Key Laboratory of Military Stomatology, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, China; Research and Development Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, China; State Key Laboratory of Military Stomatology, Department of Oral Histology and Pathology, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, China; Zhenjiang Entry-Exit Inspection And Quarantine Bureau, Jiangsu, China.
authors: Yulin
authors: Y
authors: An
authors: Department of Orthodontics, Stomatology Hospital of Xi'an Jiaotong University College of Medicine, Shaanxi, China.
authors: Xiaoxia
authors: X
authors: Su
authors: State Key Laboratory of Military Stomatology, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, China; Research and Development Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, China; State Key Laboratory of Military Stomatology, Department of Oral Histology and Pathology, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors: Shiyu
authors: S
authors: Liu
authors: State Key Laboratory of Military Stomatology, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, China; Research and Development Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, China; State Key Laboratory of Military Stomatology, Department of Oral Histology and Pathology, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors: Yi
authors: Y
authors: Shuai
authors: Department of Prothodontics, Stomatological Hospital of Chongqing Medical University, Chongqing, China.
authors: Xinjing
authors: X
authors: Zhang
authors: State Key Laboratory of Military Stomatology, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, China; Research and Development Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, China. Electronic address: yanjin@fmmu.edu.cn.
authors: Yan
authors: Y
authors: Jin
mesh_terms: D017667:Adipocytes / Q000166:cytology*; D000818:Animals; D002454:Cell Differentiation; D019175:DNA Methylation; D004195:Disease Models, Animal; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D055785:Gene Knockdown Techniques; D006657:Histones / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000473:pathology; D051379:Mice; D010012:Osteogenesis; D010024:Osteoporosis / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000235:genetics
chemical_list: D006657:Histones; D051153:Wnt Proteins; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D063151:Polycomb Repressive Complex 2