Bmi-1 Epigenetically Orchestrates Osteogenic and Adipogenic Differentiation of Bone Marrow Mesenchymal Stem Cells to Delay Bone Aging

被引：6

作者：

Zhao, Jingyu ^{[1
]}

Chen, Ao ^{[1
]}

Wang, Rong ^{[1
]}

Qiu, Dong ^{[2
]}

Chen, Haiyun ^{[1
]}

Li, Jiyu ^{[1
]}

Zhang, Jin'ge ^{[1
]}

Wang, Tianxiao ^{[3
]}

Wang, Yue ^{[1
]}

Lin, Yujie ^{[1
]}

Zhou, Jiawen ^{[1
]}

Du, Yifei ^{[2
]}

Yuan, Hua ^{[2
]}

Zhang, Yongjie ^{[1
]}

Miao, Dengshun ^{[1
]}

Wang, Yuli ^{[2
]}

Jin, Jianliang ^{[1
]}

机构：

[1] Nanjing Med Univ, Res Ctr Bone & Stem Cells, Sch Basic Med Sci, Sch Biomed Engn & Informat,Key Lab Aging & Dis,Dep, Nanjing 211166, Jiangsu, Peoples R China

[2] Nanjing Med Univ, Affiliated Stomatol Hosp, Jiangsu Prov Engn Res Ctr Stomatol Translat Med, Dept Oral & Maxillofacial Surg,State Key Lab Culti, Nanjing 210029, Jiangsu, Peoples R China

[3] Nanjing Med Univ, Sch Pharm, Nanjing 211166, Jiangsu, Peoples R China

来源：

ADVANCED SCIENCE | 2024年 / 11卷 / 46期

基金：

中国国家自然科学基金;

关键词：

Bmi-1; bone marrow mesenchymal stem cells; DNA methylation; DNMT3A; senile osteoporosis; SENESCENCE; METHYLATION; EXPRESSION; COMPLEX; OSTEOPOROSIS; TISSUE; GENES; GAMMA;

D O I：

10.1002/advs.202404518

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

With the increase in the aging population, senile osteoporosis (SOP) has become a major global public health concern. Here, it is found that Prx1 and Bmi-1 co-localized in trabecular bone, bone marrow cavity, endosteum, and periosteum. Prx1-driven Bmi-1 knockout in bone-marrow 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, Prx1-driven Bmi-1 overexpression showed a contrasting phenotype to Prx1-driven Bmi-1 knockout in BMSCs. Regarding mechanism, Bmi-1-RING1B bound to DNMT3A and promoted its ubiquitination and inhibited DNA methylation of Runx2 at the region from 45047012 to 45047313 bp, thus promoting the osteogenic differentiation of BMSCs. Moreover, Bmi-1-EZH2 repressed the transcription of Cebpa by promoting H3K27 trimethylation at the promoter region -1605 to -1596 bp, thus inhibiting the adipogenic differentiation of BMSCs. It is also found that Prx1-driven Bmi-1 overexpression rescued the SOP induced by Prx1-driven Bmi-1 knockout in BMSCs. Thus, Bmi-1 functioned as a hub protein in the epigenetic regulation of BMSCs differentiation to delay bone aging. The Prx1-driven Bmi-1 overexpression in BMSCs can be used as an approach for the translational therapy of SOP. Bmi-1 epigenetically orchestrates osteogenic and adipogenic differentiation of bone-marrow mesenchymal stem cells (BMSCs) to prevent senile osteoporosis (SOP). Prx1-driven Bmi-1 overexpression in BMSCs rescues the SOP phenotype induced by Prx1-driven Bmi-1 knockout in BMSCs. The Prx1-driven Bmi-1 overexpression in BMSCs can be used as an approach for the translational therapy of SOP. (Image created with BioRender.com). image

引用

页数：21

共 53 条

[11] TGF-β1/IL-11/MEK/ERK signaling mediates senescence-associated pulmonary fibrosis in a stress-induced premature senescence model of Bmi-1 deficiency [J].

Chen, Haiyun ;

Chen, Hongjie ;

Liang, Jialong ;

Gu, Xin ;

Zhou, Jiawen ;

Xie, Chunfeng ;

Lv, Xianhui ;

Wang, Rong ;

Li, Qing ;

Mao, Zhiyuan ;

Sun, Haijian ;

Zuo, Guoping ;

Miao, Dengshun ;

Jin, Jianliang .

EXPERIMENTAL AND MOLECULAR MEDICINE, 2020, 52 (01) :130-151

[12] Function of matrix IGF-1 in coupling bone resorption and formation [J].

Crane, Janet L. ;

Cao, Xu .

JOURNAL OF MOLECULAR MEDICINE-JMM, 2014, 92 (02) :107-115

[13] Radioprotective Effects of Bmi-1 Involve Epigenetic Silencing of Oxidase Genes and Enhanced DNA Repair in Normal Human Keratinocytes [J].

Dong, Qinghua ;

Oh, Ju-Eun ;

Chen, Wei ;

Kim, Roy ;

Kim, Reuben H. ;

Shin, Ki-Hyuk ;

McBride, William H. ;

Park, No-Hee ;

Kang, Mo K. .

JOURNAL OF INVESTIGATIVE DERMATOLOGY, 2011, 131 (06) :1216-1225

[14] Enhancer of zeste homolog 2 (Ezh2) controls bone formation and cell cycle progression during osteogenesis in mice [J].

Dudakovic, Amel ;

Camilleri, Emily T. ;

Paradise, Christopher R. ;

Samsonraj, Rebekah M. ;

Gluscevic, Martina ;

Paggi, Carlo Alberto ;

Begun, Dana L. ;

Khani, Farzaneh ;

Pichurin, Oksana ;

Ahmed, Farah S. ;

Elsayed, Ranya ;

Elsalanty, Mohammed ;

McGee-Lawrence, Meghan E. ;

Karperien, Marcel ;

Riester, Scott M. ;

Thaler, Roman ;

Westendorf, Jennifer J. ;

van Wijnen, Andre J. .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2018, 293 (33) :12894-12907

[15] Enhancer of Zeste Homolog 2 Inhibition Stimulates Bone Formation and Mitigates Bone Loss Caused by Ovariectomy in Skeletally Mature Mice [J].

Dudakovic, Amel ;

Camilleri, Emily T. ;

Riester, Scott M. ;

Paradise, Christopher R. ;

Gluscevic, Martina ;

O'Toole, Thomas M. ;

Thaler, Roman ;

Evans, Jared M. ;

Yan, Huihuang ;

Subramaniam, Malayannan ;

Hawse, John R. ;

Stein, Gary S. ;

Montecino, Martin A. ;

Mcgee-Lawrence, Meghan E. ;

Westendorf', Jennifer J. ;

van Wijnen, Andre J. .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2016, 291 (47) :24594-24606

[16] The retinoblastoma-histone deacetylase 3 complex inhibits PPARγ and adipocyte differentiation [J].

Fajas, L ;

Egler, V ;

Reiter, R ;

Hansen, J ;

Kristiansen, K ;

Debril, MB ;

Miard, S ;

Auwerx, J .

DEVELOPMENTAL CELL, 2002, 3 (06) :903-910

[17] Primary human bone marrow adipocytes support TNF-α-induced osteoclast differentiation and function through RANKL expression [J].

Goto, Hisataka ;

Hozumi, Akira ;

Osaki, Makoto ;

Fukushima, Tatsuya ;

Sakamoto, Kazutaka ;

Yonekura, Akihiko ;

Tomita, Masato ;

Furukawa, Keizo ;

Shindo, Hiroyuki ;

Baba, Hideo .

CYTOKINE, 2011, 56 (03) :662-668

[18]

Hagh MF, 2015, CELL J, V17, P71

[19] Osteogenesis and aging: lessons from mesenchymal stem cells [J].

Infante, Arantza ;

Rodriguez, Clara I. .

STEM CELL RESEARCH & THERAPY, 2018, 9 :244

[20] Regulation of Cellular Senescence by Polycomb Chromatin Modifiers through Distinct DNA Damage-and Histone Methylation-Dependent Pathways [J].

Ito, Takahiro ;

Teo, Yee Voan ;

Evans, Shane A. ;

Neretti, Nicola ;

Sedivy, John M. .

CELL REPORTS, 2018, 22 (13) :3480-3492

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