DZNep promotes mouse bone defect healing via enhancing both osteogenesis and osteoclastogenesis.
DZNep promotes mouse bone defect healing via enhancing both osteogenesis and osteoclastogenesis.
复制标题
DZNep 通过增强成骨和破骨细胞生成促进小鼠骨缺损愈合
DOI：
10.1186/s13287-021-02670-6
复制
发表时间：
2021-12-20
影响因子：
7.5
通讯作者：
Zhao J
中科院分区：
文献类型：
--
作者：
Cao X;He W;Rong K;Xu S;Chen Z;Liang Y;Han S;Zhou Y;Yang X;Ma H;Qin A;Zhao J
Zeste增强子同源物2（Enhancer of zeste homolog 2，EZH 2）是一种新的癌基因，能特异性地将组蛋白H3赖氨酸27（H3 K27 me 3）三甲基化，从而抑制下游抑癌基因的表达。作为EZH 2的小分子抑制剂，3-去氮普兰诺星（DZNep）因其抑瘤作用而被广泛研究。近年来，随着骨细胞表观遗传调控作用的研究，DZNep促进成骨的特性和分子机制的研究不断被报道，并引起了人们的广泛关注。本研究旨在阐明DZNep对破骨细胞和成骨细胞形成过程中EZH 2-H3 K27 me 3轴及其下游因子的作用，以及DZNep对骨缺损愈合的治疗可能性。体外培养骨髓间充质干细胞（BMSC），采用细胞计数试剂盒-8、碱性磷酸酶（ALP）和AR染色法检测BMSC对DZNep的反应性。采用qPCR和western blotting检测核因子-κB（NF-κB）、丝裂原活化蛋白激酶（MAPK）、Wnt信号通路的表达。建立小鼠骨缺损模型，拯救DZNep注射，并通过X射线和显微CT和组织学staining. ResultsConsistently与以前的研究，DZNep通过Wnt家族成员1（Wnt 1），Wnt 6，和Wnt 10a增强成骨作用，我们的研究结果表明，DZNep还通过EZH 2-H3 K27 me 3-Wnt 4轴促进成骨细胞的分化和矿化。此外，我们确定DZNep通过促进IKKα/β、IκB的磷酸化以及随后的NF-κB核转位来促进核因子-κB（NF-κB）配体（RANKL）诱导的破骨细胞形成，这归功于EZH 2-H3 K27 me 3-Foxc 1轴。结论靶向EZH 2-H3 K27 me 3轴的DZNep通过促进成骨细胞骨吸收和成骨细胞骨形成促进小鼠骨缺损愈合。
BackgroundEnhancer of zeste homolog 2 (EZH2) is a novel oncogene that can specifically trimethylate the histone H3 lysine 27 (H3K27me3) to transcriptionally inhibit the expression of downstream tumor-suppressing genes. As a small molecular inhibitor of EZH2, 3-Deazaneplanocin (DZNep) has been widely studied due to the role of tumor suppression. With the roles of epigenetic regulation of bone cells emerged in past decades, the property and molecular mechanism of DZNep on enhancing osteogenesis had been reported and attracted a great deal of attention recently. This study aims to elucidate the role of DZNep on EZH2-H3K27me3 axis and downstream factors during both osteoclasts and osteoblasts formation and the therapeutic possibility of DZNep on bone defect healing.MethodsBone marrow-derived macrophages (BMMs) cells were cultured, and their responsiveness to DZNep was evaluated by cell counting kit-8, TRAP staining assay, bone resorption assay, podosome actin belt. Bone marrow-derived mesenchymal stem cells (BMSC) were cultured and their responsiveness to DZNep was evaluated by cell counting kit-8, ALP and AR staining assay. The expression of nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), Wnt signaling pathway was determined by qPCR and western blotting. Mouse bone defect models were created, rescued by DZNep injection, and the effectiveness was evaluated by X-ray and micro-CT and histological staining.ResultsConsistent with the previous study that DZNep enhances osteogenesis via Wnt family member 1(Wnt1), Wnt6, and Wnt10a, our results showed that DZNep also promotes osteoblasts differentiation and mineralization through the EZH2-H3K27me3-Wnt4 axis. Furthermore, we identified that DZNep promoted the receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL)-induced osteoclast formation via facilitating the phosphorylation of IKKα/β, IκB, and subsequently NF-κB nuclear translocation, which credit to the EZH2-H3K27me3-Foxc1 axis. More importantly, the enhanced osteogenesis and osteoclastogenesis result in accelerated mice bone defect healing in vivo.ConclusionDZNep targeting EZH2-H3K27me3 axis facilitated the healing of mice bone defect via simultaneously enhancing osteoclastic bone resorption and promoting osteoblastic bone formation.
登录
查看更多内容
影响因子：
11.5
作者：
Gannon, Orla M.;de Long, Lilia Merida;Saunders, Nicholas A.
通讯作者：
Saunders, Nicholas A.
DOI：
10.4049/jimmunol.1501466
发表时间：
2016-06-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Fang C;Qiao Y;Mun SH;Lee MJ;Murata K;Bae S;Zhao B;Park-Min KH;Ivashkiv LB
通讯作者：
Ivashkiv LB
影响因子：
11.5
作者：
Chase, Andrew;Cross, Nicholas C. P.
通讯作者：
Cross, Nicholas C. P.
影响因子：
82.9
作者：
Dankbar, Berno;Fennen, Michelle;Pap, Thomas
通讯作者：
Pap, Thomas
DOI：
10.1186/bcr2781
发表时间：
2010
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Chen YC;Sosnoski DM;Mastro AM
通讯作者：
Mastro AM