NOTCH2 promotes osteoclast maturation and metabolism and modulates the transcriptome profile during osteoclastogenesis.
NOTCH2 promotes osteoclast maturation and metabolism and modulates the transcriptome profile during osteoclastogenesis.
复制标题
NOTCH2促进破骨细胞成熟和代谢，并调节破骨细胞发生过程中的转录组谱。
DOI：
10.1016/j.jbc.2023.105613
复制
发表时间：
2024-02
影响因子：
4.8
通讯作者：
Denker, Emily
中科院分区：
文献类型：
--
作者：
Canalis, Ernesto;Schilling, Lauren;Yu, Jungeun;Denker, Emily
Noch信号在骨重建中起着关键的调节作用，而NOTCH2促进破骨细胞的形成，这种作用主要是由其靶基因Hes1介导的。在本研究中，我们探索了NOTCH2功能获得突变的Notch2tm1.1Ecan在骨髓来源的巨噬细胞(BMM)中促进破骨细胞生成的机制，并与对照组小鼠进行了比较。Notch2tm1.1Ecan小鼠是骨量减少的，并增强了破骨细胞的生成。Notch2tm1.1Ecan BMMS在巨噬细胞集落刺激因子和NF-κB受体激活剂配体存在下培养，大量RNASeq和基因集浓缩分析表明，与增强细胞代谢、有氧呼吸和线粒体功能相关的基因丰富，这些基因都与破骨细胞的形成有关。在Hes1失活的情况下，这些通路没有增强。对混合对照和Notch2tm1.1Ecan BMMS经M-κ或M-CSF和NF-CSF B受体激活剂处理3天后的单细胞RNASeq数据分析，确定了11个明确的细胞簇。假时间轨迹分析表明，表达与破骨细胞前体、破骨细胞前体和成熟细胞相关的基因的簇的轨迹。与对照BMMS相比，Notch2tm1.1Ecan中表达破骨细胞相关基因标记物的细胞数量增加，并且Notch2tm1.1Ecan细胞中破骨细胞前体和前体相关基因的表达增强。综上所述，骨髓基质细胞培养显示出细胞异质性，NOTCH2促进破骨细胞的生成，增加线粒体和破骨细胞的代谢活性，并影响骨髓基质细胞的细胞团分配。
Notch signaling plays a key regulatory role in bone remodeling and NOTCH2 enhances osteoclastogenesis, an effect that is mostly mediated by its target gene Hes1. In the present study, we explored mechanisms responsible for the enhanced osteoclastogenesis in bone marrow–derived macrophages (BMM) from Notch2tm1.1Ecan, harboring a NOTCH2 gain-of-function mutation, and control mice. Notch2tm1.1Ecan mice are osteopenic and have enhanced osteoclastogenesis. Bulk RNA-Seq and gene set enrichment analysis of Notch2tm1.1Ecan BMMs cultured in the presence of macrophage colony stimulating factor (M-CSF) and receptor activator of NF-κB ligand revealed enrichment of genes associated with enhanced cell metabolism, aerobic respiration, and mitochondrial function, all associated with osteoclastogenesis. These pathways were not enhanced in the context of a Hes1 inactivation. Analysis of single cell RNA-Seq data of pooled control and Notch2tm1.1Ecan BMMs treated with M-CSF or M-CSF and receptor activator of NF-κB ligand for 3 days identified 11 well-defined cellular clusters. Pseudotime trajectory analysis indicated a trajectory of clusters expressing genes associated with osteoclast progenitors, osteoclast precursors, and mature cells. There were an increased number of cells expressing gene markers associated with the osteoclast and with an unknown, albeit related, cluster in Notch2tm1.1Ecan than in control BMMs as well as enhanced expression of genes associated with osteoclast progenitors and precursors in Notch2tm1.1Ecan cells. In conclusion, BMM cultures display cellular heterogeneity, and NOTCH2 enhances osteoclastogenesis, increases mitochondrial and metabolic activity of osteoclasts, and affects cell cluster allocation in BMMs.
影响因子：
3.7
作者：
Canalis E
通讯作者：
Canalis E