长非编码 RNA hottip 通过抑制泽斯特同源增强子 2（Ezh2）/组蛋白甲基化调控轴维持骨骼稳态

IF 5.9 3区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Non-coding RNA Research Pub Date : 2025-02-28 DOI:10.1016/j.ncrna.2025.01.003

Zhi-Peng Li , Yong-Xin Mai , Shu-Ting Zhou , Chuan-jian Shi , Jiang Shao , Pu-ping Liang , Wei-cheng Liang , Jin-fang Zhang

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引用次数: 0

摘要

最近的证据强调了长链非编码rna （lncRNAs）通过协调成骨细胞和破骨细胞的发育在协调骨重塑和骨骼稳态中的关键作用。值得注意的是，与成骨调控有关的致癌lncRNA Hottip仍未得到充分阐明。本研究旨在描述Hottip在骨重塑和骨骼稳态中的作用。方法采用骨尖敲除小鼠，观察其对骨代谢的影响。体外实验探讨了Hottip对细胞的影响机制，并探讨了分子相互作用的基础。通过体内实验研究了Hottip过表达的治疗潜力。结果骨尖敲除小鼠表现出骨代谢紊乱、组织异常和质量下降，导致骨折愈合延迟。在体外，Hottip敲低抑制成骨细胞分化，同时促进破骨细胞分化，对Hottip过表达有相反的作用。机制上，Hottip与EZH2物理相互作用，诱导其降解，并通过抑制H3K9me3和H3K27me3促进成骨基因转录。体内实验证实了Hottip过表达促进骨再生和加速骨折愈合的潜力。综上所述，本研究确定Hottip是成骨细胞和破骨细胞分化的关键调节因子，对维持骨骼稳态至关重要。Hottip是一种很有前景的骨再生治疗靶点。这些发现为lncrna介导的骨骼动力学机制提供了有价值的见解。

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Long noncoding RNA hottip maintained skeletal homeostasis via suppressing the enhancer of zeste homolog 2 (Ezh2)/histone methylation regulatory axis

Objective

Recent evidence underscores the pivotal role of long noncoding RNAs (lncRNAs) in orchestrating bone remodeling and skeletal homeostasis by harmonizing osteoblast and osteoclast development. Notably, the oncogenic lncRNA, Hottip, implicated in osteogenesis regulation, remains insufficiently elucidated. This study aims to delineate Hottip's role in bone remodeling and skeletal homeostasis.

Methods

Hottip knockout mice were generated to discern its impact on bone metabolism. In vitro experiments probed cellular mechanisms influenced by Hottip, while molecular interactions were explored to understand its basis. The therapeutic potential of Hottip overexpression was investigated through in vivo experiments.

Results

Hottip knockout mice displayed disrupted bone metabolism, aberrant tissue, and compromised quality, leading to delayed fracture healing. In vitro, Hottip knockdown impeded osteoblast differentiation, while promoting osteoclast differentiation, with converse effects upon Hottip overexpression. Mechanistically, Hottip physically interacted with EZH2, inducing its degradation and enhancing osteogenic gene transcription by suppressing H3K9me3 and H3K27me3. In vivo experiments validated Hottip overexpression's potential to promote bone regeneration and hasten fracture healing.

Conclusion

In summary, this study identifies Hottip as a critical regulator in osteoblast and osteoclast differentiation, crucial for maintaining skeletal homeostasis. Hottip emerges as a promising therapeutic target for enhancing bone regeneration. These findings contribute valuable insights into lncRNA-mediated mechanisms governing skeletal dynamics.

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来源期刊

Non-coding RNA Research Medicine-Biochemistry (medical)

CiteScore

7.70

自引率

6.00%

发文量

审稿时长

49 days

期刊介绍： Non-coding RNA Research aims to publish high quality research and review articles on the mechanistic role of non-coding RNAs in all human diseases. This interdisciplinary journal will welcome research dealing with all aspects of non-coding RNAs-their biogenesis, regulation and role in disease progression. The focus of this journal will be to publish translational studies as well as well-designed basic studies with translational and clinical implications. The non-coding RNAs of particular interest will be microRNAs (miRNAs), small interfering RNAs (siRNAs), small nucleolar RNAs (snoRNAs), U-RNAs/small nuclear RNAs (snRNAs), exosomal/extracellular RNAs (exRNAs), Piwi-interacting RNAs (piRNAs) and long non-coding RNAs. Topics of interest will include, but not limited to: -Regulation of non-coding RNAs -Targets and regulatory functions of non-coding RNAs -Epigenetics and non-coding RNAs -Biological functions of non-coding RNAs -Non-coding RNAs as biomarkers -Non-coding RNA-based therapeutics -Prognostic value of non-coding RNAs -Pharmacological studies involving non-coding RNAs -Population based and epidemiological studies -Gene expression / proteomics / computational / pathway analysis-based studies on non-coding RNAs with functional validation -Novel strategies to manipulate non-coding RNAs expression and function -Clinical studies on evaluation of non-coding RNAs The journal will strive to disseminate cutting edge research, showcasing the ever-evolving importance of non-coding RNAs in modern day research and medicine.