Targeting casein kinase 2 and ubiquitin-specific protease 7 to modulate RUNX2-mediated osteogenesis in chronic kidney disease.

IF 6 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Medicine Pub Date : 2025-05-30 DOI:10.1186/s10020-025-01222-5

Haifeng Lan, Xiao-Jun Yu, Guangsheng Ling, Yuwei Zeng, Yixi Yang, Meiyang He, Yixiao Yu, Ming Shao

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引用次数: 0

Abstract

Objective: Chronic Kidney Disease (CKD) frequently leads to Mineral Bone Disorder (MBD), which significantly affects patient quality of life due to bone fragility and metabolic disturbances. This study investigates the role of Casein Kinase 2 (CK2) and Ubiquitin-Specific Protease 7 (USP7) in modulating Runt-related Transcription Factor 2 (RUNX2)-driven osteogenesis in a CKD-MBD mouse model.

Methods: A CKD-MBD mouse model was established using 5/6 nephrectomy. Bioinformatic analysis of CKD-related datasets identified RUNX2 and USP7 as key genes implicated in bone metabolism. In vivo and in vitro experiments were conducted to assess the effects of CK2-mediated phosphorylation and USP7-induced deubiquitination on RUNX2 stability and function. Histomorphometry, Enzyme-Linked Immunosorbent Assay (ELISA), and micro-CT analyses were performed to evaluate bone density, strength, and metabolic markers.

Results: RUNX2 and USP7 were significantly downregulated in CKD-MBD mice. Silencing RUNX2 impaired osteoblast differentiation, reduced bone density, and increased bone turnover, while CK2 overexpression restored RUNX2 activity by phosphorylation, recruiting USP7 to stabilize RUNX2. Enhanced osteoblast differentiation and improved bone metabolism were observed in CKD-MBD mice upon CK2 activation.

Conclusion: CK2 activation promotes RUNX2 phosphorylation and stabilization by USP7, leading to improved osteogenesis and bone metabolism in CKD-MBD. Targeting the CK2/USP7/RUNX2 axis presents a potential therapeutic strategy for managing CKD-related bone disorders.

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靶向酪蛋白激酶2和泛素特异性蛋白酶7调节runx2介导的慢性肾脏疾病成骨。

目的：慢性肾脏疾病（CKD）常导致矿物质骨障碍（MBD），由于骨骼脆弱和代谢紊乱，严重影响患者的生活质量。本研究探讨了酪蛋白激酶2 （CK2）和泛素特异性蛋白酶7 （USP7）在CKD-MBD小鼠模型中调节runt相关转录因子2 （RUNX2）驱动的成骨过程中的作用。方法：采用5/6肾切除术建立CKD-MBD小鼠模型。对ckd相关数据集的生物信息学分析发现RUNX2和USP7是参与骨代谢的关键基因。通过体内和体外实验评估ck2介导的磷酸化和usp7诱导的去泛素化对RUNX2稳定性和功能的影响。采用组织形态测定法、酶联免疫吸附测定法（ELISA）和显微ct分析来评估骨密度、强度和代谢标志物。结果：RUNX2和USP7在CKD-MBD小鼠中显著下调。沉默RUNX2会破坏成骨细胞分化，降低骨密度，增加骨转换，而CK2过表达通过磷酸化恢复RUNX2活性，招募USP7来稳定RUNX2。CK2激活后，CKD-MBD小鼠成骨细胞分化增强，骨代谢改善。结论：CK2激活促进RUNX2磷酸化和USP7的稳定，导致CKD-MBD的成骨和骨代谢改善。靶向CK2/USP7/RUNX2轴为ckd相关骨疾病的治疗提供了一种潜在的治疗策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Medicine 医学-生化与分子生物学

CiteScore

8.60

自引率

0.00%

发文量

137

审稿时长

1 months

期刊介绍： Molecular Medicine is an open access journal that focuses on publishing recent findings related to disease pathogenesis at the molecular or physiological level. These insights can potentially contribute to the development of specific tools for disease diagnosis, treatment, or prevention. The journal considers manuscripts that present material pertinent to the genetic, molecular, or cellular underpinnings of critical physiological or disease processes. Submissions to Molecular Medicine are expected to elucidate the broader implications of the research findings for human disease and medicine in a manner that is accessible to a wide audience.