Lan Haifeng, Yu Xiao-Jun, Ling Guangsheng, Zeng Yuwei, Yang Yixi, He Meiyang, Yu Yixiao, Shao Ming
Department of Orthopedics, Guangdong Provincial Key Laboratory of Major Obstetric Diseases; Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology; The Third Affiliated Hospital, Guangzhou Medical University, No. 63, Duobao Road, Liwan District, Guangzhou, Guangdong Province, 510150, P. R. China.
Department of Spine Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, 710054, China.
Mol Med. 2025 May 30;31(1):214. doi: 10.1186/s10020-025-01222-5.
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.
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.
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.
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.
慢性肾脏病（CKD）常导致矿物质骨代谢紊乱（MBD），由于骨脆性和代谢紊乱，严重影响患者生活质量。本研究在CKD-MBD小鼠模型中探究酪蛋白激酶2（CK2）和泛素特异性蛋白酶7（USP7）在调节 runt 相关转录因子2（RUNX2）驱动的成骨过程中的作用。
采用5/6肾切除建立CKD-MBD小鼠模型。对CKD相关数据集进行生物信息学分析，确定RUNX2和USP7为参与骨代谢的关键基因。进行体内和体外实验，以评估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。进行组织形态计量学、酶联免疫吸附测定（ELISA）和显微CT分析，以评估骨密度、强度和代谢标志物。
CKD-MBD小鼠中RUNX2和USP7显著下调。敲低RUNX2会损害成骨细胞分化，降低骨密度，并增加骨转换，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小鼠的成骨细胞分化增强，骨代谢改善。
CK2激活促进USP7对RUNX2的磷酸化和稳定作用，从而改善CKD-MBD中的成骨和骨代谢。靶向CK2/USP7/RUNX2轴为管理CKD相关骨疾病提供了一种潜在的治疗策略。
