Jiang Jishi, Li Dan, Cui Di, Wan Yunpeng, Zhou Pinghui, Cui Xilong, Yu Haiyang
Department of Orthopedics, Affiliated Fuyang People's Hospital of Anhui Medical University, Fuyang, Anhui, China.
Clinical Research Center for Spinal Deformity of Anhui Province, Fuyang, Anhui, China.
Biochem Genet. 2025 Apr 13. doi: 10.1007/s10528-025-11099-y.
Osteoporosis (OS) is a prevalent skeletal disorder characterized by reduced bone mass and increased fracture risk, often linked to compromised functions of bone mesenchymal stem cells (BMSCs). Mitochondrial dysfunction and aberrant mitophagy are implicated in OS pathogenesis. This study aimed to identify a novel mitochondrial-related gene signature in BMSCs from OS patients by integrating single-cell and bulk transcriptome data. We analyzed single-cell RNA sequencing data from GSE147287 and bulk transcriptome data from GSE35956 to identify differentially expressed mitochondrial-related genes (MRGs) in BMSCs between healthy individuals and OS patients. Key genes were identified using LASSO logistic regression and random forest algorithms, and their differential expression was validated by RT-qPCR, Western blot, and immunofluorescence. Functional assays, including osteogenic differentiation and β-galactosidase staining, were conducted following siRNA-mediated knockdown of DUT. We identified 28 differentially expressed MRGs, with four key genes (DUT, UQCR10, DNAJC4, and MRPL33) further confirmed. Electron microscopy scanning showed damage to BMSCs mitochondria and decreased osteogenic differentiation ability in OS. Silencing DUT significantly impairs the mitochondrial function and osteogenic differentiation ability of BMSCs, indicating its potential role in OS development. This study identifies a mitochondrial gene signature in BMSCs linked to osteoporosis, with DUT emerging as a key regulator. DUT silencing impairs mitochondrial function and osteogenic differentiation, suggesting it as a potential therapeutic target for OS.
骨质疏松症（OS）是一种常见的骨骼疾病，其特征是骨量减少和骨折风险增加，通常与骨间充质干细胞（BMSCs）功能受损有关。线粒体功能障碍和异常的线粒体自噬与OS的发病机制有关。本研究旨在通过整合单细胞和批量转录组数据，在OS患者的BMSCs中鉴定一种新的线粒体相关基因特征。我们分析了来自GSE147287的单细胞RNA测序数据和来自GSE35956的批量转录组数据，以鉴定健康个体和OS患者之间BMSCs中差异表达的线粒体相关基因（MRGs）。使用LASSO逻辑回归和随机森林算法鉴定关键基因，并通过RT-qPCR、蛋白质免疫印迹和免疫荧光验证其差异表达。在siRNA介导的DUT敲低后进行功能测定，包括成骨分化和β-半乳糖苷酶染色。我们鉴定出28个差异表达的MRGs，其中四个关键基因（DUT、UQCR10、DNAJC4和MRPL33）得到进一步证实。电子显微镜扫描显示OS中BMSCs线粒体受损且成骨分化能力下降。沉默DUT显著损害BMSCs的线粒体功能和成骨分化能力，表明其在OS发展中的潜在作用。本研究鉴定了BMSCs中与骨质疏松症相关的线粒体基因特征，DUT成为关键调节因子。DUT沉默损害线粒体功能和成骨分化，表明它是OS的潜在治疗靶点。
