Identification and functional analysis of genes mediating osteoclast-driven progression of osteoporosis.

IF 2.6 4区综合性期刊 Q2 MULTIDISCIPLINARY SCIENCES

Science Progress Pub Date : 2024-10-01 DOI:10.1177/00368504241300723

Qu Xu, Gangning Feng, Zhihai Zhang, Jiangbo Yan, Zhiqun Tang, Rui Wang, Penggang Ma, Ye Ma, Guang Zhu, Qunhua Jin

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Abstract

Objective: The pathological mechanism of osteoporosis (OP) involves increased bone resorption mediated by osteoclasts and decreased bone formation mediated by osteoblasts, leading to an imbalance in bone homeostasis. Identifying key molecules in osteoclast-mediated OP progression is crucial for the prevention and treatment of OP.

Methods: Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were performed on the OP patient datasets from the GEO database. The results were intersected with the differential expression results from the osteoclast differentiation dataset to identify key genes. These key genes were then subjected to disease relevance analysis, and consensus clustering was performed on OP patient samples based on their expression profiles. The subgroups were analyzed for differences, followed by GO, KEGG, GSEA, and GSVA analyses, and immune infiltration. Finally, osteoclast differentiation model was constructed. After validating the success of the model using TRAP and F-actin staining, the differential expression of key genes was validated in vitro via Western blot.

Results: CTRL, ARHGEF5, PPAP2C, VSIG2, and PBLD were identified as key genes. These genes exhibited strong disease relevance (AUC > 0.9). Functional enrichment results also indicated their close association with OP and osteoclast differentiation. In vitro differential expression validation showed that during osteoclast differentiation, CTRL was downregulated, while ARHGEF5, PPAP2C, VSIG2, and PBLD were upregulated, with all differences being statistically significant (P < 0.05).

Discussion: Currently, there are no studies on the effects of these five genes on osteoclast differentiation. Therefore, it is meaningful to design in vivo and in vitro perturbation experiments to observe the impact of each gene on osteoclast differentiation and OP progression.

Conclusion: CTRL, ARHGEF5, PPAP2C, VSIG2, and PBLD show high potential as molecular targets for basic and clinical research in osteoclast-mediated OP.

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鉴定介导破骨细胞驱动骨质疏松症进展的基因并进行功能分析。

目的：骨质疏松症（OP）的病理机制包括破骨细胞介导的骨吸收增加和成骨细胞介导的骨形成减少，从而导致骨平衡失调。确定破骨细胞介导的 OP 进展过程中的关键分子对于预防和治疗 OP 至关重要：方法：对 GEO 数据库中的 OP 患者数据集进行差异表达分析和加权基因共表达网络分析（WGCNA）。方法：对 GEO 数据库中的 OP 患者数据集进行差异表达分析和加权基因共表达网络分析（WGCNA），并将分析结果与破骨细胞分化数据集的差异表达结果进行交叉分析，以确定关键基因。然后对这些关键基因进行疾病相关性分析，并根据其表达谱对 OP 患者样本进行共识聚类。对亚组进行差异分析，然后进行 GO、KEGG、GSEA 和 GSVA 分析以及免疫浸润分析。最后，构建了破骨细胞分化模型。在使用 TRAP 和 F-肌动蛋白染色验证模型成功后，通过 Western 印迹在体外验证了关键基因的差异表达：结果：CTRL、ARHGEF5、PPAP2C、VSIG2 和 PBLD 被确定为关键基因。这些基因具有很强的疾病相关性（AUC > 0.9）。功能富集结果也表明它们与 OP 和破骨细胞分化密切相关。体外差异表达验证显示，在破骨细胞分化过程中，CTRL 下调，而 ARHGEF5、PPAP2C、VSIG2 和 PBLD 上调，所有差异均有统计学意义（P 讨论）：目前，还没有关于这五个基因对破骨细胞分化影响的研究。因此，设计体内和体外扰动实验来观察各基因对破骨细胞分化和 OP 进展的影响是有意义的：结论：CTRL、ARHGEF5、PPAP2C、VSIG2 和 PBLD 很有可能成为破骨细胞介导的 OP 基础和临床研究的分子靶点。

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

Science Progress Multidisciplinary-Multidisciplinary

CiteScore

3.80

自引率

0.00%

发文量

119

期刊介绍： Science Progress has for over 100 years been a highly regarded review publication in science, technology and medicine. Its objective is to excite the readers'' interest in areas with which they may not be fully familiar but which could facilitate their interest, or even activity, in a cognate field.