Xiaoli Shi, Xueli Jia, Wei Liu, Liwen Shi, Zheng Yang, Jie Zhou, Xiaoxia Li, Baoli Wang
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Further mechanistic investigations revealed that ZNF750 transcriptionally suppressed the expression of Snail family transcriptional repressor 1 (SNAI1) by binding to the proximal promoter region of Snai1 gene, thereby activating Wnt/β-catenin signaling. SNAI1 exerted opposing effects on cell differentiation towards osteoblasts and adipocytes in comparison to ZNF750. The overexpression of SNAI1 counteracted the dysregulated osteogenic and adipogenic differentiation induced by ZNF750. Furthermore, the transplantation of Znf750-silenced bone marrow stromal cells into the marrow of wild-type mice resulted in a reduction in cancellous and cortical bone mass, alongside a decrease in osteoblasts and an increase in marrow adipocytes, while the number of osteoclasts remained unchanged. 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引用次数: 0
摘要
锌指蛋白750 (ZNF750)已被确定为多种恶性肿瘤的潜在肿瘤抑制因子。然而,ZNF750在调节间充质细胞分化和骨稳态中的具体作用尚未阐明。在目前的研究中,我们观察到骨组织中大量存在ZNF750,并注意到其在间充质祖细胞成骨分化过程中的表达变化。功能实验表明,ZNF750促进成骨分化,同时阻碍间充质干细胞/祖细胞的成脂分化。进一步的机制研究表明,ZNF750通过结合SNAI1基因近端启动子区,激活Wnt/β-catenin信号通路,从而抑制Snail family transcriptional repressor 1 (SNAI1)的转录表达。与ZNF750相比,SNAI1对细胞向成骨细胞和脂肪细胞分化的作用相反。SNAI1的过表达抵消了ZNF750诱导的成骨和脂肪分化失调。此外,将znf750沉默的骨髓基质细胞移植到野生型小鼠骨髓中,导致松质骨量和皮质骨量减少,成骨细胞减少,骨髓脂肪细胞增加,而破骨细胞数量保持不变。本研究首次证明ZNF750通过转录失活SNAI1信号通路调节成骨细胞和脂肪细胞从间充质干细胞/祖细胞的分化,从而有助于维持骨稳态。这表明ZNF750可能是代谢性骨疾病如骨质疏松症的一个有希望的治疗靶点。
Zinc finger protein 750 is a novel regulator of osteoblast differentiation and bone homeostasis by transcriptionally deactivating SNAI1 signaling.
Zinc finger protein 750 (ZNF750) has been identified as a potential tumor suppressor across multiple malignancies. Nevertheless, the specific involvement of ZNF750 in the regulation of mesenchymal cell differentiation and bone homeostasis has yet to be elucidated. In the current study, we observed a substantial presence of ZNF750 in bone tissue and noted alterations in its expression during osteogenic differentiation of mesenchymal progenitor cells. Functional experiments indicated that ZNF750 promoted osteogenic differentiation while impeding adipogenic differentiation from mesenchymal stem/progenitor cells. Further mechanistic investigations revealed that ZNF750 transcriptionally suppressed the expression of Snail family transcriptional repressor 1 (SNAI1) by binding to the proximal promoter region of Snai1 gene, thereby activating Wnt/β-catenin signaling. SNAI1 exerted opposing effects on cell differentiation towards osteoblasts and adipocytes in comparison to ZNF750. The overexpression of SNAI1 counteracted the dysregulated osteogenic and adipogenic differentiation induced by ZNF750. Furthermore, the transplantation of Znf750-silenced bone marrow stromal cells into the marrow of wild-type mice resulted in a reduction in cancellous and cortical bone mass, alongside a decrease in osteoblasts and an increase in marrow adipocytes, while the number of osteoclasts remained unchanged. This study presents the first demonstration that ZNF750 regulates the differentiation of osteoblasts and adipocytes from mesenchymal stem/progenitor cells by transcriptionally deactivating SNAI1 signaling, thereby contributing to the maintenance of bone homeostasis. It suggests that ZNF750 may represent a promising therapeutic target for metabolic bone disorders such as osteoporosis.
期刊介绍:
STEM CELLS Translational Medicine is a monthly, peer-reviewed, largely online, open access journal.
STEM CELLS Translational Medicine works to advance the utilization of cells for clinical therapy. By bridging stem cell molecular and biological research and helping speed translations of emerging lab discoveries into clinical trials, STEM CELLS Translational Medicine will help move applications of these critical investigations closer to accepted best patient practices and ultimately improve outcomes.
The journal encourages original research articles and concise reviews describing laboratory investigations of stem cells, including their characterization and manipulation, and the translation of their clinical aspects of from the bench to patient care. STEM CELLS Translational Medicine covers all aspects of translational cell studies, including bench research, first-in-human case studies, and relevant clinical trials.