Deletion of Rheb1 in Osteocytes Leads to Osteopenia Characterized by Reduced Bone Formation and Enhanced Bone Resorption.

IF 2.6 4区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Jun Yang, Wuju Zhang, Eryong Lai, Wen Liu, Pinglin Lai, Zhipeng Zou, Weidong Wang, X. Bai
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引用次数: 0

Abstract

Ras homologue enriched in brain 1 (Rheb1), an upstream activator of the mechanistic target of rapamycin complex 1 (mTORC1), is known to modulate various cellular processes. However, its impact on bone metabolism in vivo remains unknown. The study aimed at understanding the role of Rheb1 on bone homeostasis. We measured the serum parameters and performed histomorphometry, quantitative real-time polymerase chain reaction, and Western blotting, along with the generation of mouse gene knockout (KO) model, and conducted a microcomputed tomography analysis and tartrate-resistant acid phosphatase staining, to delineate the impacts of Rheb1 on bone homeostasis. In the Rheb1 KO mice, the results showed that Rheb1 KO caused significant damage to the bone microarchitecture, indicating that mTORC1 activity was essential for the regulation of bone homeostasis. Specifically, suppressed mineralization activity in primary osteoblasts and a decreased osteoblast number were observed in the Rheb1 KO mice, demonstrating that loss of Rheb1 led to impaired osteoblastic differentiation. Furthermore, the higher apoptotic ratio in Rheb1-null osteocytes could promote Tnfsf11 expression and lead to an increase in osteoclasts, indicating increased bone resorption activity in the KO mice. The findings confirmed that Rheb1 deletion in osteoblasts/osteocytes led to osteopenia due to impaired bone formation and enhanced bone resorption.
骨细胞中Rheb1的缺失导致骨质减少,其特征是骨形成减少和骨吸收增强。
脑内富集的Ras同源物1(Rheb1)是雷帕霉素复合物1(mTORC1)机制靶标的上游激活剂,已知可调节各种细胞过程。然而,它对体内骨代谢的影响仍然未知。本研究旨在了解Rheb1在骨稳态中的作用。我们测量了血清参数,进行了组织形态计量学、定量实时聚合酶链式反应和蛋白质印迹,以及小鼠基因敲除(KO)模型的生成,并进行了微计算机断层扫描分析和酒石酸盐抗性酸性磷酸酶染色,以描述Rheb1对骨稳态的影响。在Rheb1-KO小鼠中,结果显示Rheb1-KO对骨微结构造成显著损伤,表明mTORC1活性对骨稳态的调节至关重要。具体而言,在Rheb1-KO小鼠中观察到原代成骨细胞的矿化活性受到抑制,成骨细胞数量减少,表明Rheb1的缺失导致成骨细胞分化受损。此外,Rheb1缺失骨细胞中较高的凋亡率可以促进Tnfsf11的表达,并导致破骨细胞的增加,表明KO小鼠的骨吸收活性增加。研究结果证实,由于骨形成受损和骨吸收增强,成骨细胞/骨细胞中Rheb1缺失导致骨质减少。
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来源期刊
DNA and cell biology
DNA and cell biology 生物-生化与分子生物学
CiteScore
6.60
自引率
0.00%
发文量
93
审稿时长
1.5 months
期刊介绍: DNA and Cell Biology delivers authoritative, peer-reviewed research on all aspects of molecular and cellular biology, with a unique focus on combining mechanistic and clinical studies to drive the field forward. DNA and Cell Biology coverage includes: Gene Structure, Function, and Regulation Gene regulation Molecular mechanisms of cell activation Mechanisms of transcriptional, translational, or epigenetic control of gene expression Molecular Medicine Molecular pathogenesis Genetic approaches to cancer and autoimmune diseases Translational studies in cell and molecular biology Cellular Organelles Autophagy Apoptosis P bodies Peroxisosomes Protein Biosynthesis and Degradation Regulation of protein synthesis Post-translational modifications Control of degradation Cell-Autonomous Inflammation and Host Cell Response to Infection Responses to cytokines and other physiological mediators Evasive pathways of pathogens.
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