Deletion of Rheb1 in Osteocytes Leads to Osteopenia Characterized by Reduced Bone Formation and Enhanced Bone Resorption.
Deletion of Rheb1 in Osteocytes Leads to Osteopenia Characterized by Reduced Bone Formation and Enhanced Bone Resorption.
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DOI：
10.1089/dna.2021.0874
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发表时间：
2022-06
影响因子：
3.1
通讯作者：
Jun Yang;Wuju Zhang;Eryong Lai;Wen Liu;Pinglin Lai;Zhipeng Zou;Weidong Wang;X. Bai
中科院分区：
文献类型：
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作者：
Jun Yang;Wuju Zhang;Eryong Lai;Wen Liu;Pinglin Lai;Zhipeng Zou;Weidong Wang;X. Bai
大脑 1 (Rheb1) 中富含的 Ras 同源物是雷帕霉素复合物 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，其对体内骨代谢的影响仍不清楚。该研究旨在了解 Rheb1 对骨稳态的作用。我们测量了血清参数并进行了组织形态计量学、实时定量聚合酶链反应和蛋白质印迹，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抗酒石酸酸性磷酸酶染色，以描绘Rheb1对骨稳态的影响。在Rheb1 KO小鼠中，结果显示Rheb1 KO对骨微结构造成显着损伤，表明mTORC1活性对于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表达并导致破骨细胞增加，表明KO小鼠骨吸收活性增加。研究结果证实，成骨细胞/骨细胞中的 Rheb1 缺失会因骨形成受损和骨吸收增强而导致骨质减少。
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.