ELAVL1通过下调SIRT1促进铁中毒诱导的糖尿病骨质疏松症成骨分化的抑制

IF 2.5 4区生物学 Q1 ANATOMY & MORPHOLOGY

Tissue & cell Pub Date : 2025-07-29 DOI:10.1016/j.tice.2025.103060

Bi Huang , Jie Jiang , Xiang Ou , Meng Hao , Huige Shao

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引用次数: 0

摘要

目的：铁下垂可能参与糖尿病骨质疏松症（DOP）的发病机制。本研究旨在确定Sirtuin 1 （SIRT1）是否通过elav样RNA结合蛋白1 （ELAVL1）介导的铁凋亡调节DOP。方法将smc3t3 - e1细胞培养于高糖（HG）培养基中，通过检测RUNX2、OCN、ALP活性和茜素红S染色观察其成骨分化情况。通过测量GPX4、ACSL4、ROS、MDA和Fe2 +来评估铁下垂。采用C57BL/6 J小鼠高脂饲粮联合1 %链脲佐菌素注射液建立DOP小鼠模型。分析股骨组织病理学、体重、空腹血糖（FBG）和铁下垂情况。结果shg暴露抑制成骨分化，表现为MC3T3-E1细胞RUNX2、OCN ALP活性和钙积累降低（P <； 0.05）；诱导铁下垂，包括GPX4降低，ACSL4、ROS、MDA、Fe2+升高（P <； 0.05）。SIRT1过表达或用fe -1治疗可逆转hg诱导的铁下垂并恢复成骨分化（P <； 0.05）。SIRT1与ELAVL1结合，其过表达抑制ELAVL1（P <； 0.05）。在共过表达SIRT1和ELAVL1的HG刺激细胞中，铁下垂和成骨标志物与暴露于HG的细胞相似（P <； 0.05）。DOP小鼠表现为空腹血糖升高、体重减轻、ELAVL1升高、SIRT1降低（P <； 0.05）；这些小鼠的股骨组织学受损。DOP小鼠明显下垂（P <； 0.05）。在DOP小鼠中，沉默ELAVL1可改善股骨组织完整性，抑制铁下垂，促进成骨分化，恢复体重，上调SIRT1 （P <； 0.05）。结论elavl1抑制SIRT1翻译，中断铁凋亡介导的成骨细胞分化，从而抑制DOP进展。

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ELAVL1 promotes ferroptosis-induced inhibition of osteogenic differentiation in diabetic osteoporosis by downregulating SIRT1

Objective

Ferroptosis can implicate in the pathogenesis of diabetic osteoporosis (DOP). This study aimed to determine whether Sirtuin 1 (SIRT1) modulates DOP through ELAV-like RNA binding protein 1 (ELAVL1)-mediated ferroptosis.

Methods

MC3T3-E1 cells were cultured in high glucose (HG) medium, and osteogenic differentiation was assessed by evaluating RUNX2, OCN, ALP activity, and calcium deposition via Alizarin Red S staining. Ferroptosis was evaluated by measuring GPX4, ACSL4, ROS, MDA, and Fe^2 + . A DOP mouse model was established using C57BL/6 J mice fed a high-fat diet combined with 1 % streptozotocin injection. Femoral histopathology, body weight, fasting blood glucose (FBG), and ferroptosis were analyzed.

Results

HG exposure inhibited osteogenic differentiation, characterized by the reduction in RUNX2, OCN ALP activity and calcium accumulation in MC3T3-E1 cells (P < 0.05); it induced ferroptosis, including the decrease in GPX4 and the increase in ACSL4, ROS, MDA and Fe²⁺ (P < 0.05). SIRT1 overexpression or treatment with Fer-1 reversed HG-induced ferroptosis and restored osteogenic differentiation (P < 0.05). SIRT1 was shown to bind ELAVL1, and its overexpression suppressed ELAVL1(P < 0.05). In HG-stimulated cells co-overexpressing SIRT1 and ELAVL1, both ferroptosis and osteogenic markers resembled those in cells exposed to HG (P < 0.05). DOP mice exhibited elevated FBG, reduced body weight, increased ELAVL1, and decreased SIRT1(P < 0.05); these mice showed impaired femoral histology. Ferroptosis was evident in DOP mice (P < 0.05). Silencing ELAVL1 improved femoral tissue integrity, inhibited ferroptosis, promoted osteogenic differentiation, restored body weigh, and upregulated SIRT1 in DOP mice (P < 0.05).

Conclusion

ELAVL1 repressed SIRT1 translation to interrupt ferroptosis-mediated osteoblastic differentiation, thereby inhibiting DOP progression.

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来源期刊

Tissue & cell 医学-解剖学与形态学

CiteScore

3.90

自引率

0.00%

发文量

234

期刊介绍： Tissue and Cell is devoted to original research on the organization of cells, subcellular and extracellular components at all levels, including the grouping and interrelations of cells in tissues and organs. The journal encourages submission of ultrastructural studies that provide novel insights into structure, function and physiology of cells and tissues, in health and disease. Bioengineering and stem cells studies focused on the description of morphological and/or histological data are also welcomed. Studies investigating the effect of compounds and/or substances on structure of cells and tissues are generally outside the scope of this journal. For consideration, studies should contain a clear rationale on the use of (a) given substance(s), have a compelling morphological and structural focus and present novel incremental findings from previous literature.