ED-71 Ameliorates Bone Loss in Type 2 Diabetes Mellitus by Enhancing Osteogenesis Through Upregulation of the Circadian Rhythm Coregulator BMAL1.

IF 4.7 2区医学 Q1 CHEMISTRY, MEDICINAL Drug Design, Development and Therapy Pub Date : 2024-08-29 eCollection Date: 2024-01-01 DOI:10.2147/DDDT.S470684

Ting Liu, Luxu Wang, Tuo Shi, Hongrui Liu, Bo Liu, Jie Guo, Minqi Li

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Abstract

Purpose: Bone loss is a common complication of type 2 diabetes mellitus (T2DM). Circadian rhythms play a significant role in T2DM and bone remodeling. Eldecalcitol (ED-71), a novel active vitamin D analog, has shown promise in ameliorating T2DM. We aimed to investigate whether the circadian rhythm coregulator BMAL1 mediates the anti-osteoporotic effect of ED-71 in T2DM and its associated mechanisms.

Methods: A T2DM mouse model was established using high-fat diet (HDF) and streptozotocin (STZ) injection, and blood glucose levels were monitored weekly. HE staining, Masson staining, and Micro-CT were performed to assess the changes in bone mass. IHC staining and IF staining were used to detect osteoblast status and BMAL1 expression and RT-qPCR was applied to detect the change of oxidative stress factors. In vitro, high glucose (HG) stimulation was used to simulate the cell environment in T2DM. RT-qPCR, Western blot, IF, ALP staining and AR staining were used to detect osteogenic differentiation and SIRT1/GSK3β signaling pathway. DCFH-DA staining was used to detect reactive oxygen species (ROS) levels.

Results: ED-71 increased bone mass and promoted osteogenesis in T2DM mice. Moreover, ED-71 inhibited oxidative stress and promoted BMAL1 expression in osteoblasts The addition of STL1267, an agonist of the BMAL1 transcriptional repressor protein REV-ERB, reversed the inhibitory effect of ED-71 on oxidative stress and the promotional effect on osteogenic differentiation. In addition, ED-71 facilitated SIRT1 expression and reduced GSK3β activity. The inhibition of SIRT1 with EX527 partially attenuated ED-71's effects, whereas the GSK3β inhibitor LiCl further enhanced ED-71's positive effects on BMAL1 expression.

Conclusion: ED-71 ameliorates bone loss in T2DM by upregulating the circadian rhythm coregulator BMAL1 and promoting osteogenesis through inhibition of oxidative stress. The SIRT1/GSK3β signaling pathway is involved in the regulation of BMAL1.

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ED-71 通过上调昼夜节律核心调节因子 BMAL1 促进骨生成，从而改善 2 型糖尿病患者的骨质流失。

目的：骨质流失是 2 型糖尿病（T2DM）的常见并发症。昼夜节律在 T2DM 和骨重塑中起着重要作用。埃尔德卡糖醇（ED-71）是一种新型活性维生素 D 类似物，已显示出改善 T2DM 的前景。我们旨在研究昼夜节律核心调节因子 BMAL1 是否介导 ED-71 在 T2DM 中的抗骨质疏松作用及其相关机制：方法：通过高脂饮食（HDF）和注射链脲佐菌素（STZ）建立T2DM小鼠模型，每周监测血糖水平。通过 HE 染色、Masson 染色和显微 CT 来评估骨量的变化。IHC染色和IF染色用于检测成骨细胞状态和BMAL1表达，RT-qPCR用于检测氧化应激因子的变化。在体外，采用高糖（HG）刺激模拟 T2DM 的细胞环境。采用 RT-qPCR、Western 印迹、IF、ALP 染色和 AR 染色检测成骨分化和 SIRT1/GSK3β 信号通路。DCFH-DA染色用于检测活性氧（ROS）水平：结果：ED-71能增加T2DM小鼠的骨量并促进骨生成。加入 BMAL1 转录抑制蛋白 REV-ERB 的激动剂 STL1267 逆转了 ED-71 对氧化应激的抑制作用和对成骨分化的促进作用。此外，ED-71 还促进了 SIRT1 的表达并降低了 GSK3β 的活性。用EX527抑制SIRT1部分减弱了ED-71的作用，而GSK3β抑制剂氯化锂则进一步增强了ED-71对BMAL1表达的积极作用：结论：ED-71能上调昼夜节律核心调节因子BMAL1，并通过抑制氧化应激促进骨生成，从而改善T2DM患者的骨质流失。SIRT1/GSK3β信号通路参与了BMAL1的调控。

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来源期刊

Drug Design, Development and Therapy CHEMISTRY, MEDICINAL-PHARMACOLOGY & PHARMACY

CiteScore

9.00

自引率

0.00%

发文量

382

审稿时长

>12 weeks

期刊介绍： Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications. The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas. Specific topics covered by the journal include: Drug target identification and validation Phenotypic screening and target deconvolution Biochemical analyses of drug targets and their pathways New methods or relevant applications in molecular/drug design and computer-aided drug discovery* Design, synthesis, and biological evaluation of novel biologically active compounds (including diagnostics or chemical probes) Structural or molecular biological studies elucidating molecular recognition processes Fragment-based drug discovery Pharmaceutical/red biotechnology Isolation, structural characterization, (bio)synthesis, bioengineering and pharmacological evaluation of natural products** Distribution, pharmacokinetics and metabolic transformations of drugs or biologically active compounds in drug development Drug delivery and formulation (design and characterization of dosage forms, release mechanisms and in vivo testing) Preclinical development studies Translational animal models Mechanisms of action and signalling pathways Toxicology Gene therapy, cell therapy and immunotherapy Personalized medicine and pharmacogenomics Clinical drug evaluation Patient safety and sustained use of medicines.