Role of LRP5/6/GSK-3β/β-catenin in the differences in exenatide- and insulin-promoted T2D osteogenesis and osteomodulation

IF 6.8 2区医学 Q1 PHARMACOLOGY & PHARMACY

British Journal of Pharmacology Pub Date : 2024-05-28 DOI:10.1111/bph.16421

Zijun Chen, Yuxi Wang, Guanhua Zhang, Jian Zheng, Lei Tian, Yingliang Song, Xiangdong Liu

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Abstract

Background and Purpose

Insulin and exenatide are two hypoglycaemic agents that exhibit different osteogenic effects. This study compared the differences between exenatide and insulin in osseointegration in a rat model of Type 2 diabetes (T2D) and explored the mechanisms promoting osteogenesis in this model of T2D.

Experimental Approach

In vivo, micro-CT was used to detect differences in the peri-implant bone microstructure in vivo. Histology, dual-fluorescent labelling, immunofluorescence and immunohistochemistry were used to detect differences in tissue, cell and protein expression around the implants. In vitro, RT-PCR and western blotting were used to measure the expression of osteogenesis- and Wnt signalling-related genes and proteins in bone marrow mesenchymal stromal cells (BMSCs) from rats with T2D (TBMSCs) after PBS, insulin and exenatide treatment. RT-PCR was used to detect the expression of Wnt bypass cascade reactions under Wnt inactivation.

Key Results

Micro-CT and section staining showed exenatide extensively promoted peri-implant osseointegration. Both in vivo and in vitro experiments showed exenatide substantially increased the expression of osteogenesis-related and activated the LRP5/6/GSK-3β/β-catenin-related Wnt pathway. Furthermore, exenatide suppressed expression of Bmpr1a to inhibit lipogenesis and promoted expression of Btrc to suppress inflammation.

Conclusion and Implications

Compared to insulin, exenatide significantly improved osteogenesis in T2D rats and TBMSCs. In addition to its dependence on LRP5/6/GSK-3β/β-catenin signalling for osteogenic differentiation, exenatide-mediated osteomodulation also involves inhibition of inflammation and adipogenesis by BMPR1A and β-TrCP, respectively.

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LRP5/6/GSK-3β/β-catenin在艾塞那肽和胰岛素促进的T2D成骨和骨调节差异中的作用

背景与目的：胰岛素和艾塞那肽是两种降糖药物，它们具有不同的成骨作用。本研究比较了艾塞那肽和胰岛素在 2 型糖尿病（T2D）大鼠模型中骨结合的差异，并探讨了促进该 T2D 模型骨生成的机制：实验方法：在体内，使用显微CT检测体内种植体周围骨微观结构的差异。组织学、双荧光标记、免疫荧光和免疫组织化学用于检测种植体周围组织、细胞和蛋白质表达的差异。在体外，采用 RT-PCR 和 Western 印迹法检测 T2D 大鼠骨髓间充质基质细胞（BMSCs）经 PBS、胰岛素和艾塞那肽处理后的成骨和 Wnt 信号相关基因和蛋白的表达。RT-PCR 用于检测 Wnt 失活情况下 Wnt 旁路级联反应的表达：显微 CT 和切片染色显示，艾塞那肽广泛促进了种植体周围的骨结合。体内和体外实验均表明，艾塞那肽可显著增加成骨相关蛋白的表达，并激活LRP5/6/GSK-3β/β-catenin相关的Wnt通路。此外，艾塞那肽抑制Bmpr1a的表达以抑制脂肪生成，促进Btrc的表达以抑制炎症：与胰岛素相比，艾塞那肽能明显改善T2D大鼠和TBMSCs的成骨过程。除了成骨分化依赖于 LRP5/6/GSK-3β/β-catenin 信号外，艾塞那肽介导的成骨调节还涉及 BMPR1A 和 β-TrCP 对炎症和脂肪生成的抑制。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

British Journal of Pharmacology 医学-药学

CiteScore

15.40

自引率

12.30%

发文量

270

审稿时长

2.0 months

期刊介绍： The British Journal of Pharmacology (BJP) is a biomedical science journal offering comprehensive international coverage of experimental and translational pharmacology. It publishes original research, authoritative reviews, mini reviews, systematic reviews, meta-analyses, databases, letters to the Editor, and commentaries. Review articles, databases, systematic reviews, and meta-analyses are typically commissioned, but unsolicited contributions are also considered, either as standalone papers or part of themed issues. In addition to basic science research, BJP features translational pharmacology research, including proof-of-concept and early mechanistic studies in humans. While it generally does not publish first-in-man phase I studies or phase IIb, III, or IV studies, exceptions may be made under certain circumstances, particularly if results are combined with preclinical studies.

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