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IGF-1R/β-catenin signaling axis is involved in type 2 diabetic osteoporosis

IGF-1R/β-catenin 信号通路在 2 型糖尿病性骨质疏松中的作用

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Abstract

Insulin-like growth factor-1 receptor (IGF-1R) is involved in both glucose and bone metabolism. IGF-1R signaling regulates the canonical Wnt/β-catenin signaling pathway. In this study, we investigated whether the IGF-1R/ β-catenin signaling axis plays a role in the pathogenesis of diabetic osteoporosis (DOP). Serum from patients with or without DOP was collected to measure the IGF-1R level using enzyme-linked immunosorbent assay (ELISA). Rats were given streptozotocin following a four-week high-fat diet induction (DOP group), or received vehicle after the same period of a normal diet (control group). Dual energy X-ray absorption, a biomechanics test, and hematoxylin-eosin (HE) staining were performed to evaluate bone mass, bone strength, and histomorphology, respectively, in vertebrae. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting were performed to measure the total and phosphorylation levels of IGF-1R, glycogen synthase kinase-3β (GSK-3β), and β-catenin. The serum IGF-1R level was much higher in patients with DOP than in controls. DOP rats exhibited strikingly reduced bone mass and attenuated compression strength of the vertebrae compared with the control group. HE staining showed that the histo-morphology of DOP vertebrae was seriously impaired, which manifested as decreased and thinned trabeculae and increased lipid droplets within trabeculae. PCR analysis demonstrated that IGF-1R mRNA expression was significantly up-regulated, and western blotting detection showed that phosphorylation levels of IGF-1R, GSK-3β, and β-catenin were enhanced in DOP rat vertebrae. Our results suggest that the IGF-1R/β-catenin signaling axis plays a role in the pathogenesis of DOP. This may contribute to development of the underlying therapeutic target for DOP.

概要

目 的

探讨胰岛素样生长因子-1 受体 (IGF-1R)/β-联蛋白 (β-catenin) 信号通路是否在糖尿病性骨质疏松 (DOP) 病理机制中起作用。

创新点

发现 IGF-1R/β-catenin 信号通路在 DOP 病理机制中起作用, 可能是 DOP 潜在的治疗靶点。

方 法

收集 DOP 患者血清, 使用酶联免疫吸附测定 (ELISA) 法检测 IGF-1R 水**。 DOP 大鼠在 4 周高脂饲料喂养后给予链脲佐菌素建模, 对照组大鼠在普通饲料喂养 4 周后再给予链脲佐菌素溶媒 (柠檬酸钠缓冲液)。 应用双能 X 线吸收法、 生物力学测试和苏木精-伊红 (HE) 染色法分别评估椎体骨量、 骨**度和骨组织形态。 使用实时定量聚合酶链反应 (qRT-PCR) 和蛋白印迹法 (western blotting) 测定 IGF-1R、 糖原合成酶激酶-3β (GSK-3β)和 β-catenin 表达及其蛋白磷酸化水**。

结 论

DOP 患者血清 IGF-1R 较对照组高。 DOP 大鼠骨量、 压缩**度明显减小, HE 染色显示 DOP 椎体骨组织形态明显受损, IGF-1R 信使 RNA (mRNA) 表达上调, IGF-1R、 GSK-3β 和 β-catenin 蛋白磷酸化增加。 由此可见, IGF-1R/β-catenin 信号通路在 DOP 的病理机制中起作用, 该发现将有利于后期 DOP 治疗靶点的开发。

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Acknowledgments

We thank the specific pathogen free (SPF) animal laboratory of the First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China, for providing the experimental platform.

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  1. The two authors contributed equally to this work

Authors and Affiliations

  1. The First Clinical School, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China

    Zhi-da Zhang, Wei-xi Wang, **-**g Huang, Mei-qi Zhan & **ang Yu

  2. Department of Spinal Surgery, the First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510405, China

    Hui Ren, Geng-yang Shen, **g-**g Tang, De Liang, Zhi-dong Yang & **ao-bing Jiang

  3. School of Basic Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China

    Yu-zhuo Zhang

  4. Lingnan Medical Research Center of Guangzhou University of Chinese Medicine, Guangzhou, 510405, China

    **ao-bing Jiang

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  1. Zhi-da Zhang
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Contributions

Zhi-da ZHANG, Hui REN, and **ao-bing JIANG designed this study. Wei-xi WANG, Geng-yang SHEN, **-**g HUANG, Mei-qi ZHAN, and Yu-zhuo ZHANG performed these experiments. **g-**g TANG and **ang YU searched the relative literature and reviewed the methods for model establishment, Zhi-da ZHANG and Hui REN conducted statistical analysis. Zhi-da ZHANG prepared this manuscript. De LIANG and Zhi-dong YANG reviewed and edited manuscript. All authors have read and approved this manuscript. Therefore, all authors have full access to all the data in the study and take responsibility for the integrity and security of the data.

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Correspondence to **ao-bing Jiang.

Ethics declarations

Zhi-da ZHANG, Hui REN, Wei-xi WANG, Geng-yang SHEN, **-**g HUANG, Mei-qi ZHAN, **g-**g TANG, **ang YU, Yu-zhuo ZHANG, De LIANG, Zhi-dong YANG, and **ao-bing JIANG declare that they have no conflict of interest.

All institutional and national guidelines for the care and use of laboratory animals were followed. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008 (5). Informed consent was obtained from all patients for being included in the study.

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Project supported by the National Natural Science Foundation of China (Nos. 81774338 and 81674000), the Natural Science Foundation of Guangdong Province (No. 2016A030313645), the Science and Technology Projects of Guangdong Province (No. 2016A020226006), and the Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme (2018), China

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Zhang, Zd., Ren, H., Wang, Wx. et al. IGF-1R/β-catenin signaling axis is involved in type 2 diabetic osteoporosis. J. Zhejiang Univ. Sci. B 20, 838–848 (2019). https://doi.org/10.1631/jzus.B1800648

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