Full Text:   <3122>

Summary:  <1786>

CLC number: R587.2

On-line Access: 2019-09-06

Received: 2018-12-31

Revision Accepted: 2019-05-04

Crosschecked: 2019-08-08

Cited: 0

Clicked: 3861

Citations:  Bibtex RefMan EndNote GB/T7714

-   Go to

Article info.
Open peer comments

Journal of Zhejiang University SCIENCE B 2019 Vol.20 No.10 P.838-848

http://doi.org/10.1631/jzus.B1800648


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


Author(s):  Zhi-Da Zhang, Hui Ren, Wei-Xi Wang, Geng-Yang Shen, Jin-Jing Huang, Mei-Qi Zhan, Jing-Jing Tang, Xiang Yu, Yu-Zhuo Zhang, De Liang, Zhi-Dong Yang, Xiao-Bing Jiang

Affiliation(s):  The First Clinical School, Guangzhou University of Chinese Medicine, Guangzhou 510405, China; more

Corresponding email(s):   spinedrjxb@sina.com

Key Words:  Diabetic osteoporosis, Insulin-like growth factor-1 receptor (IGF-1R), Signaling axis, Pathogenesis


Zhi-Da Zhang, Hui Ren, Wei-Xi Wang, Geng-Yang Shen, Jin-Jing Huang, Mei-Qi Zhan, Jing-Jing Tang, Xiang Yu, Yu-Zhuo Zhang, De Liang, Zhi-Dong Yang, Xiao-Bing Jiang. IGF-1R/β-catenin signaling axis is involved in type 2 diabetic osteoporosis[J]. Journal of Zhejiang University Science B, 2019, 20(10): 838-848.

@article{title="IGF-1R/β-catenin signaling axis is involved in type 2 diabetic osteoporosis",
author="Zhi-Da Zhang, Hui Ren, Wei-Xi Wang, Geng-Yang Shen, Jin-Jing Huang, Mei-Qi Zhan, Jing-Jing Tang, Xiang Yu, Yu-Zhuo Zhang, De Liang, Zhi-Dong Yang, Xiao-Bing Jiang",
journal="Journal of Zhejiang University Science B",
volume="20",
number="10",
pages="838-848",
year="2019",
publisher="Zhejiang University Press & Springer",
doi="10.1631/jzus.B1800648"
}

%0 Journal Article
%T IGF-1R/β-catenin signaling axis is involved in type 2 diabetic osteoporosis
%A Zhi-Da Zhang
%A Hui Ren
%A Wei-Xi Wang
%A Geng-Yang Shen
%A Jin-Jing Huang
%A Mei-Qi Zhan
%A Jing-Jing Tang
%A Xiang Yu
%A Yu-Zhuo Zhang
%A De Liang
%A Zhi-Dong Yang
%A Xiao-Bing Jiang
%J Journal of Zhejiang University SCIENCE B
%V 20
%N 10
%P 838-848
%@ 1673-1581
%D 2019
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B1800648

TY - JOUR
T1 - IGF-1R/β-catenin signaling axis is involved in type 2 diabetic osteoporosis
A1 - Zhi-Da Zhang
A1 - Hui Ren
A1 - Wei-Xi Wang
A1 - Geng-Yang Shen
A1 - Jin-Jing Huang
A1 - Mei-Qi Zhan
A1 - Jing-Jing Tang
A1 - Xiang Yu
A1 - Yu-Zhuo Zhang
A1 - De Liang
A1 - Zhi-Dong Yang
A1 - Xiao-Bing Jiang
J0 - Journal of Zhejiang University Science B
VL - 20
IS - 10
SP - 838
EP - 848
%@ 1673-1581
Y1 - 2019
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B1800648


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 histomorphology 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.

IGF-1R/β-catenin信号通路在2型糖尿病性骨质疏松中的作用

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水平.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、骨强度和骨组织形态.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平.
结论:DOP患者血清IGF-1R较对照组高.DOP大鼠骨量、压缩强度明显减小,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.

关键词:糖尿病性骨质疏松;胰岛素样生长因子-1受体;信号通路;发病机制

Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article

Reference

[1]Agholme F, Aspenberg P, 2011. Wnt signaling and orthopedics, an overview. Acta Orthop, 82(2):125-130.

[2]American Diabetes Association, 2016. Standards of medical care in diabetes—2016 abridged for primary care providers. Clin Diabetes, 34(1):3-21.

[3]Boucher J, Kleinridders A, Kahn CR, 2014. Insulin receptor signaling in normal and insulin-resistant states. Cold Spring Harb Perspect Biol, 6(1):a009191.

[4]Boura-Halfon S, Shuster-Meiseles T, Beck A, et al., 2010. A novel domain mediates insulin-induced proteasomal degradation of insulin receptor substrate 1 (IRS-1). Mol Endocrinol, 24(11):2179-2192.

[5]Bozic J, Markotic A, Cikes-Culic V, et al., 2018. Ganglioside GM3 content in skeletal muscles is increased in type 2 but decreased in type 1 diabetes rat models: implications of glycosphingolipid metabolism in pathophysiology of diabetes. J Diabetes, 10(2):130-139.

[6]Cheng PW, Chen YY, Cheng WH, et al., 2015. Wnt signaling regulates blood pressure by downregulating a GSK-3β-mediated pathway to enhance insulin signaling in the central nervous system. Diabetes, 64(10):3413-3424.

[7]Cheng YY, Liu SC, Zhang X, et al., 2016. Expression profiles of IGF-1R gene and polymorphisms of its regulatory regions in different pig breeds. Protein J, 35(3):231-236.

[8]Cosman F, de Beur SJ, LeBoff MS, et al., 2014. Clinician’s guide to prevention and treatment of osteoporosis. Osteoporos Int, 25(10):2359-2381.

[9]Daniele G, Winnier D, Mari A, et al., 2015. Sclerostin and insulin resistance in prediabetes: evidence of a cross talk between bone and glucose metabolism. Diabetes Care, 38(8):1509-1517.

[10]de Meyts P, Whittaker J, 2002. Structural biology of insulin and IGF1 receptors: implications for drug design. Nat Rev Drug Discov, 1(10):769-783.

[11]Desbois-Mouthon C, Cadoret A, Blivet-van Eggelpoël MJ, et al., 2001. Insulin and IGF-1 stimulate the β-catenin pathway through two signalling cascades involving GSK-3β inhibition and Ras activation. Oncogene, 20(2):252-259.

[12]Engberding N, San Martin A, Martin-Garrido A, et al., 2009. Insulin-like growth factor-1 receptor expression masks the antiinflammatory and glucose uptake capacity of insulin in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol, 29(3):408-415.

[13]Flanagan AM, Brown JL, Santiago CA, et al., 2008. High-fat diets promote insulin resistance through cytokine gene expression in growing female rats. J Nutr Biochem, 19(8):505-513.

[14]Fowlkes JL, Nyman JS, Bunn RC, et al., 2013. Osteo-promoting effects of insulin-like growth factor I (IGF-I) in a mouse model of type 1 diabetes. Bone, 57(1):36-40.

[15]Fulzele K, DiGirolamo DJ, Liu ZY, et al., 2007. Disruption of the insulin-like growth factor type 1 receptor in osteoblasts enhances insulin signaling and action. J Biol Chem, 282(35):25649-25658.

[16]Geng YT, Ju YF, Ren FL, et al., 2014. Insulin receptor substrate 1/2 (IRS1/2) regulates Wnt/β-catenin signaling through blocking autophagic degradation of Dishevelled2. J Biol Chem, 289(16):11230-11241.

[17]Gheibi S, Kashfi K, Ghasemi A, 2017. A practical guide for induction of type-2 diabetes in rat: incorporating a high-fat diet and streptozotocin. Biomed Pharmacother, 95:605-613.

[18]Hough FS, Pierroz DD, Cooper C, et al., 2016. MECHANISMS IN ENDOCRINOLOGY: mechanisms and evaluation of bone fragility in type 1 diabetes mellitus. Eur J Endocrinol, 174(4):R127-R138.

[19]Ikeda S, Kishida S, Yamamoto H, et al., 1998. Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK-3β and β-catenin and promotes GSK-3β-dependent phosphorylation of β-catenin. EMBO J, 17(5):1371-1384.

[20]Iyer S, Ambrogini E, Bartell SM, et al., 2013. FOXOs attenuate bone formation by suppressing Wnt signaling. J Clin Invest, 123(8):3409-3419.

[21]Janghorbani M, Feskanich D, Willett WC, et al., 2006. Prospective study of diabetes and risk of hip fracture: the nurses’ health study. Diabetes Care, 29(7):1573-1578.

[22]Jiao YK, Wang XQ, Jiang X, et al., 2017. Antidiabetic effects of Morus alba fruit polysaccharides on high-fat diet- and streptozotocin-induced type 2 diabetes in rats. J Ethnopharmacol, 199:119-127.

[23]Kavran JM, McCabe JM, Byrne PO, et al., 2014. How IGF-1 activates its receptor. eLife, 3:e03772.

[24]Kim IG, Kim SY, Choi SI, et al., 2014. Fibulin-3-mediated inhibition of epithelial-to-mesenchymal transition and self-renewal of ALDH+ lung cancer stem cells through IGF1R signaling. Oncogene, 33(30):3908-3917.

[25]Krishnan V, Bryant HU, MacDougald OA, 2006. Regulation of bone mass by Wnt signaling. J Clin Invest, 116(5):1202-1209.

[26]Leng SH, Zhang WS, Zheng YB, et al., 2010. Glycogen synthase kinase 3β mediates high glucose-induced ubiquitination and proteasome degradation of insulin receptor substrate 1. J Endocrinol, 206(2):171-181.

[27]Li BX, Wang Y, Liu Y, et al., 2013. Altered gene expression involved in insulin signaling pathway in type II diabetic osteoporosis rats model. Endocrine, 43(1):136-146.

[28]Liu XJ, Xu Q, Wang XM, et al., 2015. Irbesartan ameliorates diabetic cardiomyopathy by regulating protein kinase D and ER stress activation in a type 2 diabetes rat model. Pharmacol Res, 93:43-51.

[29]Looker AC, Eberhardt MS, Saydah SH, 2016. Diabetes and fracture risk in older U.S. adults. Bone, 82:9-15.

[30]Lu JM, Wang YF, Yan HL, et al., 2016. Antidiabetic effect of total saponins from Polygonatum kingianum in streptozotocin-induced daibetic rats. J Ethnopharmacol, 179:291-300.

[31]Ma R, Wang L, Zhao B, et al., 2017. Diabetes perturbs bone microarchitecture and bone strength through regulation of Sema3A/IGF-1/β-catenin in rats. Cell Physiol Biochem, 41(1):55-66.

[32]Napoli N, Chandran M, Pierroz DD, et al., 2017. Mechanisms of diabetes mellitus-induced bone fragility. Nat Rev Endocrinol, 13(4):208-219.

[33]NCD Risk Factor Collaboration, 2016. Worldwide trends in diabetes since 1980: a pooled analysis of 751 population-based studies with 4.4 million participants. Lancet, 387(10027):1513-1530.

[34]Palsgaard J, Emanuelli B, Winnay JN, et al., 2012. Cross-talk between insulin and Wnt signaling in preadipocytes: role of Wnt co-receptor low density lipoprotein receptor-related protein-5 (LRP5). J Biol Chem, 287(15):12016-12026.

[35]Pelosi P, Lapi E, Cavalli L, et al., 2017. Bone status in a patient with insulin-like growth factor-1 receptor deletion syndrome: bone quality and structure evaluation using dual-energy X-ray absorptiometry, peripheral quantitative computed tomography, and quantitative ultrasonography. Front Endocrinol (Lausanne), 8:227.

[36]Reed MJ, Meszaros K, Entes LJ, et al., 2000. A new rat model of type 2 diabetes: the fat-fed, streptozotocin-treated rat. Metabolism, 49(11):1390-1394.

[37]Rota LM, Wood TL, 2015. Crosstalk of the insulin-like growth factor receptor with the Wnt signaling pathway in breast cancer. Front Endocrinol (Lausanne), 6:92.

[38]Rota LM, Albanito L, Shin ME, et al., 2014. IGF1R inhibition in mammary epithelia promotes canonical Wnt signaling and Wnt1-driven tumors. Cancer Res, 74(19):5668-5679.

[39]Schlupf J, Steinbeisser H, 2014. IGF antagonizes the Wnt/ β-catenin pathway and promotes differentiation of extra-embryonic endoderm. Differentiation, 87(5):209-219.

[40]Schwartz AV, Hillier TA, Sellmeyer DE, et al., 2002. Older women with diabetes have a higher risk of falls: a prospective study. Diabetes Care, 25(10):1749-1754.

[41]Siddle K, 2012. Molecular basis of signaling specificity of insulin and IGF receptors: neglected corners and recent advances. Front Endocrinol (Lausanne), 3:34.

[42]Slaaby R, Schäffer L, Lautrup-Larsen I, et al., 2006. Hybrid receptors formed by insulin receptor (IR) and insulin-like growth factor I receptor (IGF-IR) have low insulin and high IGF-1 affinity irrespective of the IR splice variant. J Biol Chem, 281(36):25869-25874.

[43]Solomon-Zemler R, Basel-Vanagaite L, Steier D, et al., 2017. A novel heterozygous IGF-1 receptor mutation associated with hypoglycemia. Endocr Connect, 6(6):395-403.

[44]Srinivasan K, Viswanad B, Asrat L, et al., 2005. Combination of high-fat diet-fed and low-dose streptozotocin-treated rat: a model for type 2 diabetes and pharmacological screening. Pharmacol Res, 52(4):313-320.

[45]Sroga GE, Wu PC, Vashishth D, 2015. Insulin-like growth factor 1, glycation and bone fragility: implications for fracture resistance of bone. PLoS ONE, 10(1):e0117046.

[46]Szkudelski T, 2012. Streptozotocin-nicotinamide-induced diabetes in the rat. Characteristics of the experimental model. Exp Biol Med (Maywood), 237(5):481-490.

[47]Thrailkill KM, Lumpkin CK Jr, Bunn RC, et al., 2005. Is insulin an anabolic agent in bone? Dissecting the diabetic bone for clues. Am J Physiol Endocrinol Metab, 289(5):E735-E745.

[48]Yan Y, Du CH, Li ZY, et al., 2018. Comparing the antidiabetic effects and chemical profiles of raw and fermented Chinese Ge-Gen-Qin-Lian decoction by integrating untargeted metabolomics and targeted analysis. Chin Med, 13(1):54.

[49]Zhang ZD, Ren H, Shen GY, et al., 2016. Animal models for glucocorticoid-induced postmenopausal osteoporosis: an updated review. Biomed Pharmacother, 84:438-446.

[50]Zhao HH, Li ZG, Tian GH, et al., 2013. Effects of traditional Chinese medicine on rats with Type II diabetes induced by high-fat diet and streptozotocin: a urine metabonomic study. Afr Health Sci, 13(3):673-681.

Open peer comments: Debate/Discuss/Question/Opinion

<1>

Please provide your name, email address and a comment





Journal of Zhejiang University-SCIENCE, 38 Zheda Road, Hangzhou 310027, China
Tel: +86-571-87952783; E-mail: cjzhang@zju.edu.cn
Copyright © 2000 - 2024 Journal of Zhejiang University-SCIENCE