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The study of GPX3 methylation in patients with Kashin-Beck Disease and its mechanism in chondrocyte apoptosis.
Bone. 2018 12; 117:15-22.BONE

Abstract

OBJECTIVE

Selenium deficiency is a risk factor for Kashin-Beck Disease (KBD), an endemic osteoarthropathy. Although promoter hypermethylation of glutathione peroxidase 3 (GPX3) (a selenoprotein) has been identified in several cancers, little is known about promoter methylation and expression of GPX3 and their relation to selenium in KBD. The present study was thus conducted to investigate this research question.

METHODS

Methylation and expressions of GPX3 in whole blood drawn from 288 KBD patients and 362 healthy controls and in chondrocyte cell line were evaluated using methylation-specific PCR and qRT-PCR, respectively. The protein levels of PI3K/Akt/c-fos signaling in the whole blood and chondrocyte cell line were determined with Western blotting. Chondrocytes apoptosis were detected by Hoechst 33342 and Annexin V-FITC/PI staining.

RESULTS

GPX3 methylation was increased, GPX3 mRNA was decreased, and protein levels in the PI3K/Akt/c-fos signaling pathway were up-regulated in the whole blood collected from KBD patients as compared with healthy controls. Similar results were obtained for chondrocytes injured by oxidative stress. There was a significant, decreasing trend in GPX3 expression across groups of unmethylation, partial methylation, and complete methylation for GPX3, in sequence. Compared with unmethylation group, protein levels in PI3K/Akt/c-fos pathway were enhanced in partial and complete methylation groups. Treatment of chondrocytes with sodium selenite resulted in reduced methylation and increased expression of GPX3 as well as down-regulated level of PI3K/Akt/c-fos proteins.

CONCLUSIONS

The methylation and expression of GPX3 and expression of PI3K/Akt/c-fos pathway are altered in KBD and these changes are reversible by selenium supplementation.

Authors+Show Affiliations

Institute of Endemic Diseases and Key Laboratory of Trace Elements and Endemic Diseases, National Health Commission of the People's Republic of China, School of Public Health, Xi'an Jiaotong University Health Science Center, No.76 Yanta West Road, Xi'an, Shaanxi 710061, P.R. China.Institute of Endemic Diseases and Key Laboratory of Trace Elements and Endemic Diseases, National Health Commission of the People's Republic of China, School of Public Health, Xi'an Jiaotong University Health Science Center, No.76 Yanta West Road, Xi'an, Shaanxi 710061, P.R. China.Institute of Endemic Diseases and Key Laboratory of Trace Elements and Endemic Diseases, National Health Commission of the People's Republic of China, School of Public Health, Xi'an Jiaotong University Health Science Center, No.76 Yanta West Road, Xi'an, Shaanxi 710061, P.R. China.Institute of Endemic Diseases and Key Laboratory of Trace Elements and Endemic Diseases, National Health Commission of the People's Republic of China, School of Public Health, Xi'an Jiaotong University Health Science Center, No.76 Yanta West Road, Xi'an, Shaanxi 710061, P.R. China.Institute of Endemic Diseases and Key Laboratory of Trace Elements and Endemic Diseases, National Health Commission of the People's Republic of China, School of Public Health, Xi'an Jiaotong University Health Science Center, No.76 Yanta West Road, Xi'an, Shaanxi 710061, P.R. China.Institute of Endemic Diseases and Key Laboratory of Trace Elements and Endemic Diseases, National Health Commission of the People's Republic of China, School of Public Health, Xi'an Jiaotong University Health Science Center, No.76 Yanta West Road, Xi'an, Shaanxi 710061, P.R. China.Institute of Endemic Diseases and Key Laboratory of Trace Elements and Endemic Diseases, National Health Commission of the People's Republic of China, School of Public Health, Xi'an Jiaotong University Health Science Center, No.76 Yanta West Road, Xi'an, Shaanxi 710061, P.R. China.Institute of Endemic Diseases and Key Laboratory of Trace Elements and Endemic Diseases, National Health Commission of the People's Republic of China, School of Public Health, Xi'an Jiaotong University Health Science Center, No.76 Yanta West Road, Xi'an, Shaanxi 710061, P.R. China.Institute of Endemic Diseases and Key Laboratory of Trace Elements and Endemic Diseases, National Health Commission of the People's Republic of China, School of Public Health, Xi'an Jiaotong University Health Science Center, No.76 Yanta West Road, Xi'an, Shaanxi 710061, P.R. China.Institute of Endemic Diseases and Key Laboratory of Trace Elements and Endemic Diseases, National Health Commission of the People's Republic of China, School of Public Health, Xi'an Jiaotong University Health Science Center, No.76 Yanta West Road, Xi'an, Shaanxi 710061, P.R. China.Institute of Endemic Diseases and Key Laboratory of Trace Elements and Endemic Diseases, National Health Commission of the People's Republic of China, School of Public Health, Xi'an Jiaotong University Health Science Center, No.76 Yanta West Road, Xi'an, Shaanxi 710061, P.R. China.Department of Epidemiology, Indiana University Richard M. Fairbanks School of Public Health, Indianapolis, 1050 Wishard Boulevard, IN 46202, USA.Institute of Endemic Diseases and Key Laboratory of Trace Elements and Endemic Diseases, National Health Commission of the People's Republic of China, School of Public Health, Xi'an Jiaotong University Health Science Center, No.76 Yanta West Road, Xi'an, Shaanxi 710061, P.R. China. Electronic address: xiongym@mail.xjtu.edu.cn.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30153510

Citation

Han, LiXin, et al. "The Study of GPX3 Methylation in Patients With Kashin-Beck Disease and Its Mechanism in Chondrocyte Apoptosis." Bone, vol. 117, 2018, pp. 15-22.
Han L, Yang X, Sun W, et al. The study of GPX3 methylation in patients with Kashin-Beck Disease and its mechanism in chondrocyte apoptosis. Bone. 2018;117:15-22.
Han, L., Yang, X., Sun, W., Li, Z., Ren, H., Li, B., Zhang, R., Zhang, D., Shi, Z., Liu, J., Cao, J., Zhang, J., & Xiong, Y. (2018). The study of GPX3 methylation in patients with Kashin-Beck Disease and its mechanism in chondrocyte apoptosis. Bone, 117, 15-22. https://doi.org/10.1016/j.bone.2018.08.017
Han L, et al. The Study of GPX3 Methylation in Patients With Kashin-Beck Disease and Its Mechanism in Chondrocyte Apoptosis. Bone. 2018;117:15-22. PubMed PMID: 30153510.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The study of GPX3 methylation in patients with Kashin-Beck Disease and its mechanism in chondrocyte apoptosis. AU - Han,LiXin, AU - Yang,XiaoLi, AU - Sun,WenYan, AU - Li,ZhaoFang, AU - Ren,Hao, AU - Li,BaoRong, AU - Zhang,RongQiang, AU - Zhang,DanDan, AU - Shi,ZiYun, AU - Liu,JiFeng, AU - Cao,JunLing, AU - Zhang,JianJun, AU - Xiong,YongMin, Y1 - 2018/08/25/ PY - 2018/05/29/received PY - 2018/08/06/revised PY - 2018/08/23/accepted PY - 2018/8/29/pubmed PY - 2019/9/5/medline PY - 2018/8/29/entrez KW - DNA methylation KW - Glutathione peroxidase 3 KW - Kashin-Beck disease KW - PI3K/Akt/c-fos signaling pathway KW - Selenium SP - 15 EP - 22 JF - Bone JO - Bone VL - 117 N2 - OBJECTIVE: Selenium deficiency is a risk factor for Kashin-Beck Disease (KBD), an endemic osteoarthropathy. Although promoter hypermethylation of glutathione peroxidase 3 (GPX3) (a selenoprotein) has been identified in several cancers, little is known about promoter methylation and expression of GPX3 and their relation to selenium in KBD. The present study was thus conducted to investigate this research question. METHODS: Methylation and expressions of GPX3 in whole blood drawn from 288 KBD patients and 362 healthy controls and in chondrocyte cell line were evaluated using methylation-specific PCR and qRT-PCR, respectively. The protein levels of PI3K/Akt/c-fos signaling in the whole blood and chondrocyte cell line were determined with Western blotting. Chondrocytes apoptosis were detected by Hoechst 33342 and Annexin V-FITC/PI staining. RESULTS: GPX3 methylation was increased, GPX3 mRNA was decreased, and protein levels in the PI3K/Akt/c-fos signaling pathway were up-regulated in the whole blood collected from KBD patients as compared with healthy controls. Similar results were obtained for chondrocytes injured by oxidative stress. There was a significant, decreasing trend in GPX3 expression across groups of unmethylation, partial methylation, and complete methylation for GPX3, in sequence. Compared with unmethylation group, protein levels in PI3K/Akt/c-fos pathway were enhanced in partial and complete methylation groups. Treatment of chondrocytes with sodium selenite resulted in reduced methylation and increased expression of GPX3 as well as down-regulated level of PI3K/Akt/c-fos proteins. CONCLUSIONS: The methylation and expression of GPX3 and expression of PI3K/Akt/c-fos pathway are altered in KBD and these changes are reversible by selenium supplementation. SN - 1873-2763 UR - https://www.unboundmedicine.com/medline/citation/30153510/The_study_of_GPX3_methylation_in_patients_with_Kashin_Beck_Disease_and_its_mechanism_in_chondrocyte_apoptosis_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S8756-3282(18)30321-1 DB - PRIME DP - Unbound Medicine ER -