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Inhibition of EZH2 ameliorates cartilage endplate degeneration and attenuates the progression of intervertebral disc degeneration via demethylation of Sox-9.
EBioMedicine 2019; 48:619-629E

Abstract

BACKGROUND

Cartilaginous endplate (CEP) degeneration is considered as one of the major causes of intervertebral disc degeneration (IVDD) which causes low back pain. Recent studies have proved that epigenetic alteration is involved in a variety of diseases. This work explored the role of histone methyltransferase enhancer of zeste homologue 2 (EZH2) in CEP degeneration, as well as its underlying epigenetic mechanisms, and confirmed the effect of EZH2 knockdown on delaying IVDD development.

METHODS

Western blotting, immunofluorescence staining, and ChIP assay were applied to demonstrate the molecular mechanism of EZH2 in CEP tissue. The therapeutic potential of EZH2 was investigated using puncture-induced rat models.

FINDINGS

The EZH2 expression was upregulated in human and rat CEP tissue. It was also found that the overexpression of EZH2 suppressed the expression of Collagen II, aggrecan and Sox-9, and promoted the expression of ADTAMTS5 and MMP13 in rat endplate chondrocytes (EPCs), which could be reversed by EZH2 silencing. The correlation between EZH2 and Sox-9 was further explored, while overexpression of Sox-9 could reverse the effect of EZH2 in rat EPCs. Moreover, inhibition of EZH2 upregulated the level of Sox-9 by demethylating H3K27me3 at Sox-9 promoter sites, revealing the regulatory mechanism of EZH2 on Sox-9. Meanwhile, puncture-induced rat models showed that EZH2 knockdown exerted a protective effect on CEP and disc degeneration.

INTERPRETATION

This study reveals that EZH2 inhibition is a promising strategy for mitigating the symptoms and progression of IVDD.

FUNDING

This study was funded by the Natural Science Foundation of Zhejiang Province (Y16H060034). Authors declare that the funders had no involvement in the study design, data analysis and interpretation of the results.

Authors+Show Affiliations

Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou 325000, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou 325000, China.Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou 325000, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou 325000, China.Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou 325000, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou 325000, China.Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou 325000, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou 325000, China.Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou 325000, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou 325000, China.Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou 325000, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou 325000, China.Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou 325000, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou 325000, China.Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou 325000, China.Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou 325000, China. Electronic address: sunliaojun@wmu.edu.cn.Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou 325000, China. Electronic address: zhangxiaolei@wmu.edu.cn.Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou 325000, China. Electronic address: wuyaosen@wmu.edu.cn.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31631036

Citation

Jiang, Chao, et al. "Inhibition of EZH2 Ameliorates Cartilage Endplate Degeneration and Attenuates the Progression of Intervertebral Disc Degeneration Via Demethylation of Sox-9." EBioMedicine, vol. 48, 2019, pp. 619-629.
Jiang C, Guo Q, Jin Y, et al. Inhibition of EZH2 ameliorates cartilage endplate degeneration and attenuates the progression of intervertebral disc degeneration via demethylation of Sox-9. EBioMedicine. 2019;48:619-629.
Jiang, C., Guo, Q., Jin, Y., Xu, J. J., Sun, Z. M., Zhu, D. C., ... Wu, Y. S. (2019). Inhibition of EZH2 ameliorates cartilage endplate degeneration and attenuates the progression of intervertebral disc degeneration via demethylation of Sox-9. EBioMedicine, 48, pp. 619-629. doi:10.1016/j.ebiom.2019.10.006.
Jiang C, et al. Inhibition of EZH2 Ameliorates Cartilage Endplate Degeneration and Attenuates the Progression of Intervertebral Disc Degeneration Via Demethylation of Sox-9. EBioMedicine. 2019;48:619-629. PubMed PMID: 31631036.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of EZH2 ameliorates cartilage endplate degeneration and attenuates the progression of intervertebral disc degeneration via demethylation of Sox-9. AU - Jiang,Chao, AU - Guo,Qiang, AU - Jin,Yu, AU - Xu,Jia-Jing, AU - Sun,Ze-Ming, AU - Zhu,Ding-Chao, AU - Lin,Jia-Hao, AU - Tian,Nai-Feng, AU - Sun,Liao-Jun, AU - Zhang,Xiao-Lei, AU - Wu,Yao-Sen, Y1 - 2019/10/17/ PY - 2019/07/21/received PY - 2019/09/23/revised PY - 2019/10/03/accepted PY - 2019/10/22/pubmed PY - 2019/10/22/medline PY - 2019/10/22/entrez KW - Cartilaginous endplate KW - EZH2 KW - Epigenetic alteration KW - Intervertebral disc degeneration KW - Sox-9 SP - 619 EP - 629 JF - EBioMedicine JO - EBioMedicine VL - 48 N2 - BACKGROUND: Cartilaginous endplate (CEP) degeneration is considered as one of the major causes of intervertebral disc degeneration (IVDD) which causes low back pain. Recent studies have proved that epigenetic alteration is involved in a variety of diseases. This work explored the role of histone methyltransferase enhancer of zeste homologue 2 (EZH2) in CEP degeneration, as well as its underlying epigenetic mechanisms, and confirmed the effect of EZH2 knockdown on delaying IVDD development. METHODS: Western blotting, immunofluorescence staining, and ChIP assay were applied to demonstrate the molecular mechanism of EZH2 in CEP tissue. The therapeutic potential of EZH2 was investigated using puncture-induced rat models. FINDINGS: The EZH2 expression was upregulated in human and rat CEP tissue. It was also found that the overexpression of EZH2 suppressed the expression of Collagen II, aggrecan and Sox-9, and promoted the expression of ADTAMTS5 and MMP13 in rat endplate chondrocytes (EPCs), which could be reversed by EZH2 silencing. The correlation between EZH2 and Sox-9 was further explored, while overexpression of Sox-9 could reverse the effect of EZH2 in rat EPCs. Moreover, inhibition of EZH2 upregulated the level of Sox-9 by demethylating H3K27me3 at Sox-9 promoter sites, revealing the regulatory mechanism of EZH2 on Sox-9. Meanwhile, puncture-induced rat models showed that EZH2 knockdown exerted a protective effect on CEP and disc degeneration. INTERPRETATION: This study reveals that EZH2 inhibition is a promising strategy for mitigating the symptoms and progression of IVDD. FUNDING: This study was funded by the Natural Science Foundation of Zhejiang Province (Y16H060034). Authors declare that the funders had no involvement in the study design, data analysis and interpretation of the results. SN - 2352-3964 UR - https://www.unboundmedicine.com/medline/citation/31631036/Inhibition_of_EZH2_ameliorates_cartilage_endplate_degeneration_and_attenuates_the_progression_of_intervertebral_disc_degeneration_via_demethylation_of_Sox-9 L2 - https://linkinghub.elsevier.com/retrieve/pii/S2352-3964(19)30670-X DB - PRIME DP - Unbound Medicine ER -