Inhibition of EZH2 ameliorates cartilage endplate degeneration and attenuates the progression of intervertebral disc degeneration via demethylation of Sox-9
Chao Jiang,
Qiang Guo,
Yu Jin,
Jia-Jing Xu,
Ze-Ming Sun,
Ding-Chao Zhu,
Jia-Hao Lin,
Nai-Feng Tian,
Liao-Jun Sun,
Xiao-Lei Zhang,
Yao-Sen Wu
Affiliations
Chao Jiang
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
Qiang Guo
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
Yu Jin
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
Jia-Jing Xu
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
Ze-Ming Sun
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
Ding-Chao Zhu
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
Jia-Hao Lin
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
Nai-Feng Tian
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
Liao-Jun Sun
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; Corresponding authors: Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China.
Xiao-Lei Zhang
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; Corresponding authors: Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China.
Yao-Sen Wu
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; Corresponding authors: Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China.
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. Keywords: EZH2, Sox-9, Epigenetic alteration, Cartilaginous endplate, Intervertebral disc degeneration
