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Histone methyltransferase EZH2 in proliferation, invasion, and migration of fibroblast-like synoviocytes in rheumatoid arthritis

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Journal of Bone and Mineral Metabolism Aims and scope Submit manuscript

Abstract

Objective

Rheumatoid arthritis (RA) may lead to irreversible joint damage. The role of histone modifications in RA has been emphasized. This study investigated the effect of histone methyltransferase EZH2 on fibroblast-like synoviocytes (FLSs) in RA.

Materials and methods

Synovial tissues were collected from RA patients and non-RA patients (NC). RA-FLSs and NC-FLSs were isolated and identified using flow cytometry. EZH2 expression in synovial tissues and FLSs was detected using RT-qPCR and Western blot. The proliferation, migration, and invasion of RA-FLSs and NC-FLSs were measured using MTT, EdU, and Transwell assays. The binding of EZH2, H3K27me3, and miR-22-3p was analyzed using ChIP assay. The targeting relationship between miR-22-3p and CYR61 was verified using dual-luciferase assay. miR-22-3p and CYR61 expressions were detected using RT-qPCR. CYR61 and H3K27me3 levels were detected using Western blot. Functional rescue experiments were performed to verify the effect of miR-22-3p or CYR61 on RA-FLSs.

Results

EZH2 was highly expressed in synovial tissues and FLSs from RA patients. The proliferation, migration, and invasion ability of RA-FLSs was stronger than that of NC-FLSs. Downregulation of EZH2 repressed proliferation, migration, and invasion of RA-FLSs. EZH2 inhibited miR-22-3p expression by binding to the miR-22-3p promoter and increasing H3K27me3 methylation level, and thereby upregulated CYR61 expression. Downregulation of miR-22-3p or overexpression of CYR61 annulled the inhibitory effect of EZH2 silencing on RA-FLS proliferation, migration, and invasion.

Conclusion

EZH2 bound to the miR-22-3p promoter and inhibited miR-22-3p expression by upregulating H3K27me3 level, thereby promoting CYR61 expression and inducing the proliferation, migration, and invasion of RA-FLSs.

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Authors and Affiliations

  1. Department of Rheumatology and Immunology, Shengjing Hospital of China Medical University, Shenyang City, 110000, Liaoning Province, China

    Lihua Chang

  2. Department of Orthopaedics, The First Hospital of China Medical University, No.155 Nan Jing North Street, Shenyang City, 110001, Liaoning Province, China

    Renyi Zhou

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  1. Lihua Chang
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LC designed the research and contributed unpublished reagents; RZ performed the research and wrote the paper. All authors provided critical comments on the manuscript.

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Correspondence to Renyi Zhou.

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Chang, L., Zhou, R. Histone methyltransferase EZH2 in proliferation, invasion, and migration of fibroblast-like synoviocytes in rheumatoid arthritis. J Bone Miner Metab 40, 262–274 (2022). https://doi.org/10.1007/s00774-021-01299-y

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  • DOI: https://doi.org/10.1007/s00774-021-01299-y

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