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EZH2 regulates the balance between osteoclast and osteoblast differentiation to inhibit arthritis-induced bone destruction

Abstract

Enhancer of zeste homolog 2 (EZH2) has been noted to contribute to the pathogenesis of autoimmune diseases. This study sought to investigate the mechanism of EZH2 in osteoclast (OCL) and osteoblast (OBL) differentiation (OCLD/OBLD) and bone destruction in RA. The animal model of collagen-induced arthritis (CIA) was established, followed by arthritis index (AI) scoring and histological staining, and measurements of inflammatory cytokines levels. The number of OCLs was detected via Tartrate-resistant acid phosphatase (TRAP) staining, and levels of OBL markers were determined by Western blot analysis. Trimethylated histone H3 at lysine 27 (H3K27me3) expression and its enrichment in the Ndrg2 promoter were detected. Collaborative experiments were performed with GSK-J1 or sh-Ndrg2 in CIA mice with EZH2 knockdown. EZH2 was upregulated while Ndrg2 was downregulated in knee joint tissues of CIA mice. Silencing EZH2 reduced AI scores, pathological injury of the knee joint, levels of inflammatory cytokines, and TRAP-positive cells, and increased protein levels of RUNX2 and BMP2. EZH2 promoted H3K27me3 level in the Ndrg2 promoter to inhibit Ndrg2 transcription. H3K27me3 upregulation or Ndrg2 downregulation reversed the role of silencing EZH2 in bone destruction. Overall, EZH2 repressed OBLD and promoted OCLD to aggravate bone destruction in CIA mice through H3K27me3/Ndrg2.

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Fig. 1: Experimental follow chart.
Fig. 2: RA mice and silencing EZH2 alleviates bond destruction in RA mice.
Fig. 3: Silencing EZH2 promotes OBLD and inhibits OCLD to alleviate bone destruction.
Fig. 4: EZH2 promotes H3K27me3 in the Ndrg2 promoter to inhibit Ndrg2 transcription.
Fig. 5: H3K27me3 upregulation reverses the role of silencing EZH2 in promoting OBLD and inhibiting OCLD.
Fig. 6: Decreasing Ndrg2 mRNA level reverses the role of silencing EZH2 in promoting OBLD and inhibiting OCLD.

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Data availability

The data that support this study are available from the corresponding author upon reasonable request.

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Funding

This work was supported by Jiangsu TCM Science and Technology Development Plan (MS2021062).

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FC and HL: Conceived and designed the experiments, and participated in its design and coordination and helped to draft the manuscript and revise the manuscript. JL and FY: Performed investigation, statistical analysis and drafted the manuscript. YC and HH: Contributed to the acquisition and analysis of data. All authors read and approved the final manuscript.

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Correspondence to Haiyan Hu.

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Cheng, F., Li, H., Liu, J. et al. EZH2 regulates the balance between osteoclast and osteoblast differentiation to inhibit arthritis-induced bone destruction. Genes Immun 23, 141–148 (2022). https://doi.org/10.1038/s41435-022-00174-8

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