EZH2 is associated with cartilage degeneration in osteoarthritis by promoting SDC1 expression via histone methylation of the microRNA-138 promoter
| Autor: | Jian Wang, Tao Huang, Dengxin Song, Hairong Tao, Xiang Wang, Xu Ding |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Adult Cartilage Articular Male Primary Cell Culture macromolecular substances Osteoarthritis Pathology and Forensic Medicine Syndecan 1 03 medical and health sciences Mice 0302 clinical medicine microRNA Histone methylation medicine Animals Humans Enhancer of Zeste Homolog 2 Protein Epigenetics Enhancer Molecular Biology Chemistry Cartilage EZH2 Cell Biology Middle Aged medicine.disease Arthritis Experimental Cell biology MicroRNAs 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Histone Methyltransferases Female Syndecan-1 Biomarkers |
| Zdroj: | Laboratory investigation; a journal of technical methods and pathology. 101(5) |
| ISSN: | 1530-0307 |
| Popis: | Cartilage degeneration has been reported to deteriorate osteoarthritis (OA), a prevalent joint disease caused by intrinsic and epigenetic factors. This study aimed to examine the molecular mechanism of enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2)/microRNA-138 (miR-138)/syndecan 1 (SDC1) and its epigenetic regulation in cartilage degeneration in OA. An OA cell model was induced by stimulating chondrocytes with interleukin (IL)-1β at a final concentration of 10 ng/mL, followed by alterations in EZH2 and miR-138 expression. Afterwards, cell apoptosis was analyzed using flow cytometry. The expression patterns of cartilage catabolism-related factors (MMP-13, ADAMTS-4, and ADAMTS-5) were determined using RT-qPCR and western blot analyses. The EZH2 and H3K27me3 enrichment at the miR-138 promoter region were determined using ChIP-qPCR. Finally, an OA mouse model was constructed to verify the function of EZH2 in vivo. EZH2 was expressed at high levels in OA models. EZH2 depletion ameliorated OA, as evidenced by reduced cell apoptosis in IL-1β-treated chondrocytes and decreased levels of cartilage catabolism-related factors. Moreover, EZH2 promoted histone methylation at the miR-138 promoter to suppress miR-138 expression, thereby upregulating the expression of SDC1, a target gene of miR-138. Changes in this pathway increased the expression of cartilage catabolism-related factors in vitro while promoting cartilage degeneration in vivo. Our data provided evidence that EZH2 inhibits miR-138 expression by promoting the histone methylation of its promoter, which induces cartilage degeneration in OA models by upregulating SDC1 expression, suggesting a novel mechanistic strategy for OA treatment. The authors provide evidence that EZH2 inhibits miR-138 expression by histone methylation of its promoter, which induces cartilage degeneration in osteoarthritis models by upregulating expression of the syndecan proteoglycan SDC1. These results suggest a novel mechanistic strategy for future treatments. |
| Databáze: | OpenAIRE |
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