Epigenetic regulation is highly correlated with osteoarthritis (OA) development, whereas its role and detailed mechanisms remain elusive. In this study, we explored the expression of EZH2, an H3K27me3 transferase, in human OA cartilages and its roles in regulating OA pathogenesis. Here, we found EZH2 was highly expressed in both mice and human OA cartilage samples by using histological analysis and RNA sequencing (RNA-Seq). The medial meniscectomy (MMx) OA model results indicated the conditional knockout of Ezh2 deteriorated OA pathological conditions. Furthermore, we showed the positive role of Ezh2 in cartilage wound healing and inhibition of hypertrophy through activating TNFSF13B, a member of the tumor necrosis factor superfamily. Further, we also indicated that the effect of TNFSF13B, increased by Ezh2, might boost the healing of chondrocytes through increasing the phosphorylation of Akt. Taken together, our results uncovered an EZH2-positive subpopulation existed in OA patients, and that EZH2-TNFSF13B signaling was responsible for regulating chondrocyte healing and hypertrophy. Thus, EZH2 might act as a new potential target for OA diagnosis and treatment. © 2020 American Society for Bone and Mineral Research.

中文翻译：

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Ezh2 通过激活 TNFSF13B 改善骨关节炎。

表观遗传调控与骨关节炎 (OA) 发展高度相关，而其作用和详细机制仍然难以捉摸。在本研究中，我们探讨了 EZH2（一种 H3K27me3 转移酶）在人 OA 软骨中的表达及其在调节 OA 发病机制中的作用。在这里，我们通过使用组织学分析和 RNA 测序 (RNA-Seq) 发现 EZH2 在小鼠和人类 OA 软骨样本中均高度表达。内侧半月板切除术 (MMx) OA 模型结果表明条件性敲除 Ezh2 恶化了 OA 病理状况。此外，我们通过激活肿瘤坏死因子超家族成员 TNFSF13B 显示 Ezh2 在软骨伤口愈合和抑制肥大中的积极作用。此外，我们还表明 TNFSF13B 的作用随着 Ezh2 的增加而增加，可能通过增加 Akt 的磷酸化来促进软骨细胞的愈合。总之，我们的结果揭示了 OA 患者中存在 EZH2 阳性亚群，并且 EZH2-TNFSF13B 信号传导负责调节软骨细胞愈合和肥大。因此，EZH2 可能成为 OA 诊断和治疗的新潜在靶点。© 2020 美国骨与矿物研究学会。