Department of Rheumatology and Immunology, China-Japan Union Hospital of Jilin University, 126 Xiantai Street, Changchun, 130033, Jilin, China.
Department of Gynecologic Oncosurgery-1, Ji Lin Tumor Hospital, Changchun, 130031, Jilin, China.
Biochem Genet. 2021 Dec;59(6):1427-1440. doi: 10.1007/s10528-021-10042-1. Epub 2021 Apr 28.
In rheumatoid arthritis (RA), fibroblast-like synoviocytes (FLS) present a unique aggressive phenotype and have a passive response to the inflammatory microenvironment, which are critical for the disease's progression. KDM4B, as a histone demethylase, functions as an oncogenic factor in many cancers and is implicated in osteoclastogenesis as well as pro-inflammatory cytokine release in inflammatory diseases. However, the effects of KDM4B on RA FLS have not been reported. To investigate this issue, our study determined the expression of KDM4B in RA FLS using RT-qPCR and western blot. The effects of KDM4B on RA FLS viability, apoptosis, migration, and invasion were detected by MTT, flow cytometry, transwell migration, and invasion assays. Furthermore, the interaction of KDM4B with STAT3 signaling was studied by western blot, MTT, flow cytometry, transwell migration, and invasion assays. The experimental results showed that KDM4B expression was upregulated in RA synovial tissues and FLS as compared to healthy control tissues and normal FLS. Knockdown of KDM4B obviously suppressed RA FLS viability, migration and invasion, and induced apoptosis. In addition, knockdown of KDM4B in RA FLS decreased the expression of p-STAT3 and MMP-9 but increased cleaved caspase-3 expression compared with the control group. Moreover, KDM4B overexpression could promote cell growth, migration and invasion, and suppress apoptosis in RA FLS by activating STAT3 signaling. Therefore, these findings provide new insight for understanding the pathogenesis of RA and indicate that KDM4B may have a potential to be an effective therapeutic target for RA.
在类风湿关节炎 (RA) 中，成纤维样滑膜细胞 (FLS) 呈现出独特的侵袭性表型，并对炎症微环境产生被动反应，这对于疾病的进展至关重要。KDM4B 作为一种组蛋白去甲基化酶，在许多癌症中作为致癌因子发挥作用，并与破骨细胞生成以及炎症性疾病中促炎细胞因子的释放有关。然而，KDM4B 对 RA FLS 的影响尚未报道。为了研究这个问题，我们通过 RT-qPCR 和 Western blot 确定了 RA FLS 中 KDM4B 的表达。通过 MTT、流式细胞术、Transwell 迁移和侵袭实验检测了 KDM4B 对 RA FLS 活力、凋亡、迁移和侵袭的影响。此外，通过 Western blot、MTT、流式细胞术、Transwell 迁移和侵袭实验研究了 KDM4B 与 STAT3 信号的相互作用。实验结果表明，与健康对照组织和正常 FLS 相比，RA 滑膜组织和 FLS 中 KDM4B 的表达上调。与对照组相比，KDM4B 的敲低明显抑制了 RA FLS 的活力、迁移和侵袭，并诱导了凋亡。此外，与对照组相比，RA FLS 中 KDM4B 的敲低降低了 p-STAT3 和 MMP-9 的表达，但增加了 cleaved caspase-3 的表达。此外，KDM4B 的过表达通过激活 STAT3 信号通路，可促进 RA FLS 中的细胞生长、迁移和侵袭，并抑制凋亡。因此，这些发现为理解 RA 的发病机制提供了新的见解，并表明 KDM4B 可能成为 RA 的一个有潜力的治疗靶点。
