Abstract
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.
Highlights
Rheumatoid arthritis (RA) is known as a chronic autoimmune disease (Safiri et al 2019)
We speculate that KDM4B may have important roles in inflammatory diseases, and our study tried to explore the roles of KDM4B in RA
Knockdown of KDM4B suppressed the viability of RA fibroblast-like synoviocytes (FLS) but induced apoptosis
Summary
Rheumatoid arthritis (RA) is known as a chronic autoimmune disease (Safiri et al 2019) Both environmental and genetic risk factors can cause a cascade of immune reactions and firstly lead to the hyperplasia of synovial tissue that lines the joint capsules and produces synovial fluid for polyarticular joints (Gibofsky 2012; Kumar et al 2016). FLS, the dominant cellular component of synovial tissues, play an important role in the progression of RA (Bartok and Firestein 2010). Midkine is a key mediator for cell growth and several inflammatory conditions, which is found to be overexpressed in RA patients and RA FLS and has important diagnostic value in RA patients (Abdel Ghafar et al 2020). Further exploring the molecular mechanisms of FLS will help understand the pathogenesis of RA and identify new therapeutic methods
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