KDM4B Overexpression Promotes the Growth, Migration, and Invasion of Rheumatoid Arthritis Fibroblast-Like Synoviocytes by Activating STAT3 Pathway

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.

Sleep and Late-Onset Alzheimer’s Disease: Shared Genetic Risk Factors, Drug Targets, Molecular Mechanisms, and Causal Effects

“…KDM4B (lysine demethylase 4B) is a protein-coding gene and is engaged in chromatin organization, chromatin-modifying enzymes, and DNA double strand break response. Studies have shown that the KDM4B overexpression leads to inflammation and intellectual disability ( Taniguchi and Moore, 2014 ; Zhang et al, 2021 ). Index SNPs rs12292911 (11p11.2, P meta = 1.51 × 10 –9 , mapped gene: PSMC3 ), rs2310752 (1p31.3, P meta = 3.68 × 10 –9 , mapped gene: PDE4B ), rs359539 (3q25.31, P meta = 3.18 × 10 –9 , mapped gene: PLCH1 ), and rs56249331 (1p35.2, P meta = 8.48 × 10 –9 , mapped gene: PUM1 ) were shared between AD and sleep duration.…”

Role and mechanism of fibroblast-activated protein-α expression on the surface of fibroblast-like synoviocytes in rheumatoid arthritis

“…A study in cancer-associated fibroblasts confirmed that FAP suppresses immune cell response by enhancing MDSC recruitment by promoting the STAT3 C-C motif chemokine ligand 2 signaling (118). Meanwhile, some studies have also indicated that FAP has immunosuppressive effects, and that CD4 + /CD8 + T cell activity is increased after removing FAP + cells in mice (119). These findings, which are outside the field of RA and have been reported inconsistently, highlight the importance of carefully considering whether FAP on the surface of FLSs is an indispensable player in the immunomodulatory function in RA and elucidating the role of FAP in immunomodulation.…”

KDM4B: A promising oncology therapeutic target

“…The stimulation of SOX9 expression, in conjunction with SMAD3, by KDM4B promotes the process of human mesenchymal stem cell differentiation into osteoblasts. 16 The receptor activator of nuclear factor-kappa B ligand (RANKL) can stimulate osteoclasts and induce expression and stabilization of KDM4B. 17 The investigation of cancer therapies that disrupt the process of histone demethylation has been undertaken in consideration of the aforementioned association.…”

“…Similarly, KDM4B plays a crucial role in various types of bone cells. The stimulation of SOX9 expression, in conjunction with SMAD3, by KDM4B promotes the process of human mesenchymal stem cell differentiation into osteoblasts 16 . The receptor activator of nuclear factor‐kappa B ligand (RANKL) can stimulate osteoclasts and induce expression and stabilization of KDM4B 17 .…”