Histone demethylase JMJD3 regulates fibroblast‐like synoviocyte‐mediated proliferation and joint destruction in rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is an immune-mediated disease with the characteristics of progressive joint destruction, deformity, and disability. Epigenetic changes have been implicated in the development of some autoimmune disorders, resulting in an alteration of gene transcription. Here, we investigated how Jumonji C family of histone demethylases (JMJD3) regulated the proliferation and activation of fibroblast-like synoviocytes (FLSs), which are involved in RA joint destruction and pathologic process. The JMJD3 expression and proliferation markers in RA-FLS were higher than those in healthy-FLS and were upregulated in platelet-derived growth factor (PDGF)-induced FLS. Elevated JMJD3 promoted the proliferation and migration of FLS. Treatment with JMJD3 small interfering RNA or inhibitor glycogen synthase kinase (GSK) J4 led to decreased proliferation and migration of FLS. Interestingly, induction of proliferating cell nuclear antigen (PCNA), a major player of the cell-cycle regulation, was correlated with trimethylated lysine 27 in histone H3 loss around the gene promoters. The knockdown of JMJD3 abolished PCNA expression in PDGF-induced FLS and further inhibited cell proliferation and migration, suggesting that JMJD3/PCNA played a crucial role in aspects of FLS proliferation and migration. In vivo, the ability of GSK J4 to hinder collagen-induced arthritis (CIA) in DBA/1 mice was evaluated. We found that GSK J4 markedly attenuated the severity of arthritis in CIA mice. The therapeutic effects were associated with ameliorated joint swelling and reduced bone erosion and destruction. This study revealed how JMJD3 integrated with epigenetic processes to regulate RA-FLS proliferation and invasion. These data suggested that JMJD3 might contribute to rheumatoid synovial hyperplasia and have the potential as a novel therapeutic target for RA.-Jia, W., Wu, W., Yang, D., Xiao, C., Su, Z., Huang, Z., Li, Z., Qin, M., Huang, M., Liu, S., Long, F., Mao, J., Liu, X., Zhu, Y. Z. Histone demethylase JMJD3 regulates fibroblast-like synoviocyte-mediated proliferation and joint destruction in rheumatoid arthritis.

Knockdown of long non-coding RNA PVT1 induces apoptosis of fibroblast-like synoviocytes through modulating miR-543-dependent SCUBE2 in rheumatoid arthritis

“…The important function of PCNA, a main player of the cell cycle modulation, on proliferation and migration of FLSs has been previously investigated [27]. In line with our findings, the anti-apoptotic protein Bcl2 was enhanced, whereas the pro-apoptotic gene Bax was suppressed by silencing of signal transducer and activator of transcription 3 through delivering small interfering RNA in RA-FLSs [28].…”

Inhibition of H3K27me3 demethylases attenuates asthma by reversing the shift in airway smooth muscle phenotype

“…5,7 PDGF, which is associated with those changes in airway structure and function in asthma, 34 has been confirmed as an important factor for ASMCs proliferation, synthesis and migration. 5 A previous study demonstrated that GSK-J4 led to decreased proliferation and migration of fibroblast-like synoviocytes, 35 our study confirmed that GSK-J4 pretreatment partially counteracted PDGF-induced ASMCs proliferation and migration as well. Considering that targeting H3K27me3 demethylation in lung cancer is promising, 36,37 further studies on the effect of H3K27me3 demethylation in asthma are also of great interest.…”

Epigenetics and Vascular Senescence–Potential New Therapeutic Targets?

“…Moreover, deficiency of JMJD3 reduces neointima formation after vascular injury by inhibits the Nox4-autophagy signaling pathway. These observations suggesting that JMJD3 may represent a novel target for the development of new anti-inflammatory therapeutics for treating RA, the prevention and treatment of intima hyperplasia-related vascular diseases, and other pro-inflammatory conditions (Liu et al, 2018;Jia et al, 2018a;Luo et al, 2018;Wu et al, 2019). Likewise, the transcription factor GATA4, a key regulator of angiogenesis and persistence of inflammation in RA may also hold promise as a therapeutic target (Jia et al, 2018).…”

“…Additional research from our group has identified histone demethylase Jumonji domain-containing protein 3 (JMJD3) as a key epigenetic regulator of the inflammatory response in cells (Liu et al, 2018). JMJD3 playing a pivitol role in rheumatoid synovial hyperplasia in rheumatoid arthritis (RA) (Jia et al, 2018a;Wu et al, 2019). Moreover, evidence also points to potential roles for JMJD3 in vascular remodeling (Luo et al, 2018) and in the regulation of the transcription factor GATA4.…”