Targeting transcription factors for therapeutic benefit in rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is a destructive inflammatory autoimmune disease that causes pain and disability. Many of the currently available drugs for treating RA patients are aimed at halting the progression of the disease and alleviating inflammation. Further, some of these treatment options have drawbacks, including disease recurrence and adverse effects due to long-term use. These inefficiencies have created a need for a different approach to treating RA. Recently, the focus has shifted to direct targeting of transcription factors (TFs), as they play a vital role in the pathogenesis of RA, activating key cytokines, chemokines, adhesion molecules, and enzymes. In light of this, synthetic drugs and natural compounds are being explored to target key TFs or their signaling pathways in RA. This review discusses the role of four key TFs in inflammation, namely NF-κB, STATs, AP-1 and IRFs, and their potential for being targeted to treat RA.

Curcumin Co-Encapsulation Potentiates Anti-Arthritic Efficacy of Meloxicam Biodegradable Nanoparticles in Adjuvant-Induced Arthritis Animal Model

“…These cytokines induce local and subsequent systemic inflammation and cause the stimulation of osteoclasts, all of which lead to cartilage damage, bone resorption, and the degradation of extracellular matrix. Synoviocytes serve as a reservoir for these inflammatory mediators [7,11,63,64]. TNF-α amplifies inflammation by stimulating synovial fibroblasts, which increases the cellular adhesion of mediators and leukocyte movement, subsequently resulting in joint injury.…”

“…These therapies are mostly used to reduce joint pain and inflammation and also slow the progression of disease by interfering with immune system signaling to suppress the inflammatory processes that cause joint degeneration. However, these agents are relatively costly and have a number of unfavorable side effects [10,11]. With the increasing need for medications to treat RA, there has been a rise in research interest in understanding the pathophysiology of RA and developing novel treatments.…”

Unveiling the Nexus: Cellular Metabolomics Unravels the Impact of Estrogen on Nicotinamide Metabolism in Mitigating Rheumatoid Arthritis Pathogenesis

“…STAT1 was the foremost target, with the highest GDA score of 0.4. Upregulated expression of STAT1 protein and its phosphorylated form has been studied in RA synoviocytes [52], and its activation in the cell, primarily stimulated by different pro-inflammatory cytokines (IFNγ, IL-2, IL-6, IL-7, and IL-21), has been reported to promote cartilage degradation [53]. To evaluate the effect of E2 treatment on STAT1 activation, we analyzed its protein and mRNA expression and found that E2 treatment significantly downregulated the STAT1 expression compared to the control (Figure 5A,E).…”

DNA Damage and Cellular Senescence in Osteoarthritis: An Unexpected Role for Interferon Regulatory Factor 1 in Chondrocyte DNA Repair

“…This may be relevant to the relationship between the protective effect of IRF1 in OA seen here and the potentially pathogenic role for IRF1 in rheumatoid arthritis. In that setting, IRF1 is known to contribute to the tumor necrosis factor α–driven interferon response and has therefore been considered a potential therapeutic target 13–15 . Although this context should be considered for any translational studies building off the findings of Cho et al, 11 the authors showed that producing IRF1 at high levels in the knee joint of mice by injecting adeno‐associated virus–expressing Irf1 did not lead to inflammation or joint pathology, at least at the investigated time points of four and eight weeks after injection.…”