Upon understanding the mechanism behind the current MTX treatment commonly used to treat Rheumatoid Arthritis, researchers discovered another potential treatment option using TAp63 protein as a drug target.
Rheumatoid arthritis (RA) is an autoimmune and inflammatory disease characterised by chronic and destructive joint pain. As an autoimmune disorder, RA occurs when one’s immune system fails to recognise their own body’s tissue and mistakenly attacks it. Failure to treat RA may result in debilitating effects, namely functional disability and premature mortality. In the past 20 years, the drug methotrexate (MTX) has been used as the standard first-line therapeutic strategy for RA. However, the precise mechanism behind its effectiveness is still unclear.
On the cellular level, inflammation of a body part can be attributed to a spike in immune cells around the area. As such, treatments for inflammatory diseases usually target metabolic pathways that promote the production of immune cells. In the case of MTX, previous research has demonstrated its ability to suppress the upregulation of folate metabolism—a pathway involved in DNA synthesis and cell proliferation—in patients with active RA. In addition, it has been suggested that the increased concentration of a particular type of white blood cell, CD4+ T cells, plays a key role in the pathogenesis of RA.
For scientists at Chiba University in Japan, this limited understanding of the role of CD4+ T cells in the pathogenesis of RA becomes the motivation for their study. Led by Dr Akiro Suto, Associate Professor at the Department of Allergy and Clinical Immunology at the Graduate School of Medicine, the team aimed to identify the genes that are targeted and regulated by MTX treatment in patients with active RA. Their study was published on 22 May 2023 in the JCI Insight journal.
In order to get a sense of the genes involved in RA pathology, the researchers first analysed comprehensive gene expression profiles of RA patients before and after MTX treatments. In this first stage, they found a significant reduction in the expression of TAp63 genes in CD4+ T cells after treatment with MTX. Using a combination of advanced molecular techniques, the researchers then induced the suppression of TAp63 gene in mice models. In doing so, they found that the suppression of TAp63 promotes the activation of another gene, Foxp3, a gene that suppresses and limits the production of T cells. As such, these findings suggest that MTX reduces RA-induced inflammation by decreasing the expression of TAp63 genes, which consequently activates the Foxcp3 metabolic pathway that limits the excess production of immune cells.
The authors acknowledge that there are limitations to their study and that more research needs to be done to address them. For example, they noticed that the expression levels of TAp63 gene are very different in naturally produced T cells and those induced in cell culture. Hence, the efficiency of a TAp63-targeting drug may look very different in an actual human body. Furthermore, the researchers were able to identify four genes that were upregulated by TAp63 genes, but only the role of Foxcp3 was expounded upon. This is mainly because the functions of the other three genes are less well known or controversial. Thus, additional studies need to be carried out before their role in RA pathology can be inferred.
Overall, the authors were able to provide new insight on the cellular mechanism behind MTX treatment. These findings reveal the potential for TAp63 as a new drug target for RA, which could translate into a more targeted and effective drug to treat this complex disorder. [APBN]
Source: Suga et al. (2023). TAp63, a methotrexate target in CD4+ T cells, suppresses Foxp3 expression and exacerbates autoimmune arthritis. JCI Insight, 8(10). https://doi.org/10.1172/jci.insight.164778