Novel combination therapy targets m6A pathway to combat joint erosion in rheumatoid arthritis

A recent study published in Engineering has shed light on a novel combination therapy for rheumatoid arthritis (RA) that significantly reduces bone destruction by targeting the m⁶A methylation pathway. The research, conducted by a team from the China-Japan Friendship Clinical Medical College and other institutions, explores the synergistic effects of triptolide (TP) and medicarpin (Med) in mitigating RA-associated bone erosion.

Rheumatoid arthritis is a progressive autoimmune disease characterized by chronic inflammation and bone destruction, primarily driven by the overactivation of osteoclasts (OCs). Current treatments often fail to reverse existing joint damage and can be accompanied by significant side effects. This study investigates the potential of combining TP, a potent anti-inflammatory compound with a narrow therapeutic window, and Med, a flavonoid with anti-inflammatory and anti-bone destruction properties, to enhance efficacy and reduce toxicity.

The researchers utilized a collagen-induced arthritis (CIA) rat model to evaluate the effects of TP, Med, and their combination on disease progression and bone erosion. The results showed that the combination therapy significantly alleviated arthritis symptoms and delayed disease onset. Specifically, the combined treatment of TP and Med at half the doses of their monotherapies demonstrated superior efficacy in reducing bone erosion and inhibiting osteoclastogenesis compared to either drug alone.

Micro-CT scans and histological analyses revealed that the combination treatment effectively reduced bone surface-to-volume ratios and increased bone volume in the ankle and knee joints of CIA rats. Additionally, tartrate-resistant acid phosphatase (TRAP) staining and F-actin ring assays indicated that the combination therapy significantly decreased the number and function of OCs, highlighting its potential in inhibiting bone resorption.

The study further explored the molecular mechanisms underlying the synergistic effects of TP and Med. The researchers identified that TP and Med modulate the m⁶A methylation pathway by targeting methyltransferase-like 3 (METTL3) and YT521-B homology domain family protein 1 (YTHDF1), respectively. METTL3 is an m⁶A methyltransferase that promotes the methylation of OC-related mRNAs, while YTHDF1 is an m⁶A reader protein that enhances their translation and stability. The combination of TP and Med effectively disrupted this pathway, leading to decreased expression of key OC-related genes such as Nfatc1, c-Fos, Dc-stamp, Atp6v0d2, and Ctsk.

To validate these findings, the researchers conducted in vitro experiments using primary bone marrow mononuclear cells (BMMs) from mice. The results confirmed that TP and Med inhibited receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclastogenesis and bone resorption in a dose-dependent manner. Moreover, RNA immunoprecipitation (RIP) assays demonstrated that METTL3 and YTHDF1 directly interact with OC-related mRNAs, providing further evidence of their role in regulating osteoclastogenesis.

The study also examined the effects of TP and Med on the inflammatory response in CIA rats. The combination therapy was found to modulate the levels of pro-inflammatory and anti-inflammatory cytokines, with significant reductions in IL-1β and IL-6 levels. Additionally, the treatment helped replenish regulatory T cells (Tregs) in the spleen, which play a crucial role in maintaining bone tissue homeostasis.

This study provides compelling evidence that the combination of TP and Med offers a promising therapeutic strategy for RA by targeting the m⁶A methylation pathway. The findings highlight the potential of METTL3 and YTHDF1 as novel therapeutic targets and underscore the importance of exploring combination therapies to enhance treatment efficacy and reduce side effects. Future research may focus on optimizing dosing regimens and further elucidating the mechanisms of action to translate these findings into clinical practice.

The paper "Increased Alleviation of Bone Destruction in Individuals with Rheumatoid Arthritis via the Coinhibition of the METTL3 and YTHDF1 Axis by the Combination of Triptolide and Medicarpin," is authored by Yi Jiao, Zhaoran Wang, Wenya Diao, Qishun Geng, Xing Wang, Xiaoxue Cao, Tong Shi, Jiahe Xu, Lu Zhao, Zihan Wang, Tiantian Deng, Lei Yang, Tingting Deng, Cheng Xiao.