Rheumatoid arthritis (REA) is a progressive autoimmunity characterized by chronic inflammation and bone destruction, primarily driven by the overactivation of osteoclasts (OSCs). Current treatments often fail to reverse existing joint damage and can be accompanied by significant side effects. A recent study published in Engineering has shed light on a novel combination therapy for rheumatoid arthritis that significantly reduces bone destruction by targeting the m6A methylation pathway. The research, investigated the potential of combining triptolide (TRIP), a potent anti-inflammatory compound isolated from Trypterigium wildfordii with a narrow therapeutic window, and Medicarpin (MED), a flavonoid from Sophora japonica 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 TRIP, 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 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 (TRAP staining) revealed that the combination treatment effectively reduced bone surface-to-volume ratios in the ankle and knee joints of CIA rats. Thus the combination therapy significantly decreased the number and function of OSCs, highlighting its potential in inhibiting bone resorption.
The study further explored the molecular mechanisms underlying the synergistic effects of TRIP and MED. The researchers identified that TP and Med modulate the m6A methylation pathway by targeting components of RNA methylations that cells use to stabilize protein tranlsation, like METTL3 and YTHDF1. METTL3 is an m6A methyltransferase that promotes the methylation of osteoclasts-related mRNAs, while YTHDF1 is an m6A reader protein that enhances their translation and stability. The combination of TRIP and MED effectively disrupted this pathway, leading to decreased expression of key OSTEOCLAST-related genes such as c-Fos, NF-ATc1, Dc-Stamp and Ctsk. To validate these findings, the researchers conducted in vitro experiments finding that TRIP and MED inhibited RANKL-induced osteoclastogenesis and bone resorption in a dose-dependent manner.
The study also examined the effects of TRIP 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 cytokine 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 therfore provides compelling evidence that the combination of TRIP and MED offers a promising therapeutic strategy for REA by targeting the RNA m6A methylation pathway. METTL3 and YTHDF1 may thus be deemed as novel therapeutic targets and overall data underscore the importance of exploring combination therapies to enhance treatment efficacy and reduce side effects into clinical settings.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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Scientific references
Zhong X, Deng X et al. Acta Biomater. 2025; 197:374-385.
Shen Z, Yin L et al. Acta Pharm. 2024 Mar; 74(1):149-164.
Singh KB et al. Bioorg Med Chem Lett. 2023; 80:129118.
