Mechanistic diagram of the study (created using BioRender). (IMAGE)

Higher Education Press

Mechanistic diagram of the study (created using BioRender).

Caption

This study presents a detailed mechanism by which TP and Med synergistically inhibit osteoclastogenesis and RA-associated bone destruction through the METTL3/YTHDF1 axis. Following the stimulation of macrophage colony-stimulating factor (M-CSF) and RANKL, monocytes/macrophages differentiate and fuse into mature OCs through a process regulated by the transcription factors NFATc1 and c-Fos, which promote the expression of OC-related genes such as Ctsk, Dc-stamp, and Atp6v0d2. METTL3 facilitates this process by promoting the m6A methylation of OC-related mRNAs, whereas YTHDF1 increasing their translation and stabilization, driving OC formation and function. TP and Med disrupt this pathway by targeting the METTL3/YTHDF1 axis, with TP suppressing METTL3 expression and Med inhibiting YTHDF1 expression. The combined treatment effectively impairs METTL3/YTHDF1-mediated OC formation and function, leading to the synergistic inhibition of RA-associated bone destruction. TRAF6: tumor necrosis factor receptor-associated factor 6.

Credit

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

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License

CC BY-NC-ND

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