YTHDF1 transcriptionally activated by TCF4 suppresses osteoblast ferroptosis in titanium nanoparticle-induced osteolysis by accelerating GPX4 and SLC7A11 translation.

BACKGROUND: Aseptic loosening and periprosthetic osteolysis driven by wear particles are major causes of total joint arthroplasty (TJA) failure. Investigating the upstream mechanisms of osteoblast ferroptosis in periprosthetic osteolysis is essential for developing therapeutic strategies to lengthen the lifespan of artificial joints. METHOD: Titanium nanoparticle (TN)-induced osteolysis models were established in vivo and in vitro. Bone parameters including bone mineral density, bone volume, bone volume to tissue volume ratio, and total porosity were measured by micro-CT in mice. Commercial kits were applied to test the levels of glutathione, malondialdehyde, and iron. BODIPY 581/591 C11 staining was used to detect lipid peroxidation. ChIP and dual-luciferase reporter assay were utilized to investigate the interaction among TCF4 protein and YTHDF1 promoter region. RIP was employed to detect the relationship between YTHDF1 and GPX4 or SLC7A11 mRNAs. RESULTS: Our findings revealed a marked enhancement of ferroptosis in clinical synovial tissues surrounding implants and TN-induced periprosthetic osteolysis models both in vitro and in vivo. Ferroptosis inhibitors significantly attenuated TN-induced osteolysis. TCF4 and YTHDF1 were both downregulated in TN-induced osteolysis, and overexpression of them improved bone microarchitecture and alleviated osteoblast ferroptosis. TCF4 bound to the promoter region of YTHDF1 to transcriptionally upregulate its expression, which subsequently promoted translation of GPX4 and SLC7A11 mRNAs. Finally, the activation of Wnt/β-catenin pathway boosted TCF4/YTHDF1 axis, and restrained osteoblast ferroptosis in osteolysis. CONCLUSION: TCF4 targeted the promoter region of m6A reader YTHDF1 to promote its transcription, thereby reducing osteoblast ferroptosis in TN-induced periprosthetic osteolysis by promoting the translation of GPX4 and SLC7A11.