Tauroursodeoxycholate improves zoledronate-induced vascular endothelial dysfunction by suppressing the GCN2/eIF2α and...

Medication-related osteonecrosis of the jaw (MRONJ), a severe complication of antiresorptive agents, such as zoledronate (ZOL), significantly affects patients' quality of life. Impaired angiogenesis and vascular endothelial cell (EC) function are core features of MRONJ, although the underlying mechanisms remain largely unknown. In this study, we show that ZOL induces human umbilical vein endothelial cell (HUVEC) dysfunction, which is characterized by suppressed cell viability, migration, tube formation, and angiogenesis-osteogenesis uncoupling. ZOL triggers reactive oxygen species (ROS) accumulation and apoptosis in vascular ECs. Most importantly, we first demonstrate that ZOL activates the general control nonderepressible 2 (GCN2)/eukaryotic translation initiation factor 2A (eIF2α) pathways, leading to suppressed protein synthesis and increased expressions of activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP) in vascular ECs. Moreover, the inositol-requiring enzyme 1 (IRE1)/c-Jun N-terminal kinase (JNK) pathway, a branch of the unfolded protein response (UPR), is activated after ZOL treatment. Tauroursodeoxycholate (TUDCA), a chemical chaperone, partially alleviates the deleterious effects of ZOL on vascular ECs in vitro. Local application of the TUDCA-loaded silk fibroin methacryloyl (SilMA) hydrogel significantly improves mucosal healing and bone regeneration in a rat MRONJ model. These results reveal novel mechanisms underlying MRONJ and suggest that TUDCA is a promising therapeutic candidate for ameliorating MRONJ.