Particle-induced osteolysis is mediated by endoplasmic reticulum stress-associated osteoblast apoptosis

Abstract

Osteoblast dysfunction plays a crucial role in periprosthetic osteolysis and aseptic loosening, and endoplasmic reticulum (ER) stress is recognized as an important causal factor of wear particle-induced osteolysis. However, the influence of ER stress on osteoblast activity during osteolysis and its underlying mechanisms remain elusive. This study aims to investigate whether ER stress is involved in the detrimental effects of wear particles on osteoblasts. Through our investigation, we observed elevated expression levels of ER stress and apoptosis markers in particle-stimulated bone specimens and osteoblasts. To probe further, we employed the ER stress inhibitor, 4-PBA, to treat particle-stimulated osteoblasts. The results revealed that 4-PBA effectively alleviated particle-induced osteoblast apoptosis and mitigated osteogenic reduction. Furthermore, our study revealed that wear particle-induced ER stress in osteoblasts coincided with mitochondrial damage, calcium overload, and oxidative stress, all of which were effectively alleviated by 4-PBA treatment. Encouragingly, 4-PBA administration also improved bone formation and attenuated osteolysis in a mouse calvarial model. In conclusion, our results demonstrate that ER stress plays a crucial role in mediating wear particle-induced osteoblast apoptosis and impaired osteogenic function. These findings underscore the critical involvement of ER stress in wear particle-induced osteolysis and highlight ER stress as a potential therapeutic target for ameliorating wear particle-induced osteogenic reduction and bone destruction.