Kaempferol attenuates particle-induced osteogenic impairment by regulating ER stress via the IRE1α–XBP1s pathway
Xin Yu, Zhengrong Ren, Yuxiang Wang, G Yuan, Jianlun Hu, Lin Song, Cheng Pan, Kexiang Feng, Yuqiao Liu, Longgang Shao, Zhang Li, Jinjuan Wang, Jianning Zhao, Nirong Bao, Zhongyang Sun
Abstract
Periprosthetic osteolysis and subsequent aseptic loosening are the primary causes of failure following total joint arthroplasty. Wear particle–induced osteogenic impairment is recognized as an important contributing factor in the development of osteolysis, with endoplasmic reticulum (ER) stress emerging as a pivotal underlying mechanism. Hence, searching for potential therapeutic targets and agents capable of modulating ER stress in osteoblasts is crucial for preventing aseptic loosening. Kaempferol (KAE), a natural flavonol compound, has shown promising osteoprotective effects and anti-ER stress properties in diverse diseases. However, the influence of KAE on ER stress-mediated osteogenic impairment induced by wear particles remains unclear. In this study, we observed that KAE effectively relieved TiAl 6 V 4 particles–induced osteolysis by improving osteogenesis in a mouse calvarial model. Furthermore, we demonstrated that KAE could attenuate ER stress-mediated apoptosis in osteoblasts exposed to TiAl 6 V 4 particles, both in vitro and in vivo . Mechanistically, our results revealed that KAE mitigated ER stress-mediated apoptosis by upregulating the IRE1α–XBP1s pathway while concurrently partially inhibiting the IRE1α-regulated RIDD and JNK activation. Collectively, our findings suggest that KAE is a prospective therapeutic agent for treating wear particle–induced osteolysis and highlight the IRE1α–XBP1s pathway as a potential therapeutic target for preventing aseptic loosening.