Mechanotransduction pathways regulating YAP nuclear translocation under Yoda1 and vibration in osteocytes
Chun-Yu Lin, Amel Sassi, Yuning Wu, Kimberly Seaman, Wentian Tang, Xin Song, Raphael Bienenstock, Hiroki Yokota, Yu Sun, Fei Geng, Liyun Wang, Lidan You
Abstract
Yes-associated protein (YAP) is a mechanosensitive protein crucial for bone remodeling. Although research has identified pathways and components involved in YAP regulation, the precise mechanisms of its localization during Piezo1 activation or vibration remain unclear. Piezo1, a mechanosensitive ion channel, allows calcium ions to flow into cells upon activation. Recent studies suggest that combining Yoda1, a Piezo1 activator, with low-magnitude high-frequency (LMHF) vibration (>30 Hz, <1 g acceleration) enhances YAP nuclear translocation. This combination potentially improves the mechanoresponse and therapeutic efficacy of LMHF vibration in bone cells. This study aims to elucidate how Yoda1 and LMHF vibration regulate mechanosensitive structures and pathways, leading to YAP nuclear translocation in MLO-Y4 osteocyte like cells. We investigated the roles of the cytoskeleton and nuclear envelope (NE) in YAP activation under combined LMHF vibration and Yoda1 treatments. Additionally, we analyzed differentially expressed genes (DEGs) in MLO-Y4 cells subjected to these treatments and in Piezo1 knockdown MLO-Y4 cells exposed to vibration. Our findings indicated that increased YAP nuclear translocation with combined treatment may result from the distinct effects of Yoda1 and vibration. Specifically, Yoda1 influenced YAP through mechanisms involving actin and NE dynamics, while LMHF vibration may modulate YAP via the interleukin 6 (IL6)/signal transducer and activator of transcription 3 (STAT3) axis. This study provides new insights and potential therapeutic targets for osteocyte-related pathologies. • Yoda1 influenced YAP nuclear translocation via actin and nuclear envelope wrinkling. • LMHF vibration modulated YAP nuclear translocation through the IL6/STAT3 axis. • Combined treatment showed involvement of both pathways for maximum YAP localization. • Piezo1-knockdown MLO-Y4 led to downregulated bone development and actin filament organization.