Mechanical Loading remodels transcriptional regulation in Osteocytes through Nucleus translocation of NRF2 [ChIP-seq]

The mechano-responsiveness of osteocytes is critical for maintaining bone health, yet the molecular mechanisms underlying this process remain poorly understood. Here, we investigate the impact of mechanical loading on transcriptional and epigenetic remodeling in osteocytes. Using MLO-Y4 cells, we subjected osteocytes to mechanical loading and profiled their transcriptome and histone modifications. Our findings revealed significant transcriptional and epigenetic changes, with NRF2 emerging as a key regulator. We demonstrated that mechanical loading stabilizes NRF2 protein levels and promotes its nucleus translocation, leading to enhanced genomic binding of NRF2 and activation of its target genes. Further analysis confirmed cell type-specific functions of NRF2, with distinct binding profiles in osteocytes compared to astrocytes. These results highlight the pivotal role of NRF2 in the mechano-responsiveness of osteocytes. Unlike pharmacologic agents that stabilize NRF2, mechanical loading uniquely promoted NRF2 nucleus translocation and transcriptional activity. This underscores the irreplaceable role of mechanical stimuli, such as exercise, in promoting bone health. This study advances our understanding of osteocyte mechanotransduction and identifies potential therapeutic interventions for bone diseases.