Exercise‐Mediated Mechanical Stress Promotes Osteogenic Differentiation of <scp>BMSCs</scp> Through Upregulation of Lactylation via the <scp>IER3</scp> / <scp>LDHB</scp> Axis

Despite decades of research, senile osteoporosis still lacks effective treatments. Exercise-mediated mechanical loading enhances bone density, strength, and microstructure, while lack of exercise leads to significant bone loss. In this study, we used treadmill exercise and tail-suspension mouse models to explore the effects of exercise on bone metabolism. We found that osteoblast signal transduction factors and the activity of the Immediate Early Response 3 (IER3) protein aligned with exercise-induced changes in bone mass and metabolic levels. Mechanical forces were shown to enhance IER3 activity, which is associated with the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), as demonstrated by in vitro experiments using the Cell Tank Uniaxial Cell Retraction Stretching System. Conversely, downregulation of IER3 expression inhibited force-induced osteoblastic differentiation. Interestingly, mechanical stress-induced increases in lactate content and lactylation levels in BMSCs were blocked when IER3 expression was inhibited. Mass spectrometry analysis identified L-lactate dehydrogenase B chain (LDHB) as a downstream target of IER3, further confirming the critical role of exercise-mediated bone metabolism in osteogenic differentiation. In summary, this study highlights the significant role of IER3 in maintaining exercise-mediated bone homeostasis via bone metabolism, suggesting that IER3 could serve as a potential therapeutic target for osteoporosis.