HEPATOKINE AGP2 MEDIATES PHYSICAL EXERCISE-INDUCED BONE AUGMENTATION THROUGH LIVER-BONE AXIS

Physical exercise has been demonstrated to be beneficial for bone health. However, the mechanisms behind physical exercise induced osteogenesis are still unclear, preventing us from developing “exercise mimetics” to resist osteoporosis. Emerging evidence underscores the liver as a central regulator in metabolic bone diseases, mediated by hepatokines. To investigate the role of AGP2, a hepatokine, in modulating bone density and strength through exercise-induced mechanisms, with a focus on how AGP2 regulates bone anabolism by modulating osteoblast and osteoclast activities in response to physical exercise. We employed a multifaceted approach, including genetic manipulation of AGP2 expression in hepatocytes and biochemical assays to examine its function. Before and after exercise, we screened and evaluated AGP2 expression levels in human and mouse models through proteomic analysis. In mice, we utilized hepatocyte-specific knockout and liver-specific overexpression models to assess the effects of AGP2 on bone health. Using Cut-tag technology and base editing, we analyzed histone lactylation at H3K14 within hepatocytes to understand the regulatory mechanisms of AGP2 expression during exercise. Additionally, we used in vitro experiments to assess the impact of AGP2 on osteoblast mineralization and osteoclast activity through the Wnt/β-catenin signaling pathway. Our results showed that exercise significantly elevated AGP2 levels in the serum of both human participants and mouse models. Hepatocyte-specific knockout of AGP2 eliminated the bone anabolic effects of exercise, even affecting the trajectory and thickness of trabecular bone and cortical bone. Meanwhile, liver-specific overexpression of AGP2 mitigated bone loss in ovariectomized mice, confirming AGP2's osteogenic potential. We found that exercise-induced AGP2 expression is regulated by histone lactylation at the H3K14 site, which is triggered by lactate accumulation during intense exercise. AGP2 activates the Wnt/β-catenin signaling pathway through interaction with the LRP5 receptor on osteoblasts, promoting their mineralization and activity. Our findings provide insights into the liver-bone axis, identifying AGP2 as a critical mediator of bone anabolism through exercise-induced metabolic signaling. These results highlight the potential of AGP2 as a therapeutic target for the treatment of metabolic bone diseases, particularly osteoporosis, by enhancing hepatokine signaling pathways.