Secreted factors mediate the crosstalk between liver fibrosis, atherosclerosis, and bone metabolism

This study investigates the potential bidirectional communication between non-skeletal organs and bone in disease states such as liver fibrosis and atherosclerosis. Transcriptomic analysis of mouse models of liver fibrosis and atherosclerosis identified 782 and 878 differentially expressed potential secreted factors, respectively. Mendelian randomization analysis revealed causal associations between multiple secreted factors (e.g., Sfrp1, Il18bp, Adam11) and bone mineral density, with shared bone-influencing factors across both disease models. Integration with population-based proteome-phenome databases further indicated that these factors predominantly correlate with osteoporosis risk, primarily as risk factors. Concurrently, proteomic analysis of bone tissue from disease model mice revealed that liver fibrosis significantly impacts pathways related to bone development and cartilage formation, while atherosclerosis primarily disrupts bone remodeling and resorption processes. Furthermore, simultaneous detection of proteins in bone tissue and bone marrow supernatant revealed significant alterations in osteokines (e.g., CD5L, SERPING1) in disease conditions, which suggested genetic or epidemiological associations with multiple systemic diseases. Collectively, by integrating multi-omics data from murine models and human populations, this study screens candidate proteins for liver-bone and artery-bone crosstalk, suggesting that the liver and arteries may remotely regulate bone metabolism via secreted factors in pathological states, and that bone may influence systemic processes through endocrine feedback, thereby laying a theoretical foundation for future functional validation of these bidirectional regulatory mechanisms.