Identification of Therapeutic Targets for Osteoporosis through Multiomics Integration and the Potential Dual Role of Androgen Receptor Signaling in Its Pathophysiology

This study investigates potential therapeutic targets for osteoporosis using a multiomics approach and explores the dual role of androgen receptor (AR) signaling in its pathophysiology. By analyzing single-cell RNA sequencing data (GSE147287), we identified nine major cell types and their specific developmental trajectories in osteoporosis samples. Differential miRNA analysis revealed 19 significantly dysregulated miRNAs, and integrated database analysis identified six hub genes, including AR, which is highly expressed in tissue stem cells. Further pathway analysis highlighted the involvement of AR in myeloid cell activation and osteoclast differentiation, key processes in bone resorption. We also constructed a drug-gene-miRNA interaction network, identifying potential interactions between AR and drugs such as norethisterone (AR agonist) and cyproterone acetate (AR antagonist). DeepPurpose analysis, drug MoA, and molecular docking predictions indicated that cyproterone acetate exhibited a stronger binding affinity to AR and could inhibit overactivation of AR signaling, offering a more effective therapeutic option than norethisterone. In vitro experiments confirmed that both drugs inhibited RANKL-induced osteoclastogenesis, with cyproterone acetate showing superior efficacy at lower concentrations. This work provides preliminary evidence for the dual role of AR signaling in osteoporosis and suggests that targeting AR with antagonists (cycloacetate) could be a promising strategy for treating bone resorption.