Loss of androgen receptor promotes adipogenesis but suppresses osteogenesis in bone marrow stromal cells

Gender differences have been described in osteoporosis with females having a higher risk of osteoporosis than males. The differentiation of bone marrow stromal cells (BMSCs) into bone or fat is a critical step for osteoporosis. Here we demonstrated that loss of the androgen receptor (AR) in BMSCs suppressed osteogenesis but promoted adipogenesis. The mechanism dissection studies revealed that AR deficiency suppressed osteogenesis-related genes to inhibit osteoblast differentiation from BMSCs. Knockout of AR promoted adipogenesis of BMSCs via Akt activation through IGFBP3-mediated IGF signaling, and the 5' promoter assay and chromatin immunoprecipitation assays further proved that AR could modulate IGFBP3 expression at the transcriptional level. Finally, addition of IGF inhibitors successfully masked the AR deficiency-induced Akt activation, and inhibitions of Akt, IGF1, and IGF2 pathways reversed the AR depletion effects on the adipogenesis process. These results suggested that AR-mediated changes in IGFBP3 might modulate the IGF-Akt axis to regulate adipogenesis in BMSCs.