Abstract MicroRNAs play crucial roles in bone metabolism. In the present study, we found that miR-148a is dramatically upregulated during osteoclastic differentiation of circulating CD14+ peripheral blood mononuclear cells (PBMCs) induced by macrophage colony stimulating factor (M-CSF) and receptor activator of nuclear factor-κB ligand (RANKL). Overexpression of miR-148a in CD14+ PBMCs promoted osteoclastogenesis, while inhibition of miR-148a attenuated osteoclastogenesis. V-maf musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB) is a transcription factor negatively regulating RANKL-induced osteoclastogenesis. MiR-148a directly targeted MAFB mRNA by binding to the 3'UTR and repressed MAFB protein expression. In vivo, our study showed that silencing of miR-148a using a specific antagomir inhibited bone resorption and increased bone mass in both ovariectomy (OVX) and sham-operated control mice. Furthermore, our results showed that miR-148a levels significantly increased in CD14+ PBMCs from lupus patients and resulted in enhanced osteoclastogenesis, which contributed to the lower BMD in lupus patients compared with normal control. Thus, our study provided a new insight into the roles of miRNAs in osteoclastogenesis, and contributed to a new therapeutic way for osteoporosis. © 2012 American Society for Bone and Mineral Research.