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OBJECTIVES Osteoclast differentiation is regulated by transcriptional, post-transcriptional and post-translational mechanisms. Micro-ribonucleic acids (miRNAs) are 20-24 nucleotides long non-coding RNAs involved in post-translational regulation of gene expressions during osteoclast differentiation. The objective of the present study was to investigate the role played by the miRNA, miR-338-3p, in osteoclastogenesis. METHODS Osteoclastogenesis was induced in murine RAW264.7 cells using M-CSF and RANKL. The differentiated cells were harvested at designated times for TRAP staining and detection of designated gene expressions. A synthetic miR-338-3p mimic or its inhibitor was transfected into RAW264.7 cells prior to the induction of osteoclastogenesis. The effects of mimic or inhibitor on osteoclastogenesis were examined by qRT-PCR and TRAP staining. Bioinformatic analysis and luciferase activity were performed to identify the relationship between miR-338-3p and the transcription factor MafB. The miR-338-3p mimic and MafB siRNA were co-transfected into RAW264.7 cells to evaluate the cross-talk between miR-338-3p and MafB. RESULTS miR-338-3p was increased significantly during osteoclast differentiation. Overexpression of miR-338-3p promoted osteoclastogenesis while its inhibition had the opposite effect. Bioinformatic analysis and dual luciferase assays indicated that miR-338-3p targeted MafB to repress its gene expression. MafB knockdown by RNA silencing blocked the promotional effect of miR-338-3p on osteoclast differentiation. CONCLUSION Because miR-338-3p is crucial for osteoclastic differentiation via targeting of the transcription factor MafB, inhibition of this miRNA represents a potential strategy for modulating osteoporosis in an aging population. CLINICAL SIGNIfiCANCE: Understanding the role played by miR-338-3p in osteoclast differentiation bridges the gap between the pathogenesis of osteoporosis and the quest for novel therapeutics to reduce the risk of bone fracture associated with this global disease.