Elucidation of the molecular mechanisms governing the osteogenic differentiation of human mesenchymal stem cells (hMSCs) is of great importance for improving the treatment of bone-related diseases. MicroRNAs (miRNAs or miRs), a class of small non-coding RNAs, are critical in a number of biological processes, including the proliferation, differentiation and survival of cells and organisms. Emerging evidence indicates that miRNAs are essential in regulating osteoblastogenesis and bone formation. However, the role of miRNAs in osteoblast mechanotransduction remains to be defined. The present study aimed to examine the role of miR-153 in the osteogenesis of hMSCs and to investigate the impact of miR-153 on bone morphogenetic protein receptor type II (BMPR2) expression. The overexpression of miR-153 inhibited the osteogenic differentiation of hMSCs, whereas downregulation of miR-153 enhanced the process. Furthermore, bioinformatic analysis predicted that miR-153 is a potential regulator of BMPR2. The direct binding of miR-153 to the BMPR2 3'-untranslated region (3'-UTR) was demonstrated by a luciferase reporter assay using a construct containing the BMPR2 3'-UTR. In addition, knockdown of BMPR2 by RNA interference inhibited the osteogenic differentiation of hMSCs, with a similar effect to the upregulation of miR-153. In conclusion, the results suggest that miR-153 is a mechano-sensitive miRNA that regulates osteoblast differentiation by directly targeting BMPR2, and that therapeutic inhibition of miR-153 may be an efficient anabolic strategy for skeletal disorders caused by pathological mechanical loading.