Differentiation-specific microRNAs may play a critical role in MSC differentiation, and they can be altered by PDGF signaling. We propose that PDGF modulates MSC differentiation by regulating microRNA expression. Therefore, we investigated whether PDGF treatment could alter the expression profile of miRNAs in MSCs. Furthermore, we assessed the osteoblast phenotype of MSCs after inducing osteogenic differentiation. We found that PDGF treatment significantly inhibits the osteogenic differentiation of MSCs and that miR-138 gene transcription is controlled by PDGF signaling. Our results confirm that miR-138 inhibits the osteogenic differentiation of MSCs and suppresses the phosphorylation of FAK, ERK1/2, and Runx2. Furthermore, our study clearly demonstrates that downregulation of Runx2 by miR-138 is critical for the PDGF-mediated inhibition of osteogenic differentiation of MSCs. These findings indicate that inhibition of miR-138 function in MSCs, either by treatment with anti-miR-138 or by overexpression of the miR-138 target sequence (miRNA sponge), could represent a potential therapeutic strategy for the treatment of bone homeostasis disorders caused by activation of the PDGF pathway. (C) 2014 Elsevier Inc. All rights reserved.