miR-181a promotes osteoblastic differentiation through repression of TGF-β signaling molecules.

Osteoblastic differentiation is controlled by complex interplay of several signaling pathways and associated key transcription factors, as well as by microRNAs (miRNAs). In our current study, we found miR-181a to be highly upregulated during BMP induced osteoblastic differentiation of C2C12 and MC3T3 cells. Overexpression of miR-181a led to upregulation of key markers of osteoblastic differentiation as well as enhanced ALP levels and Alizarin red staining, indicating the importance of this miRNA for osteoblastic differentiation. Further, we show that miR-181 isoforms (181a, 181b, 181c) are expressed during different stages of mouse calvarial and tibial development, implying their role in both endochondral and intramembranous ossification. We found several direct and indirect targets of miR-181a to be downregulated by global mRNA expression profiling. Our results demonstrate that miR-181a promotes osteoblastic differentiation via repression of TGF-β signaling molecules by targeting the negative regulator of osteoblastic differentiation Tgfbi (Tgf-beta induced) and TβR-I/Alk5 (TGF-β type I receptor). Furthermore, our findings suggest that Rgs4 and Gata6 are direct targets of miR-181a. Taken together, we provide evidence for a crucial functional link between a specific miRNA, miR-181a and osteoblastic differentiation.
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