Wnt signaling pathways are a highly conserved pathway, which plays an important 
role from the embryonic development to bone formation. The effect of Wnt pathway 
on osteogenesis relies on their cellular environment and the expression of 
target genes. However, the molecular mechanism of that remains unclear. On the 
basis of the preliminary results, we observed the contrary effect of canonical 
Wnt signaling on osteogenic differentiation of periodontal ligament stem cells 
(PDLSCs) in the different culture environment. Furthermore, we found that the 
expression level of miR-17 was also varied with the change in the culture 
environment. Therefore, we hypothesized that miR-17 and canonical Wnt signaling 
may have potential interactions, particularly the inner regulation relationship 
in different microenvironments. In this paper, we observed that canonical Wnt 
signaling promoted osteogenesis of PDLSCs in the fully culture medium, while 
inhibited it in the osteogenic differentiation medium. Interestingly, alteration 
in the expression level of endogenous miR-17 could partially reverse the 
different effect of canonical Wnt signaling. Furthermore, the role of miR-17 was 
because of its target gene TCF3 (transcription factor 3), a key transcription 
factor of canonical Wnt pathway. Overexpression of TCF3 attenuated the effect of 
miR-17 on modulating canonical Wnt signaling. Finally, we elucidated that TCF3 
enhanced osteogenesis both in vitro and in vivo. In brief, the different level 
of miR-17 was the main cause of the different effect of canonical Wnt signaling, 
and TCF3 was the crucial node of miR-17-canonial Wnt signaling regulation loop. 
This understanding of microRNAs regulating signaling pathways in different 
microenvironments may pave the way for fine-tuning the process of osteogenesis 
in bone-related disorders.