Periodontal ligament (PDL) cells are comprised of heterogenous cell populations including mesenchymal stem cells and osteogenic progenitor cells. We previously reported that differentiation of human PDL cells into osteoblasts requires phosphoinositide 3-kinase (PI3K) activities. Here, we investigate osteoblast differentiation using TGF- 1, BMP-2/BMP-7, and dexamethasone (Dex) in human PDL cells, focusing on the PI3K/Akt pathway. We found that in TGF- 1-treated cells, Dex increased IGF-1 expression as well as phosphorylated Akt, which is a main target molecule of PI3K. Downregulation of IGF-1 expression and enhanced phosphorylation of Akt were observed in BMPs with Dex-treated cells, even though alkaline phosphatase expression and activities were enhanced. These results indicate that IGF-1 is a key regulator in TGF- 1-induced osteogenesis, but it is not required in osteoblast differentiation initiated by BMPs. Because BMPs require PI3K activation for osteoblast differentiation, and because BMP treatment upregulates Akt phosphorylation, signaling molecules other than IGF-1 may support BMP-induced osteoblast differentiation.