Differential Signaling by TGF-^|^beta;1 and BMP-2/-7 During Induction of Osteogenic Differentiation of Human Periodontal Ligament Cells-Involvement of a PI3K/mTOR/p70S6K Mechanism

Abstract

Periodontal ligament (PDL) cells are composed of several different kinds of cells including mesenchymal stem cells (MSC). It is well known that these MSC play an important role in the regeneration of periodontal ligament and alveolar bone. The heterodimeric bone morphogenetic protein (BMP-2/-7) is a very potent BMP. However, BMP and TGF-1 signaling pathways that induce and regulate osteogenesis of HPDL cells are not well understood. It was reported that phosphatidylinositol 3-kinase (PI3K), which is activated by insulin-like growth factor-1 (IGF-1) and subsequently promotes the Akt phosphorylation, might play an important role in BMP-2/-7 and TGF-1-induced osteogenesis. There are numerous signaling pathways located downstream of PI3K/Akt, including the mTOR/p70S6K pathways that was the focus of this study. Here we show that TGF-1 is a more potent inducer of osteogenesis of HPDL cells than BMP-2/-7. LY294002, a PI3K inhibitor, and rapamycin, an inhibitor of mammalian target of rapamycin (mTOR), decreased both the Smad 3 phosphorylation and the osteogenic differentiation induced by TGF-1 treatment. In contrast, the phosphorylation of Smad1/5/ 8 by BMP-2/-7 treatment was affected by neither LY294002 nor rapamycin treatment and mTOR inhibition failed to reduce BMP-2/-7-induced osteogenesis of HPDL cells. Thus the PI3K -mTOR pathway is required for TGF-1-induced osteogenesis but is not essential for osteogenesis induced by BMP-2/-7. In conclusion, the PI3K/mTOR/p70S6K pathway plays different roles in the regulation of osteogenic differentiation by TGF-1 and BMP-2/-7.

Synergistic and Mutual Antagonistic Regulations of Wnt Inhibitors Play an Important Role in Osteoblast Differentiation of Human Periodontal Ligament Cells

“…The PDL is a connective tissue comprising a heterogeneous cell population, including undifferentiated mesenchymal cells, osteoprogenitors, fibroblasts, and cementoblasts. 19) We previously reported that the phosphatidylinositide 3-kinase (PI3K)/Akt/mTOR/p70S6K pathway plays pivotal roles in the regulation of osteogenic differentiation by transforming growth factor-1 (TGF-1) 20) . We also reported that an experimental model that repeated or highdose administration of TGF-1 inhibited osteoblast differentiation of HPDL cells by decreasing insulin-like growth factor-1 (IGF-1) expression and subsequently downregulating PI3K/Akt signaling 21,22) , but Dex combined with BMP2/7 promotes osteoblast differentiation independently of IGF-1 expression unlike TGF-1 23) .…”