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

• Published in: Journal of hard tissue biology 2012-10, Vol.21 (4), p.359-366
• Main Authors: Aida, Natsuko, Ochiai, Hiromi, Tezen, Chikara, Yoshizawa, Yuusei, Matsuzaka, Kenichi, Morinaga, Kazuki, Azuma, Toshifumi
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Bone (alveolar); Bone morphogenetic protein 2; Bone morphogenetic proteins; Differentiation; Insulin-like growth factor I; Mesenchyme; Osteogenesis; periodontal ligament; Phosphorylation; Rapamycin; Regeneration; Signal transduction; Smad protein; Stem cells; TOR protein
• ISSN: 1341-7649; 1880-828X
• DOI: 10.2485/jhtb.21.359

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-[beta]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-[beta]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-[beta]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-[beta]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-[beta]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-[beta]1 and BMP-2/-7.