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Phosphoinositide 3-kinase/Akt signaling is essential for prostaglandin E2-induced osteogenic differentiation of rat tendon stem cells

Liu, Junpeng, Chen, Lei, Tao, Xu, Tang, Kanglai
Biochemical and biophysical research communications 2013 v.435 pp. 514-519
alkaline phosphatase, bone formation, bone morphogenetic proteins, calcification, gene expression, histopathology, messenger RNA, mineralization, models, osteocalcin, phosphatidylinositol 3-kinase, prostaglandins, rats, stem cells, tissues
Tissue calcification is a typical histopathological feature of tendinopathy. The osteogenic differentiation of tendon stem cells (TSCs) induced by inflammatory mediators is believed to play a key role in this process. Previous studies showed that the major inflammatory mediator prostaglandin E2 (PGE2) induced osteogenic differentiation of TSCs via bone morphogenetic protein (BMP)-2 production. Using a rat TSC culture model, we showed that PGE2 induced BMP-2 production through up-regulation of BMP-2 mRNA expression. PGE2 activated Akt, but not extracellular-signal-regulated kinase, in TSCs. Increased BMP-2 mRNA expression mediated by PGE2 was prevented by phosphoinositide 3-kinase (PI3K) and Akt inhibitors, but not by a MEK inhibitor. Furthermore, in the presence of exogenous BMP-2, PI3K and Akt inhibitors blocked Runx2 and osteocalcin expression, although BMP-2 did not activate Akt. BMP-2-induced alkaline phosphatase activity and mineralization were also inhibited by PI3K and Akt inhibitors. However, these inhibitors did not block activation of Smad, implying that Akt was involved downstream of Smad. Taken together, these results indicate that the PI3K-Akt signaling cascade is essential for PGE2-induced BMP-2 production and BMP-2-mediated osteogenic differentiation, suggesting that PI3-kinase-Akt signaling contributes to the formation of calcified tissues in tendinopathy.