Exchange protein activated by cyclic adenosine monophosphate regulates the switch between adipogenesis and osteogenesis of human mesenchymal stem cells through increasing the activation of phosphatidylinositol 3-kinase

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• 作者：Zihua Tang^a ; Dongyan Shi^a ; Bingbing Jia^a ; Jiarong Chen^a ; Chen Zong^a ; Dan Shen^b ; Qiang Zheng^c ; Jinfu Wang^a ; ^{wjfu@zju.edu.cn} ; Xiangming Tong^b ; ^{xmtong2003@yahoo.com.cn}
• 关键词：hMSCs ; Epac ; PI3K ; Adipogenesis ; Osteogenesis
• 刊名：The International Journal of Biochemistry and Cell Biology
• 出版年：2012
• 期刊代码：127_13572725
• 类别：med
• 出版时间：July, 2012
• 卷：44
• 期：7
• 页码：1106-1120
• 文件大小：2023 K

摘要

Epac, exchange protein activated by cyclic adenosine monophosphate (cAMP), could regulate the trans-differentiation between adipogenesis and osteogenesis of human mesenchymal stem cells (hMSCs). Epac activated by 8-pCPT-2鈥?O-Me-cAMP, a cAMP analog preferentially activating Epac, resulted in the increase of adipogenic gene expression and the decrease of osteogenic gene expression. The pro-adipogenic and anti-osteogenic effect of 8-pCPT-2鈥?O-Me-cAMP was attributed to that 8-pCPT-2鈥?O-Me-cAMP led to the activation of protein kinase B (PKB) and cAMP response element-binding protein (CREB) as well as the inhibition of Ras homolog gene family member A (RhoA), focal adhesion kinase (FAK), extracellular-signal-regulated kinase (ERK) and runt-related transcription factor 2 (Runx2) activities. Inhibition of Epac by a dominant-negative form of Epac1 resulted in the decrease of phosphatidylinositol 3-kinase (PI3K), PKB and CREB activities as well as down-regulation of peroxisome proliferator activated receptor-纬 (PPAR纬) expression. Inhibition of PI3K by a specific inhibitor or inhibition of Arf and Rho GAP adapter protein 3 (ARAP3, a phosphatidylinositol (PtdIns)(3,4,5)P₃ binding protein) by ARAP3 siRNA led to the recovery of RhoA and FAK activities. RhoA-V14, a constitutively active form of RhoA, could activate the MEK/ERK/Runx2 signaling. Therefore, we conclude that PI3K activated by Epac leads to the activation of PKB/CREB signaling and the up-regulation of PPAR纬 expression, which in turn activate the transcription of adipogenic genes; whereas osteogenesis is driven by Rho/FAK/MEK/ERK/Runx2 signaling, which can be inhibited by Epac via PI3K. These results should be helpful to provide new targets for treatment of osteoporosis and related bone-wasting diseases.