Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8324643 | The International Journal of Biochemistry & Cell Biology | 2012 | 15 Pages |
Abstract
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-2â²-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-2â²-O-Me-cAMP was attributed to that 8-pCPT-2â²-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-γ (PPARγ) 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 PPARγ 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.
Related Topics
Life Sciences
Biochemistry, Genetics and Molecular Biology
Biochemistry
Authors
Zihua Tang, Dongyan Shi, Bingbing Jia, Jiarong Chen, Chen Zong, Dan Shen, Qiang Zheng, Jinfu Wang, Xiangming Tong,