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.
Int J Biochem Cell Biol
; 44(7): 1106-20, 2012 Jul.
Article
in En
| MEDLINE
| ID: mdl-22497928
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-2'-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'-O-Me-cAMP was attributed to that 8-pCPT-2'-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)P(3) 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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Guanine Nucleotide Exchange Factors
/
Phosphatidylinositol 3-Kinase
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Mesenchymal Stem Cells
Limits:
Humans
Language:
En
Journal:
Int J Biochem Cell Biol
Journal subject:
BIOQUIMICA
Year:
2012
Type:
Article