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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
- Source :
- The International Journal of Biochemistry & Cell Biology. 44:1106-1120
- Publication Year :
- 2012
- Publisher :
- Elsevier BV, 2012.
-
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.
- Subjects :
- MAPK/ERK pathway
RHOA
Gene Expression
Transfection
CREB
Biochemistry
chemistry.chemical_compound
Osteogenesis
Cyclic AMP
Guanine Nucleotide Exchange Factors
Humans
Cyclic adenosine monophosphate
Phosphatidylinositol
Phosphorylation
Protein kinase B
Cells, Cultured
PI3K/AKT/mTOR pathway
Adipogenesis
biology
Kinase
Cell Differentiation
Mesenchymal Stem Cells
Cell Biology
Cell biology
Enzyme Activation
chemistry
biology.protein
Cancer research
Phosphatidylinositol 3-Kinase
Signal Transduction
Subjects
Details
- ISSN :
- 13572725
- Volume :
- 44
- Database :
- OpenAIRE
- Journal :
- The International Journal of Biochemistry & Cell Biology
- Accession number :
- edsair.doi.dedup.....0c445b5aa7d05f0bb0f235a8b007ab4d