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1-(5-oxohexyl)-3,7-Dimethylxanthine, a phosphodiesterase inhibitor, activates MAPK cascades and promotes osteoblast differentiation by a mechanism independent of PKA activation (pentoxifylline promotes osteoblast differentiation)
- Source :
- Endocrinology. 142(11)
- Publication Year :
- 2001
-
Abstract
- We have investigated the effect of 1-(5-oxohexyl)-3,7-dimethylxanthine or pentoxifylline (PeTx), a nonselective phosphodiesterase inhibitor, on osteoblastic differentiation in vitro by using two mesenchymal cell lines, C3H10T1/2 and C2C12, which are able to acquire the osteoblastic phenotype in the presence of bone morphogenetic protein-2 (BMP-2). PeTx induced the osteoblastic markers, osteocalcin and Osf2/Cbfa1, in C3H10T1/2 and C2C12 cells and enhanced BMP-2-induced expression of osteocalcin, Osf2/Cbfa1, and alkaline phosphatase. This activity was partially attributed to the fact that PeTx is able to enhance BMP-2-induced Smad1 transcriptional activity. Although PeTx clearly stimulates PKA in these cells, neither pretreatment of cells with the PKA inhibitor H89 nor transfection with the specific PKA inhibitor PKI prevented the induction or enhancement of osteoblast markers by PeTx, demonstrating that these effects were independent of PKA activation. On the other hand, PeTx induced the activation of ERK1/2 and p38 kinase pathways independently of the activation of PKA. Selective inhibitors of these MAPK cascades prevented the induction of osteoblastic markers in cells treated with PeTx, suggesting that the activation of these two pathways plays a role in the effect of PeTx on osteoblastic differentiation.
- Subjects :
- MAPK/ERK pathway
medicine.medical_specialty
Phosphodiesterase Inhibitors
Biology
p38 Mitogen-Activated Protein Kinases
Pentoxifylline
Cell Line
Mice
Endocrinology
Internal medicine
medicine
Animals
Phosphodiesterase inhibitor
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Osteoblasts
Osteoblast
Cell Differentiation
Transfection
Cyclic AMP-Dependent Protein Kinases
Enzyme Activation
medicine.anatomical_structure
embryonic structures
Osteocalcin
biology.protein
Alkaline phosphatase
Mitogen-Activated Protein Kinases
C2C12
Biomarkers
medicine.drug
Subjects
Details
- ISSN :
- 00137227
- Volume :
- 142
- Issue :
- 11
- Database :
- OpenAIRE
- Journal :
- Endocrinology
- Accession number :
- edsair.doi.dedup.....03445d575be80d1336219978c32edef1