Extra-cellular matrix suppresses expression of the apoptosis mediator Fas by epigenetic DNA methylation

The extracellular matrix (ECM) of bone consists mainly of collagen type I, which induces osteoblastic differentiation and prevents apoptosis. Fas induces apoptosis in cells improperly adhering to ECM. Recently, it was described that Fas expression is modulated by epigenetic DNA methylation. Mouse MC...

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Bibliographic Details
Published in:Apoptosis (London) 2010-06, Vol.15 (6), p.728-737
Main Authors: Thaler, Roman, Karlic, Heidrun, Spitzer, Silvia, Klaushofer, Klaus, Varga, Franz
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Biochemistry
Biomedical and Life Sciences
Biomedicine
Cancer Research
Cell Biology
Cell Differentiation
Cell Line
Collagen - metabolism
DNA Methylation
Down-Regulation
Epigenesis, Genetic
Extracellular Matrix - metabolism
Fas Ligand Protein - genetics
Fas Ligand Protein - metabolism
Gene Expression Regulation
Mice
Oncology
Original Paper
Osteoblasts - cytology
Osteoblasts - metabolism
Promoter Regions, Genetic
Virology
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Summary:The extracellular matrix (ECM) of bone consists mainly of collagen type I, which induces osteoblastic differentiation and prevents apoptosis. Fas induces apoptosis in cells improperly adhering to ECM. Recently, it was described that Fas expression is modulated by epigenetic DNA methylation. Mouse MC3T3-E1 pre-osteoblastic cells were cultured either on collagen coated or on uncoated culture dishes for control. mRNA was isolated and gene expression was analyzed by quantitative RT–PCR. Furthermore, we measured global and specific DNA methylation. Compared to controls, cells cultured on collagen-coated dishes increased the expression of Runx2 and OCN indicating differentiation of pre-osteoblastic cells. Additionally, collagen up-regulated cyclin-A2 and down-regulated Fas expression suggesting increased cell multiplication. Furthermore, the expression of Dnmt1 and Hells, key mediators of the DNA-methylation process, was increased. As a consequence, we demonstrate that global DNA methylation and specific methylation of the Fas promoter was higher in MC3T3-E1 cells cultured on collagen when compared to controls. Investigation of signal transduction pathways by mean of inhibitors suggests that focal adhesion kinase, MAP- and Jun-kinases and AP-1 are involved in this process. In summary, we demonstrate that ECM prevents activation of Fas by epigenetic DNA-methylation.
ISSN:1360-8185
1573-675X
DOI:10.1007/s10495-010-0462-3