RRC ID 62239
Author Mori K, Kitazawa R, Kondo T, Mori M, Hamada Y, Nishida M, Minami Y, Haraguchi R, Takahashi Y, Kitazawa S.
Title Diabetic osteopenia by decreased β-catenin signaling is partly induced by epigenetic derepression of sFRP-4 gene.
Journal PLoS One
Abstract In diabetics, methylglyoxal (MG), a glucose-derived metabolite, plays a noxious role by inducing oxidative stress, which causes and exacerbates a series of complications including low-turnover osteoporosis. In the present study, while MG treatment of mouse bone marrow stroma-derived ST2 cells rapidly suppressed the expression of osteotrophic Wnt-targeted genes, including that of osteoprotegerin (OPG, a decoy receptor of the receptor activator of NF-kappaB ligand (RANKL)), it significantly enhanced that of secreted Frizzled-related protein 4 (sFRP-4, a soluble inhibitor of Wnts). On the assumption that upregulated sFRP-4 is a trigger that downregulates Wnt-related genes, we sought out the molecular mechanism whereby oxidative stress enhanced the sFRP-4 gene. Sodium bisulfite sequencing revealed that the sFRP-4 gene was highly methylated around the sFRP-4 gene basic promoter region, but was not altered by MG treatment. Electrophoretic gel motility shift assay showed that two continuous CpG loci located five bases upstream of the TATA-box were, when methylated, a target of methyl CpG binding protein 2 (MeCP2) that was sequestered upon induction of 8-hydroxy-2-deoxyguanosine, a biomarker of oxidative damage to DNA. These in vitro data suggest that MG-derived oxidative stress (not CpG demethylation) epigenetically and rapidly derepress sFRP-4 gene expression. We speculate that under persistent oxidative stress, as in diabetes and during aging, osteopenia and ultimately low-turnover osteoporosis become evident partly due to osteoblastic inactivation by suppressed Wnt signaling of mainly canonical pathways through the derepression of sFRP-4 gene expression.
Volume 9(7)
Pages e102797
Published 2014-1-1
DOI 10.1371/journal.pone.0102797
PII PONE-D-13-29140
PMID 25036934
PMC PMC4103869
MeSH Animals Bone Diseases, Metabolic / genetics* Bone Diseases, Metabolic / metabolism Cell Line DNA Methylation / genetics Diabetes Mellitus / genetics* Diabetes Mellitus / metabolism Down-Regulation / genetics Epigenesis, Genetic / genetics* Epigenomics / methods Gene Expression / genetics Mesenchymal Stem Cells / metabolism Methyl-CpG-Binding Protein 2 / genetics Methyl-CpG-Binding Protein 2 / metabolism Mice Oxidative Stress / genetics Promoter Regions, Genetic / genetics Proto-Oncogene Proteins / genetics* Proto-Oncogene Proteins / metabolism Pyruvaldehyde / metabolism Receptor Activator of Nuclear Factor-kappa B / genetics Receptor Activator of Nuclear Factor-kappa B / metabolism Signal Transduction / genetics* Up-Regulation / genetics Wnt Proteins / genetics Wnt Proteins / metabolism beta Catenin / genetics* beta Catenin / metabolism
IF 2.74
Human and Animal Cells ST2(RCB0224)