論文 - 詳細
| RRC ID | 62239 |
|---|---|
| 著者 | Mori K, Kitazawa R, Kondo T, Mori M, Hamada Y, Nishida M, Minami Y, Haraguchi R, Takahashi Y, Kitazawa S. |
| タイトル | Diabetic osteopenia by decreased β-catenin signaling is partly induced by epigenetic derepression of sFRP-4 gene. |
| ジャーナル | 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. |
| 巻・号 | 9(7) |
| ページ | e102797 |
| 公開日 | 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 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 2 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | ST2(RCB0224) |