Diabetic osteopenia by decreased β-catenin signaling is partly induced by epigenetic derepression of sFRP-4 gene.
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 rapidl...
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2014
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oai:doaj.org-article:a9bfbcff677140e7a88001f5703c99f32021-11-25T06:08:02ZDiabetic osteopenia by decreased β-catenin signaling is partly induced by epigenetic derepression of sFRP-4 gene.1932-620310.1371/journal.pone.0102797https://doaj.org/article/a9bfbcff677140e7a88001f5703c99f32014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/25036934/?tool=EBIhttps://doaj.org/toc/1932-6203In 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.Kiyoshi MoriRiko KitazawaTakeshi KondoMichiko MoriYasuhiro HamadaMichiru NishidaYasuhiro MinamiRyuma HaraguchiYutaka TakahashiSohei KitazawaPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 7, p e102797 (2014) |
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Medicine R Science Q Kiyoshi Mori Riko Kitazawa Takeshi Kondo Michiko Mori Yasuhiro Hamada Michiru Nishida Yasuhiro Minami Ryuma Haraguchi Yutaka Takahashi Sohei Kitazawa Diabetic osteopenia by decreased β-catenin signaling is partly induced by epigenetic derepression of sFRP-4 gene. |
| description |
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. |
| format |
article |
| author |
Kiyoshi Mori Riko Kitazawa Takeshi Kondo Michiko Mori Yasuhiro Hamada Michiru Nishida Yasuhiro Minami Ryuma Haraguchi Yutaka Takahashi Sohei Kitazawa |
| author_facet |
Kiyoshi Mori Riko Kitazawa Takeshi Kondo Michiko Mori Yasuhiro Hamada Michiru Nishida Yasuhiro Minami Ryuma Haraguchi Yutaka Takahashi Sohei Kitazawa |
| author_sort |
Kiyoshi Mori |
| title |
Diabetic osteopenia by decreased β-catenin signaling is partly induced by epigenetic derepression of sFRP-4 gene. |
| title_short |
Diabetic osteopenia by decreased β-catenin signaling is partly induced by epigenetic derepression of sFRP-4 gene. |
| title_full |
Diabetic osteopenia by decreased β-catenin signaling is partly induced by epigenetic derepression of sFRP-4 gene. |
| title_fullStr |
Diabetic osteopenia by decreased β-catenin signaling is partly induced by epigenetic derepression of sFRP-4 gene. |
| title_full_unstemmed |
Diabetic osteopenia by decreased β-catenin signaling is partly induced by epigenetic derepression of sFRP-4 gene. |
| title_sort |
diabetic osteopenia by decreased β-catenin signaling is partly induced by epigenetic derepression of sfrp-4 gene. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2014 |
| url |
https://doaj.org/article/a9bfbcff677140e7a88001f5703c99f3 |
| work_keys_str_mv |
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| _version_ |
1718414181398478848 |