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Suppression of TLR4 prevents diabetic bone loss by regulating FTO-mediated m6A modification.
Shen, Ximei; Lan, Chao; Lin, Youfen; Zhang, Fuyashi; Zhang, Yongze; Chen, Mingyun; Yan, Sunjie.
Afiliação
  • Shen X; Department of Endocrinology, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; Department of Endocrinology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China; Clinical Research Center for Me
  • Lan C; Department of Endocrinology, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; Department of Endocrinology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China; Clinical Research Center for Me
  • Lin Y; Department of Endocrinology, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; Department of Endocrinology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China; Clinical Research Center for Me
  • Zhang F; Department of Endocrinology, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China.
  • Zhang Y; Department of Endocrinology, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; Department of Endocrinology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China; Clinical Research Center for Me
  • Chen M; Department of Endocrinology, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; Department of Endocrinology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China; Clinical Research Center for Me
  • Yan S; Department of Endocrinology, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; Department of Endocrinology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China; Clinical Research Center for Me
Int Immunopharmacol ; 122: 110510, 2023 Sep.
Article em En | MEDLINE | ID: mdl-37413932
Toll-like receptor-4 (TLR4) has been implicated in the development and progression of diabetic osteoporosis. However, the mechanisms underlying TLR4-regulated bone metabolism in diabetes are yet to be fully understood. Epigenetic modifications have been indicated as a possible mechanism leading to increased risk of osteoporosis and bone fracture. As N6-methyladenosine (m6A) is the most common epigenetic modification in eukaryotic mRNAs, we hypothesized that TLR4 regulates m6A modification in bone tissues of diabetic rats, thereby potentially explaining the pathogenesis of diabetic bone loss. m6A sequencing (m6A-seq) was performed in samples of the femur of TLR4-wild type (TLR4WT) and TLR4-knockout (TLR4KO) diabetic rats to identify genes with differential m6A modifications that may be associated with the bone loss phenotype. We found that in TLR4KO rats, the rapid weight loss of diabetic rats was prevented, and bone mineral density (BMD) was significantly increased. m6A-seq and Gene Ontology enrichment analysis revealed that m6A-modified genes in the femur of TLR4KO diabetic rats were associated with regulation of biological processes such as osteoclast differentiation. qRT-PCR analysis on the expression levels of the m6A-modified methyltransferases and demethylases demonstrated that only the m6A demethylase fat mass and obesity-associated protein(FTO)was decreased. Using an osteoclast cell model, we confirmed that TLR4-mediated osteoclast differentiation was induced by glycolipid toxicity via inhibition of FTO expression. Taken together, these results suggest that inhibition of TLR4 may prevent diabetic bone loss via regulation of FTO-mediated m6A modification.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Osteoporose / Doenças Ósseas Metabólicas / Diabetes Mellitus Experimental Limite: Animals Idioma: En Revista: Int Immunopharmacol Assunto da revista: ALERGIA E IMUNOLOGIA / FARMACOLOGIA Ano de publicação: 2023 Tipo de documento: Article País de publicação: Holanda

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Osteoporose / Doenças Ósseas Metabólicas / Diabetes Mellitus Experimental Limite: Animals Idioma: En Revista: Int Immunopharmacol Assunto da revista: ALERGIA E IMUNOLOGIA / FARMACOLOGIA Ano de publicação: 2023 Tipo de documento: Article País de publicação: Holanda