Vitamin C effects on 5-hydroxymethylcytosine and gene expression in osteoblasts and chondrocytes: Potential involvement of PHD2

Autor: Shaohong Cheng, Richard C Lindsey, Subburaman Mohan
Rok vydání: 2019
Předmět:
0301 basic medicine
Cell
Gene Expression
Organic chemistry
Ascorbic Acid
Biochemistry
Mice
0302 clinical medicine
Animal Cells
Gene expression
Medicine and Health Sciences
Vitamin C
Cells
Cultured
Connective Tissue Cells
Regulation of gene expression
Gene knockdown
Multidisciplinary
DNA methylation
Chemistry
Osteoblast
Cell Differentiation
Vitamins
Osteoblast Differentiation
Chromatin
Cell biology
Physical sciences
Nucleic acids
medicine.anatomical_structure
Connective Tissue
5-Methylcytosine
Medicine
Epigenetics
Anatomy
Cellular Types
DNA modification
Chromatin modification
Research Article
Chromosome biology
Science
030209 endocrinology & metabolism
Cartilage metabolism
Chondrocyte
Hypoxia-Inducible Factor-Proline Dioxygenases
03 medical and health sciences
Chemical compounds
Chondrocytes
Organic compounds
medicine
Genetics
Animals
Gene Regulation
Osteoblasts
Biology and Life Sciences
Cell Biology
DNA
Ascorbic acid
030104 developmental biology
Biological Tissue
Cartilage
Developmental Biology
Articular Cartilage
Zdroj: PLoS ONE
PLoS ONE, Vol 14, Iss 8, p e0220653 (2019)
ISSN: 1932-6203
Popis: Vitamin C (ascorbic acid, AA) is a well-known regulator of bone and cartilage metabolism. However, the mechanisms of AA's action in these tissues are only partly understood. In this study, we confirmed that AA contributes to bone and cartilage metabolism by showing decreased articular cartilage and trabecular bone in AA-deficient spontaneous fracture (sfx) mutant mice. In vitro, we found that AA exerts differential effects on chondrocyte and osteoblast differentiation. Since AA is known to increase levels of 5-hydroxymethylcytosine (5-hmC) and induce DNA demethylation via the ten-eleven translocases (TETs), and since prolyl hydroxylase domain-containing protein 2 (PHD2), a known mediator of AA's effects in these tissues, is part of the same enzyme family as the TETs, we next investigated whether increases in 5-hmC might mediate some of these effects. All TETs and PHDs are expressed in chondrocytes and osteoblasts, and PHD2 is localized in both the cytoplasm and nucleus of the cell, lending plausibility to the hypothesis of altered 5-hmC content in these cells. We found that AA treatment increased levels of 5-hmC in both cell types globally, notably including promoter regions of osteoblast differentiation genes. Furthermore, inhibition of PHD2 decreased 5-hmC levels in chondrocyte differentiation gene promoters, and knockdown of Phd2 in chondrocytes reduced global 5-hmC levels, suggesting for the first time that PHD2 may itself directly mediate increases in 5-hmC in chondrocyte and osteoblast genes. Further investigation of this mechanism could lead to novel therapeutic approaches to treat debilitating diseases such as osteoarthritis and osteoporosis.
Databáze: OpenAIRE
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