PMID- 31390373
OWN - NLM
STAT- MEDLINE
DCOM- 20200317
LR  - 20220716
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 14
IP  - 8
DP  - 2019
TI  - Vitamin C effects on 5-hydroxymethylcytosine and gene expression in osteoblasts 
      and chondrocytes: Potential involvement of PHD2.
PG  - e0220653
LID - 10.1371/journal.pone.0220653 [doi]
LID - e0220653
AB  - 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.
FAU - Lindsey, Richard C
AU  - Lindsey RC
AUID- ORCID: 0000-0001-9911-4136
AD  - Musculoskeletal Disease Center, VA Loma Linda Healthcare System, Loma Linda, CA, 
      United States of America.
AD  - Center for Health Disparities and Molecular Medicine, School of Medicine, Loma 
      Linda University, Loma Linda, CA, United States of America.
AD  - Division of Biochemistry, Department of Basic Sciences, School of Medicine, Loma 
      Linda University, Loma Linda, CA, United States of America.
FAU - Cheng, Shaohong
AU  - Cheng S
AD  - Musculoskeletal Disease Center, VA Loma Linda Healthcare System, Loma Linda, CA, 
      United States of America.
FAU - Mohan, Subburaman
AU  - Mohan S
AUID- ORCID: 0000-0003-0063-986X
AD  - Musculoskeletal Disease Center, VA Loma Linda Healthcare System, Loma Linda, CA, 
      United States of America.
AD  - Center for Health Disparities and Molecular Medicine, School of Medicine, Loma 
      Linda University, Loma Linda, CA, United States of America.
AD  - Division of Biochemistry, Department of Basic Sciences, School of Medicine, Loma 
      Linda University, Loma Linda, CA, United States of America.
AD  - Department of Medicine, School of Medicine, Loma Linda University, Loma Linda, 
      CA, United States of America.
AD  - Department of Orthopedics, School of Medicine, Loma Linda University, Loma Linda, 
      CA, United States of America.
LA  - eng
GR  - I01 BX001396/BX/BLRD VA/United States
GR  - IK6 BX005381/BX/BLRD VA/United States
GR  - R25 GM060507/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20190807
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 1123-95-1 (5-hydroxymethylcytosine)
RN  - 6R795CQT4H (5-Methylcytosine)
RN  - EC 1.14.11.29 (Egln1 protein, mouse)
RN  - EC 1.14.11.29 (Hypoxia-Inducible Factor-Proline Dioxygenases)
RN  - PQ6CK8PD0R (Ascorbic Acid)
SB  - IM
MH  - 5-Methylcytosine/*analogs & derivatives/metabolism
MH  - Animals
MH  - Ascorbic Acid/*pharmacology
MH  - Cell Differentiation/genetics
MH  - Cells, Cultured
MH  - Chondrocytes/*metabolism
MH  - Gene Expression/*drug effects
MH  - Hypoxia-Inducible Factor-Proline Dioxygenases/pharmacology
MH  - Mice
MH  - Osteoblasts/*metabolism
PMC - PMC6685624
COIS- The authors have declared that no competing interests exist.
EDAT- 2019/08/08 06:00
MHDA- 2020/03/18 06:00
PMCR- 2019/08/07
CRDT- 2019/08/08 06:00
PHST- 2019/04/26 00:00 [received]
PHST- 2019/07/20 00:00 [accepted]
PHST- 2019/08/08 06:00 [entrez]
PHST- 2019/08/08 06:00 [pubmed]
PHST- 2020/03/18 06:00 [medline]
PHST- 2019/08/07 00:00 [pmc-release]
AID - PONE-D-19-11933 [pii]
AID - 10.1371/journal.pone.0220653 [doi]
PST - epublish
SO  - PLoS One. 2019 Aug 7;14(8):e0220653. doi: 10.1371/journal.pone.0220653. 
      eCollection 2019.