PMID- 30323246
OWN - NLM
STAT- MEDLINE
DCOM- 20191104
LR  - 20191104
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 8
IP  - 1
DP  - 2018 Oct 15
TI  - Hydrogen Sulfide Promotes Bone Homeostasis by Balancing Inflammatory Cytokine 
      Signaling in CBS-Deficient Mice through an Epigenetic Mechanism.
PG  - 15226
LID - 10.1038/s41598-018-33149-9 [doi]
LID - 15226
AB  - Previously, we have shown hyperhomocysteinemia (HHcy) to have a detrimental 
      effect on bone remodeling, which is associated with osteoporosis. During 
      transsulfuration, Hcy is metabolized into hydrogen sulfide (H(2)S), a 
      gasotransmitter molecule known to regulate bone formation. Therefore, in the 
      present study, we examined whether H(2)S ameliorates HHcy induced epigenetic and 
      molecular alterations leading to osteoporotic bone loss. To test this mechanism, 
      we employed cystathionine-beta-synthase heterozygote knockout mice, fed with a 
      methionine rich diet (CBS(+/-) +Met), supplemented with H(2)S-donor NaHS for 8 
      weeks. Treatment with NaHS, normalizes plasma H(2)S, and completely prevents 
      trabecular bone loss in CBS(+/-) mice. Our data showed that HHcy caused 
      inhibition of HDAC3 activity and subsequent inflammation by imbalancing redox 
      homeostasis. The mechanistic study revealed that inflammatory cytokines (IL-6, 
      TNF-alpha) are transcriptionally activated by an acetylated lysine residue in histone 
      (H3K27ac) of chromatin by binding to its promoter and subsequently regulating 
      gene expression. A blockade of HDAC3 inhibition in CBS(+/-) mice by HDAC 
      activator ITSA-1, led to the remodeling of histone landscapes in the genome and 
      thereby attenuated histone acetylation-dependent inflammatory signaling. We also 
      confirmed that RUNX2 was sulfhydrated by administration of NaHS. Collectively, 
      restoration of H(2)S may provide a novel treatment for CBS-deficiency induced 
      metabolic osteoporosis.
FAU - Behera, Jyotirmaya
AU  - Behera J
AD  - Bone Biology Laboratory, Department of Physiology, School of Medicine, University 
      of Louisville, Louisville, KY, 40292, USA.
FAU - Kelly, Kimberly E
AU  - Kelly KE
AD  - Bone Biology Laboratory, Department of Physiology, School of Medicine, University 
      of Louisville, Louisville, KY, 40292, USA.
FAU - Voor, Michael J
AU  - Voor MJ
AD  - Department of Orthopaedic Surgery, School of Medicine, University of Louisville, 
      Louisville, KY, 40292, USA.
AD  - Department of Bioengineering, Speed School of Engineering, University of 
      Louisville, Louisville, KY, 40292, USA.
FAU - Metreveli, Naira
AU  - Metreveli N
AD  - Bone Biology Laboratory, Department of Physiology, School of Medicine, University 
      of Louisville, Louisville, KY, 40292, USA.
FAU - Tyagi, Suresh C
AU  - Tyagi SC
AD  - Bone Biology Laboratory, Department of Physiology, School of Medicine, University 
      of Louisville, Louisville, KY, 40292, USA.
FAU - Tyagi, Neetu
AU  - Tyagi N
AD  - Bone Biology Laboratory, Department of Physiology, School of Medicine, University 
      of Louisville, Louisville, KY, 40292, USA. n0tyag01@louisville.edu.
LA  - eng
GR  - R01 AR067667/AR/NIAMS NIH HHS/United States
GR  - R01 HL107640/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20181015
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (Chromatin)
RN  - 0 (Core Binding Factor Alpha 1 Subunit)
RN  - 0 (Histones)
RN  - 0 (Interleukin-6)
RN  - 0 (Runx2 protein, mouse)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 3.5.1.98 (Histone Deacetylases)
RN  - EC 3.5.1.98 (histone deacetylase 3)
RN  - EC 4.2.1.22 (Cystathionine beta-Synthase)
RN  - YY9FVM7NSN (Hydrogen Sulfide)
SB  - IM
MH  - Acetylation/drug effects
MH  - Animals
MH  - Bone Remodeling/drug effects
MH  - Chromatin/drug effects
MH  - Core Binding Factor Alpha 1 Subunit/genetics
MH  - Cystathionine beta-Synthase/antagonists & inhibitors/*genetics
MH  - Epigenesis, Genetic
MH  - Gene Expression Regulation/drug effects
MH  - Genome/drug effects
MH  - Histone Deacetylases/*genetics
MH  - Histones/genetics
MH  - Humans
MH  - Hydrogen Sulfide/*metabolism
MH  - Hyperhomocysteinemia/genetics/pathology
MH  - Inflammation/genetics/metabolism/pathology
MH  - Interleukin-6/genetics
MH  - Mice
MH  - Osteoporosis/*genetics/metabolism/pathology
MH  - Oxidative Stress/drug effects
MH  - Tumor Necrosis Factor-alpha/genetics
PMC - PMC6189133
COIS- The authors declare no competing interests.
EDAT- 2018/10/17 06:00
MHDA- 2019/11/05 06:00
PMCR- 2018/10/15
CRDT- 2018/10/17 06:00
PHST- 2018/06/28 00:00 [received]
PHST- 2018/09/18 00:00 [accepted]
PHST- 2018/10/17 06:00 [entrez]
PHST- 2018/10/17 06:00 [pubmed]
PHST- 2019/11/05 06:00 [medline]
PHST- 2018/10/15 00:00 [pmc-release]
AID - 10.1038/s41598-018-33149-9 [pii]
AID - 33149 [pii]
AID - 10.1038/s41598-018-33149-9 [doi]
PST - epublish
SO  - Sci Rep. 2018 Oct 15;8(1):15226. doi: 10.1038/s41598-018-33149-9.