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Cited by 59Bone Metabolism and DiseasesSulfur Compounds in BiologyBone health and osteoporosis research

Hydrogen Sulfide Promotes Bone Homeostasis by Balancing Inflammatory Cytokine Signaling in CBS-Deficient Mice through an Epigenetic Mechanism

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Behera, Jyotirmaya, Kelly, Kimberly E., Voor, Michael J., Metreveli, Naira, Tyagi, Suresh C., Tyagi, Neetu·2018·Scientific Reports
DOI 10.1038/s41598-018-33149-9PMC PMC6189133
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Abstract

Abstract 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 (H2S), a gasotransmitter molecule known to regulate bone formation. Therefore, in the present study, we examined whether H2S 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 H2S-donor NaHS for 8 weeks. Treatment with NaHS, normalizes plasma H2S, 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-α) 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 H2S may provide a novel treatment for CBS-deficiency induced metabolic osteoporosis.

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  • ITSA-1 counteracts the activity of TSA, a potent inhibitor of class I and II HDACs, on histone acetylation and transcriptional activation.

    “ITSA-1 is an activator of HDACs and counteracts the activity of TSA, a potent inhibitor of class I and II HDACs, on histone acetylation and transcriptional activation [48–50].”

    From CI-994 is a dual modulator of class I HDACs and Wnt/β-catenin signaling for the treatment of Alzheimer's disease (2026) · cites this paper as [50]

    The Results section (page unavailable) calls ITSA-1 “Inhibitor-1 of Trichostatin A” and reports that it reversed changes in HDAC activity and histone acetylation in CBS-deficient mice. The Discussion (page unavailable) calls it an HDAC activator and reports suppressed inflammatory cytokine expression. Our copy does not show ITSA-1 directly counteracting TSA’s effects on histone acetylation or transcriptional activation, or describe TSA as a potent inhibitor of class I and II HDACs. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • ITSA-1 is an activator of HDACs.

    “ITSA-1 is an activator of HDACs and counteracts the activity of TSA, a potent inhibitor of class I and II HDACs, on histone acetylation and transcriptional activation [48–50].”

    From CI-994 is a dual modulator of class I HDACs and Wnt/β-catenin signaling for the treatment of Alzheimer's disease (2026) · cites this paper as [50]

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References 57 · Cited by 59

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Authors
Behera, J., Kelly, K. E., Voor, M. J., Metreveli, N., Tyagi, S. C., & Tyagi, N.
Affiliations
University of Louisville (US)
Corresponding author
Tyagi, Neetu
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2018-10-15
Volume
8
Issue
1
Pages
15226-15226
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-018-33149-9
PMC
PMC6189133
OpenAlex
W2897530735
Cited by
59
References
57
Citations by year
2026: 8 · 2025: 5 · 2024: 5 · 2023: 2 · 2022: 9 · 2021: 19 · 2020: 6 · 2019: 5
FWCI
4.71
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health (AR‐067667)
  • National Heart, Lung, and Blood Institute (R01HL107640)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR067667)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Sulfur Compounds in Biology
  • Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
Keywords
hydrogen sulfide, bone homeostasis, hyperhomocysteinemia, cystathionine beta-synthase deficiency, osteoporosis, bone remodeling, HDAC3, histone acetylation, H3K27ac, inflammatory cytokines, interleukin-6, TNF-α, redox homeostasis, epigenetic regulation
MeSH terms
Histone Deacetylase 3, Acetylation, Animals, Chromatin, Cystathionine beta-Synthase, Gene Expression Regulation, Histone Deacetylases, Histones, Humans, Hydrogen Sulfide, Inflammation, Osteoporosis, Tumor Necrosis Factor-alpha, Interleukin-6, Genome, Bone Remodeling, Oxidative Stress, Hyperhomocysteinemia, Epigenesis, Genetic, Core Binding Factor Alpha 1 Subunit, Mice

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