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

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 t...

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Autores principales:	Jyotirmaya Behera, Kimberly E. Kelly, Michael J. Voor, Naira Metreveli, Suresh C. Tyagi, Neetu Tyagi
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	HDAC Activity Bone Marrow Mesenchymal Stem Cells (BMMSCs) BMMSCs Culture Bone Volume Per Tissue Volume (BV/TV) Total TRAP Medicine R Science Q
Acceso en línea:	https://doaj.org/article/60688e9c04ba4b2b856d492aa7d065d3
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spelling	oai:doaj.org-article:60688e9c04ba4b2b856d492aa7d065d32021-12-02T15:09:03ZHydrogen Sulfide Promotes Bone Homeostasis by Balancing Inflammatory Cytokine Signaling in CBS-Deficient Mice through an Epigenetic Mechanism10.1038/s41598-018-33149-92045-2322https://doaj.org/article/60688e9c04ba4b2b856d492aa7d065d32018-10-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-33149-9https://doaj.org/toc/2045-2322Abstract 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.Jyotirmaya BeheraKimberly E. KellyMichael J. VoorNaira MetreveliSuresh C. TyagiNeetu TyagiNature PortfolioarticleHDAC ActivityBone Marrow Mesenchymal Stem Cells (BMMSCs)BMMSCs CultureBone Volume Per Tissue Volume (BV/TV)Total TRAPMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-16 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	HDAC Activity Bone Marrow Mesenchymal Stem Cells (BMMSCs) BMMSCs Culture Bone Volume Per Tissue Volume (BV/TV) Total TRAP Medicine R Science Q
spellingShingle	HDAC Activity Bone Marrow Mesenchymal Stem Cells (BMMSCs) BMMSCs Culture Bone Volume Per Tissue Volume (BV/TV) Total TRAP Medicine R Science Q Jyotirmaya Behera Kimberly E. Kelly Michael J. Voor Naira Metreveli Suresh C. Tyagi Neetu Tyagi Hydrogen Sulfide Promotes Bone Homeostasis by Balancing Inflammatory Cytokine Signaling in CBS-Deficient Mice through an Epigenetic Mechanism
description	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.
format	article
author	Jyotirmaya Behera Kimberly E. Kelly Michael J. Voor Naira Metreveli Suresh C. Tyagi Neetu Tyagi
author_facet	Jyotirmaya Behera Kimberly E. Kelly Michael J. Voor Naira Metreveli Suresh C. Tyagi Neetu Tyagi
author_sort	Jyotirmaya Behera
title	Hydrogen Sulfide Promotes Bone Homeostasis by Balancing Inflammatory Cytokine Signaling in CBS-Deficient Mice through an Epigenetic Mechanism
title_short	Hydrogen Sulfide Promotes Bone Homeostasis by Balancing Inflammatory Cytokine Signaling in CBS-Deficient Mice through an Epigenetic Mechanism
title_full	Hydrogen Sulfide Promotes Bone Homeostasis by Balancing Inflammatory Cytokine Signaling in CBS-Deficient Mice through an Epigenetic Mechanism
title_fullStr	Hydrogen Sulfide Promotes Bone Homeostasis by Balancing Inflammatory Cytokine Signaling in CBS-Deficient Mice through an Epigenetic Mechanism
title_full_unstemmed	Hydrogen Sulfide Promotes Bone Homeostasis by Balancing Inflammatory Cytokine Signaling in CBS-Deficient Mice through an Epigenetic Mechanism
title_sort	hydrogen sulfide promotes bone homeostasis by balancing inflammatory cytokine signaling in cbs-deficient mice through an epigenetic mechanism
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/60688e9c04ba4b2b856d492aa7d065d3
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_version_	1718387940464263168

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

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