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During transsulfuration, Hcy is metabolized into hydrogen sulfide (H<jats:sub>2<\/jats:sub>S), a gasotransmitter molecule known to regulate bone formation. Therefore, in the present study, we examined whether H<jats:sub>2<\/jats:sub>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<jats:sup>+\/\u2212<\/jats:sup> +Met), supplemented with H<jats:sub>2<\/jats:sub>S-donor NaHS for 8 weeks. Treatment with NaHS, normalizes plasma H<jats:sub>2<\/jats:sub>S, and completely prevents trabecular bone loss in CBS<jats:sup>+\/\u2212<\/jats:sup> 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-\u03b1) 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<jats:sup>+\/\u2212<\/jats:sup> 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<jats:sub>2<\/jats:sub>S may provide a novel treatment for CBS-deficiency induced metabolic osteoporosis.<\/jats:p>","DOI":"10.1038\/s41598-018-33149-9","type":"journal-article","created":{"date-parts":[[2018,10,9]],"date-time":"2018-10-09T09:17:59Z","timestamp":1539076679000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":55,"title":["Hydrogen Sulfide Promotes Bone Homeostasis by Balancing Inflammatory Cytokine Signaling in CBS-Deficient Mice through an Epigenetic Mechanism"],"prefix":"10.1038","volume":"8","author":[{"given":"Jyotirmaya","family":"Behera","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberly E.","family":"Kelly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Voor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naira","family":"Metreveli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suresh C.","family":"Tyagi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neetu","family":"Tyagi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,10,15]]},"reference":[{"key":"33149_CR1","doi-asserted-by":"publisher","first-page":"2033","DOI":"10.1056\/NEJMoa032546","volume":"350","author":"JB van Meurs","year":"2004","unstructured":"van Meurs, J. 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