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.
Highlights
Histone deacetylases (HDACs) are important enzyme complexes that cause various physiological processes
The results showed that the plasma level of total Hcy (tHcy) was significantly higher in CBS+/− mice in comparison to WT and CBS inhibitor treated mice (Fig. 1f)
The results showed that decreased HDAC activity was observed in CBS knockout bone marrow mesenchymal stem cells (BMMSCs) (Fig. 3d)
Summary
Histone deacetylases (HDACs) are important enzyme complexes that cause various physiological processes They are known to act as a transcriptional corepressors that epigenetically control gene transcription by removing acetyl groups from lysine side chains of nucleosomal histone tails, leading to chromatin condensation and gene repression[14,15,16]. CBS-deficient mice typically produce the HHcy phenotype, which promotes resident monocyte inflammation and blood brain barrier damage[39,40]. This prompted us to gain an understanding as to whether CBS-deficiency induces BMMSCs inflammation and to discover the epigenetic role of H2S in HHcy induced bone loss in CBS-deficient mice. We show that pharmacological restoration of H2S could prevent HHcy induced histone acetylation that leads to bone loss in CBS-deficient mice
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