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Hydrogen sulfide epigenetically mitigates bone loss through OPG/RANKL regulation during hyperhomocysteinemia in mice.

ABSTRACT: Hydrogen sulfide (H2S) is a novel gasotransmitter produced endogenously in mammalian cells, which works by mediating diverse physiological functions. An imbalance in H2S metabolism is associated with defective bone homeostasis. However, it is unknown whether H2S plays any epigenetic role in bone loss induced by hyperhomocysteinemia (HHcy). We demonstrate that diet-induced HHcy, a mouse model of metabolite induced osteoporosis, alters homocysteine metabolism by decreasing plasma levels of H2S. Treatment with NaHS (H2S donor), normalizes the plasma level of H2S and further alleviates HHcy induced trabecular bone loss and mechanical strength. Mechanistic studies have shown that DNMT1 expression is higher in the HHcy condition. The data show that activated phospho-JNK binds to the DNMT1 promoter and causes epigenetic DNA hyper-methylation of the OPG gene. This leads to activation of RANKL expression and mediates osteoclastogenesis. However, administration of NaHS could prevent HHcy induced bone loss. Therefore, H2S could be used as a novel therapy for HHcy mediated bone loss.

SUBMITTER: Behera J

PROVIDER: S-EPMC6084464 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Hydrogen sulfide epigenetically mitigates bone loss through OPG/RANKL regulation during hyperhomocysteinemia in mice.

Behera Jyotirmaya J George Akash K AK Voor Michael J MJ Tyagi Suresh C SC Tyagi Neetu N

Bone 20180613

Hydrogen sulfide (H2S) is a novel gasotransmitter produced endogenously in mammalian cells, which works by mediating diverse physiological functions. An imbalance in H2S metabolism is associated with defective bone homeostasis. However, it is unknown whether H2S plays any epigenetic role in bone loss induced by hyperhomocysteinemia (HHcy). We demonstrate that diet-induced HHcy, a mouse model of metabolite induced osteoporosis, alters homocysteine metabolism by de ...[more]

PMID: 29908298

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Project description:Osteoblasts are specialized cells that form new bone and also indirectly influence bone resorption by producing factors that modulate osteoclast differentiation. Although the methylation of CpG islands plays an important role in the regulation of gene expression, there is still scanty information about its role in human bone. The aim of this study was to investigate the influence of CpG methylation on the transcriptional levels of two osteoblast-derived critical factors in the regulation of osteoclastogenesis: the receptor activator of nuclear factor NF-?B ligand (RANKL) and its soluble decoy receptor osteoprotegerin (OPG). Quantitative methylation specific PCR (qMSP) and pyrosequencing analysis in various cell types showed that the methylation of regulatory regions of these genes, in the vicinity of the transcription start sites, repressed gene transcription, whereas an active transcription was associated with low levels of methylation. In addition, treatment with the DNA demethylating agent 5-azadeoxycitidine promoted a 170-fold induction of RANKL and a 20-fold induction of OPG mRNA expression in HEK-293 cells, which showed hypermethylation of the CpG islands and barely expressed RANKL and OPG transcripts at baseline. Transcriptional levels of both genes were also explored in bone tissue samples from patients with hip fractures and hip osteoarthritis. Although RANKL transcript abundance and the RANKL:OPG transcript ratio were significantly higher in patients with fractures than in those with osteoarthritis (RANKL: 0.76 ± 0.23 vs. 0.24 ± 0.08, p = 0.012; RANKL/OPG: 7.66 ± 2.49 vs. 0.92 ± 0.21, p = 0.002), there was no evidence for differential methylation across patient groups. In conclusion, the association between DNA methylation and the repression of RANKL and OPG expression strongly suggests that methylation-dependent mechanisms influence the transcription of these genes, which play a critical role in osteoclastogenesis. However, other mechanisms appear to be involved in the increased RANKL/OPG ratio of patients with osteoporotic fractures.

Project description:Insufficient hydrogen sulfide (H2S) has been implicated in Type 2 diabetic mellitus (T2DM) and hyperhomocysteinemia (HHcy)-related cardiovascular complications. We investigated the role of H2S in T2DM and HHcy-induced endothelial dysfunction in small mesenteric artery (SMA) of db/db mice fed a high methionine (HM) diet. HM diet (8 weeks) induced HHcy in both T2DM db/db mice and non-diabetic db/+ mice (total plasma Hcy: 48.4 and 31.3 µM, respectively), and aggravated the impaired endothelium-derived hyperpolarization factor (EDHF)-induced endothelium-dependent relaxation to acetylcholine (ACh), determined by the presence of eNOS inhibitor N(ω)-nitro-L-arginine methyl ester (L-NAME) and prostacyclin (PGI2) inhibitor indomethacin (INDO), in SMA from db/db mice but not that from db/+ mice. A non-selective Ca2+-active potassium channel (KCa) opener NS309 rescued T2DM/HHcy-impaired EDHF-mediated vascular relaxation to ACh. EDHF-induced relaxation to ACh was inhibited by a non-selective KCa blocker TEA and intermediate-conductance KCa blocker (IKCa) Tram-34, but not by small-conductance KCa (SKCa) blocker Apamin. HHcy potentiated the reduction of free sulfide, H2S and cystathionine γ-lyase protein, which converts L-cysteine to H2S, in SMA of db/db mice. Importantly, a stable H2S donor DATS diminished the enhanced O2- production in SMAs and lung endothelial cells of T2DM/HHcy mice. Antioxidant PEG-SOD and DATS improved T2DM/HHcy impaired relaxation to ACh. Moreover, HHcy increased hyperglycemia-induced IKCa tyrosine nitration in human micro-vascular endothelial cells. EDHF-induced vascular relaxation to L-cysteine was not altered, whereas such relaxation to NaHS was potentiated by HHcy in SMA of db/db mice which was abolished by ATP-sensitive potassium channel blocker Glycolamide but not by KCa blockers.ConclusionsIntermediate HHcy potentiated H2S reduction via CSE-downregulation in microvasculature of T2DM mice. H2S is justified as an EDHF. Insufficient H2S impaired EDHF-induced vascular relaxation via oxidative stress and IKCa inactivation in T2DM/HHcy mice. H2S therapy may be beneficial for prevention and treatment of micro-vascular complications in patients with T2DM and HHcy.

Project description:BACKGROUND:Osteopenia have been well documented in adolescent idiopathic scoliosis (AIS). Adiponectin has been shown to be inversely proportional to body mass index and to affect bone metabolism. However, the circulating levels of adiponectin and the relationship between adiponectin and low bone mass in AIS remain unclear. METHODS:A total of 563 AIS and 281 age-matched controls were recruited for this study. Anthropometry and bone mass were measured in all participants. Plasma adiponectin levels were determined by enzyme-linked immunosorbent assay (ELISA) in the AIS and control groups. An improved multiplex ligation detection reaction was performed to study on single nucleotide polymorphism. Facet joints were collected and used to measure the microstructure, the expression of RANKL, OPG, osteoblast-related genes, inflammatory factors, adiponectin and its receptors by qPCR, western blotting and immunohistochemistry. Furthermore, primary cells were extracted from facet joints to observe the reaction after adiponectin stimulation. RESULTS:Compared with the controls, lower body mass index and a marked increase in circulating adiponectin were observed in AIS osteopenia (17.09?±?1.09 kg/m2 and 21.63?±?10.30 mg/L). A significant difference in the presence of rs7639352?was detected in the AIS osteopenia, AIS normal bone mass and control groups. The T allele showed a significant higher proportion in AIS osteopenia than AIS normal bone mass and control groups (41.75% vs 31.3% vs 25.7%, p?<?0.05). micro-CT demonstrated that the AIS convex side had a significant lower bone volume than concave side. RNA and protein analyses showed that in cancellous bone, higher RANKL/OPG and adipoR1 levels and lower runx2 levels were observed, and in cartilage, higher adipoR1 and IL6 levels were observed in AIS. Furthermore, convex side had higher RANKL/OPG, IL6 and adipoR1 than concave side. Compared with normal primary cells, convex side primary cells showed the most acute action, and concave side primary cells showed the second-most acute action when exposed under same adiponectin concentration gradient. CONCLUSION:Our results indicated that high circulating adiponectin levels may result from gene variations in AIS osteopenia. Adiponectin has a negative effect on bone metabolism, and this negative effect might be mediated by the ADR1-RANKL/OPG and ADR1-IL6 pathways.

Dataset Information

Hydrogen sulfide epigenetically mitigates bone loss through OPG/RANKL regulation during hyperhomocysteinemia in mice.

Publications

Hydrogen sulfide epigenetically mitigates bone loss through OPG/RANKL regulation during hyperhomocysteinemia in mice.

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