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

Abstract

Hydrogen sulfide (HS) is a novel gasotransmitter produced endogenously in mammalian cells, which works by mediating diverse physiological functions. An imbalance in HS metabolism is associated with defective bone homeostasis. However, it is unknown whether HS 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 HS. Treatment with NaHS (HS donor), normalizes the plasma level of HS 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, HS could be used as a novel therapy for HHcy mediated bone loss.

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

“…H 2 S has an important physiological role in a variety of cells and is enzymatically produced by CBS and CSE. It can be found as free H 2 S or in the form of sulfur 31 , 41 . In investigating whether CBS ablation in mice affects the systemic level of H 2 S and its production in bone, 16-week-old female CBS +/− were used.…”

“…Mutation of CBS leads to advancement of the HHcy phenotype and decreased bioavailability of H 2 S 49 . Previously we also demonstrated that CBS expression was downregulated in excess high methionine diet (HMD) fed mice, leading to decreased H 2 S biosynthesis by elevating the intracellular pool of Hcy in BMMSCs of mice 41 . Administration of H 2 S restores the physiological level of H 2 S and also decreases the Hcy level in mice.…”

Hydrogen sulfide attenuates homocysteine‐induced osteoblast dysfunction by inhibiting mitochondrial toxicity

“…Cells were given treatment for 24 hr and harvested for further experiments. The concentration of NaHS in this study was set to 30 μM, as described in our previous research (Behera, George, Voor, Tyagi, & Tyagi, 2018).…”

Nitric oxide restores peripheral blood mononuclear cell adhesion against hypoxia via NO‐cGMP signalling

“…Cultured PBMNCs were harvested using trypsinization. Cell lysates were prepared on ice using RIPA lysis buffer (1% Triton X‐100, 50 m m Tris [pH 7.4], 150 m m NaCl, 0.1 m m EDTA, 0.1 m m EGTA, 1 m m PMSF, 10 μg/mL aprotinin, 10 μg/mL leupeptin, 1 m m Na3VO4, and 50 m m NaF), as previously described . The equal amount of proteins (40 μg) were loaded on a sodium dodecyl sulfate‐polyacrylamide gel electrophoresis (SDS‐PAGE).…”