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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.
AuthorsJyotirmaya Behera, Akash K George, Michael J Voor, Suresh C Tyagi, Neetu Tyagi
JournalBone (Bone) Vol. 114 Pg. 90-108 (09 2018) ISSN: 1873-2763 [Electronic] United States
PMID29908298 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
CopyrightCopyright © 2018 Elsevier Inc. All rights reserved.
Chemical References
  • Osteoprotegerin
  • RANK Ligand
  • Tnfrsf11b protein, mouse
  • Tnfsf11 protein, mouse
  • Hydrogen Sulfide
Topics
  • Animals
  • Bone Diseases, Metabolic (drug therapy, genetics, metabolism)
  • Epigenomics (methods)
  • Female
  • Hydrogen Sulfide (pharmacology, therapeutic use)
  • Hyperhomocysteinemia (drug therapy, genetics, metabolism)
  • Mice
  • Mice, Inbred C57BL
  • Osteogenesis (drug effects, physiology)
  • Osteoprotegerin (genetics, metabolism)
  • RANK Ligand (genetics, metabolism)

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