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.