Hydrogen sulfide maintains mesenchymal stem cell function and bone homeostasis via regulation of Ca(2+) channel sulfhydration

Cell Stem Cell. 2014 Jul 3;15(1):66-78. doi: 10.1016/j.stem.2014.03.005. Epub 2014 Apr 10.


Gaseous signaling molecules such as hydrogen sulfide (H2S) are produced endogenously and mediate effects through diverse mechanisms. H2S is one such gasotransmitters that regulates multiple signaling pathways in mammalian cells, and abnormal H2S metabolism has been linked to defects in bone homeostasis. Here, we demonstrate that bone marrow mesenchymal stem cells (BMMSCs) produce H2S in order to regulate their self-renewal and osteogenic differentiation, and H2S deficiency results in defects in BMMSC differentiation. H2S deficiency causes aberrant intracellular Ca(2+) influx because of reduced sulfhydration of cysteine residues on multiple Ca(2+) TRP channels. This decreased Ca(2+) flux downregulates PKC/Erk-mediated Wnt/β-catenin signaling which controls osteogenic differentiation of BMMSCs. Consistently, H2S-deficient mice display an osteoporotic phenotype that can be rescued by small molecules that release H2S. These results demonstrate that H2S regulates BMMSCs and that restoring H2S levels via nontoxic donors may provide treatments for diseases such as osteoporosis that can arise from H2S deficiencies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow Cells / physiology*
  • Calcium Channels, T-Type / chemistry
  • Calcium Channels, T-Type / metabolism*
  • Calcium Signaling / genetics
  • Cell Differentiation / genetics
  • Cells, Cultured
  • Cystathionine beta-Synthase / genetics
  • Homeostasis
  • Humans
  • Hydrogen Sulfide / metabolism*
  • Mesenchymal Stem Cells / physiology*
  • Mice
  • Mice, Knockout
  • Osteogenesis / genetics
  • Osteoporosis / metabolism*
  • Osteoporosis / pathology
  • Protein Kinase C / metabolism
  • RNA, Small Interfering / genetics
  • Sulfurtransferases / genetics
  • Transaminases / genetics
  • beta Catenin / metabolism


  • Calcium Channels, T-Type
  • RNA, Small Interfering
  • beta Catenin
  • Transaminases
  • cysteine aminotransferase
  • Protein Kinase C
  • Sulfurtransferases
  • 3-mercaptopyruvate sulphurtransferase
  • Cystathionine beta-Synthase
  • Hydrogen Sulfide