Hydrogen Sulfide Maintains Mesenchymal Stem Cell Function and Bone Homeostasis via Regulation of Ca2+ Channel Sulfhydration

Summary Gaseous signaling molecules such as hydrogen sulfide (H 2 S) are produced endogenously and mediate effects through diverse mechanisms. H 2 S is one such gasotransmitters that regulates multiple signaling pathways in mammalian cells, and abnormal H 2 S metabolism has been linked to defects in bone homeostasis. Here, we demonstrate that bone marrow mesenchymal stem cells (BMMSCs) produce H 2 S in order to regulate their self-renewal and osteogenic differentiation, and H 2 S deficiency results in defects in BMMSC differentiation. H 2 S 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, H 2 S-deficient mice display an osteoporotic phenotype that can be rescued by small molecules that release H 2 S. These results demonstrate that H 2 S regulates BMMSCs and that restoring H 2 S levels via nontoxic donors may provide treatments for diseases such as osteoporosis that can arise from H 2 S deficiencies.