title: Hydrogen sulfide maintains mesenchymal stem cell function and bone homeostasis via regulation of Ca(2+) channel sulfhydration.
abstract: 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.
authors.affiliation: Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, 2250 Alcazar Street, CSA 103, Los Angeles, CA 90033, USA; Department of Periodontics, Capital Medical University School of Stomatology, Tian Tan Xi Li Number 4, Beijing 100050, China. Electronic address: liuyi@ccmu.edu.cn.
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, 2250 Alcazar Street, CSA 103, Los Angeles, CA 90033, USA.
authors.forename: Ruili
authors.initials: R
authors.lastname: Yang
authors.affiliation: Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, Bethesda, MD 20892, USA.
authors.forename: Xibao
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Molecular Microbiology and Immunology, University of Southern California, 2011 Zonal Avenue, Los Angeles, CA 90033, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, 2250 Alcazar Street, CSA 103, Los Angeles, CA 90033, USA.
authors.forename: Cunye
authors.initials: C
authors.lastname: Qu
authors.affiliation: Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, 2250 Alcazar Street, CSA 103, Los Angeles, CA 90033, USA.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kikuiri
authors.affiliation: Department of Periodontics, Capital Medical University School of Stomatology, Tian Tan Xi Li Number 4, Beijing 100050, China.
authors.forename: Songlin
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Molecular Microbiology and Immunology, University of Southern California, 2011 Zonal Avenue, Los Angeles, CA 90033, USA.
authors.forename: Ebrahim
authors.initials: E
authors.lastname: Zandi
authors.affiliation: Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.
authors.forename: Junbao
authors.initials: J
authors.lastname: Du
authors.affiliation: Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, Bethesda, MD 20892, USA.
authors.forename: Indu S
authors.initials: IS
authors.lastname: Ambudkar
authors.affiliation: Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, 2250 Alcazar Street, CSA 103, Los Angeles, CA 90033, USA. Electronic address: songtaos@usc.edu.
authors.forename: Songtao
authors.initials: S
authors.lastname: Shi
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000502:physiology*; D020747:Calcium Channels, T-Type / Q000737:chemistry / Q000378:metabolism*; D020013:Calcium Signaling / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D003541:Cystathionine beta-Synthase / Q000235:genetics; D006706:Homeostasis; D006801:Humans; D006862:Hydrogen Sulfide / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D010012:Osteogenesis / Q000235:genetics; D010024:Osteoporosis / Q000378:metabolism* / Q000473:pathology; D011493:Protein Kinase C / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D013466:Sulfurtransferases / Q000235:genetics; D000637:Transaminases / Q000235:genetics; D051176:beta Catenin / Q000378:metabolism
chemical_list: D020747:Calcium Channels, T-Type; D034741:RNA, Small Interfering; D051176:beta Catenin; D000637:Transaminases; C019968:cysteine aminotransferase; D011493:Protein Kinase C; D013466:Sulfurtransferases; C021550:3-mercaptopyruvate sulphurtransferase; D003541:Cystathionine beta-Synthase; D006862:Hydrogen Sulfide
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