title: Molecular hydrogen suppresses activated Wnt/β-catenin signaling.
abstract: Molecular hydrogen (H2) is effective for many diseases. However, molecular bases of H2 have not been fully elucidated. Cumulative evidence indicates that H2 acts as a gaseous signal modulator. We found that H2 suppresses activated Wnt/β-catenin signaling by promoting phosphorylation and degradation οf β-catenin. Either complete inhibition of GSK3 or mutations at CK1- and GSK3-phosphorylation sites of β-catenin abolished the suppressive effect of H2. H2 did not increase GSK3-mediated phosphorylation of glycogen synthase, indicating that H2 has no direct effect on GSK3 itself. Knock-down of adenomatous polyposis coli (APC) or Axin1, which form the β-catenin degradation complex, minimized the suppressive effect of H2 on β-catenin accumulation. Accordingly, the effect of H2 requires CK1/GSK3-phosphorylation sites of β-catenin, as well as the β-catenin degradation complex comprised of CK1, GSK3, APC, and Axin1. We additionally found that H2 reduces the activation of Wnt/β-catenin signaling in human osteoarthritis chondrocytes. Oral intake of H2 water tended to ameliorate cartilage degradation in a surgery-induced rat osteoarthritis model through attenuating β-catenin accumulation. We first demonstrate that H2 suppresses abnormally activated Wnt/β-catenin signaling, which accounts for the protective roles of H2 in a fraction of diseases.
authors: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Yingni
authors: Y
authors: Lin
authors: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Bisei
authors: B
authors: Ohkawara
authors: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Mikako
authors: M
authors: Ito
authors: Department of Pathology and Biological Responses, Graduate school of Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Nobuaki
authors: N
authors: Misawa
authors: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Kentaro
authors: K
authors: Miyamoto
authors: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Yasuhiko
authors: Y
authors: Takegami
authors: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Akio
authors: A
authors: Masuda
authors: Department of Pathology and Biological Responses, Graduate school of Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Shinya
authors: S
authors: Toyokuni
authors: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Kinji
authors: K
authors: Ohno
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D060466:Axin Protein / Q000378:metabolism; D047389:Casein Kinase I / Q000378:metabolism; D002460:Cell Line; D019902:Chondrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005740:Gases / Q000737:chemistry; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D045325:HCT116 Cells; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D006859:Hydrogen / Q000737:chemistry / Q000494:pharmacology*; D007976:Leupeptins / Q000494:pharmacology; D018021:Lithium Chloride / Q000494:pharmacology; D008297:Male; D008856:Microscopy, Fluorescence; D010003:Osteoarthritis / Q000378:metabolism / Q000473:pathology / Q000662:veterinary; D010766:Phosphorylation / Q000187:drug effects; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D055758:SOX9 Transcription Factor / Q000378:metabolism; D014867:Water / Q000737:chemistry; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D060509:Wnt3A Protein / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D060466:Axin Protein; D005740:Gases; D007976:Leupeptins; D034741:RNA, Small Interfering; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; D060509:Wnt3A Protein; D051176:beta Catenin; D014867:Water; D006859:Hydrogen; D047389:Casein Kinase I; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde