Molecular hydrogen suppresses activated Wnt/β-catenin signaling

Molecular hydrogen (H-2) is effective for many diseases. However, molecular bases of H-2 have not been fully elucidated. Cumulative evidence indicates that H-2 acts as a gaseous signal modulator. We found that H-2 suppresses activated Wnt/beta-catenin signaling by promoting phosphorylation and degradation of beta-catenin. Either complete inhibition of GSK3 or mutations at CK1- and GSK3-phosphorylation sites of beta-catenin abolished the suppressive effect of H-2. H-2 did not increase GSK3-mediated phosphorylation of glycogen synthase, indicating that H-2 has no direct effect on GSK3 itself. Knockdown of adenomatous polyposis coli (APC) or Axin1, which form the beta-catenin degradation complex, minimized the suppressive effect of H2 on beta-catenin accumulation. Accordingly, the effect of H-2 requires CK1/GSK3-phosphorylation sites of beta-catenin, as well as the beta-catenin degradation complex comprised of CK1, GSK3, APC, and Axin1. We additionally found that H-2 reduces the activation of Wnt/beta-catenin signaling in human osteoarthritis chondrocytes. Oral intake of H-2 water tended to ameliorate cartilage degradation in a surgery-induced rat osteoarthritis model through attenuating beta-catenin accumulation. We first demonstrate that H-2 suppresses abnormally activated Wnt/beta-catenin signaling, which accounts for the protective roles of H-2 in a fraction of diseases.