Molecular hydrogen suppresses activated Wnt/β-catenin signaling.

Abstract

This study investigated how molecular hydrogen (H2) modulates intracellular signaling pathways. H2 was found to downregulate aberrantly activated Wnt/β-catenin signaling by enhancing phosphorylation and subsequent degradation of β-catenin. Complete GSK3 inhibition or mutations at CK1- and GSK3-phosphorylation sites on β-catenin eliminated this effect. H2 did not alter GSK3-mediated phosphorylation of glycogen synthase, suggesting no direct action on GSK3 itself. Knockdown of APC or Axin1, key components of the β-catenin destruction complex, also abolished H2-mediated suppression. In human osteoarthritis chondrocytes, H2 reduced Wnt/β-catenin activation. In a surgically induced rat osteoarthritis model, oral hydrogen-rich water intake showed a tendency to reduce cartilage degradation, associated with attenuated β-catenin accumulation. These findings identify Wnt/β-catenin pathway modulation as a molecular basis for some of the protective effects attributed to H2.

Mechanism

H2 promotes phosphorylation and proteasomal degradation of β-catenin through the destruction complex comprising CK1, GSK3, APC, and Axin1, thereby suppressing aberrant Wnt/β-catenin pathway activation without directly modifying GSK3 kinase activity.