Clinical and translational medicine
USP25 stabilises GLI1 through K48-linked deubiquitination within a reciprocal regulatory circuit in osteoarthritis models
Door Zhang Q, Ye Y, Huang Y en 2 anderen.
Inhoud in het Engels
Abstract
Background
Osteoarthritis (OA) is characterised by progressive articular cartilage degeneration, yet effective disease-modifying targets remain limited. The post-translational mechanisms sustaining Hedgehog/GLI1 signalling during OA progression remain incompletely understood.
Methods
Bioinformatic analyses of GEO datasets were performed to evaluate GLI1 expression across OA-related tissue compartments. Independent cartilage datasets, paired human cartilage specimens, and primary human chondrocytes exposed to graded IL-1β stimulation provided tissue- and cell-relevant evidence. An unbiased deubiquitinase library screen combined with GLI1-responsive luciferase assays was used to identify GLI1-regulating deubiquitinases. The molecular function of USP25, its reciprocal regulation with GLI1, and the preclinical chondroprotective activity and target dependence of AZ1 were investigated in vitro and in vivo.