| Abstract: | BackgroundOsteoarthritis is caused by cartilage dysplasia and has fetal origin. Prenatal dexamethasone exposure (PDE) induced chondrodysplasia in fetal rats by inhibiting transforming growth factor β (TGFβ) signaling. This study aimed to determine the effect of dexamethasone on fetal cartilage development and illustrate the underlying molecular mechanism.MethodsDexamethasone (0.2 mg/kg.d) was injected subcutaneously every morning in pregnant rats from gestational day (GD) 9 to GD21. Harvested fetal femurs and tibias at GD21 for immunofluorescence and gene expression analysis. Fetal chondrocytes were treated with dexamethasone (100, 250 and 500 nM), endoplasmic reticulum stress (ERS) inhibitor, and ryanodine receptor 1 (RYR1) antagonist for subsequent analyses.ResultsIn vivo, prenatal dexamethasone exposure (PDE) decreased the total length of the fetal cartilage, the proportion of the proliferation area and the cell density and matrix content in fetal articular cartilage. Moreover, PDE increased RYR1 expression and intracellular calcium levels and elevated the expression of ERS-related genes, while downregulated the TGFβ signaling pathway and extracellular matrix (ECM) synthesis in fetal chondrocytes. In vitro, we verified dexamethasone significantly decreased ECM synthesis through activating RYR 1 mediated-ERS.ConclusionsPDE inhibited TGFβ signaling pathway and matrix synthesis through RYR1 / intracellular calcium mediated ERS, which ultimately led to fetal dysplasia. This study confirmed the molecular mechanism of ERS involved in the developmental toxicity of dexamethasone and suggested that RYR1 may be an early intervention target for fetal-derived adult osteoarthritis. |
