IRE1a Negative Regulates Chondrocyte Differentiation

We present evidences demonstrating that overexpression of IRE1a inhibits chondrocyte differentiation, as revealed by reduced expression of Col,,SOX9, ColX, MMP-13, IHH, Runx2. Furthmore, IRE1a-mediated inhibition of chondrogenesis depends on its enzymatic activity, since its point mutant lacking enzymatic activity completely loses this activity. The RNase and Kinase domains of IRE1a C-terminal is necessary for its full enzymatic activity and inhibition of chondrocyte differentiation. Mechanism studies demonstrate that granulin-epithelin precursor (GEP),a growth factor known to stimulate chondrogenesis, induced IRE1a expression in chondrogenesis. In addition, IRE1a inhibits GEP-mediated chondrocyte differentiation as a negative regulator. Altered expression of IRE1a in chondrocyte hypertrophy was accompanied by altered levels of IHH and PTHrP.Collectively,IRE1a may be a novel regulator of chondrocyte differentiation by 1) inhibition GEP-mediated chondrocyte differentiation as a negative regulator; 2) promoting IHH/PTHrP signaling.