Inhibition of β‐catenin signaling in articular chondrocytes results in articular cartilage destruction

<jats:title>Abstract</jats:title><jats:sec><jats:title>Objective</jats:title><jats:p>Osteoarthritis is a degenerative joint disease whose molecular mechanism is currently unknown. Wnt/β‐catenin signaling has been demonstrated to play a critical role in the development and function of articular chondrocytes. To determine the role of β‐catenin signaling in articular chondrocyte function, we generated <jats:italic>Col2a1‐ICAT</jats:italic>–transgenic mice to inhibit β‐catenin signaling in chondrocytes.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>The expression of the <jats:italic>ICAT</jats:italic> transgene was determined by immunostaining and Western blot analysis. Histologic analyses were performed to determine changes in articular cartilage structure and morphology. Cell apoptosis was determined by TUNEL staining and the immunostaining of cleaved caspase 3 and poly(ADP‐ribose) polymerase (PARP) proteins. Expression of Bcl‐2, Bcl‐x<jats:sub>L</jats:sub>, and Bax proteins and caspase 9 and caspase 3/7 activities were examined in primary sternal chondrocytes isolated from 3‐day‐old neonatal <jats:italic>Col2a1‐ICAT</jats:italic>–transgenic mice and their wild‐type littermates and in primary chicken and porcine articular chondrocytes.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Expression of the <jats:italic>ICAT</jats:italic> transgene was detected in articular chondrocytes of the transgenic mice. Associated with this, age‐dependent articular cartilage destruction was observed in <jats:italic>Col2a1‐ICAT</jats:italic>–transgenic mice. A significant increase in cell apoptosis in articular chondrocytes was identified by TUNEL staining and the immunostaining of cleaved caspase 3 and PARP proteins in these transgenic mice. Consistent with this, Bcl‐2 and Bcl‐x<jats:sub>L</jats:sub> expression were decreased and caspase 9 and caspase 3/7 activity were increased, suggesting that increased cell apoptosis may contribute significantly to the articular cartilage destruction observed in <jats:italic>Col2a1‐ICAT</jats:italic>–transgenic mice.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Inhibition of β‐catenin signaling in articular chondrocytes causes increased cell apoptosis and articular cartilage destruction in <jats:italic>Col2a1‐ICAT</jats:italic>– transgenic mice.</jats:p></jats:sec>