Inhibition of β-Catenin Signaling in Articular Chondrocytes Results in Articular Cartilage Destruction

Osteoarthritis (OA) is a degenerative joint disease. Numerous genetic and environmental factors have been proposed as contributors to the development of OA. The progression of the disease is slow and eventually results in degeneration and loss of the articular cartilage in various joints, including fingers, knees, hips, and spine. The disease process leads to limitation of joint movement, joint deformity, joint stiffness, inflammation, and severe pain. The mechanism of OA pathogenesis remains undefined. OA is mediated by a dynamic interplay between the articular chondrocytes, their matrix, and synovial cells. Articular chondrocytes, the cell type present in articular cartilage, are responsible for producing and maintaining the extracellular matrix (ECM), which supports the appropriate biomechanical function of the tissue. Phenotypic changes seen in OA are often accompanied by ECM degradation, which eventually results in cartilage destruction (1). Synovial fibroblasts are mesenchyme-derived cells that form a thin lining of synovial tissue surrounding the fibrous capsule of the joint. The physiologic roles of synovial tissue are to produce synovial fluid that lubricates the joints and to supply nutrients to the articular chondrocytes. Articular cartilage plays a crucial role in joint function during adulthood, and destruction of articular cartilage has severe consequences. While most cartilages are replaced by bone during development, only a few cartilages are permanent, including articular cartilage. Articular chondrocytes, which function to maintain the matrix, are unique among growth plate chondrocytes in that they exhibit very limited mitotic activity, have a slow rate of matrix synthesis and degradation, and do not progress fully to the terminally differentiated phenotype displayed by cells in the growth plate (2). Very little is known regarding the mechanisms involved in establishing and maintaining this articular chondrocyte phenotype. The function of articular chondrocytes is regulated by a variety of growth factors, including Wnt/β-catenin signaling molecules, which play a critical role in chondrocyte proliferation, differentiation, and apoptosis. Beta-catenin is a key molecule in the canonical Wnt signaling pathway and plays a critical role in multiple steps during chondrocyte formation and maturation (3,4). Inhibitor of β-catenin and T cell factor (ICAT) is an 82-amino-acid small molecule (5) whose crystal structure reveals binding capacity to the armadillo repeats of β-catenin. This binding disrupts the complex formation of β-catenin with T cell factor (TCF)/lymphoid enhancer factor (LEF) (6,7) and thus leads to inhibition of signaling in this pathway. To investigate the role of β-catenin signaling in the maintenance of articular cartilage function under physiologic and pathophysiologic conditions, we generated Col2a1-ICAT–transgenic mice in which the ICAT transgene was targeted specifically to chondrocytes using the Col2a1 promoter. We found that the ICAT transgene was highly expressed in articular chondrocytes in 6-month-old transgenic mice, leading to inhibition of β-catenin signaling in transgenic mouse chondrocytes. Associated with this, severe articular cartilage destruction was observed in Col2a1-ICAT–transgenic mice. Articular chondrocyte apoptosis was significantly increased, providing novel evidence regarding the contribution of β-catenin signaling to the maintenance of normal articular cartilage function.