Cell‐Cell Interaction Mediated by Cadherin‐11 Directly Regulates the Differentiation of Mesenchymal Cells Into the Cells of the Osteo‐Lineage and the Chondro‐Lineage*

We studied cadherin‐11 function in the differentiation of mesenchymal cells. Teratomas harboring the cadherin‐11gene generated bone and cartilage preferentially. Cadherin‐11 transfectants of C2C12 cells and cadherin‐11 and/or N‐cadherin transfectants of L cells showed that cadherin‐11 together with N‐cadherin‐induced expression of ALP and FGF receptor 2. These results suggest that cadherin‐11 directly regulates the differentiation of mesenchymal cells into the cells of the osteo‐lineage and the chondro‐lineage in a different manner from N‐cadherin.Introduction:Cell‐cell interaction is an essential event for tissue formation; however, the role of cell‐cell adhesion in mesenchymal tissue formation as well as in cell differentiation in this tissue remains unclear. cadherins, which are calcium‐dependent cell adhesion receptors, form adherence junctions after adherence and aggregation of cells. Because cadherin‐11 as well as N‐cadherin has been reported to be a mesenchyme‐related cadherin, we examined the cadherin‐11 action in teratomas and in the cell lines C2C12 and L cell. Herein, we show that cell‐cell interaction mediated by cadherin‐11 is responsible for bone and cartilage formation.Materials and Methods:It has been previously reported that N‐cadherin‐expressing E‐cadherin−/−ES transfectants formed neuroepithelium and cartilage in teratomas. Thus, we transfected the E‐cadherin−/−ES cell line with the cadherin‐11gene. Moreover, we also transfected C2C12 cells and L cells with the cadherin‐11gene for morphological analysis and study of the induced differentiation at the molecular level.Results and Conclusion:Teratomas derived from embryonic stem cells in which the cadherin‐11gene had been expressed exogenously contained bone and cartilage preferentially, showing that cadherin‐11 is involved in mesenchymal tissue formation, specifically in controlling the differentiation of these cells into osteoblasts and chondrocytes. Therefore, we further examined the functional difference between cadherin‐11 and N‐cadherin. The expression patterns of cadherin‐11 and N‐cadherin in cells of the mouse osteoblastic cell line MC3T3‐E1 showed that each cadherin was located independently of the cell‐cell adhesion site and acted individually. In hanging drop cultures, cadherin‐11 L cell transfectants aggregated in a sheet‐like structure, whereas N‐cadherin transfectants aggregated in a spherical form, indicating that each cadherin confers a different 3D architecture because of its individual adhesive property. To investigate the molecular mechanism of cadherin‐11 action in cell differentiation, we analyzed cadherin‐11 transfectants of C2C12 cells and cadherin‐11 and/or N‐cadherin transfectants of L cells and showed that cadherin‐11, together with N‐cadherin, induced expression of alkaline phosphatase (ALP) and fibroblast growth factor receptor 2. These results suggest that cadherin‐11 directly regulates the differentiation of mesenchymal cells into the cells of the osteo‐lineage and the chondro‐lineage in a different manner from N‐cadherin.