The synovial cadherin (cadherin-11) mediates tissue formation and promotes invasion of fibroblast-like synoviocytes

Cadherins are integral membrane homophilic adhesion proteins that mediate adhesion between cells of the same type within a tissue. Cadherins mediate tissue morphogenesis during development and maintenance of tissue architecture in adults. We recently found that cadherin-11 is expressed in human fibroblast-like synoviocytes. We demonstrate that the expression of the synovial cadherin promotes cell invasion and confers on cells the ability to become organized into synovial lining-like architecture in vitro.

We generated cadherin-11-expressing fibroblast L-cell clones and empty vector transfected L-cell controls. Phase-contrast microscopy analysis demonstrated that cadherin-11-transfected L-cells form extensive and intimate contacts along their surfaces, and condense together at higher cell density to form a continuous sheet of cells in vitro. In contrast, L-cells transfected with control empty vector are loosely organized and do not form a tissue-like structure. We have established an in vitro model for synovial lining formation. Interestingly, at the edge of fibronectin-coated culture areas, the cadherin-11-expressing L-cells piled up and formed a continuous lining layer-like architecture after 2 days in culture, whereas the control L-cells failed to form this lining morphology.

Matrigel invasion assays revealed a twofold to threefold increased invasive capacity of the cadherin-11-transfected L-cells when compared with L-cells transfected with control vector. To determine the molecular mechanisms of cadherin-11-dependent cell invasion, we generated cadherin-11 constructs of the cytoplasmic tail that delete domains implicated in binding critical intracellular molecules that control cadherin function. Strikingly, deletion of the juxtamembrane domain, known to bind p120-catenin, profoundly altered the invasive capacity of these cells.

These in vitro studies suggest a role for cadherin-11 in tissue and lining layer formation in the synovium and the invasive nature of fibroblast-like synoviocytes in chronic synovitis and in rheumatoid arthritis.