We investigate the cellular and molecular basis of chronic joint inflammation.
The inflammatory changes in chronic polyarthritis initially affect the synovial membrane, a thin tissue structure formed predominantly by mesenchymal cells that line the joint cavity. Recent findings demonstrate that the cells of the synovial membrane actively contribute to the inflammatory process. In particular, the chronic destructive character of arthritis is crucially shaped by the properties and behavior of synovial fibroblasts.
We developed a three-dimensional culture system in which synovial fibroblasts spontaneously form a tissue structure that closely resembles the synovial membrane. At the surface of the three-dimensional structure, the cells condense into an intima consisting of multiple rows of reticularly connected cells. The intima overlies a less tightly organized subintima. The cells of the subintima are connected by long tubular projections. Functionally, the synovial organ culture also resembles the in vivo conditions. The cells of the intima form proteoglycans and glycoproteins (lubricin); substances that are of great importance for joint homeostasis. Under inflammatory conditions, after stimulation with TNF, changes take place in the 3D culture that mirror the pathological process in rheumatoid synovitis. Cells reorganize into a condensed cell mass and produce increased levels of the pro-inflammatory cytokine IL-6. 3D culture can therefore be considered a simplified synovial organ model and provides an opportunity to study the adaptive response of the synovial membrane in the inflammatory process.
Thomas Karonitsch investigates molecular mechanisms and functional significance of cytokine-mediated cell activation (Characterization of inflammatory signaling circuits). Ruth Byrne is investigating pathways of cell communication, in particular the direct transfer of cell organelles via tubular cell-to-cell connections (Cellcommunication via intercellular transfer of organelles). Felix Kartnig investigates the functional significance of molecules of the intercellular adhesion complex in inflammatory tissue behavior (p120-catenin in inflammatory tissue behavior). Isabel Olmos Calvo is investigating subcellular mechanisms of inflammatory tissue response (Membrane trafficking as a means for inflammatory tissue remodeling). The projects are actively supported by Karolina von Dalwigk and Birgit Niederreiter.
Synovial fibroblasts in a 3D culture: The cells are connected by long tubular projections.
Green: Actin cytoskeleton
Blue: Cell nuclei
Red: Intercellular connections