Interactions of fibroblasts with the extracellular matrix: implications for the understanding of fibrosis

The cellular organization and the compartmentalization in multicellular organisms is mediated by the extracellular matrix (ECM). This structure is composed by a wide variety of different macromolecules which carry distinct domains with defined structural and/or biological activities. Cells are known to interact with these molecules via specific receptors. Following activation, these receptors transduce signals either directly to the intracellular cytoskeleton or via different signalling cascades. Cell-matrix interactions, therefore, not only control the shape and orientation of cells but can also directly regulate cellular functions, including migration, differentiation, proliferation, and the expression of different genes. These cell-matrix interactions have been elucidated in detail for several biological processes, especially morphogenesis and differentiation, but also play an important role during pathological situations, e.g. wound healing and tumor progression. Although much less investigated, similar mechanisms are thought to regulate the biological behavior of fibroblastic cells, the final target cells in fibrosis. The activity of these cells depends in various ways on the presence of ECM molecules. First, some of the molecules are known to bind to and modulate the activity of those growth factors and cytokines, which lead to the activation of fibroblasts during the early phases of fibrosis. Second, deposition of large amounts of ECM molecules alters the environment and the mechanical load on the cells which are embedded in this matrix. Third, ECM molecules directly modulate fibroblast metabolism via certain integrin receptors. This review summarizes recent developments in all three domains. It mainly focuses on the direct role of ECM molecules in the biosynthetic activity of fibroblasts.