The relevance of the stroma and epithelial- mesenchymal transition for rheumatic diseases

Epithelial-mesenchymal transition (EMT) is a term applied to the process whereby cells undergo a switch from an epithelial phenotype with tight junctions, lateral, apical, and basal membranes, and lack of mobility into mesenchymal cells that have loose interactions with other cells, are non-polarized, motile and produce an extracellular matrix. The importance of this process was initially recognized from a very early step in embryology, but more recently as a potential mechanism for the progression and spread of epithelial cancers. As the sequence of morphological changes has become understood in molecular terms, diseases characterized by alterations in stromal elements and fibrosis are being considered as examples of EMT. This review will focus on the pathogenetic features of immune-mediated renal disease, systemic sclerosis and rheumatoid arthritis that could be explained by EMT. The relevance of the stroma and epithelialmesenchymal transition for rheumatic diseases Epithelial-mesenchymal transition (EMT) describes a process wherein static epithelial cells lose cell-cell contacts, acquire mesenchymal features and manifest a migratory phenotype. Multiple alternative terms, including epithelial-mesenchymal interactions, transformation, transdifferentation, and transition, have been used interchangeably to describe this process. I’ve chosen ‘transition’ for the reasons elaborated by Kalluri and Neilson [1], whose excellent publication is recommended to any reader interested in the entire subject. EMT, which was first appreciated by developmental biologists in the 1980s, is now attracting the attention of investigators interested in metastatic cancers and diseases characterized by fibrosis [1,2]. This review will explain these observations briefly and consider how they might be relevant to certain rheumatic diseases. In the embryo the first and only tissue formed is epithelium [3]. Sheets of epithelial cells are held together tightly at strong adherens junctions containing E-cadherin in complexes with catenins linked to the actin cytoskeleton. The epithelial cells are firmly attached through integrins to an underlying extracellular matrix (ECM) containing type IV collagen and laminin; the basement membrane. Around day 15 the epiblast cells of the developing human embryo migrate into a structure called the primitive streak [4]. Once in place they assume the features of embryonic mesoderm and endoderm in a process known as gastrulation. From the mesoderm arise the visceral and limb bud mesenchyme. The latter is the source of bone, cartilage, fibroblasts, fat, skeletal muscle and the bone marrow stroma. Although mesenchymal cells are secretory and produce collagens, fibronectin, vimentin, and alpha smooth muscle actin (αSMA), no one of these is unique to this cell type. The attribute that sets mesenchymal cells apart is their ability to invade and move through the three-dimensional structure of the ECM. Accordingly, mesenchymal cells are defined by morphology and behavior: front end to back end polarity; elongated morphology; filopodia; and invasive motility [3]. Signaling pathways used in development The wnt and transforming growth factor (TGF)-β signaling families are essential for development of the primitive streak and the induction of EMT [5,6]. Each acts through the transcription factor LEF-1/TCF, a member of the family of HMG-box DNA binding proteins, which has binding sites for both Smads and catenin signaling molecules [7]. The primacy of LEF-1/TCF can be demonstrated by transfecting epithelial cells with LEF-1/TCF DNA and observing that they lose their epithelial features and acquire a motile mesencyhmal Review Relevance of the stroma and epithelial-mesenchymal transition (EMT) for the rheumatic diseases