Wnt/β-catenin signaling pathway. In resting cells, glycogen synthase kinase 3 (GSK3β) is in a complex with CK1, β-catenin, axin and adenomatous polyposis coli protein. In this state, β-catenin is primed for phosphorylation by GSK3β. The phosphorylated β-catenin is degraded by ubiquitination. In the activated state (upon Wnt binding to Fz), Wnt-Fz and LDL receptor-related protein 5/6 (LRP) coordinate Dvl (disheveled, an adaptor protein) activation, which results in recruitment of axin to the plasma membrane. This leads to dissociation and inactivation of GSK3β, which can no longer phosphorylate β-catenin. Free β-catenin translocates to the nucleus and induces gene expression in a complex with LEF-1/T cell factor (TCF) family transcription factors, down regulating E-cadherin genes and initiating epithelial mesenchymal transition. (Adapted from [8].)

Drivers and mediators of epithelial-mesenchymal transition (EMT). Early stage tumor cells maintain epithelial properties similar to the neighboring normal epithelium. The accidental overexpression of master regulators of EMT, such as the transcription factors Twist, Snail, and SIP1, in cancer cells leads to dramatic changes in gene expression profiles and cellular behavior. Twist, Snail, and SIP1 repress the expression of E-cadherin via E boxes in its promoter and trigger expression of an entire EMT transcriptional program through as yet unknown mechanisms. Several pathways are known to regulate Twist, Snail, and SIP1 expression in tumor cells while others (shown in parentheses) do so at least in developmental contexts. (Adapted from [21].)

Microscopic sections of synovial tissue from a patient with rheumatoid arthritis stained with the STRO-1 antibody. In the bone marrow STRO-1 reacts with stromal elements that are progenitors of fibroblasts (CFU-F) [55], but staining in the synovium is limited to perivascular mesenchymal cells (pericytes). JS, joint space.

The canonical transforming growth factor (TGF)-β/Smad signaling pathway. Members of the TGF-β family of growth factors (TGF-βs, activins, nodals) interact sequentially with two membrane receptors. TGF binds first to the constitutively active type II receptor (R) and then the ligand-recepor complex associates with type I TGF-R. TGF-IIR (TβIIR) phosphorylates TGF-IR (TβIR) on a cluster of serine threonine residues. Activated TGF-RI propogates the signal downstream by directly phosphorylating Smad2 and Smad3. These form heterodimeric or trimeric complexes with Smad 4 and translocate into the nucleus where, in combination with LEF-1/T cell factor (TCF) family transcription factors, they down-regulate E-cadherin genes and initiate epithelial-mesenchymal transition. Complexes of Smad7 and Smurf1 or Smurf2 promote ubiquination and degradation of activated receptors limiting the intensity and duration of signaling. P, phosphorylation sites; SARA, small anchor for receptor activity. (Adapted from [61].)

Schematic illustration of the key events of epithelial-mesenchymal transition (EMT) involving the renal tubular basement membrane (TBM) and possible therapeutic interventions. The diagram illustrates four key events essential for the completion of EMT: loss of epithelial adhesion properties; de novo alpha smooth muscle actin (αSMA) expression and actin reorganization; disruption of TBM; and enhanced cell migration and invasion capacity. Transforming growth factor (TGF)-1 alone is capable of inducing tubular epithelial cells to undergo all four steps. Strategies to block any steps during EMT would have a major impact on EMT and, thereby, on renal fibrosis. For instance, hepatocyte growth factor (HGF) and bone morphogenic protein (BMP)-7 could antagonize TGF-1 and consequently inhibit the initiation of EMT (step 1). Blockade of angiotensin (Ang)II by losartan abolishes its activity as an EMT promoter and attenuates renal fibrosis (step 2). Preservation of TBM integrity in tPA-/- mice selectively blocked EMT in obstructive nephropathy (step 3). Finally, pharmacological inhibition of ROCK kinase impairs cell migration and reduces renal fibrosis (step 4). MMP, matrix metalloproteinase. (Adapted from [35].)