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 12. 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 (α SMA), 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.

The wnt and transforming growth factor (TGF)-β signaling families are essential for development of the primitive streak and the induction of EMT 56. 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 phenotype. Conversely, mesenchymal cell lines become epithelial when transformed by E-cadherin genes 6.

The wnt signaling pathway regulates the amounts of β-catenin protein available within the cell for binding to the cytoplasmic tail domain of cadherins, which mediates cell-cell adhesion, and to cytoskeletal (F actin) elements 8. In the resting state, β-catenin is in the cytoplasm associated with adenomatous polyposis coli protein and axin, which results in its ubiquination and subsequent degradation by the proteosome (Figure 1). Normally, a balance is maintained between a relatively stable pool of β-catenin associated with adherens junctions and a small, rapidly degraded cytosolic pool 9. Engagement of wnt glycoprotein by cell surface frizzled receptors results in an excess of free cytosolic, non-phosphorylated β-catenin, which can enter the nucleus and engage LEF-1/TCF DNA binding proteins, transforming them into transcriptional activators of the genes central to EMT, including the down-regulation of E-cadherin genes.

Binding of TGF-β ligands to their tetrameric type I and II receptors causes sequential activation of MKK-4/JNK and the complex of Smad 2/3 and Smad 4 proteins (Figure 2). This complex can enter the nucleus and engage LEF-1/TCF at a site separate from the β-catenin binding site 7, but with similar results; namely, induction of EMT genes, E-cadherin down-regulation, and acquisition of mesenchymal features 1011.

In addition to LEF-1/TCF, a family of transcription factors that can cause EMT and down-regulate E-cadherin expression has recently been identified (Figure 3). These repressors, bearing fanciful names like Snail, Slug, Sip-1, and Twist, exert their effects by binding to different E-boxes in the E-cadherin promoter 12. Wnt and TGF-β can also up-regulate these E-cadherin repressors.

Often genes important in embryogenesis have an oncogenic potential (i.e., the ability to initiate tumors), but the propagation and spread of these tumors depends on several different processes 13. Many separate steps are involved in metastasis of neoplastic epithelial cells, namely expansion into local tissues, penetration of blood and lymphatic vessels, entrance into the systemic circulation (intravasation), subsequent extravasation through the vascular endothelium at distant locations, and the establishment of new tumors. Each of these steps has been analyzed by gene-expression microarrays in both experimental animals and man 14151617. The conversion from a sessile tumor to an invasive carcinoma results from the loss of constraints imposed by cell-cell adhesion, that is, EMT. The level of E-cadherin expression is often inversely correlated with tumor grade and stage and inactivating mutations of E-cadherin are present in 50% of lobular breast carcinomas 1819.

Equally important are E-cadherin repressors. In a very influential paper, Yang and colleagues 20 found elevated levels of Twist expression in mouse mammary gland tumors at every stage of metastasis. Reduction of the expression level of Twist substantially reduced tumor cell intravasation, but had no effect on the histology or growth rate of the primary tumor. Kang and Massague 21 recently reviewed the contribution of additional pathways and E-cadherin repressors to metastatic disease (Figure 3). They also pointed out that the number of carcinoma cells that have undergone EMT and appear as stromal elements is likely to be underestimated. This is an important consideration given the interest in the influence of the stromal environment on neoplasia.

Stroma is the tissue that forms the ground substance, framework or matrix of an organ. New studies suggest that the cancer cell microenvironment not only facilitates tumor progression, but also may occasionally initiate the oncogenic conversion of epithelial cells 2223. An example of the former is the study of Orimo and colleagues 24, who isolated cancer associated fibroblasts (CAFs) from six human breast cancers and compared them to fibroblasts isolated from a nearby non-cancerous region of the same breast (counterpart fibroblasts). CAFs were more competent in supporting in vivo growth of tumor cells and enhanced tumor angiogenesis and the recruitment and mobilization of endothelial progenitor cells. Cancer associated fibroblasts express traits of activated fibroblasts (myofibroblasts with increased α SMA staining) when compared to counterpart fibroblasts or normal fibroblasts. CAFs expressed high levels of stromal derived factor (SDF)-1, which is responsible for the chemotaxis of endothelial progenitor cells and contributes to angiogenesis and tumor growth by acting in a paracrine manner on the CXCR4 receptors of tumor cells. A comprehensive gene expression profile of breast carcinomas noted significant overexpression of the chemokines CXCL14 and CXCL12 in tumor myoepithelial cells and myofibroblasts 25. These authors proposed that locally produced chemokines bind to receptors on epithelial cells, enhancing their proliferation, migration, and invasion.

Rat mammary adenocarcinomas develop when just the stroma is treated with a carcinogen (N-nitrosomethyl-urea) regardless of the exposure of epithelial cells 26. In a related study, TGFβ-1 and the extracellular matrix protein laminin-5 induced EMT and hepatocellular carcinoma cell invasion by upregulating Snail and Slug, down regulating E-cadherin, translocating β-catenin into nuclei, and inducing dramatic spreading and morphological changes in the cancer cells 27. Similar changes were not observed with the peritumoral tissues from the same hepatocellular carcinoma patients. EMT was blocked by antibody to alpha 3, but not alpha 6 integrins, supporting the critical role of laminin 5 in these processes 27. In a related study, tissue derived fibroblasts modulated the integrin-dependent interactions (alpha-5, alpha-6, beta 1) between the gastric cell line HGT-1 and fibronectin 28. Hepatocyte growth factor produced by autologous stromal fibroblasts augments the growth of human small cell lung cancer in nude mice 29. Exposure to CAFs transformed non-tumorogenic prostate epithelial cells into neoplasms 3031 and fibroblasts from tumor stroma induced malignant transformation with dysregulation of several chromosones in the non-tumorogenic SV40 immortalized, prostate line BPH-1 32.

Conversely, in some experimental models, the stroma can normalize carcinomatous epithelial cells. For instance, mammary gland stroma from mature and multiparous rats interferes with the development of neoplastic breast tissue and encourages normal ductal growth of grafted epithelial cancer cells, whereas 6 months after inoculation tumors developed in 75%, 100% and 50% of 24-, 52-, and 80-day old virgin rats 33. These observations, although unexplained, have obvious clinical implications.

Until recently, scleroderma research focused mainly on the unique nature of the systemic sclerosis (SSc) fibroblast, its ability to produce ECM molecules, especially collagens, and the responsible growth factors, especially TGF-β 474849. Lately, the emphasis has shifted, prompted by recognition of the heterogeneity in the origins and phenotype of fibroblasts 50. But, as with renal fibrosis, opinions about the SSc fibroblast vary. Postlewaite and colleagues 51, in an admirable review, elaborated the prevailing theories and, based on studies from their own laboratory, suggested that conventional, circulating CD14(+) monocytes transdifferentiate into SSc fibroblasts. Another cell, the fibrocyte, initially described in the context of wound repair, can participate in granuloma formation, antigen presentation and is a source of contractile myofibroblasts found in a variety of fibrosing lesions 52 (discussed below). British workers favor a link between vascular damage (an essential requirement in any scheme of SSc pathogenesis) and the formation of myofibroblasts from pericytes 53. The latter are derived primarily from mesenchymal cell precursors. Under the influence of various growth factors they become either endothelial cells (vascular endothelial growth factor) or pericyte/smooth muscle cells (platelet-derived growth factor-BB) 54. A monoclonal antibody, STRO-1, identifies a subpopulation of bone marrow stromal cells that give rise to fibroblasts (colony forming units [CFUs]) 55. Yet the same antibody applied to rheumatoid arthritis (RA) synovium only stains periadventitial vascular cells (pericytes) (Figure 5). Pericytes provide structure to blood vessel walls, synthesize basement membrane proteins, and regulate blood flow and vascular permeability. In their capacity as primitive mesenchymal cells, pericytes can be a source of several tissues, including cartilage and bone 5657. Thus, both tissue fibrosis and ectopic calcification (features of SSc) could be attributed to pericytes.

Human myofibroblasts reside in a fraction of fibroblasts that react with Thy-1 antibody 58. Myofibroblasts are the hallmark of idiopathic pulmonary fibrosis 5859. Rat alveolar epithelial cells exposed in vitro to TGF-β for 6 days develop a fibroblast morphology and molecular markers associated with EMT. This effect is enhanced by tumor necrosis factor (TNF)-α 59. Cells co-expressing epithelial markers and αSMA are abundant in lung tissues from idiopathic pulmonary fibrosis patients. Mice with a targeted deletion of Smad3, a critical molecule in the TGF-β signaling pathway, fail to develop EMT and tissue fibrosis in experimental models of pulmonary, renal, liver, ocular and radiation induced skin injury 60.

Overexpression of the inhibitory Smad7 protein or treatment with a small molecule inhibitor of Smad 3 reduces the fibrotic response in all of these animal models (including murine systemic lupus erythematosus) and holds out a promise for treatment of pathological fibrotic human diseases 6061.

EMT cannot explain all fibrotic conditions, however. Bleomycin treatment is complicated by pulmonary fibrosis, akin to SSc. Repeated local injections of bleomycin induces a murine model of scleroderma 62. Yet in vitro studies of alveolar epithelial cell lines and immunohistochemical analysis of pulmonary fibrosis from bleomycin-treated mice and rats show no features of EMT 63.

The tissue invasion and destruction of cartilage and bone by stromal elements (known as pannus) as seen in RA joints is often compared to cancer. HG Fassbender, a student of RA pathology, remarked on the changes in the synovial stroma: "Normally this consists of loosely arranged collagen fibers with a small number of spindle shaped fibrocytes. In association with exudation of fibrin the local connective tissue cells proliferate. These cells may resemble the cells of the surface layer to such an extent that recognition of separate layers becomes impossible. In particularly gross examples, these large cells may lie so close together that any interstitial substance becomes unrecognizable" – he called this appearance "mesenchymoid transformation" (figures 124 to 126 in 64). More recent research on RA pathogenesis has concentrated on the immuno-hematological and angiogenic elements found in the synovium. Mast cells, important in modifying ECM by elaborating proteases and tryptic enzymes, are reviewed elsewhere 65. Only in the past 10 to 15 years has the import of synovial fibroblasts, lining cells and other mesenchymal elements been reconsidered 66676869.

How might such cells contribute to the pathogenesis of joint inflammation and bone and cartilage destruction? First, by their sheer bulk and metabolic needs. Most standard texts report that the number of intimal cells (fibroblast like synoviocytes (FLSs)) increase with inflammation from a few cells to 8 to 10 lining cells. But this is only what can be seen in thin (5 to 6 micron) histological sections. In reality, however, even in a large joint like the knee, the normal synovial membrane is a thin, filmy structure weighing just a few milligrams, whereas the inflamed, redundant synovium that is removed at surgery can weigh kilograms, a million-fold increase over normal. Much of the increased weight results from tissue edema, hypervascularity and the ingress of numerous blood cells, but tissue fibroblasts and FLSs also make a significant contribution.

Second, fibroblasts are not inert cells. They both make and degrade matrix elements, especially collagen and fibronectin, into numerous bioactive peptides. Fibroblasts operate through both cytokine independent and dependent pathways; they recruit and stimulate T cells and monocytes by the production of chemokines, especially IL-6 and SDF-1 (CXCL12) and they can attract and retain B lymphocytes by B cell activation factor of the TNF family (Blys) production. Fibroblasts are antigen presenting cells and elaborate numerous pro-inflammatory cytokines, including TNF-α and IL-1 (detailed in 68).

What accounts for the massive increase in fibroblasts? Knowledge of their origins, or the origin of any RA stromal element, is incomplete. Local proliferation of resident fibroblasts responding to the inflammatory milieu of the RA synovium is certainly a possibility 66. This explanation was initially invoked, then rejected, and later reconsidered, but proliferation alone cannot account for all of the increase. Subsequently, a prolonged life span of FLSs was recognized (reviewed in 6869), although even a combination of enhanced proliferation of the normally slow growing FLSs plus defective apoptosis seems an insufficient explanation.

What about EMT? Several factors that can modulate fibroblast formation are found in the RA synovium, either as genes or proteins; for example, large amounts of both latent and activated TGF-βI and II are present in RA synovium and synovial fluids 707172. Rheumatoid articular tissues have mesenchymal appearing cells that stain with an antibody to phosphorylated Smad 2/3, suggesting engagement of TGF-β receptors and activation of ECM through the TGF-β signaling pathway 73 (Figure 2). Myofibroblasts and/or cells that react with an antibody to αSMA are absent from normal or osteoarthritis synovium, but are detected in a proportion of synovial fibroblasts 7475. Common constituents of the ECM, such as MMPs and hyaluronan, can stimulate fibroblast formation through EMT. For example, ectopic expression of MMP3 (also known as stromelysin-1) in normal epithelial cells induces a fibroblast-like phenotype by mediating transcriptional upregulation of Rac-1b and enhanced production of reactive oxygen species. This results in genomic instability and increased expression of the Snail transcription factor. Snail down modulates E-cadherin and initiates the EMT cascade 76 (Figure 3). Hyaluronan (a major glycosamino-glycan of the ECM) is critical for EMT in the embryo 3. It can induce a fibroblast morphology, anchorage independent growth, loss of adhesion molecules at cell junctions, up-regulate vimentin expression in epithelial cells and supports tumor growth and invasion in vivo 7778. However, there are some important reservations about the role of EMT in the synovium because: very few cells have epithelial features; classical E-cadherins are scant; and the synovial lining lacks a basement membrane 79. Normal FLSs probably stick together through homotypic adhesion mediated by a newly described molecule, cadherin 11 80, whose regulation and role in the RA synovium is currently under investigation 81.

Since neither increased proliferation, inadequate apoptosis, nor EMT is responsible for the accumulation of fibroblasts in the joint, how do we explain abnormalities, quantitative or qualitative, of the articular stroma? The ingress of mesenchymal elements or their progenitors must be considered. There is certainly a precedent, because most inflammatory, immunological, and angiogenic cells in the synovium come from the blood. Are there such mesenchymal cells? One candidate is the fibrocyte, a marrow derived cell of hematopoetic lineage, thus CD34+, that circulates in the blood and responds to inflammatory cues 52. Fibrocytes participate in wound healing 82, are thought to be responsible for the thick, hard skin seen in some dialysis patients with renal insufficiency (nephrogenic fibrosing dermopathy) 83, and could have a role in other fibrotic disorders 51. However, fibrocytes have not been reported in synovial tissues and their numbers in the blood of RA patients are not different from normal individuals (NJZ, personal observation).

A second candidate, a mesenchymal stem cell (MSC) or mesenchymal progenitor cell (MPC), resides in the bone marrow 84, circulates in the blood 85, and has been found in a variety of normal tissues, including periarticular marrow, periosteum and synovium 86878889. MSCs/MPCs are CD34(-) and lack a single, defining antigen, but can be phenotyped by a combination of cell surface markers, including thy-1 (CD90), endoglin (CD105), ALCAM (CD166) 84, and receptors for low affinity nerve growth factor (LNGFR1) and BMP (BMPR1A and II) 89. Cells with these features are present in joints. Marinova and colleagues 90 recognized a small population of large, adherent, stromal-appearing cells in primary cultures of inflammatory joint effusions. These stained with antibodies to mesenchymal elements (collagen I, vimentin, αSMA and BMP receptors), and maintained this phenotype through multiple passages in tissue culture 89. An anti-BMPR II antibody reacted with 11.6% of the FLSs from RA synovial fluids (passages 3 to 6), but only 2% from non-inflammatory osteoarthritis fluids. BMPR IA and II expressing cells were identified in RA synovial tissues – approximately 25% of intimal lining cells and 7% in the sublining tissues. Strong staining was seen at the advancing front of pannus and sites of bone erosions 90.

Jones and colleagues 91 used a fibroblast CFU assay to quantify MPCs in synovial effusions from various kinds of arthritis (53 RA, 20 osteoarthritis, 27 miscellaneous). Unlike the earlier study 90, the numbers of MSCs per ml of synovial fluid was higher in osteoarthritis than in RA effusions. Fibroblasts from synovial fluids had trilineage potential and under appropriate conditions could be induced to become either fat, cartilage, or bone cells. The synovial fluid fibroblasts stained with standard mesenchymal cell antibodies. Rare cells expressed the low affinity nerve growth factor receptor. Whether they are the same as the BMPR(+) cells remains to be determined. The authors interpreted their findings as evidence that the MSCs were derived from "injured joint structures" (i.e., cartilage) 91. Synovial tissues were not examined in this study.

Patients with a diagnosis of RA differ from each other in many ways: clinical features, disease course, response to treatment, serologies and synovial immunohistology can all be cited. Of late, cDNA microarray technology has identified distinctive profiles among articular tissues from RA subjects and the relationship of particular genes to specific disease features is being examined 7592939495. Given the complex cellular makeup of RA synovitis, the finding of different gene patterns in intact synovial tissues is not surprising. Less anticipated have been the differences found in presumably homogeneous FLS 'lines' 75929495.

But how 'homogenous' are FLSs from intact synovial tissues? Several potentially confusing methodological problems must be recognized. Typically, synovium obtained either by arthroscopic biopsy or at joint surgery is enzymatically digested, disrupted, and maintained as single cells in tissue culture. The cells that adhere and grow are designated as FLSs, but no markers exist to indicate whether they originated as lining cells or came from subintimal stroma. Death and attrition eliminate blood cells in the cultures. Leukocytes and non-adherent lymphocytes go first, but monocyte/macrophages remain through several passages, during which time the slow growing fibroblasts are exposed to their cytokines and growth factors. To minimize contamination with other cells, FLS analysis is usually performed around the fourth passage or later. But the question arises: are changes observed at that time inherent to all the fibroblasts or did they develop during culture?

What is the impact of inflammatory cells present at the initiation of the culture on subsequent features of the FLSs? For instance, certain genes are found in FLSs from inflamed RA synovial tissues, but they differ from genes in the FLSs from non-inflammatory RA lesions. Were these genes induced in vivo or could products from the inflammatory cells in the primary culture (in vitro) have influenced them? Zimmermann and colleagues 96 used negative selection with anti-CD14 magnetic beads to obtain a relatively clean population of RA FLSs (passage 1). These differed considerably from conventional fourth passage FLSs in phenotype and proliferation rates. Thus, depending on the isolation procedures, gene arrays might also be different.

Do culture conditions modify FLSs? The growth of FLSs maintained at low density is faster than in high density cultures because proliferation is impeded by contact inhibition. For instance, Masuda and colleagues 97 compared the molecular profile of the same RA FLSs cultured at low density (proliferating) and high density (quiescent). Certain genes were only identified in the low density-proliferating cells. For some this was not a tissue culture artifact, because the genes were present in intact RA synovium, as confirmed by in situ hybridization The authors concluded, however, that the expression of many other genes likely depends on the stage of FLS proliferation in the culture. If FLSs are heterogeneous, then might certain culture conditions favor the expression of one subpopulation over another? For instance, low cell density, selected growth media, and low oxygen tensions are known to favor rapidly growing MSCs 98.

Might a small number of 'activated' or 'aggressive' FLSs present in a primary culture (passage 1) overgrow other elements and appear as a major population in later (passage 4) cultures? Is either normal or osteoarthritis synovium an appropriate control for RA synovitis or should RA synovium only be compared to other forms of chronic inflammatory synovitis? And might the influence on gene profiles depend on the stage and duration of the disease or prior treatment? Finally, the RA pannus invading cartilage and bone needs to be analyzed for unique mesenchymal elements, perhaps analogous to the CAFs found in the tumor stroma. For instance, there is evidence that cells isolated from RA tissues eroding cartilage have a distinctive morphology and features of both FLSs and chondrocytes (pannocytes) 99100. They also are oligoclonal, whereas non-erosion FLSs are polyclonal 101. Might pannocytes have a different profile of chemokines and tumor suppressor genes?

With these caveats in mind, several recent studies should be considered. Evidence for genetic heterogeneity of FLSs obtained from individual RA patients was described by Kasperkovitz and colleagues 75. Employing gene arrays they identified two distinctive patterns in multipassaged RA synovial fibroblasts. The FLSs from highly inflamed RA synovium had significant up-regulation of genes associated with immune activity and high expression signatures of several genes in the TGF-β signaling pathway, as seen in myofibroblasts. The molecular features that identified myofibroblasts were confirmed by immuno-histochemistry of cultured FLSs and in companion synovial tissues, which makes it less likely that the findings were artifactual. Material from a second group of RA patients with little inflammatory synovitis had a gene profile consistent with low immune activity and increase in the insulin-like growth factor/insulin-like growth factor binding protein pathway. The idea of two separate pathogenic mechanisms in RA synovitis – one T cell mediated and the other a T cell independent (stromal?) pathway – has been proposed before 69. But linking the immune (T cell) activated pathway to TGF-β (which is associated with myofibroblast formation and stromal activation) is counter-intuitive, given that TGF-β is known to suppress a number of T lymphocyte functions 72. Perhaps differences in stroma are dictating the type of cells found in the joint?

Evidence in support of differences in the stromal elements in some RA patients comes from an analysis of synovial tissue samples from 17 early RA patients, obtained prior to disease-modifying anti-rheumatic drug (DMARD) therapy. These were examined by immunohistochemistry and microarrays 102. In both whole tissues and FLS cultures, two clearly separate groups were identified. Samples from 10 patients had very high co-expression of genes encoding MMP1 and MMP3 and a collection of nuclear factor κB genes. Increased expression of these genes was not identified in tissues from the other seven patients. Other MMPs, cytokine, chemokine, and T and B cell related genes were similar in the two sets of patients and no other clinical, serological, or histological features distinguished them. Long-term follow-up will be needed to see if the two groups have a different outcome.

The idea that cells behave in a context-dependent manner and that stromal elements can modify the behavior of carcinomas (described above) is provocative. Can this be translated to RA synovium?

As noted by Fassbender, there is considerable histological evidence of stromal abnormalities 64. Significant differences in cell cycle related gene products were found in synovial stroma and lining cells in tissues from RA patients with active compared to quiescent disease 103. RA synovial tissues obtained by arthroscopic biopsy before and 10 months after adalimumab treatment were analyzed by western blot and histochemistry with antibodies to phosphorylated Smad1-5-8.9 73. A variety of p-Smad positive mesenchymal appearing cells were identified in synovial sections located around blood vessels (pericytes?) and in the stroma. The mononuclear cells in the pretreatment biopsies were reduced after anti-TNF therapy, but Smad staining was unchanged. Joint inflammation usually recurs soon after stopping anti-TNF agents. Is that because even after anti-inflammatory treatment a unique stromal environment remains, which attracts and retains inflammatory and immunological cells; a view championed by Buckley and Salmon 104? If this were the case, then therapies that modify the mesenchymal elements of the synovium will be needed.

This review is meant to introduce the rheumatological community to a rapidly emerging area of great biological and medical interest. References were not selected for the cognoscenti and are not comprehensive. Rather they were chosen to stimulate the reader unfamiliar with this area of inquiry. Thus, many are recent reviews or commentaries. Only time will tell how these concepts of the stroma and EMT will influence future thinking about the pathogenesis and treatment of rheumatic diseases. But new viewpoints are always worth considering, for as John Maynard Keynes famously said, "the difficulty lies not so much in developing new ideas, as in escaping from the old ones."

αSMA = alpha smooth muscle actin; BMP = bone morphogenic protein; CAF = cancer associated fibroblast; ECM = extracellular matrix; EMT = epithelial-mesenchymal transition; FLS = fibroblast-like synoviocyte; FSP-1 = fibroblast specific protein 1; MMP = matrix metalloproteinase; MPC = mesenchymal progenitor cell; MSC = mesenchymal stem cell; RA = rheumatoid arthritis; RTE = renal tubular epithelium; SDF = stromal derived factor; SSc = systemic sclerosis; TGF = transforming growth factor; TNF = tumor necrosis factor.

The authors declare that they have no competing interests.