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In this issue of Rheumatology, Carole Galligan and co-authors [1] present a study that detects a specific cell population, fibrocytes, in the serum of patients with RA and in healthy controls. Fibrocytes are rare cells (1–2% of the leucocytes in healthy individuals) that share surface characteristics of both leucocytes and mesenchymal cells [2]. Previous studies show that fibrocytes can function as immune cells and also have properties of mesenchymal stem cells [3]. In addition, this study also shows that the fibrocytes in RA have an activated profile that detects different phosphorylated molecules in the mitogen activated protein kinase (MAPK), and signal transducers and activators of transcription (STAT) pathways. The total number of circulating fibrocytes, however, was not different between the control and RA groups. The data contribute to our understanding of the role of mesenchymal cells in the pathogenesis of RA. In a joint affected by RA, the synovium undergoes dramatic changes. It transforms from a quiescent tissue with nutritional and homeostatic properties into an intense battleground with ongoing immune and inflammatory reactions, cell accumulation, proliferation and transformation, and has a key role in cartilage and bone destruction, leading to loss of joint function. The role of classic immune and inflammatory cells such as macrophages, T-, Band dendritic cells have been studied extensively, and successful therapies that target these cells types or some of the key cytokines that they produce have been introduced over the past decade. In parallel, further research into the mesenchymal cell populations in the synovium, in particular, the so-called synovial fibroblastlike synovial cell (FLS) has led to new concepts in RA [4]. The FLS population is not only a major player in tissue destruction in RA but also contains cells that have in vitro and in vivo characteristics of mesenchymal stem cells capable of differentiating into cartilage, bone, fat or muscle [5]. In addition, one study highlighted the immune-modulating properties of mesenchymal (stem) cells [6]. The definition and characterization of the cell types in the mesenchymal population are still ongoing. FLS can be considered to be a group of cells; some of which have the characteristics of mesenchymal stem cells but others may not. Fibrocytes, found in peripheral blood, may migrate to the synovium and become part of the FLS population. The specific identification and isolation of these cells types from the synovium are still a major challenge. Most attention has been paid to the role of FLS in pannus tissue, because effector cells produce tissuedestructive enzymes such as MMPs and stimulate the differentiation and activation of osteoclasts through the receptor of nuclear factor kappa B (RANK) system. The increased number of cells in pannus tissue contrasts with the relatively low number of mitotic cells in the tissue [7]. This observation stimulated Galligan et al. [1] to study the role of circulating fibroblast-like cells in RA and hypothesize that such a cell population can migrate into the RA synovium. Multi-colour flow cytometry is introduced as a method to adequately phenotype fibrocytes from peripheral blood, as these cells are rare and therefore complex to detect. Current flow cytometry approaches allow the concurrent detection of surface markers and intracellular markers. Moreover, detection of phosphorylated proteins also allows visualization of activated signalling pathways. In an attempt to corroborate these findings in a more controlled setting, similar cells were detected with CIA, a well-known model of RA. In this model, an increase in activated fibrocytes was found in the early, pre-clinical disease stages. Of specific interest, cells with phenotypical characteristics of fibrocytes, both CD45-positive, a common leucocyte marker and a-smooth muscle actin-postive (aSMA), a marker for myofibroblasts, were found in affected joints of mice. The authors propose that fibrocytes might contribute to the mesenchymal cell population in the arthritic synovium and thereby influence the disease process. Previous studies have suggested that circulating or migrating mesenchymal cells have a role in joint diseases [8, 9]. In particular, bone morphogenetic protein (BMP) receptorpositive cells originating from the bone marrow have been identified in patients with RA and in mice with CIA [8, 9]. Of interest, the migration of such cells from the bone marrow into the synovial tissue in CIA preceded the onset of clinical symptoms and the development of the hallmark histological features of the disease. Verschueren and colleagues [10] showed that BMP-responsive cells are found in different synovial compartments in RA patients and some of these cells are also aSMA positive. All these data provide experimental support for an evolving hypothesis about the different roles of mesenchymal cell populations in the joint. Increasing evidence supports a key role for these cells in defining the stromal code, which interacts with immune cells in different ways. Specific cell types may be attracted to the synovium, whereas other signals may be responsible for retaining specific cell types [4]. Some of

Activated fibrocytes: Circulating cells that populate the arthritic synovium?