Search

Rheumatoid arthritis is characterised by a progressive, intermittent inflammation at the synovial membrane, which ultimately leads to the destruction of the synovial joint. The synovial membrane as the joint capsule's inner layer is lined with fibroblast-like synoviocytes that are the key player supporting persistent arthritis leading to bone erosion and cartilage destruction. While microfluidic models that model molecular aspects of bone erosion between bone-derived cells and synoviocytes have been established, RA's synovial-chondral axis has not yet been realised using a microfluidic 3D model based on human patient in vitro cultures. Consequently, we established a chip-based three-dimensional tissue coculture model that simulates the reciprocal cross talk between individual synovial and chondral organoids. When co-cultivated with synovial organoids, we could demonstrate that chondral organoids induce a higher degree of cartilage physiology and architecture and show differential cytokine response compared to their respective monocultures highlighting the importance of reciprocal tissue-level cross talk in the modelling of arthritic diseases.

The theory of mental models allows modal truth values (‘possibly true and possibly false’) and counterfactual truth values (‘true but it could have been false’), which are outside standard logics. Naive individuals have the intuition that the disjunction, ‘You arrived at Preston or at Crewe,’ is true if you arrived at Preston, but their deliberations consider the status of the alternative destination. If this counterfactual possibility is false, e.g., the road to Crewe is blocked, they are likely to select a modal truth value (in Experiment 1), or a counterfactual truth value (in Experiment 2). The results are pertinent to claims that cognition cannot be algorithmic (as Gödel argued on the grounds that consistent formal systems cannot prove truths that mathematicians grasp about the arithmetic of natural numbers). Human thinking, however, differs from formal logics: it relies on semantic algorithms that can evaluate truth and falsity.

Fibroblast-like synoviocytes (FLS) are major contributors to joint inflammation in rheumatoid arthritis (RA). Forkhead box O 3 (FOXO3) perturbations in immune cells are increasingly linked to RA pathogenesis. Here, we show that FOXO3 is distinctly inactivated/phosphorylated in the FLS of rheumatoid synovitis. In vitro, stimulation of FLS with tumor necrosis factor-alpha α (TNFα) induced a rapid and sustained inactivation of FOXO3. mRNA profiling revealed that the inactivation of FOXO3 is important for the sustained pro-inflammatory interferon response to TNFα (CXCL9, CXCL10, CXCL11, and TNFSF18). Mechanistically, our studies demonstrate that the inactivation of FOXO3 results from TNF-induced downregulation of phosphoinositide-3-kinase-interacting protein 1 (PIK3IP1). Thus, we identified FOXO3 and its modulator PIK3IP1 as a critical regulatory circuit for the inflammatory response of the resident mesenchymal cells to TNFα and contribute insight into how the synovial tissue brings about chronic inflammation that is driven by TNFα. Fibroblast-like synoviocytes (FLS) are major contributors to joint inflammation in rheumatoid arthritis (RA). Here, the authors identified a previously unknown signaling circuit that contributes to tumor necrosis factor (TNF)-induced activation of FLS. The authors show that FOXO3 and its modulator PIK3IP1 are crucial for the TNF-driven interferon (IFN) response in RA-FLS.

Rheumatoid arthritis is a chronic, systemic joint disease in which an autoimmune response translates into an inflammatory attack resulting in joint damage, disability and decreased quality of life. Despite recent introduction of therapeutic agents such as anti-TNFα, even the best current therapies fail to achieve disease remission in most arthritis patients. Therefore, research into the mechanisms governing the destructive inflammatory process in rheumatoid arthritis is of great importance and may reveal novel strategies for the therapeutic interventions. To gain deeper insight into its pathogensis, we have developed for the first time a three-dimensional synovium-on-a-chip system in order to monitor the onset and progression of inflammatory synovial tissue responses. In our study, patient-derived primary synovial organoids are cultivated on a single chip platform containing embedded organic-photodetector arrays for over a week in the absence and presence of tumor-necrosis-factor. Using a label-free and non-invasive optical light-scatter biosensing strategy inflammation-induced 3D tissue-level architectural changes were already detected after two days. We demonstrate that the integration of complex human synovial organ cultures in a lab-on-a-chip provides reproducible and reliable information on how systemic stress factors affect synovial tissue architectures.

Surgical nerve transfers lead to superior regeneration and specific muscular changes for potentially improved prosthesis control., Selective nerve transfers surgically rewire motor neurons and are used in extremity reconstruction to restore muscle function or to facilitate intuitive prosthetic control. We investigated the neurophysiological effects of rewiring motor axons originating from spinal motor neuron pools into target muscles with lower innervation ratio in a rat model. Following reinnervation, the target muscle’s force regenerated almost completely, with the motor unit population increasing to 116% in functional and 172% in histological assessments with subsequently smaller muscle units. Muscle fiber type populations transformed into the donor nerve’s original muscles. We thus demonstrate that axons of alternative spinal origin can hyper-reinnervate target muscles without loss of muscle force regeneration, but with a donor-specific shift in muscle fiber type. These results explain the excellent clinical outcomes following nerve transfers in neuromuscular reconstruction. They indicate that reinnervated muscles can provide an accurate bioscreen to display neural information of lost body parts for high-fidelity prosthetic control.

Introduction The synovium demonstrates a distinct cellular structure with a densely packed synovial lining layer that sits on top of a loosely organised sublining layer. In rheumatoid arthritis (RA), this tissue hosts the inflammatory reaction and undergoes drastic structural changes. We hypothesise that this inflammatory remodelling results in tissue dysfunction, thereby perpetuating the inflammatory process. To explore the relationship between tissue structure and function, we use a 3D human synovial organoid culture system to model healthy and diseased synovium. Methods FLS from RA patients were resuspended in Matrigel and cultured as 3D organoids for an extended period of time. This allows FLS to re-establish a synovial tissue-like structure. To mimic inflammation, 3D synovial organoids were challenged with TNF. A re-stimulation experiment was designed in which synovial organoids were exposed to TNF for 10 days, followed by a 3 day wash out phase. Thereafter, the organoids were re-stimulated with TNF. To prevent TNF-driven remodelling, Marimastat, a broad MMP inhibitor, was added during the first TNF stimulation. For selected experiments, synovial tissue-like structure was assessed by HE staining in paraffin embedded sections of synovial organoids. qPCR and RNA Seq were used in gene expression profiling. IL-6, IL-8 and MMP3 protein production was determined by ELISA. Results TNF-stimulated synovial organoids demonstrated lining layer hyperplasia and cellular condensation in the sublining layer. After TNF-stimulation, gene expression of MMP1, MMP3 and IL-6 and protein production of IL-6, IL-8 and MMP3 was upregulated. Upon re-stimulation of synovial organoids with TNF, protein levels of IL-6, IL-8 and MMP3 were significantly increased when compared to previous stimulations. In order to explore whether this effect is due to TNF-induced structural changes, tissue remodelling was blocked using Marimastat. IL-6 protein level was reduced in 21%. To further explore the increased TNF response upon re-stimulation, epigenetic mechanisms are currently being tested. Conclusions TNF stimulation has a direct effetc in synovial organoids function and structure. TNF-driven tissue remodelling is associated with an increased in IL-6, IL-8 and MMP3 expression response upon re-stimulation. Inhibition of TNF-induced remodelling partially prevents this effect. Additional epigenetic mechanisms may account for tissue memory. Disclosure of interest None declared

Introduction The synovium is primarily built by fibroblast-like-synoviocytes (FLS). In the healthy synovium FLS form a complex tissue network via long-distance intercellular connexions (nanotubes). Using a 3D synovial micromass culture system, our previous research demonstrated that FLS exchange cytoplasmic cargo, i.e. organelles like mitochondria, via transfer through direct cell-to-cell connexions. The adaptive synovial tissue response to inflammation (i.e. to TNFa) likely depends upon the concerted communication between FLS. Objectives To determine how the cellular organisation of the synovial tissue affects intercellular cargo exchange and how it changes under inflammatory conditions. Methods Human FLS were isolated from joint tissues after synovectomies; passaged FLS were used to generate 3D micromass cultures using Matrigel (BD). For ultrastructural 3D reconstruction ultrathin sections of fixed micromasses were cut with an ATUMtom for FE-SEM scanning, followed by alignment and reconstruction of individual cells with Fiji TrackEM. To compare unstimulated and TNF-stimulated micromass cultures, cells were dyed with Cell- and Mitotracker dyes (TF). Using confocal microscopy, micromass cultures were analysed for cellular organisation within the 3D sphere, cell volume of individual cells, cell-to-cell interconnectivity and cargo transfer between cells. Analyses of the 3D confocal imaging data were done in Bitplane Imaris. Results SEM 3D reconstruction of synovial micromass tissue revealed that FLS are compartmentalised, and thus, much larger and extended than expected. Thin membrane tubes not only connect different cells but also compartments of the same cell. Additionally, one nanotube may provide a link to several other cells and these connexions are in general separated by membranes. Treatment of micromasses with TNFa resulted in cellular condensation, reduced cell volume as well as diminished cellular connectivitiy when compared to unstimulated micromasses. In particular, the abundance of interconnecting nanotubes was significantly attenuated. The mitochondrial transfer rate increased as FLS clustered upon TNFa stimulation. Conclusions TNFa directs FLS cellular re-organisation that is associated with increased intercellular transfer of mitochondria. These studies may provide insight into the concerted cooperation of FLS that is likely critical for the adaptive synovial response to inflammation. Disclosure of interest None declared

Background Emerging evidence suggests that fibroblast-like synoviocytes (FLS) are key effector cells in rheumatoid arthritis (RA) and research into the mechanisms defining FLS activity in RA indicate that cytokines secreted by leukocytes play a crucial role. Nevertheless, the contribution of IFNγ, which is increased in rheumatoid synovitis, to the inflammatory synovial tissue reaction is not known. Objectives To explore the function of the T-cell cytokine IFNγ for mesenchymal tissue remodeling in RA, and to determine whether IFNγ-signaling controls the invasive potential of FLS. Methods To assess architectural responses, FLS were cultured in three-dimensional micromasses. FLS motility was analyzed in migration-, spreading- and invasion assays. Signaling events relevant to cellular motility were defined by western blots. Baricitinb and siRNA pools were used to suppress Janus Kinase (JAK) functions. Results Histological analyses of micromasses revealed unique effects of IFNγ on FLS shape and tissue organization. This was consistent with accelerated migration, pronounced actin and focal adhesion (FA) re-organization upon IFNγ stimulation. Since actin and FA dynamics and, thus, cell motility are integrated by the focal adhesion kinase (FAK), we next analyzed its activity. Indeed, IFNγ stimulation induced the phosphorylation of FAK-Y925, a phosphosite implicated in FAK-mediated cell migration. siRNA knockdown of JAK2, but not JAK1, abrogated FAK activation by IFNγ. Correspondingly, IFNγ-inudced FAK activation and invasion of FLS was abrogated by the JAK-inhibitor baricitinib. Conclusions Our study contributes insight into the synovial response to IFNγ and reveals JAK2 as a potential therapeutic target for FLS-mediated joint destruction in arthritis, especially in RA. Disclosure of Interest None declared

Social learning is considered one of the hallmarks of cognition. Observers learn from demonstrators that a particular behavior pattern leads to a specific consequence or outcome, which may be either positive or negative. In the last few years, social learning has been studied in a variety of taxa including birds and bony fish. To date, there are few studies demonstrating learning processes in cartilaginous fish. Our study shows that the cartilaginous fish freshwater stingrays (Potamotrygon falkneri) are capable of social learning and isolates the processes involved. Using a task that required animals to learn to remove a food reward from a tube, we found that observers needed significantly (P

Objectives The aim was to explore the function of the T-cell cytokine IFNγ for mesenchymal tissue remodelling in RA and to determine whether IFNγ signalling controls the invasive potential of fibroblast-like synoviocytes (FLS). Methods To assess architectural responses, FLS were cultured in three-dimensional micromasses. FLS motility was analysed in migration and invasion assays. Signalling events relevant to cellular motility were defined by western blots. Baricitinib and small interfering RNA pools were used to suppress Janus kinase (JAK) functions. Results Histological analyses of micromasses revealed unique effects of IFNγ on FLS shape and tissue organization. This was consistent with accelerated migration upon IFNγ stimulation. Given that cell shape and cell motility are under the control of the focal adhesion kinase (FAK), we next analysed its activity. Indeed, IFNγ stimulation induced the phosphorylation of FAK-Y925, a phosphosite implicated in FAK-mediated cell migration. Small interfering RNA knockdown of JAK2, but not JAK1, substantially abrogated FAK activation by IFNγ. Correspondingly, IFNγ-induced FAK activation and invasion of FLS was abrogated by the JAK inhibitor, baricitinib. Conclusion Our study contributes insight into the synovial response to IFNγ and reveals JAK2 as a potential therapeutic target for FLS-mediated joint destruction in arthritis, especially in RA.

PURPOSE To explore the utility of multimodal microscopy as a noninvasive tool to assess corneal collagen cross-linking (CXL) efficacy, we investigated the correlation between riboflavin (RF) axial profile, second harmonic generation (SHG) imaging, and histological/biochemical changes of human corneas after RF-ultraviolet A (UVA)-catalyzed CXL. METHODS De-epithelialized human corneoscleral tissues were imaged by confocal and multiphoton microscopy to study RF tissue diffusion profile and SHG-based roughness index (Rq) after CXL. We installed 0.1% RF for 5, 10, and 20 minutes, respectively, followed by UVA irradiation, while dextran drug vehicle-treated corneas served as controls. Masson's trichrome staining and collagenase digestion assay were employed to assess ultrastructural modifications of collagen lamellae and bioenzymatic strength following RF-UVA CXL. RESULTS Stromal absorption of RF was significantly higher in 20 minutes compared with 5- and 10-minute drug instillations. The roughness index of SHG images was reduced after RF-UVA CXL at all RF instillation time points compared with dextran controls. Interestingly, correlation between axial profiles of RF dosage and Rq index was only observed in 10- and 20-minute RF instillations (R(2) = 0.13 and 0.28, respectively, all P < 0.05), but not in the 5-minute group. Masson's trichrome staining revealed collagen fibril compaction in cross-linked corneas in an RF dose-dependent manner. Collagenase digestion assay showed significantly increased biochemical strength by higher RF doses in cross-linked corneas. CONCLUSIONS Intrastromal RF distribution profiles correlated with histological and functional property changes in RF-UVA cross-linked corneas. A riboflavin-defined threshold further determined the sensitivity of SHG imaging as a noninvasive imaging modality to assess the efficacy of RF-UVA CXL.

Neutrophilic granulocytes and monocytes (granulomonocytic cells; GMC) drive the inflammatory process at the earliest stages of rheumatoid arthritis (RA). The migratory behavior and functional properties of GMC within the synovial tissue are, however, only incompletely characterized. Here we have analyzed GMC in the murine collagen-induced arthritis (CIA) model of RA using multi-photon real time in vivo microscopy together with ex vivo analysis of GMC in tissue sections. GMC were abundant as soon as clinical arthritis was apparent. GMC were motile and migrated randomly through the synovial tissue. In addition, we observed the frequent formation of cell clusters consisting of both neutrophilic granulocytes and monocytes that actively contributed to the inflammatory process of arthritis. Treatment of animals with a single dose of prednisolone reduced the mean velocity of cell migration and diminished the overall immigration of GMC. In summary, our study shows that the combined application of real time in vivo microscopy together with elaborate static post-mortem analysis of GMC enables the description of dynamic migratory characteristics of GMC together with their precise location in a complex anatomical environment. Moreover, this approach is sensitive enough to detect subtle therapeutic effects within a very short period of time.

Objective The binding of abatacept (CTLA-4Ig) to the B7 ligands CD80 and CD86 prevents the engagement of CD28 on T cells and thereby prevents effector T cell activation. In addition, a direct effect of CTLA-4Ig on antigen-presenting cells (APCs) could contribute to the therapeutic effect. To further elucidate the mechanism of CTLA-4Ig, we performed phenotype and functional analyses of APCs in patients with rheumatoid arthritis (RA) before and after the initiation of CTLA-4Ig therapy. Methods Peripheral blood mononuclear cells were analyzed before and at 2 and 4 weeks after the initiation of CTLA-4Ig therapy. Proportions of APCs were determined by flow cytometry. CD14+ monocytes were further analyzed for the expression of costimulatory and adhesion molecules and for their transendothelial migratory capacity in vitro. In addition, CD14+ monocytes from healthy controls were analyzed for their migratory and spreading capacity. Results Proportions and absolute numbers of monocytes were significantly increased in RA patients treated with CTLA-4Ig. The expression of several adhesion molecules was significantly diminished. In addition, monocytes displayed a significant reduction in their endothelial adhesion and transendothelial migratory capacity upon treatment with CTLA-4Ig. Likewise, isolated monocytes from healthy controls revealed a significant reduction in their migratory and spreading activity after preincubation with CTLA-4Ig or anti-CD80 and anti-CD86 antibodies. Conclusion We describe direct effects of CTLA-4Ig therapy on phenotype and functional characteristics of monocytes in RA patients that might interfere with the migration of monocytes to the synovial tissue. This additional mechanism of CTLA-4Ig might contribute to the beneficial effects of CTLA-4Ig treatment in RA patients.

SummaryOctopuses are intelligent, soft-bodied animals with keen senses that perform reliably in a variety of visual and tactile learning tasks [1–6]. However, researchers have found them disappointing in that they consistently fail in operant tasks that require them to combine central nervous system reward information with visual and peripheral knowledge of the location of their arms [6–8]. Wells [6] claimed that in order to filter and integrate an abundance of multisensory inputs that might inform the animal of the position of a single arm, octopuses would need an exceptional computing mechanism, and “There is no evidence that such a system exists in Octopus, or in any other soft bodied animal.” Recent electrophysiological experiments, which found no clear somatotopic organization in the higher motor centers, support this claim [9]. We developed a three-choice maze that required an octopus to use a single arm to reach a visually marked goal compartment. Using this operant task, we show for the first time that Octopus vulgaris is capable of guiding a single arm in a complex movement to a location. Thus, we claim that octopuses can combine peripheral arm location information with visual input to control goal-directed complex movements.Video Abstract

We describe for the first time fluorescent virus-like particles decorated with biologically active mono- and multisubunit immune receptors of choice and the basic application of such fluorosomes (FSs) to visualize and target immune receptor-ligand interactions. For that purpose, human embryonic kidney (HEK)-293 cells were stably transfected with Moloney murine leukemia virus (MoMLV) matrix protein (MA) GFP fusion constructs. To produce FSs, interleukins (ILs), IL-receptors (IL-Rs), and costimulatory molecules were fused to the glycosyl phosphatidyl inositol anchor acceptor sequence of CD16b and coexpressed along with MoMLV group-specific antigen-polymerase (gag-pol) in MA::GFP+ HEK-293 cells. We show that IL-2 decorated but not control-decorated FSs specifically identify normal and malignant IL-2 receptor-positive (IL-2R+) lymphocytes by flow cytometry. In addition to cytokines and costimulatory molecules, FSs were also successfully decorated with the heterotrimeric IL-2Rs, allowing identification of IL-2+ target cells. Specificity of binding was proven by complete inhibition with nonlabeled, soluble ligands. Moreover, IL-2R FSs efficiently neutralized soluble IL-2 and thus induced unresponsiveness of T cells receiving full activation stimuli via T-cell antigen receptor and CD28. FSs are technically simple, multivalent tools for assessing and blocking mono- and multisubunit immune receptor-ligand interactions with natural constituents in a plasma membrane context.—Kueng, H. J., Manta, C., Haiderer, D., Leb, V. M., Schmetterer, K. G., Neunkirchner, A., Byrne, R. A., Scheinecker, C., Steinberger, P., Seed, B., Pickl, W. F. Fluorosomes: a convenient new reagent to detect and block multivalent and complex receptor-ligand interactions.

Testing the cognitive abilities of cartilaginous fishes is important in understanding the evolutionary origins of cognitive functions in higher vertebrates. We used five South American fresh water stingrays (Potamotrygon castexi) in a learning and problem-solving task. A tube test apparatus was developed to provide a simple but sophisticated procedure for testing cognitive abilities of aquatic animals. All five subjects quickly learned to use water as a tool to extract food from the testing apparatus. The experimental protocol, which gave the animals the opportunity of correcting a wrong visual cue decision, resulted in four out of five subjects correcting an error rather than making an initial right choice. One of five subjects reached 100% correct trials in the visual discrimination task. The ability to use water as an agent to extract food from the testing apparatus is a first indication of tool use in batoid fishes. Performance in the instrumental task of retrieving food from a novel testing apparatus and the rapid learning in the subsequent discrimination/error correction task shows that cartilaginous fish can be used to study the origins of cognitive functions in the vertebrate lineage.

Polymorphonuclear neutrophils (PMNs) participate in the initiation of rheumatoid arthritis (RA), but their precise role at the earliest stages of the synovial inflammatory response is only partially understood. We therefore analysed the initial steps of synovial inflammation in the mouse model of collagen-induced arthritis (CIA) with regard to the role of PMN. CIA was induced in C57/BL6 mice. Mice were tested for anti-CII serum antibodies by ELISA. Mice were killed on days 10 and 20 after the first immunisation before clinical …

In rheumatoid arthritis (RA), a systemic autoimmune response translates into an inflammatory attack on the synovium that yields the formation of an aggressive cell mass, called pannus, which invades into and destroys the articular cartilage. Cartilage destruction is primarily mediated by fibroblast-like synoviocytes (FLS). Among the pro-inflammatory mediators produced by infiltrating T cells, interferon γ (IFNγ) may contribute to FLS driven joint destruction. Of note, IFNγ elicits its effects via the JAK1/JAK2-Stat1 signaling pathway. To establish a role for IFNγ in the invasive potential of FLS, the authors used an in-vitro invasion assay (matrix-associated trans-epithelial resistance invasion-(MATRIN)-assay). Strikingly, FLS that were stimulated with IFNγ demonstrated a markedly increased invasive capacity when compared to un-stimulated FLS. Cell invasion involves several steps, including attachment to extracellular matrix (ECM), cell migration, and digestion of the ECM by proteases. As determined by qPCR, however, IFNγ did not up-regulate the expression of metalloproteinases (MMPs) by FLS. Therefore, the authors hypothesised that IFNγ directs FLS motility. Indeed, exposure of FLS to IFNγ resulted in their increased migratory activity as determined in Boyden chamber assays. Since cell motility is partly controlled by focal adhesion kinase (FAK), the authors next analysed whether or not IFNγ modulates FAK activity in FLS. Western blot analysis revealed that activation of the IFNγ-JAK1/2-Stat1 signaling cascade is associated with phosphorylation of FAK. As Stat1 deficient U3A cells similarly responded to IFNγ stimulation, activation of FAK was independent of Stat1. Instead, inhibition of JAK1/2 abrogated IFNγ induced activation of FAK in FLS, indicating that IFNγ regulates FAK activity through JAK1/2, but not Stat1. Importantly, inhibition of JAKs abrogated IFNγ induced invasive activity of FLS. These results confirm that JAK1/2 play a critical role in translating the signal induced by IFNγ to promote invasion in FLS. These studies suggest a role for IFNγ in the destructive mesenchymal tissue response to inflammation and may provide insight into FLS behavior and function in RA.

Background Granulomonocytic cells (GMC) drive the inflammatory process at the earliest stages of rheumatoid arthritis (RA). The migratory behavior and functional properties of GMC within the synovial tissue are, however, only incompletely understood. This tempted us to study GMC in the murine collagen induced arthritis (CIA) model of RA with the help of multi-photon real time in vivo microscopy together with the subsequent and sequential ex vivo analysis of GMC on tissue sections. Methods CIA was induced in LysM-EGFP C57BL/6 transgenic animals that carry the EGFP fluorescence protein under the lysozyme promoter. Individual joints were prepared by surgical microscopy in healthy control and in CIA subjects and EGFP + GMC were analysed by 2-photon laser microscopy over 2 h. One group of animals received one single dose (0.25 mg) of prednisolone intravenously before in vivo imaging. Afterwards, the animals were killed and cryo-, and paraffin sections were prepared for immunofluorescence and histomorphological analysis, respectively. Results GMC were barely detectable in healthy animals but were abundant in the synovial tissue as soon as clinical arthritis was apparent. GMC were motile and migrated randomly through the synovial tissue with a reduced mean velocity (2.75±1.17 µm/min) of as compared to healthy controls (3.11±1.51 µm/min; p high neutrophilic granulocytes and EGFP low monocytes. In addition EGFPl low F4/80 + TRAP + osteoclast precursor cells were occasionally observed at the synovial-bone junction and areas of bone erosions.Prednisolone treatment reduced the mean velocity of cell migration (2.19±1.06 µm/min; p Conclusion The combined application of real time in vivo microscopy together with elaborate static postmortem analysis of GMC enabled the description of dynamic migratory characteristics of GMC together with their precise allocation in a complex anatomical environment. Moreover, this approach was found sensitive enough to detect subtle therapeutic effects within a very short period of time.

Rheumatoid arthritis (RA) is the most common chronic inflammatory joint disease. In RA, a systemic autoimmune response translates into an inflammatory attack on the synovium that yields the formation of an aggressive cell mass called pannus which attaches to, encroaches over and destroys the articular cartilage. Cartilage destruction is mediated by fibroblast-like synoviocytes (FLS) which are the prevailing cell type of the …