BackgroundNuclear receptor 4A2 (NR4A2) is an orphan nuclear receptor and constitutively active transcription factor expressed at elevated levels in inflamed joint tissues from patients with arthritis. Inflammatory mediators rapidly and potently induce NR4A2 expression in resident joint cells and infiltrating immune cells. This receptor promotes synovial hyperplasia by increasing proliferation of synoviocytes and inducing transcription of matrix degrading enzymes and pro-inflammatory mediators. In order to further elucidate the molecular mechanisms of NR4A2, we conducted a gene expression screen to identify novel transcriptional targets of NR4A2 that may contribute to arthritis progression.MethodsNR4A2 was over-expressed in human synoviocytes by lentiviral transduction and gene expression changes were measured using qPCR arrays specific for inflammation, proliferation, adhesion, and migration pathways. Subsequent analysis focused on the most potently induced gene prolactin (PRL). Messenger RNA levels of PRL and PRL receptor (PRL-R) were measured by RT-qPCR and protein levels were measured by ELISA. PRL promoter studies were conducted in synoviocytes transiently transfected with NR4A2 and PRL reporter constructs. Molecular responses to PRL in synoviocytes were addressed using qPCR arrays specific for JAK/STAT signaling pathways.ResultsPRL was the most potently induced gene on the qPCR arrays, exhibiting a 68-fold increase in response to ectopic NR4A2. This gene encodes an immunomodulatory peptide hormone with roles in autoimmune diseases and inflammation. Induction of PRL mRNA and secreted protein by NR4A2 was confirmed in subsequent experiments, with increases of 300-fold and 18-fold respectively. Depletion of endogenous NR4A receptors with shRNA reduced basal and PGE2-induced PRL levels by 95%. At the transcriptional level, NR4A2 requires a functional DNA binding domain to transactivate the distal PRL promoter. Deletional analysis indicates that NR4A2 targets a region of the distal PRL promoter spanning −270 to -32 bp. In synoviocytes, recombinant PRL regulates several genes involved in inflammation, proliferation, and cell survival, suggesting that NR4A2 induced PRL may also impact these pathways and contribute to arthritis progression.ConclusionsThese results provide the first evidence for transcriptional regulation of the immunomodulatory peptide hormone PRL by NR4A2 in synoviocytes, and highlight a novel molecular pathway in inflammatory arthritis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12950-015-0059-2) contains supplementary material, which is available to authorized users.
High-resolution magnetic resonance imaging (MRI) has been used to visualise the changes that occur in both soft tissue and bone during antigen-induced, monoarticular arthritis (AIMA) of the rat knee. Extensive optimisation studies were performed in order to minimise the time of the experiments and to maximise both the signal-to-noise ratio and the contrast in the MR images. The study was cross-sectional rather than longitudinal and at each of the 13 time points studied during the progression of the disease, corresponding X-radiographs and histological sections were obtained. Interpretation of the spin echo MR images was aided by the use of chemical shift-selective imaging, magnetisation transfer contrast and relaxation time experiments, as well as by correlation with the histology and X-radiography data. The MR images clearly show invasion of the synovium by an inflammatory pannus which spreads over the articular cartilage and invades the bone, leading to erosion and later remodelling. Two distinct types of bony erosion were observed: focal erosions, especially at the margins of the joint, and subchondral erosions. It is concluded that MRI provides a sensitive, non-invasive method for investigating both early-stage inflammatory changes and late-stage bony changes in the knee joints of the arthritic rat.
High-resolution magnetic resonance imaging (MRI) was used to investigate antigen-induced monoarticular arthritis (AIMA) in the rat. In sagittal, spin-echo images of the knee, characteristic parallel bands, in the order dark-light-dark, were consistently observed 5-8 days after arthritis induction; the bands ran concentric with, and just beneath, the femoral and tibial articular surfaces. Concurrent radiology, histology and MRI (chemical shift-selective imaging and contrast enhancement with magnetisation transfer and gadolinium) established that the phenomenon reflected subchondral erosion, not artefact. The outer hypointense band corresponded to calcified cartilage underlying the articular surface. The central hyperintense band reflected inflammatory matrix displacing normal haematopoietic tissue immediately subchondrally; here, trabecular bone had mostly disappeared, but adjacent articular cartilage, although under attack and lacking proteoglycan, appeared structurally normal. The inner hypointense band reflected deeper, truncated trabeculae within inflammatory matrix, layered with pallisading osteoblast-like cells. This study exemplifies the power of MRI for revealing localised joint pathology non-invasively, and shows that rat AIMA shares many pathological features with arthritis in human beings.
Accessible summary There is a need for more voiced opinions from Special Olympic (SO) athletes in contemporary literature. Five SO athletes presented their own views on their experiences of participating in sport. SO athletes would welcome more autonomy, responsibility and roles in their everyday sporting participation. Implications for coaches and parents are presented as a consequence of sporting involvement. Abstract BackgroundIn the past, academic literature and research relating to the Special Olympics (SO) have focused mainly on the parents', professionals' and coaches' views, with some concentrating on the effects of SO on athletes' quality of life. Relatively little has concentrated on the athlete's own perspectives. Therefore, this study set out to examine the under‐researched area of SO athletes' opinions of taking part in sporting activities and their satisfaction during training and competition. Materials and MethodsFive athletes from one SO athletic club agreed to take part in the study. Thematic analysis was used for generating themes in relation to participants' responses. ResultsFour themes were identified: (a) platform for voice; (b) intense emotions; (c) social reasons to participate; and (d) nutrition, health and sport. ConclusionsSO athletes' views suggest the need for changes in practice during training and competition. Recommendations are made with the view to further support SO athletes' needs.
Arthritis is a group of over 100 musculoskeletal disorders affecting approximately 50 million adults in the US. In an effort to develop new drugs to treat arthritis, we are exploring the function of the orphan nuclear receptor 4A2 (NR4A2), a transcription factor over-expressed in inflamed joints. The transcriptional targets of NR4A2 include angiogenesis factors and matrix metalloproteinases (MMPs). NR4A2 appears to have a deleterious effect in synoviocytes by promoting tissue degradation, while in chondrocytes it seems to have a protective function. Previous work on human synoviocytes has shown NR4A2 to rise early in response to inflammation, leading us to hypothesize that NR4A2 may be a preliminary mediator of arthritis. To test this hypothesis in vivo, we studied NR4A2 expression patterns in two mouse models of RA: Antigen Induced Arthritis (AIA) and Serum Transfer Arthritis (STA). Tissue sections were obtained from healthy and arthritic mice at early, mid, and late time-points following induction. Joint cross-sections were examined via immunohistochemical staining, and NR4A2 positive cells were quantified in synovial and cartilage tissues. In the AIA model, NR4A2 protein levels peaked in synovium at day 10 of disease (mid stage, 50% positive) and declined later in disease. In cartilage, protein levels reached a maximum at day 8 (early stage, 70%) and subsequently declined as well. In contrast, NR4A2 was not expressed in the STA model, despite apparent joint degradation. NR4A2 has been shown to be expressed in STA arthritis by other researchers, so it is unknown why STA samples did not show NR4A2 expression in our experiment.
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