This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Juvenile Idiopathic Arthritis (JIA) is the most common rheumatic disease of childhood. Although disease course is important in the outcome for patients, reliable predictors of disease course have not been identified. Additionally, the pathogenesis of this disease has yet to be elucidated. Our first hypothesis is that gene expression profiles of fibroblast-like synoviocytes (FLS) from the joints of children with JIA reflect intrinsic differences in synovial pathology early in disease which dictate disease course.
We aim to identify synovial biomarkers capable of predicting disease course in JIA. Based on preliminary work, our second hypothesis is that dysregulation of the TGFb signaling pathway is central to the pathogenesis of JIA. Although significant work has been done on FLS from the joints of adult patients with rheumatoid arthritis (RA), investigations of these critical cells are lacking in children. We are in the unique position of having a rich repository of synovial fluid and tissue from which to obtain samples. We will use gene expression profiling of cultured FLS to identify differences in synovial biology in patients with differing disease courses. We will use these data to generate predictive synovial biomarkers to allow for determination of course early in disease. In addition, we will investigate the causal significance in the role of altered expression of members of the TGFb signaling pathway in the pathogenesis of JIA. Our preliminary studies revealed altered levels of members of the TGFb signaling pathways, including bone morphogenetic protein 4 (BMP4), in the FLS of patients with JIA when compared with controls. To further understand the relevance of these perturbations, we will examine the ability of FLS from JIA to promote chondrogenesis and osteogenesis using co-culture with cell lines known to differentiate along chondrocyte and osteoblast lineages upon stimulation with BMP4. Goals of this project are to identify predictive synovial biomarkers that can be used to anticipate course early in disease in JIA. This will allow physicians to provide accurate information regarding prognoses and help guide treatment decisions. Early prediction of children likely to develop progressive disease would allow earlier initiation of course-altering therapy to prevent joint destruction and disability. By defining the global transcriptional response of the synoviocyte in JIA, we will be much closer to understanding the underlying pathogenesis of this disease. Demonstrating the role of the TGFb signaling pathway in the pathogenesis of JIA has implications for future treatment options.
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