The Toll-like receptor pathway in Meniscal Injury and Osteoarthritis

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Candidate: Carla R. Scanzello, MD PhD is an Assistant Professor of Medicine at Rush University Medical Center (Chicago). She has recently been recruited there to the Faculty of the Department of Medicine (Section of Rheumatology), having completed her Fellowship in Rheumatology at the Hospital for Special Surgery in June 2008. She has a particular interest in the role that inflammation plays in osteoarthritis (OA) pathogenesis, which she began to pursue in earnest as a Rheumatology Fellow. During her Fellowship she designed a research project to characterize synovial cell populations and inflammatory mediators in the synovium of OA patients. Since most previously published work on inflammation in OA had focused on patients with advanced disease, her project was designed to characterize the inflammatory reaction in patients with well-defined early disease. This work has resulted in multiple manuscripts (one published, one accepted, and one under preparation), and observations from this project have led to the hypothesis addressed in this application. This award will allow Dr. Scanzello to gain further training in specific laboratory techniques used in the fields of both Immunology and Cartilage Biochemistry, in order to gain full independence as an investigator. She is committed to pursuing a translational research career working at the intersection between matrix biochemistry and immunology as it applies to OA pathophysiology, with the ultimate goal of developing novel therapies for this common disease in its early stages. Environment: Dr. Scanzello has recently accepted a tenure-track position in pursuit of her goal of becoming an independent investigator. This position allows her the access to resources she will need to accomplish the goals of this proposal. Necessary resources she will have access to include faculty expertise and support, suitable mentorship, accomplished clinical and research collaborators, adequate laboratory space and equipment, and access to appropriate patient populations via the Orthopedics Department. 75% of her time is dedicated for research, with protection from excessive teaching and administrative requirements. The Section of Rheumatology is dedicated to support her efforts to gain independence, and is supporting a research technician to help her accomplish her goals. The expectation is that she will establish a research program with focus on inflammatory pathway activation in Osteoarthritis, an area of research that is just beginning to emerge. Research: Once considered primarily a degenerative cartilage condition, we now understand that the entire joint (including bone, synovium, menisci, and periarticular soft tissues) is altered in OA. Perhaps the least understood pathologic change that occurs in the OA joint is the inflammation within the synovial membrane (SM). This inflammation can be a source pain3, and may stimulate progression of joint degeneration in certain patients4. However the precise inflammatory stimuli in the joint and the downstream mediators remain unknown. We recently demonstrated that the pro-inflammatory cytokine interleukin-15 (IL-15) is detectable in the joints of most patients with knee OA seeking surgical intervention for both early and advanced disease7. This cytokine is known to be produced following activation of certain innate immune receptors, the Toll-like receptors (TLRs), implicating their activity in OA. IL-15 has not been documented in OA previously, but its presence implicates activation of TLRs. Furthermore, IL-15 has functions that may be relevant to OA pathogenesis including induction of enzymatic mediators10,11implicated in disease. Therefore, we plan to test the hypothesis that TLR pathway activation leads to induction of IL-15 by joint tissues in the setting of meniscal injury and early OA, and furthermore that IL-15 contributes to the synovial response and cartilage degradation characteristic of OA. We will test this hypothesis through the following specific aims: Specific Aim 1: To demonstrate that TLR-2 or TLR-4 ligands are produced in patients with early knee OA and mensical injury and stimulate IL-15 production. Specific Aim 2: To demonstrate a role for HA oligosaccharides and TLR-activation in IL-15 production by cells and tissues relevant to joint pathology. Specific Aim 3: To establish the action of IL-15 on cartilage, synovium and meniscal tissue. Specific Aim 4: To verify that IL-15 and TLR activation play central roles in OA pathogenensis in a murine model of OA. We hope that these investigations lead to better understanding of the stimulating factors and consequences of a specific inflammatory pathway in early OA, and ultimately to development of novel therapeutics to interfere with this pathway. As we currently have no interventions for early OA that impact disease progression, defining important pathways in early disease is essential.