Temporomandibular Joint Involvement in Mice with Proteoglycan Induced Arthritis and the Role of TSG-6 in Proteoglycan Induced Arthritis

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The temporomandubular joint (TMJ) is a ginglymoarthrodial joint where the ball is formed by the mandibular condyle whilst the socket is provided by the glenoid fossa on the temporal bone. TMJ syndrome or temporomandibular joint disorder (TMD) is an embracing clinical term containing muscle and articular disorders which is multifactorial in origin. Symptoms of TMD can be pain around the head, face and neck region and it can be associated with certain types of headaches. One of the most common cause for TMJ pain is arthritis. Degenerative changes in the articular cartilage, meniscus displacement and rheumatoid arthritis can are all known to cause arthritis in this joint. Osteoarthritis is a degenerative joint disease. It is the most common joint disease characterized by progressive softening and disintegration of the articular cartilage. Rheumatoid arthritis (RA) is an autoimmune disease with a 0.5-1% prevalence in the human population. It is characterized by inflammation in the synovial joints including the TMJ. In order to investigate the problem, multiple animal models of inflammatory TMJ conditions have been developed. Most of these models are centred on direct injection of antigen or adjuvant into the TMJ. PGIA is a murine model of RA that has multiple common characteristics with human RA including the clinical picture, radiological changes, serum cytokines, autoantibodies (RF) and anti-citrullinated protein antibodies. Although the peripheral joint and spine affected by PGIA have been thoroughly investigated, the also synovial TMJ has not yet been examined. For this reason we used BALB/c mice with PGIA to investigate the involvement of TMJ in the early and late phases of the disease. TSG-6 has been shown to function as an anti-inflammatory and chrondroprotective protein in response to growth factors and pro-inflammatory mediators in many animal arthritis and inflammatory models like recombinant murine TSG-6 (rmTSG-6) model. It has also been detected in the synovial fluids and tissues of patients with RA in the affected joints. Studies investigating TSG-6 suggest that through multiple pathways, it has an important role in the resolution of inflammation. In the studies included in my thesis I have tried to find the answers for the following questions: Study 1: • Are there pathologic changes in the TMJ in mice with PGIA? • If there are, do these changes resemble RA or OA? Study 2: • What is the function of TSG-6 in mice with PGIA? • Is there a way to find a sensitive detection method to measure the concentrations of TSG-6 from BALB/c mice with PGIA? • Do TSG-6 levels correlate with the severity of arthritis in mice with PGIA? • Do TSG-6 levels correlate with immune responses? • Is TSG-6 expressed in any tissues or cells during the development of PGIA? In order to find the answers for the above questions I generated proteoglycan induced arthritis in genetically susceptible BALB/c mice. I harvested their TMJ and joint tissues and cartilage for histological and immunohistochemical analyses and for RNA isolation for quantitative PCR. I measured cytokine levels during the acute and chronic phase of the disease in arthritic and non-arthritic animals. I also helped to develop a highly sensitive detection system for TSG-6 to use in PGIA induced arthritis. My findings are as follows: • There are pathologic changes in the temporomandibular joint in mice with PGIA and these changes resemble OA rather than RA. • I described a simple expression system for high yield production of functionally active rmTSG-6. • Serum TSG-6 concentrations correlate with arthritis severity and serum levels of proinflammatory cytokines • but not with immune responses in PGIA • The strongest expression of TSG-6 is in mast cells in the inflamed tissues • The likely role of TSG-6 is that it modulates mast cell function via its interactions with key components of secretory granules.

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Aggrecan, Animal model, Antigen, Cartilage, Cytokine, Extracellular Matrix, Heparin, Hyaluronate, Inflammation, Mast Cell, Mouse, Osteoarthritis, Proteoglycan-induced arthritis, Rheumatoid arthritis, Temporomandibular joint, TSG-6
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