Date of Award

1-1-2011

Document Type

Campus Access Thesis

Department

Biomedical Science

First Advisor

Jennifer Nyland

Abstract

Matrix metalloproteases (MMPs) are critical to an array of homeostatic processes but have also been implicated in many pathological states. The roles they play in innate immunity, regulation of physical barriers such as the blood brain barrier, and the healing process are the same ones that contribute to their role in autoimmune disease. While MMPs are best known for being dysregulated in chronic disease states, they also have the ability to contribute to disease onset. There are highly specific regulatory differences among MMPs. This is how the proper MMP is transcribed, translated, and activated for a given situation. While some MMPs appear redundant, there are critical differences in each MMP's regulatory controls. These controls are involved in regulation of MMPs and may be easily disrupted through endogenous and exogenous factors. As such, the carefully orchestrated MMP cascade can also become misregulated and destructive. When the wrong MMP is activated or an MMP is expressed in the wrong amount, place, or time, this can result in damage or disease. These aspects of MMP regulation are part of what confers their ability to initiate, promote, and maintain autoimmune disease. The review illustrates the ways in which two MMPs, MMP-2 and MMP-9 of the gelatinase family, appear similar but are differentially regulated, have varied actions, and how they have different expression profiles in disease. First I will highlight how these MMPs are regulated. Subsequently, I will present how environmental exposures and hormonal influences can also influence these MMPs. Each way in which MMP levels can be altered has implications in autoimmune disease. The main goal of highlighting endogenous and exogenous regulators of MMPs is to illustrate the points of regulation in which MMPs may contribute to autoimmune disease. These are points that can also potentially be used for therapeutic intervention. I will also review several autoimmune diseases in which MMPs play multiple roles in pathology. The discussion of autoimmune diseases will cover autoimmune arthritic diseases (which include rheumatoid arthritis (RA), psoriatic arthritis, and juvenile idiopathic arthritis (JIA)), systemic lupus erythematosus (SLE), and multiple sclerosis (MS).

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