Date of Award

2-2014

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

First Advisor

Thomas Rothstein

Abstract

Osteopontin (OPN) is a pleomorphic cytokine expressed in several tissues including macrophages, dendritic cells, T cells and B cells. OPN is implicated in diverse physiological and pathological processes, and is elevated in autoimmunity. Sjogren's syndrome (SS) is an autoimmune disease characterized by lymphocytic infiltration of exocrine glands and anti-Ro (SSA) and/or anti-La (SSB) autoantibodies. SS primarily affects women, and is seen in two forms. The primary form (pSS) affects exocrine glands, while the secondary form (sSS) occurs with other autoimmune diseases. We hypothesized OPN is elevated and pathogenic in SS. We found increased Opn in serum and salivary tissue in a well-established SS model. In addition, we demonstrated OPN co-localized with lymphocytes in human pSS minor salivary glands. We examined transgenic mice that over-express Opn in B cells driven by the immunoglobulin enhancer/SV40 promoter to determine whether OPN contributes to SS-like pathology. Female Opn transgenic mice showed more severe disease than males that included lymphocytic infiltrates in salivary and lacrimal tissue, reduced saliva production, and increased anti-Ro antibodies in the serum. Taken together, these data support a role for OPN in SS pathogenesis. Notably, our findings identify a new animal model of spontaneous pSS that recapitulates the human disease in terms of sex predilection, histopathology, salivary deficits, and autoantibody production and will facilitate the study of this debilitating disease.

Several studies have proposed correlation between OPN and obesity as well as obesity-induced conditions such as non-alcoholic fatty liver disease (NAFLD), which comprises a spectrum of hepatic disorders (1, 2). We observed that Opn transgenic mice were noticeably overweight compared to wild type (WT) control mice. Therefore we hypothesized that the pro-inflammatory environment in the Opn transgenic mice promotes an obese profile. We investigated the role of lymphocyte specific Opn overexpression with weight gain and determined the related phenotypic changes together with mechanisms involved. Our results demonstrate that Opn transgenic mice are considerably overweight compared to WT control mice and this difference in weight is more pronounced in the male than in the female Opn transgenic mice. These mice express a metabolic profile similar to human obese subjects such as an increase in serum insulin and leptin levels and contain excess levels of fat in the liver. Therefore, we propose that an overexpression of Opn in lymphocytes alone, as in our Opn transgenic mice, is sufficient to cause an increase in weight in conjunction with obesity-associated changes in the liver.

Our data inferring a role for OPN in SS and obesity suggests the need to understand how OPN expression is regulated. In preliminary studies with primary B cells we identified critical AP-1 binding sites. Overall this work greatly extends the range of illness known to be affected by OPN and begins the process of elucidating its regulation.

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