Uniform TitleOsteopontin: role in immune regulation and stress responses
NameWang, Kathryn X. (author), Denhardt, David (chair), Werlen, Guy (internal member), Lenard, John (internal member), Shi, Yufang (outside member), Kusnecov, Alexander (outside member), Rutgers University, Graduate School - New Brunswick,
SubjectCell and Developmental Biology,
Second messengers (Biochemistry)
DescriptionOsteopontin (OPN) is a pluripotent soluble protein found in all body fluids and expressed in many tissues and cells. It stimulates signal transduction pathways via integrins and CD44 variants that regulate various cellular activities including the cell's interaction with extracellular matrix, cell survival and immune responses. OPN deficiency is linked to a reduced Th1 immune response in infectious diseases, autoimmunity and delayed type hypersensitivity. OPN is also involved in various physiological stress situations such as mechanical stress, oxidative stress and cellular stress. However, OPN's role in physical and psychological stress is largely unexplored.
In this dissertation, I used OPN-deficient mice to evaluate OPN's role in physical stress responses and to determine its influence on immune organ lymphocyte homeostasis in response to stress. Using a hindlimb-unloading (HU) stress model, I compared OPN-/- (knockout) mice with OPN+/+ mice subjected to HU for 3 days. Whereas OPN+/+ mice suffered a marked reduction of body weight and significant spleen and thymus atrophy, OPN-/- mice exhibited minor weight loss and much less spleen and thymus atrophy. The HU-induced lymphoid organ atrophy was the result of dramatically diminished numbers of T and B cells in the spleen and CD4+/CD8+ double-positive cells in the thymus of OPN+/+ mice but not in OPN-/- mice. Increased levels of corticosterone, which modulate lymphocyte activation responses and apoptosis during stress, were found only in OPN+/+ mice. Apoptotic cell death was evident in the spleen and thymus tissue of OPN+/+mice subjected to HU but not in OPN-/- mice and untreated controls.
In a different stress model, chronic restraint stress (CRS), I have demonstrated that OPN-deficient mice are resistant to CRS-induced lymphoid organ atrophy and unable to mount a significant up-regulation of corticosterone production in response to stress. Another HPA (Hypothalamus Pituitary Adrenal) axis hormone, ACTH, was also found to be unable to respond to stress challenge in the absence of OPN. Administration of soluble OPN into OPN-/- mice led to a further reduction of lymphoid organ mass in response to stress whereas administration of anti-OPN antibody 2C5 in wild type mice alleviated stress-induced organ atrophy. Taken together, these results indicate that OPN is critical in mediating stress-induced immune organ atrophy, likely through influencing the HPA axis hormone pathway.
NoteIncludes bibliographical references (p. 102-115).
CollectionGraduate School - New Brunswick Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.