Plasma Osteopontin Modulates Chronic Restraint Stress-Induced Thymus Atrophy by Regulating Stress Hormones: Inhibition by an Anti-Osteopontin Monoclonal Antibody

Abstract

Osteopontin (OPN) is a cytokine implicated in mediating responses to certain stressors, including mechanical, oxidative, and cellular stress. However, the involvement of OPN in responding to other physical and psychological stress is largely unexplored. Our previous research revealed that OPN is critical for hind limb-unloading induced lymphoid organ atrophy through modulation of corticosteroid production. In this study, we demonstrate that OPN−/− mice are resistant to chronic restraint stress (CRS)-induced lymphoid (largely thymus) organ atrophy; additionally, the stress-induced up-regulation of corticosterone production is significantly reduced in OPN−/− mice. Underlying this observation is the fact that normal adrenocorticotropic hormone levels are substantially reduced in the OPN−/− mice. Our data demonstrate both that injection of OPN into OPN-deficient mice enhances the CRS-induced lymphoid organ atrophy and that injection of a specific anti-OPN mAb (2C5) into wild-type mice ameliorates the CRS-induced organ atrophy; changes in corticosterone levels were also partially reversed. These studies reveal that circulating OPN plays a significant role in the regulation of the hypothalamus-pituitary-adrenal axis hormones and that it augments CRS-induced organ atrophy.

Pathogenesis of adolescent idiopathic scoliosis in girls - a double neuro-osseous theory involving disharmony between two nervous systems, somatic and autonomic expressed in the spine and trunk: possible dependency on sympathetic nervous system and hormones with implications for medical therapy

“…May this be, not because OPN is essential for scoliosis pathogenesis, but because OPN deficiency reduces stress reactions in mice [260]?…”

“…For, in mice, circulating OPN plays a significant role in the body's reaction to stress by regulating hormones of the hypothalamic-pituitary-adrenal axis (HPA) [260] modulated by leptin which activates the JAK/STAT pathway. Stressors cause less up-regulation of the stress hormone corticosterone in OPN-deficient mice [260].…”

Toll-Like Receptor 9 Is Required for Chronic Stress-Induced Immune Suppression

“…It has been shown that chronic stress-induced alterations of immune responses could result from increased cell death and apoptosis or decreased cell proliferation [4,5,14]. Physical or psychological stress promotes stress hormone and neuronal transmitters [15,32,33]. However, the role of TLR9 in stress-mediated immune responses has remained unexplored.…”

“…However, the mechanisms by which TLR9 participate in chronic stress-induced immune suppression are unexplored. To define the role of immune responses and stress hormones in mice, chronic restraint stress murine model has been widely employed [5,15]. We utilized this model to investigate TLR9-mediated immune responses as evaluated by alterations in the number of apoptosis, corticosterone production, and the balance of Th1 and Th2 cytokines.…”

Disruption of the Thymic Microenvironment Is Associated with Thymic Involution of Transitional Cell Cancer

“…The relevance in thymic atrophy of increased corticosteroid levels which directly induce apoptosis in developing thymocytes is well documented [34,35,36]. Recently, it was described that glucocorticoids affect the thymic epithelial network, reducing the expression of the transcription factor FoxN1 and its regulator Wnt-4 [37].…”