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Plasma Osteopontin Modulates Chronic Restraint Stress-Induced Thymus Atrophy by Regulating Stress Hormones: Inhibition by an Anti-Osteopontin Monoclonal Antibody¹

Kathryn X. Wang^*, Yufang F. Shi, Yacov Ron, Christian C. Kazanecki^* and David T. Denhardt^2,*,

^* Graduate Program in Cell and Developmental Biology and Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, Nelson Biological Laboratories, Piscataway, NJ 08854; and Department of Molecular Genetics, Microbiology and Immunology, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway, NJ 08854

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This research was supported in part by Busch Biomedical Research Grant 749164 (to D.T.D.), National Multiple Sclerosis Society Grant 3699A10 (to D.T.D.), Georgetta Harrar (to D.T.D.), and National Space Biomedical Research Institute Grant IIH00405 (to Y.F.S.).

² Address correspondence and reprint requests to Dr. David T. Denhardt, Rutgers, The State University of New Jersey, Nelson Biological Laboratories, 604 Allison Road, Piscataway, NJ 08854.

³ Abbreviations used in this paper: OPN, osteopontin; CORT, corticosterone; CRS, chronic restraint stress; HPA, hypothalamus-pituitary-adrenal; HU, hind limb unloading; ACTH, adrenocorticotropic hormone; Wt, wild type.

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