No abstract

Osteopontin (OPN), a multifunctional secreted phosphoglycoprotein, plays diverse roles in bone biology, immune regulation, cell survival, inflammation, and cancer metastasis. Here we show its role in determining lymphocyte homeostasis and body mass in response to hindlimb unloading (HU), a model for evaluating effects of weightlessness on the musculoskeletal and other physiological systems. Using this stress model, we compared OPN ؊/؊ 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, respectively, of T and B cells in the spleen and CD4 ؉ CD8 ؉ double-positive cells in the thymus of OPN ؉/؉ mice. Increased levels of corticosterone, which modulates lymphocyte activation responses and apoptosis during stress, were found only in OPN ؉/؉ mice. Apoptotic cell death was evident in the spleen and thymus of OPN ؉/؉ mice subjected to HU but not in OPN ؊/؊ mice. Importantly, lymphocytes from both OPN ؉/؉ and OPN ؊/؊ mice were equally sensitive to corticosteroid-induced apoptosis. These results reveal that OPN is required for enhanced corticosterone production, immune organ atrophy, and weight loss in mice subjected to HU. apoptosis ͉ immune ͉ stress ͉ lymphocytes ͉ space flight

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.