Osteopontin regulates hindlimb-unloading-induced lymphoid organ atrophy and weight loss by modulating corticosteroid production

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 OP[N.sup.-/-] mice with OP[N.sup.+/+] mice subjected to HU for 3 days. Whereas OP[N.sup.+/+] mice suffered a marked reduction of body weight and significant spleen and thymus atrophy, OP[N.sup.-/-] 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, ofT and B cells in the spleen and CD[4.sup.+]CD[8.sup.+] double-positive cells in the thymus of OP[N.sup.+/+] mice. Increased levels of corticosterone, which modulates lymphocyte activation responses and apoptosis during stress, were found only in OP[N.sup.+/+] mice. Apoptotic cell death was evident in the spleen and thymus of OP[N.sup.+/+] mice subjected to HU but not in OP[N.sup.-/-] mice. Importantly, lymphocytes from both OP[N.sup.+/+] and OP[N.sup.-/-] 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