disruption of pth receptor 1 in t cells protects against pth-induced bone loss中断的甲状旁腺素受体1在t细胞防止pth-induced骨质流失.pdfVIP

Disruption of PTH Receptor 1 in T Cells Protects against PTH-Induced Bone Loss 1 1 1 1 3 Hesham Tawfeek , Brahmchetna Bedi , Jau-Yi Li , Jonathan Adams , Tatsuya Kobayashi , M. Neale 1,4 3 1,2 Weitzmann , Henry M. Kronenberg , Roberto Pacifici * 1 Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory University, Atlanta, Georgia, United States of America, 2 Immunology and Molecular Pathogenesis Program, Emory University, Atlanta, Georgia, United States of America, 3 Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts, United States of America, 4 Atlanta VA Medical Center, Decatur, Georgia, United States of America Abstract Background: Hyperparathyroidism in humans and continuous parathyroid hormone (cPTH) treatment in mice cause bone loss by regulating the production of RANKL and OPG by stromal cells (SCs) and osteoblasts (OBs). Recently, it has been reported that T cells are required for cPTH to induce bone loss as the binding of the T cell costimulatory molecule CD40L to SC receptor CD40 augments SC sensitivity to cPTH. However it is unknown whether direct PTH stimulation of T cells is required for cPTH to induce bone loss, and whether T cells contribute to the bone catabolic activity of PTH with mechanisms other than induction of CD40 signaling in SCs. Methodology/Principal Findings: Here we show that silencing of PTH receptor 1 (PPR) in T cells blocks the bone loss and the osteoclastic expansion induced by cPTH, thus demonstrating that PPR signaling in T cells is central for PTH-induced reduction of bone mass. Mechanistic studies revealed that PTH activation of the T cell