T cells potentiate PTH-induced cortical bone loss through CD40L signaling.
Parathyroid hormone (PTH) promotes bone catabolism by targeting bone marrow (BM) stromal cells (SCs) and their osteoblastic progeny. Here we show that a continuous infusion of PTH that mimics hyperparathyroidism fails to induce osteoclast formation, bone resorption, and cortical bone loss in mice lacking T cells. T cells provide proliferative and survival cues to SCs and sensitize SCs to PTH through CD40 ligand (CD40L), a surface molecule of activated T cells that induces CD40 signaling in SCs. As a result, deletion of T cells or T cell-expressed CD40L blunts the bone catabolic activity of PTH by decreasing bone marrow SC number, the receptor activator of nuclear factor-kappaB ligand (RANKL)/OSTEOPROTEGERN (OPG) ratio, and osteoclastogenic activity. Therefore, T cells play an essential permissive role in hyperparathyroidism as they influence SC proliferation, life span, and function through CD40L. T cell-SC crosstalk pathways may thus provide pharmacological targets for PTH-induced bone disease.
Gao
Yuhao
Y
Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory University, Atlanta, GA 30322, USA.
Wu
Xiaojun
X
Terauchi
Masakazu
M
Li
Jau-Yi
JY
Grassi
Francesco
F
Galley
Sarah
S
Yang
Xiaoying
X
Weitzmann
M Neale
MN
Pacifici
Roberto
R
D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D001842:Bone and Bones / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D023201:CD40 Ligand / Q000276:immunology / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006961:Hyperparathyroidism / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D010010:Osteoclasts / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D010024:Osteoporosis / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D010281:Parathyroid Hormone / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D053245:RANK Ligand / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D017154:Stromal Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*
D010281:Parathyroid Hormone; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; D023201:CD40 Ligand