Estrogen prevents bone loss through transforming growth factor beta signaling in T cells.
Estrogen (E) deficiency leads to an expansion of the pool of tumor necrosis factor (TNF)-producing T cells through an IFN-gamma-dependent pathway that results in increased levels of the osteoclastogenic cytokine TNF in the bone marrow. Disregulated IFN-gamma production is instrumental for the bone loss induced by ovariectomy (ovx), but the responsible mechanism is unknown. We now show that mice with T cell-specific blockade of type beta transforming growth factor (TGFbeta) signaling are completely insensitive to the bone-sparing effect of E. This phenotype results from a failure of E to repress IFN-gamma production, which, in turn, leads to increased T cell activation and T cell TNF production. Furthermore, ovx blunts TGFbeta levels in the bone marrow, and overexpression of TGFbeta in vivo prevents ovx-induced bone loss. These findings demonstrate that E prevents bone loss through a TGFbeta-dependent mechanism, and that TGFbeta signaling in T cells preserves bone homeostasis by blunting T cell activation. Thus, stimulation of TGFbeta production in the bone marrow is a critical "upstream" mechanism by which E prevents bone loss, and enhancement of TGFbeta levels in vivo may constitute a previously undescribed therapeutic approach for preventing bone loss.
Gao
Yuhao
Y
Division of Endocrinology, Metabolism and Lipids, Emory University School of Medicine, Atlanta, GA 30322, USA.
Qian
Wei-Ping
WP
Dark
Kimberly
K
Toraldo
Gianluca
G
Lin
Angela S P
AS
Guldberg
Robert E
RE
Flavell
Richard A
RA
Weitzmann
M Neale
MN
Pacifici
Roberto
R
D000818:Animals; D017951:Antigen Presentation; D001483:Base Sequence; D001846:Bone Development; D001862:Bone Resorption / Q000209:etiology* / Q000276:immunology / Q000503:physiopathology; D002455:Cell Division; D004967:Estrogens / Q000502:physiology*; D005260:Female; D020868:Gene Silencing; D007371:Interferon-gamma / Q000096:biosynthesis; D008213:Lymphocyte Activation; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000235:genetics; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D015534:Trans-Activators / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000502:physiology*
D004967:Estrogens; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D007371:Interferon-gamma; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II