Estrogen prevents bone loss through transforming growth factor beta signaling in T cells

Proc Natl Acad Sci U S A. 2004 Nov 23;101(47):16618-23. doi: 10.1073/pnas.0404888101. Epub 2004 Nov 5.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antigen Presentation
  • Base Sequence
  • Bone Development
  • Bone Resorption / etiology*
  • Bone Resorption / immunology
  • Bone Resorption / physiopathology
  • Cell Division
  • Estrogens / physiology*
  • Female
  • Gene Silencing
  • Interferon-gamma / biosynthesis
  • Lymphocyte Activation
  • Macrophages / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Nude
  • Mice, Transgenic
  • Nuclear Proteins / genetics
  • Protein Serine-Threonine Kinases
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / genetics
  • Receptors, Transforming Growth Factor beta / metabolism
  • Signal Transduction
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology*
  • Trans-Activators / genetics
  • Transforming Growth Factor beta / physiology*

Substances

  • Estrogens
  • MHC class II transactivator protein
  • Nuclear Proteins
  • RNA, Messenger
  • Receptors, Transforming Growth Factor beta
  • Trans-Activators
  • Transforming Growth Factor beta
  • Interferon-gamma
  • Protein Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II