Role of T-cells in Post-Menopausal Osteoporosis
Condition: Osteoporosis
MeSH terms: Osteoporosis
Study type: Observational

Summary: 
      This is an observational study of women undergoing surgical menopause to determine whether
      T-cells play an important role in the etiology of post-menopausal osteoporosis. Subjects will
      examined before and after surgery and followed over a two year period to determine the
      biology of T-cells during this study period.
    

Detailed description: 
      Estrogen (E) deficiency is a major cause of post-menopausal osteoporosis. The mechanisms by
      which E deficiency causes osteoporosis has been recently linked to regulation of two key
      osteoclastic cytokines: RANKL and TNFα (TNF) , , produced by the T-cell in the bone
      micro-environment. TNF is a cytokine that has long been associated with bone destruction
      during E deficiency in both animal and human models. However, the cellular sources of TNF and
      its exact mechanism of action are poorly understood. Previous studies in animal models has
      demonstrated that in marked contrast to responses in wild type (WT) mice, ovariectomy (ovx)
      failed to induce bone loss and did not stimulate osteoclast (OC) formation in T-cell
      deficient mice. This phenomenon is reversed by T cell reconstitution with WT T cells but not
      with T cells from TNF -/- mice2,4. These findings established T-cells and T-cell produced TNF
      as essential mediators of the bone-wasting effects of E deficiency in vivo. TNF further
      enhances OC formation by up regulating the stromal cell production of RANKL and M-CSF and by
      augmenting the responsiveness of OC precursors to RANKL4. The mechanisms by which E
      deficiency leads to enhanced levels of T-cell derived TNF involve a realignment of the
      adaptive immune response that ultimately leads to an expansion in the pool of TNF secreting
      T-cells. Dr. Pacifici's group showed that these pathways in mouse models involve the
      up-regulation of antigen presentation by macrophages and dendritic cells, leading to T cell
      activation and peripheral expansion of TNF producing T cells. They also showed that E
      deficiency causes a rebound in thymic T cell output that contributes to both the T cell
      expansion and the bone loss induced by ovx in young adult mice .

      The objective of this study is to translate these critical findings in the mouse for the
      first time to E deficient women following ovx. If this work defines an important role for
      T-cells in E deficiency-induced bone loss, this could stimulate the development of novel
      therapies designed to block T-cell expansion or their contribution to cytokine production and
      thus prevent or attenuate bone loss in this common clinical setting. The hypothesis of the
      research plan is that T-cells derived from women, rendered E deficient after undergoing ovx,
      exhibit: 1) increased T-cell activation, and proliferation; 2) enhanced production of
      pro-osteoclastogenic cytokines RANKL and TNF; and 3) demonstrate increased T-cell output from
      the thymus that together cause bone loss.
    

Observational model: Case-Control
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Pre-menopausal Women
      
Biospecimen description: 
      Serum
    
Keywords: Osteoporosis, T-cells