title: Premature T cell senescence in Ovx mice is inhibited by repletion of estrogen and medicarpin: a possible mechanism for alleviating bone loss.
abstract: Presently the relationship between CD28, biological marker of senescence, and ovariectomy is not well understood. We show that ovariectomy leads to CD28 loss on T cells and estrogen (E2) repletion and medicarpin (Med) inhibits this effect. We thus propose that Med/E2 prevents bone loss by delaying premature T cell senescence.
  
  
  BACKGROUND
  Estrogen deficiency triggers reproductive aging by accelerating the amplification of TNF-α-producing T cells, thereby leading to bone loss. To date, no study has been carried out to explain the relationship between CD4(+)CD28null T cells and ovariectomy or osteoporosis. We aim to determine the effect of Ovx on CD28 expression on T cells and effects of E2 and medicarpin (a pterocarpan phytoalexin) with proven osteoprotective effect on altered T cell responses.
  
  
  METHODS
  Adult, female Balb/c mice were taken for the study. The groups were: sham, Ovx, Ovx + Med or E2. Treatments were given daily by oral gavage. At autopsy bone marrow and spleen were flushed out and cells labelled with antibodies for FACS analysis. Serum was collected for ELISA.
  
  
  RESULTS
  In Ovx mice, Med/E2 at their respective osteoprotective doses resulted in thymus involution and lowered Ovx-induced increase in serum TNF-α level and its mRNA levels in the BM T cells. Med/E2 reduced BM and spleen CD4(+) T cell proliferation and prevented CD28 loss on CD4(+) T cells. Further, Med abrogated TNF-α-induced loss of CD28 expression in the BM T cells.
  
  
  CONCLUSIONS
  To our knowledge this is the first report to determine the mechanism of CD28 loss on T cells as a result of ovariectomy. Our study demonstrates that Ovx leads to the generation of premature senescent CD4(+)CD28null T cells, an effect inhibited by E2 and Med. We propose that one of the mechanisms by which Med/E2 alleviates Ovx-induced bone loss is by delaying T cell senescence and enhancing CD28 expression.
authors.affiliation: Division of Endocrinology, Central Drug Research Institute, Council of Scientific and Industrial Research, Chattar Manzil, PO Box 173, Lucknow, India.
authors.forename: A M
authors.initials: AM
authors.lastname: Tyagi
authors.forename: K
authors.initials: K
authors.lastname: Srivastava
authors.forename: J
authors.initials: J
authors.lastname: Kureel
authors.forename: A
authors.initials: A
authors.lastname: Kumar
authors.forename: A
authors.initials: A
authors.lastname: Raghuvanshi
authors.forename: D
authors.initials: D
authors.lastname: Yadav
authors.forename: R
authors.initials: R
authors.lastname: Maurya
authors.forename: A
authors.initials: A
authors.lastname: Goel
authors.forename: D
authors.initials: D
authors.lastname: Singh
mesh_terms: D000818:Animals; D050071:Bone Density Conservation Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001854:Bone Marrow Cells / Q000187:drug effects / Q000276:immunology; D018106:CD28 Antigens / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects / Q000276:immunology*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009929:Organ Size / Q000187:drug effects; D010024:Osteoporosis / Q000276:immunology / Q000517:prevention & control*; D010052:Ovariectomy; D010750:Phosphoproteins / Q000378:metabolism; D036343:Pterocarpans / Q000494:pharmacology* / Q000627:therapeutic use; D016601:RNA-Binding Proteins / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013154:Spleen / Q000187:drug effects / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology; D013950:Thymus Gland / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000097796:Nucleolin; D000094162:Phytoalexins
chemical_list: D050071:Bone Density Conservation Agents; D018106:CD28 Antigens; D004958:Estradiol; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D; D010750:Phosphoproteins; D036343:Pterocarpans; D016601:RNA-Binding Proteins; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D000097796:Nucleolin; C000630987:Hnrpd protein, mouse; C047353:medicarpin; D000094162:Phytoalexins