Role of TNF-alpha producing T-cells in bone loss induced by estrogen deficiency.
Many study in literature have suggested a possible role of T cells and tumor necrosis factor-alpha (TNF-alpha) in the pathogenesis of bone loss that occurs in pathological conditions, such as systemic inflammatory diseases; the molecular bases through which this phenomenon occurs and the relevance of this mechanism also in estrogen deficiency induced bone loss remain unclear. In our study we observed that TNF-alpha knock-out mice (TNF-/-), as well as transgenic mice without thymus (and therefore without mature T cell), do not lose bone after ovariectomy like observed for mice of normal genetic background (wild type, WT). Moreover, after transfer into athymic mice of T cell isolated from WT ovariectomized animals (and so stimulated by estrogen deficiency to proliferate and to produce TNF-alpha), ovariectomy recovers its ability to induce bone loss; whereas there is no change in bone density after injection into athymic mice of T-cell purified from TNF-/- animals which, even if mature, are unable to produce TNF-alpha. Therefore the presence of TNF-alpha producing T-cell is essential for estrogen deficiency to influence bone metabolism. In the following study of the research group of Prof. Pacifici it has been shown that the increased activation of TNF-alpha producing T-cell in the ovariectomized mice is due to increased INF-gamma levels, resulting from ovariectomy-induced enhanced secretion of IL-12 and IL-18 by macrophages. INF-gamma promotes expression in immunocompetent cells of class II transactivator (CIITA), that, up-regulating expression of the major system of histocompatibility of class II, makes the macrophages more active in antigen presentation to T-cells, which in turn start producing TNF. For the first time an immune mechanism is involved in the pathogenesis of post-menopausal osteoporosis; nevertheless the applicability of these conclusions also in humans remains still to be proved.
Department of Internal Medicine, University of Saarland, Homburg, Germany.
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Roggia
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Tamone
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Cenci
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Pacifici
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Isaia
D000818:Animals; D004967:Estrogens / Q000172:deficiency*; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000502:physiology; D007378:Interleukins / Q000378:metabolism; D008264:Macrophages; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D008822:Mice, Transgenic; D010024:Osteoporosis / Q000209:etiology*; D010052:Ovariectomy; D013601:T-Lymphocytes / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D004967:Estrogens; D007378:Interleukins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma