Abstract
Estrogen deficiency induces bone loss by upregulating osteoclastogenesis by mechanisms not completely defined. We found that ovariectomy-enhanced T-cell production of TNF-alpha, which, acting through the TNF-alpha receptor p55, augments macrophage colony-stimulating factor-induced (M-CSF-induced) and RANKL-induced osteoclastogenesis. Ovariectomy failed to induce bone loss, stimulate bone resorption, or increase M-CSF- and RANKL-dependent osteoclastogenesis in T-cell deficient mice, establishing T cells as essential mediators of the bone-wasting effects of estrogen deficiency in vivo. These findings demonstrate that the ability of estrogen to target T cells, suppressing their production of TNF-alpha, is a key mechanism by which estrogen prevents osteoclastic bone resorption and bone loss.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antigens, CD / genetics
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Antigens, CD / metabolism*
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Bone Resorption / metabolism*
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Carrier Proteins / metabolism*
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Cells, Cultured
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Estrogens / physiology*
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Macrophage Colony-Stimulating Factor / metabolism
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Membrane Glycoproteins / metabolism*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Nude
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Osteoclasts / physiology
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Ovariectomy
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RANK Ligand
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Receptor Activator of Nuclear Factor-kappa B
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Receptors, Tumor Necrosis Factor / genetics
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Receptors, Tumor Necrosis Factor / metabolism*
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Receptors, Tumor Necrosis Factor, Type I
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Receptors, Tumor Necrosis Factor, Type II
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T-Lymphocytes / metabolism*
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Tumor Necrosis Factor-alpha / biosynthesis*
Substances
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Antigens, CD
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Carrier Proteins
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Estrogens
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Membrane Glycoproteins
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RANK Ligand
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Receptor Activator of Nuclear Factor-kappa B
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Receptors, Tumor Necrosis Factor
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Receptors, Tumor Necrosis Factor, Type I
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Receptors, Tumor Necrosis Factor, Type II
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Tnfrsf11a protein, mouse
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Tnfsf11 protein, mouse
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Tumor Necrosis Factor-alpha
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Macrophage Colony-Stimulating Factor