Estrogen deficiency induces bone loss by enhancing T-cell production of TNF-α
Simone Cenci, M. Neale Weitzmann, Cristiana Roggia, Noriyuki Namba, Deborah Novack, Jessica Woodring, Roberto Pacifici
Simone Cenci, M. Neale Weitzmann, Cristiana Roggia, Noriyuki Namba, Deborah Novack, Jessica Woodring, Roberto Pacifici
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Article

Estrogen deficiency induces bone loss by enhancing T-cell production of TNF-α

Abstract

Estrogen deficiency induces bone loss by upregulating osteoclastogenesis by mechanisms not completely defined. We found that ovariectomy-enhanced T-cell production of TNF-α, which, acting through the TNF-α 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-α, is a key mechanism by which estrogen prevents osteoclastic bone resorption and bone loss.

Authors

Simone Cenci, M. Neale Weitzmann, Cristiana Roggia, Noriyuki Namba, Deborah Novack, Jessica Woodring, Roberto Pacifici

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T cells from OVX mice produce a soluble factor upregulating RANKL- and M...
T cells from OVX mice produce a soluble factor upregulating RANKL- and M-CSF–induced osteoclast formation, which is blocked by TNF-α neutralization. Mean (± SEM) of three independent experiments (n = 6 wells per group). AP < 0.05 compared with all other groups. (a) Cocultures of purified monocytes and purified T cells from OVX and estrogen-replete mice stimulated with optimal osteoclastogenic concentrations of M-CSF and RANKL. No osteoclast formation was observed in RANKL- and M-CSF–stimulated cultures of T cells in the absence of BMMs. Similarly, osteoclast differentiation of BMMs was not induced by stimulation with either RANKL or M-CSF alone, both in the presence or the absence of T cells (not shown). (b) Purified monocytes from intact mice stimulated with optimal osteoclastogenic concentrations of M-CSF and RANKL were cultured with either purified T cells from OVX and estrogen-replete mice or T cell–conditioned media (C.M.) from OVX and estrogen-replete mice. AP < 0.05 compared with all other groups.