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In vivo studies have shown T cells to be central to the mechanism by which estrogen deficiency induces bone loss, but the mechanism involved remains, in part, undefined. In vitro, T cells from ovariectomized mice produce increased amounts of tumor necrosis factor (TNF), which augments receptor activator of NF-B ligand (RANKL)-induced osteoclastogenesis. However, both the mechanism and the relevance of this phenomenon in vivo remain to be established. In this study, we found that ovariectomy increased the number of bone marrow T cell-producing TNF without altering production of TNF per T cell. Attesting to the essential contribution of TNF, ovariectomy induced rapid bone loss in wild type (wt) mice but failed to do so in TNF-deficient (TNF ؊͞؊ ) mice. Furthermore, ovariectomy induced bone loss, which was absent in T cell-deficient nude mice, was restored by adoptive transfer of wt T cells, but not by reconstitution with T cells from TNF ؊͞؊ mice. These findings demonstrate the key causal role of T cell-produced TNF in the bone loss after estrogen withdrawal. Finally, ovariectomy caused bone loss in wt mice and in mice lacking p75 TNF receptor but failed to do so in mice lacking the p55 TNF receptor. These findings demonstrate that enhanced T cell production of TNF resulting from increased bone marrow T cell number is a key mechanism by which estrogen deficiency induces bone loss in vivo. The data also demonstrate that the bone-wasting effect of TNF in vivo is mediated by the p55 TNF receptor.ovariectomy ͉ osteoporosis ͉ mouse ͉ pQCT I t is now recognized that one of the main mechanisms by which estrogen deficiency causes bone loss is by stimulating osteoclast formation (1), a process induced by the simultaneous stimulation of osteoclast precursors by macrophage colonystimulating factor (M-CSF) and a tumor necrosis factor (TNF)-related factor known as receptor activator of NF-B ligand (RANKL) (also known as OPGL, TRANCE, or ODF) (2-4).In physiologic, unstimulated conditions, the differentiation of osteoclast precursors into mature osteoclasts in the bone marrow depends on the production of M-CSF by monocytes and stromal cells and RANKL by stromal cells and osteoblasts (5). However, in stimulated conditions, additional bone marrow cells contribute to regulating osteoclast formation by producing soluble and membrane-bound pro-and antiosteoclastogenic cytokines. Among them are naïve and activated T cells, which modulate osteoclast formation trough increased production of RANKL (6-8), osteoprotegerin (9), and IFN-␥ (10).During inflammation and autoimmune arthritis, activated T cell production of RANKL promotes bone resorption and bone loss (6) whereas release of IFN-␥ limits T cell-induced bone wasting (10). Recent studies from our laboratory have disclosed that activated T cells play an essential causal role not only in inflammation-induced bone loss, but also in the bone wasting induced by estrogen deficiency (11). In fact, whereas ovariectomy (ovx) stimulated bone resorption and induced rapid bone loss in T cell-re...