Up-regulation of TNF-producing T cells in the bone marrow:: A key mechanism by which estrogen deficiency induces bone loss in vivo
Up-regulation of TNF-producing T cells in the bone marrow:: A key mechanism by which estrogen deficiency induces bone loss in vivo
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DOI：
10.1073/pnas.251534698
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发表时间：
2001-11-20
影响因子：
11.1
通讯作者：
Pacifici, R
中科院分区：
文献类型：
--
作者：
Roggia, C;Gao, YH;Pacifici, R
体内研究表明，T细胞是雌激素缺乏诱导骨丢失的机制的核心，但所涉及的机制仍然部分不确定。在体外，来自卵巢切除小鼠的T细胞产生增加量的肿瘤坏死因子（TNF），其增强NF-κ B配体（RANKL）诱导的破骨细胞生成的受体激活剂。然而，这种现象在体内的机制和相关性仍有待建立。在这项研究中，我们发现卵巢切除术增加了骨髓T细胞产生TNF的数量，而不改变每个T细胞产生TNF的数量。证实了TNF的重要贡献，卵巢切除术诱导野生型（wt）小鼠的快速骨丢失，但在TNF缺陷型（TNF-/-）小鼠中却没有。此外，卵巢切除术诱导的骨丢失，这是不存在的T细胞缺陷的裸鼠，恢复过继转移的野生型T细胞，但不是通过重建与T细胞从TNF-/-小鼠。这些发现表明，T细胞产生的TNF在雌激素戒断后骨丢失中的关键因果作用。最后，卵巢切除术引起野生型小鼠和缺乏p75 TNF受体的小鼠的骨丢失，但在缺乏p55 TNF受体的小鼠中没有发生。这些发现表明，由骨髓T细胞数量增加引起的TNF的T细胞产生增强是雌激素缺乏诱导体内骨丢失的关键机制。数据还表明，TNF在体内的骨消耗作用是由p55 TNF受体介导的。
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-kappaB 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.