Tob deficiency superenhances osteoblastic activity after ovariectomy to block estrogen deficiency-induced osteoporosis
Tob deficiency superenhances osteoblastic activity after ovariectomy to block estrogen deficiency-induced osteoporosis
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DOI：
10.1073/pnas.0303093101
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发表时间：
2004-04-27
影响因子：
11.1
通讯作者：
Noda, M
中科院分区：
文献类型：
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作者：
Usui, M;Yoshida, Y;Noda, M
Tob（erbB 2的转换器）是抗增殖家族蛋白的成员，并且作为骨形态发生蛋白抑制剂以及T细胞增殖抑制剂起作用，T细胞增殖抑制剂与绝经后骨丢失有关。为了确定Tob缺乏对雌激素缺乏引起的骨丢失的影响，我们分析了Tobb缺乏小鼠卵巢切除术或假手术后的骨代谢。WT小鼠的卵巢切除术降低了骨小梁体积和骨矿物质密度（BMD），这与预期一致。在Tob-deficient小鼠中，卵巢切除术减少了骨体积和BIVID。然而，即使在卵巢切除术后，Tob-deficient骨中的骨小梁体积和BIVID水平与假手术WT骨中的相当。骨形成参数（矿物质沉积率和骨形成率）在卵巢切除的Tob-deficient小鼠显着高于卵巢切除的WT小鼠。相比之下，卵巢切除术诱导的骨吸收参数，破骨细胞表面，破骨细胞数量的增加是相似的之间的Tob-deficient小鼠和WT小鼠。此外，在离体结节形成测定中，在来自Tob-deficient小鼠的骨髓细胞中，卵巢切除诱导的结节形成的增强显著高于来自卵巢切除WT小鼠的骨髓细胞。Tob和雌激素信号传导都集中在成骨细胞中碱性磷酸酶的骨形态发生蛋白激活和GCCG报告基因表达，揭示了两种信号之间的相互作用。这些数据表明，Tob缺乏通过骨中成骨细胞活性的超增强来防止卵巢切除术诱导的骨丢失，并且这导致体内卵巢切除术后骨形成率和矿物质沉积率的进一步增加。
Tob (transducer of erbB2) is a member of anti proliferative family proteins and acts as a bone morphogenic protein inhibitor as well as a suppressor of proliferation in T cells, which have been implicated in postmenopausal bone loss. To determine the effect of Tob deficiency on estrogen deficiency-induced bone loss, we analyzed bone metabolism after ovariectomy or sham operation in Tob-deficient mice. Ovariectomy in WT mice decreased trabecular bone volume and bone mineral density (BMD) as expected. In Tob-deficient mice, ovariectomy reduced bone volume and BIVID. However, even after ovariectomy, both trabecular bone volume and BIVID levels in Tob-deficient bone were comparable to those in sham-operated WT bones. Bone formation parameters (mineral apposition rate and bone formation rate) in the ovariectornized Tob-deficient mice were significantly higher than those in the ovariectomized WT mice. In contrast, the ovariectomy-induced increase in the bone resorption parameters, osteoclast surface, and osteoclast number was similar between Tob-deficient mice and WT mice. Furthermore, in ex vivo nodule formation assay, ovariectomy-induced enhancement of nodule formation was significantly higher in the bone marrow cells from Tob-deficient mice than in the bone marrow cells from ovariectomized WT mice. Both Tob and estrogen signalings converge at bone morphogenic protein activation of alkaline phosphatase and GCCG-reporter gene expression in osteolblasts, revealing interaction between the two signals. These data indicate that Tob deficiency prevents ovariectomyinduced bone loss through the superenhancement of osteoblastic activities in bone and that this results in further augmentation in the bone formation rate and the mineral apposition rate after ovariectomy in vivo.