A crucial role for thiol antioxidants in estrogen-deficiency bone loss
A crucial role for thiol antioxidants in estrogen-deficiency bone loss
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DOI：
10.1172/jci200318859
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发表时间：
2003-09-01
影响因子：
15.9
通讯作者：
Chambers, TJ
中科院分区：
文献类型：
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作者：
Lean, JM;Davies, JT;Chambers, TJ
雌激素防止骨质流失的机制尚不清楚。在其他地方，雌激素通过抑制活性氧(ROS)发挥有益的作用。ROS刺激破骨细胞，即吸收骨骼的细胞。因此，雌激素可能通过增强骨骼中的氧化防御来防止骨丢失。我们发现，主要的硫醇抗氧化剂谷胱甘肽和硫氧还蛋白，以及负责维持它们处于还原状态的酶谷胱甘肽和硫氧还蛋白还原酶，在去卵巢后在啮齿动物骨髓中大幅下降，并被外源17-β-雌二醇迅速恢复正常。此外，给予N-乙酰半胱氨酸或抗坏血酸，抗氧化剂增加组织谷胱甘肽水平，消除卵巢切除所致的骨丢失，而L-丁硫氨酸-(S，R)-磺胺(谷胱甘肽合成的特异性抑制剂)则导致大量的骨丢失。17-β雌二醇在体外可增加破骨细胞中谷胱甘肽、谷胱甘肽和硫氧还蛋白还原酶的活性。此外，在体外，NAC可阻止破骨细胞的形成和核因子-kappaB的激活。BSO和过氧化氢的作用正好相反。17-β雌二醇和NAC抑制破骨细胞中肿瘤坏死因子-α的表达，肿瘤坏死因子-α是核因子-kappaB的靶标，也是与雌激素缺乏性骨丢失密切相关的细胞因子。这些观察结果强烈表明，雌激素缺乏会降低破骨细胞中的硫醇抗氧化剂，从而导致骨质丢失。这直接使破骨细胞对破骨细胞信号敏感，并携带ROS增强的细胞因子表达，促进破骨细胞性骨吸收。
The mechanisms through which estrogen prevents bone loss are uncertain. Elsewhere, estrogen exerts beneficial actions by suppression of reactive oxygen species (ROS). ROS stimulate osteoclasts, the cells that resorb bone. Thus, estrogen might prevent bone loss by enhancing oxidant defenses in bone. We found that glutathione and thioredoxin, the major thiol antioxidants, and glutathione and thioredoxin reductases, the enzymes responsible for maintaining them in a reduced state, fell substantially in rodent bone marrow after ovariectomy and were rapidly normalized by exogenous 17-beta-estradiol Moreover, administration of N-acetyl cysteine (NAC) or ascorbate, antioxidants that increase tissue glutathione levels, abolished ovariectomy-induced bone loss, while L-buthionine-(S,R)-sulphoximine (BSO), a specific inhibitor of glutathione synthesis, caused substantial bone loss. The 17-beta estradiol increased glutathione and glutathione and thioredoxin reductases in osteoclast-like cells in vitro. Furthermore, in vitro NAC prevented osteoclast formation and NF-kappaB activation. BSO and hydrogen peroxide did the opposite. Expression of TNF-alpha, a target for NF-kappaB and a cytokine strongly implicated in estrogen-deficiency bone loss, was suppressed in osteoclasts by 17-beta estradiol and NAC. These observations strongly suggest that estrogen deficiency causes bone loss by lowering thiol antioxidants in osteoclasts. This directly sensitizes osteoclasts to osteoclastogenic signals and entrains ROS-enhanced expression of cytokines that promote osteoclastic bone resorption.