Lean Jenny M, Davies Julie T, Fuller Karen, Jagger Christopher J, Kirstein Barrie, Partington Geoffrey A, Urry Zoë L, Chambers Timothy J
Department of Cellular Pathology, St. George's Hospital Medical School, Cranmer Terrace, London SW17 0RE, United Kingdom.
J Clin Invest. 2003 Sep;112(6):915-23. doi: 10.1172/JCI18859.
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.
雌激素预防骨质流失的机制尚不清楚。在其他方面，雌激素通过抑制活性氧（ROS）发挥有益作用。ROS刺激破骨细胞，即负责吸收骨质的细胞。因此，雌激素可能通过增强骨骼中的抗氧化防御来预防骨质流失。我们发现，谷胱甘肽和硫氧还蛋白这两种主要的硫醇抗氧化剂，以及负责将它们维持在还原状态的谷胱甘肽还原酶和硫氧还蛋白还原酶，在卵巢切除后的啮齿动物骨髓中大幅下降，并通过外源性17-β雌二醇迅速恢复正常。此外，给予N-乙酰半胱氨酸（NAC）或抗坏血酸（可增加组织谷胱甘肽水平的抗氧化剂）可消除卵巢切除诱导的骨质流失，而谷胱甘肽合成的特异性抑制剂L-丁硫氨酸-（S，R）-亚砜亚胺（BSO）则导致大量骨质流失。17-β雌二醇在体外增加了破骨细胞样细胞中的谷胱甘肽以及谷胱甘肽还原酶和硫氧还蛋白还原酶。此外，体外实验中NAC可防止破骨细胞形成以及NF-κB激活。BSO和过氧化氢则起相反作用。17-β雌二醇和NAC抑制了破骨细胞中TNF-α的表达，TNF-α是NF-κB的一个靶点，也是一种与雌激素缺乏性骨质流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通过降低破骨细胞中的硫醇抗氧化剂导致骨质流失。这直接使破骨细胞对破骨细胞生成信号敏感，并引发ROS增强的促进破骨细胞性骨吸收的细胞因子表达。
