Role of estrogen in bone metabolism

doi:10.3969/j.issn.2095-4344.2015.07.017

Abstract

Abstract:

BACKGROUND: Postmenopausal osteoporosis is a systemic bone metabolic disorder that is closely associated with a decrease in the level of estrogen.

OBJECTIVE: To review the influence of estrogen on bone metabolism by exploring the role of estrogen in osteoblasts and osteoclasts.

METHODS: A computer-based retrieval of Medline database and CNKI was performed by the first author to search relevant articles addressing the role of estrogen on osteoblasts and osteoclasts using the keywords of “estrogen, osteoporosis, bone metabolism, osteoblasts, osteoclasts, osteogenesis, bone resorption” both in English and Chinese. Totally 216 articles were retrieved, and according to inclusion criteria, and 48 articles were finally retained.

RESULTS AND CONCLUSION: Estrogen deficiency is associated with a gap between bone resorption and formation, characterized by the loss of bone mass and strength that leads to fragility fractures. Estrogen can regulate the levels of osteoblasts and osteoclasts, thereby inhibiting bone resorption, increasing bone formation, and maintaining bone metabolism.

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

全文链接：

Key words: Estrogen, Bone Metabolism, Osteoblasts, Osteoclasts

CLC Number:

R318

Li Hong-liang, Si Jia-wen, Shen Guo-fang. Role of estrogen in bone metabolism[J]. Chinese Journal of Tissue Engineering Research, 2015, 19(7): 1077-1081.

Figures/Tables 1

2.1 雌激素对破骨细胞的作用 Oursler 于1991年证实了破骨细胞中雌激素受体的存在[6]，说明雌激素对破骨细胞有直接的调控作用。Martin-Millan发现特异性敲除破骨细胞雌激素受体α导致了松质骨的损失[7]，这是由于减少了破骨细胞的凋亡，使破骨细胞的寿命的延长。此外在促使破骨细胞凋亡的过程中，雌激素阻断了核因子κB受体活化因子配体/巨噬细胞集落刺激因子介导的转录过程[8]，通过降低c-jun的活性，抑制核因子κB受体活化因子配体诱导的破骨细胞的分化[9]。雌激素通过诱导雌激素受体α结合于BCAR1蛋白上，来抑制核因子ΚB受体活化因子配体刺激的单核细胞向破骨的分化，隔断了TRAF6，导致了核因子κB活性的降低，阻断了核因子ΚB受体活化因子配体诱导的破骨现象，见图1[10]。除了直接对破骨细胞发生作用，雌激素还间接调节破骨细胞的形成及活性。体内体外实验均表明雌激素亦通过对成骨向细胞、T细胞、B细胞抑制核因子ΚB受体活化因子配体的生成，同时增加核因子ΚB受体活化因子配体的抑制物-骨保护素的生成[11]。在小鼠动物模型中，雌激素被证实调节一系列骨吸收相关因子，包括白细胞介素1、白细胞介素6、肿瘤坏死因子α、巨噬细胞集落刺激因子、前列腺素[12-17]，另外，肿瘤坏死因子α的促吸收作用可以被可溶性的一型肿瘤坏死因子受体逆转[18]。在绝经后雌激素显著下降的妇女中应用阿那白滞素及依那西普特异性阻碍白细胞介素1和肿瘤坏死因子α，其骨吸收相关标志物不再上调，和小鼠模型中一致，这些免疫细胞因子的调节作用在人类中也很重要[19]。有学者提出伴随着雌激素水平的显著下调而出现的快速的骨丧失，是由于T细胞的扩增到时骨微环境中的肿瘤坏死因子α水平上升引起的，同时间接地促进了破骨细胞的形成[20]。在缺乏T淋巴细胞的裸小鼠中并未出现因卵巢切除而导致的骨丢失也证实了这一点[21]。然而其他研究者在裸大鼠、RAG2和TCR-α缺陷小鼠(均缺乏有功能的T淋巴细胞)进行卵巢切除后发现，这些老鼠均出现了与野生老鼠类似的骨丢失的现象[22-23]。总之，雌激素通过直接或间接的作用对破骨细胞的形成、活性、寿命产生了影响。一方面，雌激素通过雌激素受体α对破骨细胞直接的调控作用或许占据了主导，另一方面雌激素通过T细胞和成骨细胞产生的对破骨细胞间接的调控作用亦为重要。 2.2 雌激素对成骨细胞的作用 1988年Komm等[24]发现成骨细胞中有雌激素受体(estrogen receptors，ERs)存在，提示雌激素对成骨细胞有调节作用。随着成骨前体细胞和骨细胞上雌激素受体的发现，越来越多的研究证明雌激素对成骨过程具有直接作用，也具有不依赖雌激素受体的间接的作用。 2.2.1 雌激素参与调节成骨细胞增殖与分化成骨细胞的增殖与凋亡对维持骨代谢平衡起重要作用[25-26]，雌激素对成骨细胞表现为抗凋亡与促进分化的作用。 Kousteni等[27]研究发现雌激素能够抑制成骨细胞的凋亡，延长其寿命，从而增加了每个成骨细胞的成骨能力。其作用是通过雌激素受体介导的调节激酶的快速激活实现的[28]。有报道称成骨细胞的凋亡与B淋巴细胞瘤2基因有关，雌激素能够通过促进B淋巴细胞瘤2基因的转录与表达[29]，阻断糖皮质激素所引起的成骨细胞的凋亡[30]，亦有人报道雌激素通过上调热休克蛋白而减少肿瘤坏死因子对成骨细胞的凋亡作用[31]。雌激素减少成骨细胞的凋亡也可通过Src/Shc/ERK信号通路的激活以及JNK的下调，改变了一系列转录因子的活性包括Elk-1、cJun/cFos等来实现[28]。雌激素对成骨细胞的增殖、成骨标志物(Ⅰ型胶原、骨钙素、碱性磷酸酶)的表达及细胞因子等有直接的作用[32]，对小鼠的骨髓进行培养发现，雌激素能够促进成骨细胞的分化，通过雌激素受体的作用，促进钙盐的沉积于矿化[33-35]。雌激素对成骨细胞的作用主要通过雌激素受体机制[36]。雌激素受体分为两种，雌激素受体α与雌激素受体β[37-39]，两者虽然再结构上有高度的同源性，但功能存在争议。研究证明，两者在雌激素调节成骨细胞的过程中发挥了不同的作用。在小鼠的成骨细胞系中敲除雌激素受体α后发现其几乎没有成骨的表型，在敲除雌激素受体α后的小鼠中发现皮质骨有明显的减少，然而松质骨并未受影响[40]。亦有学者称雌激素受体α缺乏抑制了鼠骨骼的纵向生长，而雌激素受体β缺乏了促进纵向的生长，表明在纵向上两者起着不同的作用，然而在对骨小梁密度方面的影响是相同的[41]。关于两种受体的不同作用仍有待进一步研究。 2.2.2 雌激素参与调节成骨细胞核因子κB活性有体内实验表明：雌激素的缺乏使得成骨细胞中的核因子κB活性显著增加[42]，另外，在去卵巢大鼠中抑制核因子κB活性可以减少骨吸收和骨形成的失衡，从而减少骨丢失的发生。核因子κB的抑制导致了Fos相关抗原1(Fra-1)表达的增加，Fra-1是骨基质形成过程中的重要的转录因子。在体外诱导成骨细胞系分化时，通过加入核因子κB的抑制剂IKK-DN和SR-IκBα，能够促进细胞的成骨向分化[42]。进一步研究证实，尽管雌激素对核因子κB没有直接的调控作用，但是它能够显著地降低肿瘤坏死因子α介导的核因子κB活性[43]，从而激活了转化生长因子β介导的Smad信号通路[44]，促进了MC3T3成骨细胞系以及骨髓间质干细胞分化与矿化的功能。另外，也有报道称核因子κB通过影响Smad7信号通路而作用于Saos2骨肉瘤细胞而抑制其成骨分化[45]。然而雌激素对核因子κB活性的具体作用机制尚不完善，仍需进一步研究证实。 2.2.3 雌激素参与调节成骨细胞氧化应激反应活性氧的水平对细胞的许多功能都会产生影响，包括细胞凋亡的时间，老化，以及年龄有关的相关疾病[46]。体内过多的积累活性氧会引起许多组织的改变，其中也包含骨组织[47]。一系列的研究表明，在年长小鼠的骨组织内，氧化应激的标志物的表达较高[45]。氧化应激的产物活性氧，能够减弱成骨细胞的生成，并减少成骨细胞和骨细胞的寿命，相反，活性氧是破骨细胞生成、发挥功能所必须的。氧化应激抑制了骨形成，其中一部分是由于阻断了Wnt信号通路以及将β-catenin从TCF转移至FoxO介导的转录因子结合位点[48]，同时雌激素缺乏对骨的影响可以通过抗氧化剂来抵消[45]。总的来说，年龄因素和雌激素缺乏对骨形成的作用可能是通过氧化应激反应来实现的。"

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