Mechanism underlying interaction between estrogen and runt-related transcription factor 2 in osteoblasts

doi:10.3969/j.issn.2095-4344.2013.02.026

Abstract

Abstract:

BACKGROUND: It is widely believed that estrogen and runt-related transcription factor 2 (Runx2) are important regulatory factors in the formation and maintenance of bone.
OBJECTIVE: To summarize the recent research progresses and to elaborate the molecular mechanism of interaction between estrogen and Runx2 in osteoblasts.
METHODS: “Estrogen”, “runt-related transcription factor 2 (Runx2)” and “osteoblast” were used as search terms in Chinese and English to retrieve PubMed, China Biology Medicine disc, VIP journal full-text database, WanFang database. Repeatability studies and irrelevant researches were excluded. Totally 62 literatures were obtained with preliminary retrieval and 22 were reserved after further study and analysis.
RESULTS AND CONCLUSION: A mass of scientific researchers have found that estrogen and Runx2 do not function independently in osteoblasts but interact with each other through multiple patterns to co-regulate osteoblasts. There exist a complex mechanism of interaction between estrogen and Runx2. Various pathways are involved besides the direct action between estrogen/estrogen receptor and Runx2, such as transforming growth factor-β pathway, Wnt/β-catenin pathway, Fas/Fas ligand pathway and nuclear factor kappa B pathway.

Key words: tissue construction, academic investigation in tissue construction, osteoblast-specific transcription factor, osteoblasts, estrogen, nuclear factor kappa B, regulation of osteogenesis, bone metabolism, signaling pathway, provincial grants-supported paper

CLC Number:

R318

Wang Hui, Sun Hui-qiang. Mechanism underlying interaction between estrogen and runt-related transcription factor 2 in osteoblasts[J]. Chinese Journal of Tissue Engineering Research, 2013, 17(2): 331-336.

Figures/Tables 4

2.2 Wnt/β-连锁蛋白信号通路 Wnt信号通路是骨骼系统发育、成熟、重构的一个重要信号系统，可以引起胞内β-连锁蛋白的积累。Chandar等[10]发现雌激素作用于ROS17/2.8细胞可显著上调由Wnt通路介导的β-连锁蛋白和碱性磷酸酶，而雌激素受体调节剂ICI 182780和三苯氧胺及雌激素受体α敲除可终止上述现象[11]。这说明Wnt/β-连锁蛋白信号通路参与雌激素对成骨细胞的调控。 Gaur 等[12]认为Wnt/β-连锁蛋白信号通路通过激活Runt基因表达从而调控成骨细胞分化和骨骼发育，其理论基于以下实验：①敲除分泌型卷曲相关蛋白1(SFRP1)的大鼠表达激活的Wnt信号通路，其T细胞因子1、Runt2及骨钙素的表达显著增加。②Runx2启动子(-97-93)存在功能性T 细胞因子调控元件。③Runt基因募集β-连锁蛋白和T细胞因子1。④T细胞因子1和经典Wnt蛋白的共表达可以使Runt启动子活性显著提高，并且其mRNA水平显著增加。通过对FABP4-Wnt10b鼠的研究发现Wnt10b可促进间质细胞向成骨细胞转化，抑制其向脂肪细胞转化，其机制之一是Wnt10b可诱导Runx2的表达而抑制PPAR-γ2的表达[13]。也有研究发现Wnts尽管可以增加依赖Runx2基因的表达，但是不能增加核内Runx2的蛋白水平，也不能促进Runx2与DNA的结合[14]。这说明Wnts可能影响Runx2与其他转录因子的相互作用。如图2：Wnt信号通过细胞表面7次跨膜受体Frizzled家族成员激活胞质Dishevelled(Dsh)蛋白，从而抑制由GSK3、Axin、APC和β-连锁蛋白组成的蛋白复合物的活性，使β-连锁蛋白免于磷酸化而不被降解，导致β-连锁蛋白在胞内积聚并易位到核内与转录因子T细胞因子家族成员结合，促进Runx2表达。 Runx2也可通过上调TβRI的表达而作用于转化生长因子β信号通路，继而增强Wnt信号系统的活性。另外，Runx2还可直接调节Wnt的基因表达。在成骨细胞分化早期，前列腺素E2诱导的Runx2的活化可增强依赖Wnt的基因表达，当抑制内源性Runx2表达时Wnt基因的表达也受到显著抑制，如图2[14]。因此，Wnt极有可能是Runx2作用于雌激素介导的生物效应的重要靶点之一。"

2.4 核因子κB信号通路雌激素也能通过抑制核因子κB信号通路而促进Runx2表达。在哺乳动物中迄今发现5种核因子kB家族成员：RelA(p65)、RelB、c-Rel、核因子kB1(p50)、核因子kB2(p52)。它们以同源或异源二聚体形式存在，最常见的二聚体是p50-p65异二聚体，也就是常说的核因子kB。在骨骼系统中核因子κB信号通路和雌激素发挥着相反的调节作用。雌激素可以通过抑制核因子κB配体激活因子(RANKL)而防止乙醇诱导的骨质丢失[18]。因卵巢切除导致的骨质减少在Bglap2-IKK-DN鼠(表达无功能IKKγ等位基因产物)中得到明显改善，说明核因子κB的激活破坏了成骨细胞骨形成[19]。核因子κB可促进多种细胞因子的合成，这些细胞因子在成骨细胞分化和骨形成中发挥重要的功能。绝经期雌激素水平的降低伴随着血清白细胞介素1，白细胞介素6，白细胞介素7和肿瘤坏死因子的升高[19]。如图4：当细胞受到炎症因子如肿瘤坏死因子α等刺激时，肿瘤坏死因子α与其受体结合，激活胞浆中IKKs(IkB激酶)，使无活性的核因子kB三聚体复合物种的IkB的N端调节区的Ser32/36磷酸化，随后发生泛素化，在蛋白酶体作用下降解，IkB的解离暴露出p50亚基的DNA结合位点，使p50-p65异二聚体从细胞浆易位至细胞核内，与kB序列结合，促进白细胞介素1，白细胞介素6，白细胞介素7和肿瘤坏死因子的基因合成。有研究发现肿瘤坏死因子可通过下调Runx2的表达而抑制细胞分化[20]。白细胞介素6可抑制骨吸收[21]。白细胞介素7不但可抑制骨吸收还可以通过抑制Runx2基因启动子的活性而下调Runx2表达从而抑制骨形成[22]。 Krum[19]假设了雌激素影响核因子κB信号通路的4个机制，包括雌激素受体α与核因子κB结合影响核因子κB的功能；雌激素受体α调节IKK和IκB的活性；雌激素受体α使辅激活蛋白远离核因子κB；雌激素受体α可阻止IκB降解从而抑制核因子κB激活。除此之外，雌激素受体α可直接与肿瘤坏死因子启动子结合而影响肿瘤坏死因子的表达。 2.5 其他雌激素和Runx2的相互作用还通过许多其他信号通路而实现，如：Runx2增强固醇/类固醇激素代谢相关的酶的基因表达活性而促进雌激素合成； Runx2通过与雌激素受体α基因的F启动子结合剂量依赖性影响雌激素受体α基因的表达；前列腺素 E2通过调控视网膜母细胞瘤结合蛋白1来上调Runx2的表达和活性等等，这些分子机制有待于进一步研究。"

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