Kim Ri Youn, Yang Hoon Joo, Song Yun Mi, Kim In Sook, Hwang Soon Jung
1 Department of Maxillofacial Cell and Developmental Biology, School of Dentistry, Seoul National University , Seoul, Republic of Korea.
2 Department of Oral and Maxillofacial Surgery, School of Dentistry, Seoul National University , Seoul, Republic of Korea.
Tissue Eng Part A. 2015 Jul;21(13-14):2076-88. doi: 10.1089/ten.TEA.2014.0585. Epub 2015 May 26.
Clinical data show that estrogen levels are inversely associated with the production of sclerostin, a Wnt antagonist that recently attracted great attention over the use of its antibody in the anabolic treatment of osteoporotic conditions. However, the molecular link between sclerostin expression and estrogen signaling is not yet known. We investigated the mechanisms by which estrogen modulates sclerostin (SOST) gene expression at the cellular level in human osteoblast cells in association with bone morphogenetic protein (BMP)2 signaling given that BMP2 is a potential inducer of SOST in human mesenchymal stromal cells (hMSCs). 17β-Estradiol (E2) alone had no effect on SOST expression, which was significantly induced by treatment with BMP2 in hMSCs and osteoblasts derived from the mandibles of female donors. However, E2 suppressed the induction of SOST and other BMP2 target genes by BMP2 in hMSCs. E2 signaling was independent of the Smad pathway, which plays a critical role in SOST induction mediated by BMP2. Instead, E2 increased the transcriptional expression of β-catenin and levels of its activated form. Silencing of the gene encoding estrogen receptor (ER)α decreased E2 activity in β-catenin activation and the suppression of SOST induction by BMP2, but had no influence on BMP2-mediated SOST induction in the same conditions. Similar results were obtained after treatment with ERα antagonist as a Wnt inhibitor. In human osteoblasts, the effect of E2 on SOST expression was either suppressive or absent, depending on the cell donor. Interestingly, the SOST expression pattern after treatment with BMP2 or BMP2/E2 in human osteoblasts showing a pattern of E2 suppression on SOST induction by BMP2 correlated with the ratio of receptor activator of nuclear factor kappa-B ligand (RANKL) to osteoprotegerin (OPG) expression. These results demonstrate that estrogen signaling in osteoblasts negatively regulates SOST expression in an indirect manner through interaction with BMP2 signaling and that this regulation involves the Wnt/ERα and β-catenin pathways. This study highlights several interactions between estrogen and BMP cascades in osteoblasts that may provide a basis for therapeutic intervention for the modification of bone mass density.
临床数据表明，雌激素水平与硬化蛋白的产生呈负相关，硬化蛋白是一种Wnt拮抗剂，其抗体在骨质疏松症的合成代谢治疗中的应用最近引起了极大关注。然而，硬化蛋白表达与雌激素信号传导之间的分子联系尚不清楚。鉴于骨形态发生蛋白（BMP）2是人间充质基质细胞（hMSCs）中硬化蛋白的潜在诱导剂，我们研究了雌激素在人成骨细胞中与BMP2信号传导相关联的情况下，在细胞水平上调节硬化蛋白（SOST）基因表达的机制。单独使用17β-雌二醇（E2）对SOST表达没有影响，而在来自女性供体下颌骨的hMSCs和成骨细胞中，BMP2处理可显著诱导SOST表达。然而，E2抑制了hMSCs中BMP2对SOST和其他BMP2靶基因的诱导。E2信号传导独立于Smad途径，而Smad途径在BMP2介导的SOST诱导中起关键作用。相反，E2增加了β-连环蛋白的转录表达及其活化形式的水平。编码雌激素受体（ER）α的基因沉默降低了E2在β-连环蛋白激活中的活性以及对BMP2诱导SOST的抑制作用，但在相同条件下对BMP2介导的SOST诱导没有影响。用ERα拮抗剂作为Wnt抑制剂处理后也获得了类似的结果。在人成骨细胞中，E2对SOST表达的影响要么是抑制性的，要么不存在，这取决于细胞供体。有趣的是，在人成骨细胞中用BMP2或BMP2/E2处理后，SOST表达模式显示E2对BMP2诱导SOST的抑制作用与核因子κB受体激活剂配体（RANKL）与骨保护素（OPG）表达的比率相关。这些结果表明，成骨细胞中的雌激素信号传导通过与BMP2信号传导相互作用以间接方式负调节SOST表达，并且这种调节涉及Wnt/ERα和β-连环蛋白途径。这项研究突出了雌激素与成骨细胞中BMP级联之间的几种相互作用，这可能为改变骨密度的治疗干预提供基础。
