Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Department of Biochemistry and Molecular Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
J Bone Miner Res. 2019 Dec;34(12):2277-2286. doi: 10.1002/jbmr.3847. Epub 2019 Sep 12.
Krox20/EGR2 is a zinc finger transcription factor, implicated in the development of the hindbrain, nerve myelination, and tumor suppression. In skeletal biology, we have demonstrated that Krox20 also regulates adult bone metabolism. We and others have characterized several functions of Krox20 in the osteoclast lineage, namely, preosteoclast proliferation and differentiation, and mature osteoclast apoptosis. We have previously reported that systemically Krox20-haploinsufficient mice have a low bone mass with increased bone resorption. However, new data have now revealed that this phenotype is restricted to females. In addition, we discovered that conditional knockout of Krox20 (cKO) restricted to osteoclast progenitors is sufficient to induce the same female-specific bone loss observed in systemic mutants. To test whether this sexual dimorphism results from an interaction between Krox20 and sex hormones, we examined the sex- and hormone-dependent role of Krox20 deficiency on proliferation and apoptosis in osteoclastic cells. Our results indicate that male and female sex hormones (dihydrotestosterone [DHT] and estradiol [E2], respectively) as well as Krox20 inhibit preosteoclast proliferation and augment osteoclast apoptosis. The observation that Krox20 expression is inhibited by DHT and E2 negates the hypothesis that the effect of sex hormones is mediated by an increase in Krox20 expression. Interestingly, the effect of Krox20 deficiency was observed only with cells derived from female animals, regardless of any sex hormones added in vitro. In addition, we have identified sexual dimorphism in the expression of several Krox20-related genes, including NAB2. This sex-specific epigenetic profile was established at puberty, maintained in the absence of sex hormones, and explains the female-specific skeletal importance of Krox20. The findings described in this study emphasize the medical importance of sex differences, which may be determined at the epigenetic level. © 2019 American Society for Bone and Mineral Research.
Krox20/EGR2 是一种锌指转录因子，参与后脑、神经髓鞘形成和肿瘤抑制的发育。在骨骼生物学中，我们已经证明 Krox20 还调节成人骨代谢。我们和其他人已经描述了 Krox20 在破骨细胞谱系中的几个功能，即前破骨细胞增殖和分化，以及成熟破骨细胞凋亡。我们之前报道过，系统性 Krox20 杂合不足的小鼠骨量减少，骨吸收增加。然而，新的数据现在表明，这种表型仅限于雌性。此外，我们发现，仅限于破骨细胞祖细胞的 Krox20 条件性敲除足以诱导在系统性突变体中观察到的相同的雌性特异性骨丢失。为了测试这种性别二态性是否来自 Krox20 与性激素之间的相互作用，我们检查了 Krox20 缺乏对破骨细胞增殖和凋亡的性别和激素依赖性作用。我们的结果表明，雄性和雌性性激素（分别为二氢睾酮[DHT]和雌二醇[E2]）以及 Krox20 抑制前破骨细胞增殖并增加破骨细胞凋亡。DHT 和 E2 抑制 Krox20 表达的观察结果否定了性激素作用是通过增加 Krox20 表达来介导的假设。有趣的是，只有来自雌性动物的细胞观察到 Krox20 缺乏的影响，而与体外添加任何性激素无关。此外，我们已经确定了几个与 Krox20 相关的基因，包括 NAB2，的表达存在性别二态性。这种性特异性表观遗传谱在青春期建立，在没有性激素的情况下维持，并解释了 Krox20 对女性骨骼的重要性。本研究描述的发现强调了性别差异的医学重要性，这种差异可能在表观遗传水平上决定。
