Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
Am J Physiol Endocrinol Metab. 2021 Jan 1;320(1):E160-E168. doi: 10.1152/ajpendo.00349.2019. Epub 2020 Nov 23.
Mutation of arginine 264 in ERα has been shown to abrogate rapid membrane ERα-mediated endothelial effects. Our novel finding that mutation of R264 is dispensable for ERα-mediated skeletal effects supports the concept that R264 determines tissue specificity of ERα. Estrogen protects against bone loss but is not a suitable treatment due to adverse effects in other tissues. Therefore, increased knowledge regarding estrogen signaling in estrogen-responsive tissues is warranted to aid the development of bone-specific estrogen treatments. Estrogen receptor-α (ERα), the main mediator of estrogenic effects in bone, is widely subjected to posttranslational modifications (PTMs). In vitro studies have shown that methylation at site R260 in the human ERα affects receptor localization and intracellular signaling. The corresponding amino acid R264 in murine ERα has been shown to have a functional role in endothelium in vivo, although the methylation of R264 in the murine gene is yet to be empirically demonstrated. The aim of this study was to investigate whether R264 in ERα is involved in the regulation of the skeleton in vivo. Dual-energy X-ray absorptiometry (DEXA) analysis at 3, 6, 9, and 12 mo of age showed no differences in total body areal bone mineral density (BMD) between R264A and wild type (WT) in either female or male mice. Furthermore, analyses using computed tomography (CT) demonstrated that trabecular bone mass in tibia and vertebra and cortical thickness in tibia were similar between R264A and WT mice. In addition, R264A females displayed a normal estrogen treatment response in trabecular bone mass as well as in cortical thickness. Furthermore, uterus, thymus, and adipose tissue responded similarly in R264A and WT female mice after estrogen treatment. In conclusion, our novel finding that mutation of R264 in ERα does not affect the regulation of the skeleton, together with the known role of R264 for ERα-mediated endothelial effects, supports the concept that R264 determines tissue specificity of ERα. Mutation of arginine 264 in ERα has been shown to abrogate rapid membrane ERα-mediated endothelial effects. Our novel finding that mutation of R264 is dispensable for ERα-mediated skeletal effects supports the concept that R264 determines tissue specificity of ERα.
突变精氨酸 264 已被证明可消除 ERα 介导的内皮细胞的快速膜效应。我们的新发现表明，R264 突变对于 ERα 介导的骨骼效应是可有可无的，这支持了 R264 决定 ERα 组织特异性的概念。雌激素可预防骨质流失，但由于其在其他组织中的不良反应，并不适合作为治疗药物。因此，增加对雌激素反应组织中雌激素信号传导的了解是有必要的，这有助于开发针对骨骼的特异性雌激素治疗方法。雌激素受体-α（ERα）是骨骼中雌激素效应的主要介质，广泛受到翻译后修饰（PTMs）的影响。体外研究表明，人 ERα 中 R260 位点的甲基化会影响受体定位和细胞内信号转导。尽管尚未通过实验证明鼠基因中 R264 的甲基化，但已经证明鼠 ERα 中的相应氨基酸 R264 在体内的内皮细胞中具有功能作用。本研究旨在研究 ERα 中的 R264 是否参与体内骨骼的调节。3、6、9 和 12 月龄时的双能 X 射线吸收法（DEXA）分析显示，R264A 和野生型（WT）雌性或雄性小鼠的全身面积骨密度（BMD）无差异。此外，使用计算机断层扫描（CT）分析表明，胫骨和椎骨的小梁骨量以及胫骨的皮质厚度在 R264A 和 WT 小鼠之间相似。此外，R264A 雌性小鼠在小梁骨量和皮质厚度方面表现出正常的雌激素治疗反应。此外，雌激素治疗后，R264A 和 WT 雌性小鼠的子宫、胸腺和脂肪组织的反应相似。总之，我们的新发现表明，ERα 中的 R264 突变不会影响骨骼的调节，再加上 R264 对 ERα 介导的内皮细胞效应的已知作用，支持了 R264 决定 ERα 组织特异性的概念。
