Osteocytes, the most abundant bone cell type, are derived from osteoblasts through a process in which they are embedded in an osteoid. We previously showed that nutrient restriction promotes the osteocyte transcriptional program and is associated with increased mitochondrial biogenesis. Here, we show that increased mitochondrial biogenesis increase reactive oxygen species (ROS) levels and consequently, NRF2 activity during osteocytogenesis. NRF2 activity promotes osteocyte-specific expression of Dmp1, Mepe, and Sost in IDG-SW3 cells, primary osteocytes, and osteoblasts, and in murine models with Nfe2l2 deficiency in osteocytes or osteoblasts. Moreover, ablation of Nfe2l2 in osteocytes or osteoblasts generates osteopenia and increases osteoclast numbers with marked sexual dimorphism. Finally, treatment with dimethyl fumarate prevented the deleterious effects of ovariectomy in trabecular bone masses of mice and restored osteocytic gene expression. Altogether, we uncovered the role of NRF2 activity in osteocytes during the regulation of osteocyte gene expression and maintenance of bone homeostasis.

骨细胞是最丰富的骨细胞类型，它是通过将它们嵌入类骨质中的过程从成骨细胞中获得的。我们之前表明，营养限制促进了骨细胞转录程序，并与线粒体生物合成增加有关。在这里，我们表明增加的线粒体生物发生会增加活性氧 (ROS) 水平，从而增加骨细胞生成过程中的 NRF2 活性。NRF2活性促进Dmp1、Mepe和Sost在IDG-SW3细胞、原代骨细胞和成骨细胞中以及在骨细胞或成骨细胞中Nfe2l2缺乏的鼠模型中的骨细胞特异性表达。此外，消融Nfe2l2在骨细胞或成骨细胞中产生骨质减少并增加破骨细胞数量并具有明显的两性异形性。最后，富马酸二甲酯治疗可防止卵巢切除术对小鼠骨小梁的有害影响，并恢复成骨细胞基因表达。总之，我们揭示了 NRF2 活性在骨细胞基因表达调节和骨稳态维持过程中在骨细胞中的作用。