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骨细胞中的NRF2功能是骨稳态所必需的，并驱动骨细胞基因表达。

NRF2 function in osteocytes is required for bone homeostasis and drives osteocytic gene expression.

作者信息

Sánchez-de-Diego Cristina, Pedrazza Leonardo, Pimenta-Lopes Carolina, Martinez-Martinez Arturo, Dahdah Norma, Valer José Antonio, Garcia-Roves Pablo, Rosa Jose Luis, Ventura Francesc

机构信息

Departament de Ciències Fisiològiques, Universitat de Barcelona, IDIBELL, L'Hospitalet de Llobregat, Spain.

Departament de Ciències Fisiològiques, Universitat de Barcelona, IDIBELL, L'Hospitalet de Llobregat, Spain.

出版信息

Redox Biol. 2021 Apr;40:101845. doi: 10.1016/j.redox.2020.101845. Epub 2020 Dec 24.

DOI:10.1016/j.redox.2020.101845
PMID:33373776
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7773566/
Abstract

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.

摘要

骨细胞是最丰富的骨细胞类型，由成骨细胞通过嵌入类骨质的过程分化而来。我们之前表明，营养限制促进骨细胞转录程序，并与线粒体生物合成增加有关。在这里，我们表明，线粒体生物合成增加会提高活性氧（ROS）水平，从而在骨细胞生成过程中提高NRF2活性。NRF2活性促进IDG-SW3细胞、原代骨细胞和成骨细胞中Dmp1、Mepe和Sost的骨细胞特异性表达，以及在骨细胞或成骨细胞中Nfe2l2缺乏的小鼠模型中的表达。此外，在骨细胞或成骨细胞中敲除Nfe2l2会导致骨质减少，并增加破骨细胞数量，具有明显的性别差异。最后，用富马酸二甲酯治疗可预防卵巢切除对小鼠小梁骨量的有害影响，并恢复骨细胞基因表达。总之，我们揭示了NRF2活性在骨细胞基因表达调控和骨稳态维持过程中在骨细胞中的作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f97/7773566/c50e06e2b14c/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f97/7773566/776fe9678a02/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f97/7773566/fe21e0825b34/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f97/7773566/9e32938c464e/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f97/7773566/8f50a2f79822/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f97/7773566/7d72ef7b027c/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f97/7773566/6e47bf717134/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f97/7773566/4d73b4a8d267/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f97/7773566/c50e06e2b14c/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f97/7773566/776fe9678a02/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f97/7773566/fe21e0825b34/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f97/7773566/9e32938c464e/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f97/7773566/8f50a2f79822/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f97/7773566/7d72ef7b027c/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f97/7773566/6e47bf717134/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f97/7773566/4d73b4a8d267/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f97/7773566/c50e06e2b14c/gr7.jpg

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