CNC-bZIP protein NFE2L1 regulates osteoclast differentiation in antioxidant-dependent and independent manners

Zhiyuan Liu; Huihui Wang; Yongyong Hou; Yang Yang; Jingkun Jia; Jinzhi Wu; Zhuo Zuo; Tianchang Gao; Suping Ren; Yiying Bian; Shengnan Liu; Jingqi Fu; Yongxin Sun; Jiliang Li; Masayuki Yamamoto; Qiang Zhang; Yuanyuan Xu; Jingbo Pi

doi:10.1016/j.redox.2021.102180

CNC-bZIP protein NFE2L1 regulates osteoclast differentiation in antioxidant-dependent and independent manners

Redox Biol. 2021 Nov 6:48:102180. doi: 10.1016/j.redox.2021.102180. Online ahead of print.

Authors

Zhiyuan Liu¹, Huihui Wang², Yongyong Hou¹, Yang Yang³, Jingkun Jia¹, Jinzhi Wu¹, Zhuo Zuo¹, Tianchang Gao¹, Suping Ren¹, Yiying Bian¹, Shengnan Liu¹, Jingqi Fu¹, Yongxin Sun³, Jiliang Li⁴, Masayuki Yamamoto⁵, Qiang Zhang⁶, Yuanyuan Xu⁷, Jingbo Pi⁸

Affiliations

¹ Program of Environmental Toxicology, School of Public Health, China Medical University, Shenyang, 110122, China.
² Laboratory of Chronic Disease and Environmental Genomics, School of Public Health, China Medical University, Shenyang, 110122, China.
³ The First Affiliated Hospital, China Medical University, Shenyang, 110001, China.
⁴ Department of Biology, Indiana University Purdue University Indianapolis, IN, 46202, USA.
⁵ Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan.
⁶ Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, GA, 30322, USA.
⁷ Laboratory of Chronic Disease and Environmental Genomics, School of Public Health, China Medical University, Shenyang, 110122, China. Electronic address: yyxu@cmu.edu.cn.
⁸ Program of Environmental Toxicology, School of Public Health, China Medical University, Shenyang, 110122, China. Electronic address: jbpi@cmu.edu.cn.

Abstract

Fine-tuning of osteoclast differentiation (OD) and bone remodeling is crucial for bone homeostasis. Dissecting the mechanisms regulating osteoclastogenesis is fundamental to understanding the pathogenesis of various bone disorders including osteoporosis and arthritis. Nuclear factor erythroid 2-related factor 1 (NFE2L1, also known as NRF1), which belongs to the CNC-bZIP family of transcription factors, orchestrates a variety of physiological processes and stress responses. While Nfe2l1 gene may be transcribed into multiple alternatively spliced isoforms, the biological function of the different isoforms of NFE2L1 in bone metabolism, osteoclastogenesis in particular, has not been reported. Here we demonstrate that knockout of all isoforms of Nfe2l1 transcripts specifically in the myeloid lineage in mice [Nfe2l1(M)-KO] results in increased activity of osteoclasts, decreased bone mass and worsening of osteoporosis induced by ovariectomy and aging. In comparison, LysM-Cre-mediated Nfe2l1 deletion has no significant effect on the osteoblast and osteocytes. Mechanistic investigations using bone marrow cells and RAW 264.7 cells revealed that deficiency of Nfe2l1 leads to accelerated and elevated OD, which is attributed, at least in part, to enhanced accumulation of ROS in the early stage of OD and expression of nuclear factor of activated T cells, cytoplasmic, calcineurin dependent 1α (Nfatc1/α). In addition, NFE2L1 regulates the transcription of multiple antioxidant genes and Nfatc1/α and OD in an isoform-specific manner. While long isoforms of NFE2L1 function as accelerators of induction of Nfatc1/α and antioxidant genes and OD, the short isoform NFE2L1-453 serves as a brake that keeps the long isoforms' accelerator effects in check. These findings provide a novel insight into the regulatory roles of NFE2L1 in osteoclastogenesis and highlight that NFE2L1 is essential in regulating bone remodeling and thus may be a valuable therapeutic target for bone disorders.

Keywords: NFATc1; NFE2L1; Osteoclast; Osteoclastogenesis; Osteoporosis; ROS.