Optineurin Regulates NRF2-mediated Antioxidant Response in a Mouse Model of Paget's Disease of Bone

Overview

Journal Sci Adv

Specialties Biology
Science

Date 2023 Jan 27

PMID 36706179

Authors

Xiangxiang Hu

Sing-Wai Wong

Kaixin Liang

Tai-Hsien Wu

Sheng Wang

Lufei Wang

Jie Liu

Mitsuo Yamauchi

Brian L Foster

Jenny P-Y Ting

Baohong Zhao

Henry C Tseng

Ching-Chang Ko

Affiliations

Soon will be listed here.

Abstract

Degenerative diseases affecting the nervous and skeletal systems affect the health of millions of elderly people. Optineurin (OPTN) has been associated with numerous neurodegenerative diseases and Paget's disease of bone (PDB), a degenerative bone disease initiated by hyperactive osteoclastogenesis. In this study, we found age-related increase in OPTN and nuclear factor E2-related factor 2 (NRF2) in vivo. At the molecular level, OPTN could directly interact with both NRF2 and its negative regulator Kelch-like ECH-associated protein 1 (KEAP1) for up-regulating antioxidant response. At the cellular level, deletion of OPTN resulted in increased intracellular reactive oxygen species and increased osteoclastogenic potential. At the tissue level, deletion of OPTN resulted in substantially increased oxidative stress derived from leukocytes that further stimulate osteoclastogenesis. Last, curcumin attenuated hyperactive osteoclastogenesis induced by OPTN deficiency in aged mice. Collectively, our findings reveal an OPTN-NRF2 axis maintaining bone homeostasis and suggest that antioxidants have therapeutic potential for PDB.

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