Optineurin regulates NRF2-mediated antioxidant response in a mouse model of Paget’s disease of bone

Author:

Hu Xiangxiang123ORCID,Wong Sing-Wai45ORCID,Liang Kaixin167ORCID,Wu Tai-Hsien3ORCID,Wang Sheng3,Wang Lufei18ORCID,Liu Jie3ORCID,Yamauchi Mitsuo2,Foster Brian L.9ORCID,Ting Jenny P.-Y.6710ORCID,Zhao Baohong111213ORCID,Tseng Henry C.14ORCID,Ko Ching-Chang3ORCID

Affiliation:

1. Oral and Craniofacial Biomedicine Program, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

2. Division of Oral and Craniofacial Health Sciences, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

3. Division of Orthodontics, The Ohio State University College of Dentistry, Columbus, OH 43210, USA.

4. Division of Comprehensive Oral Health, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

5. Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Hangzhou 310006, China.

6. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.

7. Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.

8. Guangxi Key Laboratory of the Rehabilitation and Reconstruction for Oral and Maxillofacial Research; Department of Orthodontics, College and Hospital of Stomatology, Guangxi Medical University; Nanning, Guangxi 530021, China.

9. Division of Biosciences, The Ohio State University College of Dentistry, Columbus, OH 43210, USA.

10. Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.

11. Arthritis and Tissue Degeneration Program and David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY 10021, USA.

12. Department of Medicine, Weill Cornell Medical College, Cornell University, New York, NY 10065, USA.

13. Graduate Program in Cell and Development Biology, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA.

14. Duke Eye Center and Department of Ophthalmology, Duke University Medical Center, Durham, NC 27710, USA.

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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