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Cell Rep. 2020 Feb 11;30(6):1951-1963.e4. doi: 10.1016/j.celrep.2020.01.036.

SENP3 Suppresses Osteoclastogenesis by De-conjugating SUMO2/3 from IRF8 in Bone Marrow-Derived Monocytes.

Author information

1
Trauma Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China; Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
2
Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases with Integrated Chinese-Western Medicine, Shanghai Institute of Traumatology and Orthopedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
3
Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
4
Trauma Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China.
5
Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: yijing@shsmu.edu.cn.
6
Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: xuxu.sun@shsmu.edu.cn.
7
Trauma Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China. Electronic address: wangqiugen@126.com.

Abstract

Bone metabolism depends on the balance between osteoclast-driven bone resorption and osteoblast-mediated bone formation. Diseases like osteoporosis are characterized by increased bone destruction due to partially enhanced osteoclastogenesis. Here, we report that the post-translational SUMO modification is critical for regulating osteoclastogenesis. The expression of the SUMO-specific protease SENP3 is downregulated in osteoclast precursors during osteoclast differentiation. Mice with SENP3 deficiency in bone marrow-derived monocytes (BMDMs) exhibit more severe bone loss due to over-activation of osteoclasts after ovariectomy. Deleting SENP3 in BMDMs promotes osteoclast differentiation. Mechanistically, loss of SENP3 increases interferon regulatory factor 8 (IRF8) SUMO3 modification at the K310 amino acid site, which upregulates expression of the nuclear factor of activated T cell c1 (NFATc1) and osteoclastogenesis. In summary, IRF8 de-SUMO modification mediated by SENP3 suppresses osteoclast differentiation and suggests strategies to treat bone loss diseases.

KEYWORDS:

SENP3; SUMOylation; osteoclastogenesis; osteoporosis

PMID:
32049023
DOI:
10.1016/j.celrep.2020.01.036
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Conflict of interest statement

Declaration of Interests The authors declare no competing interests.

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