SENP3 Suppresses Osteoclastogenesis by De-conjugating SUMO2/3 from IRF8 in Bone Marrow-Derived Monocytes
Yongxing Zhang,
Kai Yang,
Jie Yang,
Yimin Lao,
Lianfu Deng,
Guoying Deng,
Jing Yi,
Xuxu Sun,
Qiugen Wang
Affiliations
Yongxing Zhang
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
Kai Yang
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
Jie Yang
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
Yimin Lao
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
Lianfu Deng
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
Guoying Deng
Trauma Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China
Jing Yi
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; Corresponding author
Xuxu Sun
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; Corresponding author
Qiugen Wang
Trauma Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China; Corresponding author
Summary: 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. : Osteoclast over-activation leads to osteoporosis, but the role of post-translational modification in osteoporosis is not fully understood. Zhang et al. show that the SUMO protease SENP3 can alter the SUMO modification status on the critical osteoclast suppressor IRF8 in osteoclast precursor cells, which affects osteoclastogenesis and osteoporosis. Keywords: SENP3, osteoclastogenesis, SUMOylation, osteoporosis
