Related Experiment Video
Updated: Dec 28, 2025
Skeletal Phenotype Analysis of a Conditional Stat3 Deletion Mouse Model
Published on: July 3, 2020
SENP3 Suppresses Osteoclastogenesis by De-conjugating SUMO2/3 from IRF8 in Bone Marrow-Derived Monocytes
Yongxing Zhang1, Kai Yang2, Jie Yang3
1Trauma 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.
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.
Insights
SENP3 protease regulates bone metabolism by controlling osteoclast formation. Its deficiency enhances bone loss, suggesting SENP3 as a target for treating osteoporosis and related bone diseases.
Area of Science:
- Biochemistry
- Cell Biology
- Immunology
Background:
- Bone metabolism relies on balancing bone formation and resorption.
- Osteoporosis involves increased bone destruction from enhanced osteoclastogenesis.
- Osteoclast differentiation is a key process in bone resorption.
Purpose of the Study:
- To investigate the role of SUMO modification in regulating osteoclastogenesis.
- To determine the function of SENP3 in bone metabolism and osteoclast differentiation.
- To elucidate the molecular mechanism by which SENP3 affects osteoclast formation.
Main Methods:
- Studied SUMO-specific protease SENP3 expression in osteoclast precursors.
- Utilized SENP3-deficient mice (in bone marrow-derived monocytes) to assess bone loss after ovariectomy.
- Analyzed the impact of SENP3 deletion on osteoclast differentiation.
- Investigated the effect of SENP3 loss on interferon regulatory factor 8 (IRF8) SUMOylation and downstream targets.
Main Results:
- SENP3 expression is downregulated during osteoclast differentiation.
- SENP3 deficiency in bone marrow-derived monocytes leads to exacerbated bone loss post-ovariectomy.
- Deletion of SENP3 promotes osteoclast differentiation.
- Loss of SENP3 increases IRF8 SUMO3 modification at K310, upregulating NFATc1 and promoting osteoclastogenesis.
Conclusions:
- Post-translational SUMO modification, specifically involving SENP3, is critical for regulating osteoclastogenesis.
- SENP3 suppresses osteoclast differentiation through de-SUMO modification of IRF8.
- Targeting SENP3-mediated IRF8 de-SUMO modification offers potential therapeutic strategies for bone loss diseases like osteoporosis.
Related Concept Videos
01:31Osteoclasts in Bone Remodeling
01:17Hormones and Bone Tissue
Hormones That Influence Osteoblasts and/or Maintain the Matrix
Several hormones are necessary for controlling bone growth and maintaining the bone matrix. The pituitary gland secretes growth hormone (GH), which, as its name implies, controls bone growth. This happens in several ways: first, it triggers chondrocyte...