Sigma‐1 receptor attenuates osteoclastogenesis by promoting ER‐associated degradation of SERCA2
Abstract Sigma‐1 receptor (Sigmar1) is a specific chaperone located in the mitochondria‐associated endoplasmic reticulum membrane (MAM) and plays a role in several physiological processes. However, the role of Sigmar1 in bone homeostasis remains unknown. Here, we show that mice lacking Sigmar1 exhib...
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| Format: | Article |
| Language: | English |
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Springer Nature
2022-05-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.202115373 |
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| author | Xiaoan Wei Zeyu Zheng Zhenhua Feng Lin Zheng Siyue Tao Bingjie Zheng Bao Huang Xuyang Zhang Junhui Liu Yilei Chen Wentian Zong Zhi Shan Shunwu Fan Jian Chen Fengdong Zhao |
| author_facet | Xiaoan Wei Zeyu Zheng Zhenhua Feng Lin Zheng Siyue Tao Bingjie Zheng Bao Huang Xuyang Zhang Junhui Liu Yilei Chen Wentian Zong Zhi Shan Shunwu Fan Jian Chen Fengdong Zhao |
| author_sort | Xiaoan Wei |
| collection | DOAJ |
| description | Abstract Sigma‐1 receptor (Sigmar1) is a specific chaperone located in the mitochondria‐associated endoplasmic reticulum membrane (MAM) and plays a role in several physiological processes. However, the role of Sigmar1 in bone homeostasis remains unknown. Here, we show that mice lacking Sigmar1 exhibited severe osteoporosis in an ovariectomized model. In contrast, overexpression of Sigmar1 locally alleviated the osteoporosis phenotype. Treatment with Sigmar1 agonists impaired both human and mice osteoclast formation in vitro. Mechanistically, SERCA2 was identified to interact with Sigmar1 based on the immunoprecipitation‐mass spectrum (IP‐MS) and co‐immunoprecipitation (co‐IP) assays, and Q615 of SERCA2 was confirmed to be the critical residue for their binding. Furthermore, Sigmar1 promoted SERCA2 degradation through Hrd1/Sel1L‐dependent ER‐associated degradation (ERAD). Ubiquitination of SERCA2 at K460 and K541 was responsible for its proteasomal degradation. Consequently, inhibition of SERCA2 impeded Sigmar1 deficiency enhanced osteoclastogenesis. Moreover, we found that dimemorfan, an FDA‐approved Sigmar1 agonist, effectively rescued bone mass in various established bone‐loss models. In conclusion, Sigmar1 is a negative regulator of osteoclastogenesis, and activation of Sigmar1 by dimemorfan may be a potential treatment for osteoporosis in clinical practice. |
| format | Article |
| id | doaj-art-2b082e75e2a845d9a094c2a620d7baef |
| institution | OA Journals |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2022-05-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-2b082e75e2a845d9a094c2a620d7baef2025-08-20T02:11:21ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842022-05-0114711810.15252/emmm.202115373Sigma‐1 receptor attenuates osteoclastogenesis by promoting ER‐associated degradation of SERCA2Xiaoan Wei0Zeyu Zheng1Zhenhua Feng2Lin Zheng3Siyue Tao4Bingjie Zheng5Bao Huang6Xuyang Zhang7Junhui Liu8Yilei Chen9Wentian Zong10Zhi Shan11Shunwu Fan12Jian Chen13Fengdong Zhao14Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineAbstract Sigma‐1 receptor (Sigmar1) is a specific chaperone located in the mitochondria‐associated endoplasmic reticulum membrane (MAM) and plays a role in several physiological processes. However, the role of Sigmar1 in bone homeostasis remains unknown. Here, we show that mice lacking Sigmar1 exhibited severe osteoporosis in an ovariectomized model. In contrast, overexpression of Sigmar1 locally alleviated the osteoporosis phenotype. Treatment with Sigmar1 agonists impaired both human and mice osteoclast formation in vitro. Mechanistically, SERCA2 was identified to interact with Sigmar1 based on the immunoprecipitation‐mass spectrum (IP‐MS) and co‐immunoprecipitation (co‐IP) assays, and Q615 of SERCA2 was confirmed to be the critical residue for their binding. Furthermore, Sigmar1 promoted SERCA2 degradation through Hrd1/Sel1L‐dependent ER‐associated degradation (ERAD). Ubiquitination of SERCA2 at K460 and K541 was responsible for its proteasomal degradation. Consequently, inhibition of SERCA2 impeded Sigmar1 deficiency enhanced osteoclastogenesis. Moreover, we found that dimemorfan, an FDA‐approved Sigmar1 agonist, effectively rescued bone mass in various established bone‐loss models. In conclusion, Sigmar1 is a negative regulator of osteoclastogenesis, and activation of Sigmar1 by dimemorfan may be a potential treatment for osteoporosis in clinical practice.https://doi.org/10.15252/emmm.202115373ER‐associated degradationdimemorfanosteoporosisSERCA2Sigma‐1 receptor |
| spellingShingle | Xiaoan Wei Zeyu Zheng Zhenhua Feng Lin Zheng Siyue Tao Bingjie Zheng Bao Huang Xuyang Zhang Junhui Liu Yilei Chen Wentian Zong Zhi Shan Shunwu Fan Jian Chen Fengdong Zhao Sigma‐1 receptor attenuates osteoclastogenesis by promoting ER‐associated degradation of SERCA2 EMBO Molecular Medicine ER‐associated degradation dimemorfan osteoporosis SERCA2 Sigma‐1 receptor |
| title | Sigma‐1 receptor attenuates osteoclastogenesis by promoting ER‐associated degradation of SERCA2 |
| title_full | Sigma‐1 receptor attenuates osteoclastogenesis by promoting ER‐associated degradation of SERCA2 |
| title_fullStr | Sigma‐1 receptor attenuates osteoclastogenesis by promoting ER‐associated degradation of SERCA2 |
| title_full_unstemmed | Sigma‐1 receptor attenuates osteoclastogenesis by promoting ER‐associated degradation of SERCA2 |
| title_short | Sigma‐1 receptor attenuates osteoclastogenesis by promoting ER‐associated degradation of SERCA2 |
| title_sort | sigma 1 receptor attenuates osteoclastogenesis by promoting er associated degradation of serca2 |
| topic | ER‐associated degradation dimemorfan osteoporosis SERCA2 Sigma‐1 receptor |
| url | https://doi.org/10.15252/emmm.202115373 |
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