Sigma-1 receptor attenuates osteoclastogenesis by promoting ER-associated degradation of SERCA2.
Sigma-1 receptor attenuates osteoclastogenesis by promoting ER-associated degradation of SERCA2.
复制标题
Sigma-1 受体通过促进 ER-相关的 SERCA2 降解来减弱破骨细胞生成
DOI：
10.15252/emmm.202115373
复制
发表时间：
2022-07-07
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
Sigma-1受体(Sigmar1)是一种位于线粒体相关内质网膜(MAM)的特异性伴侣蛋白，在多种生理过程中发挥作用。然而，Sigmar1在骨骼动态平衡中的作用仍不清楚。在这里，我们显示缺乏Sigmar1的小鼠在去卵巢模型中表现出严重的骨质疏松症。相反，Sigmar1的过表达局部缓解了骨质疏松的表型。Sigmar1激动剂在 体外对人和小鼠破骨细胞的形成均有损害作用。通过免疫共沉淀-质谱仪(IP-MS)和免疫共沉淀(co-IP)分析，证实SERCA2与Sigmar1相互作用，SERCA2的Q615是SERCA2与Sigmar1结合的关键残基。此外，Sigmar1通过Hrd1/Sel1L依赖的ER相关降解(ERAD)促进SERCA2的降解。K460和K541的SERCA2泛素化是其蛋白酶体降解的原因。因此，SERCA2的抑制阻碍了Sigmar1缺乏促进破骨细胞的形成。此外，我们发现FDA批准的Sigmar1激动剂地美芬在各种已建立的骨丢失模型中有效地挽救了骨量。综上所述，Sigmar1是破骨细胞生成的负性调节因子，地塞米芬对Sigmar1的激活可能成为临床治疗骨质疏松的一种潜在方法。地美沙芬激活Sigma-1受体可促进SERCA2的降解，导致破骨细胞形成减少。靶向Sigma-1受体和地塞米芬可能是治疗骨质疏松症的一种新的潜在方法。
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. Activation of Sigma‐1 receptor by dimemorfan promoted SERCA2 degradation, causing reduction in osteoclast formation. Targeting Sigma‐1 receptor and dimemorfan may be a novel potential therapeutic approach for osteoporosis.