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.

中文翻译：

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Sigma-1 受体通过促进 ER 相关的 SERCA2 降解来减弱破骨细胞生成

Sigma-1 受体 (Sigmar1) 是一种位于线粒体相关内质网膜 (MAM) 中的特异性伴侣，在多种生理过程中发挥作用。然而，Sigmar1 在骨稳态中的作用仍然未知。在这里，我们发现缺乏 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 的过表达局部减轻了骨质疏松症的表型。用 Sigmar1 激动剂治疗在体外会损害人和小鼠破骨细胞的形成. 在机制上，基于免疫沉淀质谱 (IP-MS) 和免疫共沉淀 (co-IP) 分析，鉴定 SERCA2 与 Sigmar1 相互作用，并证实 SERCA2 的 Q615 是它们结合的关键残基。此外，Sigmar1 通过 Hrd1/Sel1L 依赖性 ER 相关降解 (ERAD) 促进 SERCA2 降解。SERCA2 在 K460 和 K541 的泛素化是其蛋白酶体降解的原因。因此，SERCA2 的抑制阻碍了 Sigmar1 缺乏增强了破骨细胞生成。此外，我们发现 FDA 批准的 Sigmar1 激动剂 dimemorfan 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调节因子，二甲莫凡对 Sigmar1 的激活可能是临床实践中治疗骨质疏松症的潜在方法。