ArticleEMBO molecular medicine2022
Sigma-1 receptor attenuates osteoclastogenesis by promoting ER-associated degradation of SERCA2.
Article in EMBO molecular medicine, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers, 1 of them a synthesis that pooled it.
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Who cites it
25 citing papers in PubMed, 1 synthesis or guideline pooled it, 33 citations in OpenAlex.
- Mitochondria: a breakthrough in combating rheumatoid arthritis.Frontiers in medicine · 2024Pooled it
- Mitochondria‑associated endoplasmic reticulum membranes in degenerative musculoskeletal disorders: Mechanistic evidence and therapeutic perspectives (Review).Molecular medicine reports · 2026Review
- SIGMAR1 Drives the Development of Neuropathic Pain by Promoting AMPA Receptor Membrane Trafficking Through Interacting with NPTX1 in Male Mice.Neuroscience bulletin · 2026Article
- SCD1 Regulates Osteoclast Differentiation by Modulating Arachidonic Acid Metabolism and Mitochondrial Homeostasis.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- Transplantation of AQP1-overexpressing mitochondria attenuates periodontitis-associated bone loss by regulating mitochondria-ER contacts of macrophages.Journal of nanobiotechnology · 2026Article
- Spectrum and functions of ion channels and transporters in osteoclasts.Bone research · 2026Review
- The pivotal role of mitochondria in osteoporosis: From pathogenesis to future therapies.Biochemistry and biophysics reports · 2026Review
- Cardiomyocyte-derived OTUD7B promotes cardiac hypertrophy by deubiquitinating SERCA2a.Theranostics · 2026Article
- Stage-dependent endoplasmic reticulum homeostasis in osteogenic differentiation.Frontiers in cell and developmental biology · 2026Review
- Sigma-1 receptor activation by PRE-084 attenuates sepsis-associated encephalopathy by targeting microglial p38 MAPK-mediated neuroinflammation and neuronal endoplasmic reticulum stress.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2025Article
- p22Nature cardiovascular research · 2025Article
- VDAC1 is a target for pharmacologically induced insulin hypersecretion in β cells.Cell reports · 2025Article
- SIGMAR1 screened by a GPCR-related classifier regulates endoplasmic reticulum stress in bladder cancer.Journal of translational medicine · 2025Article
- Metabolism and epigenetics in cancer: toward personalized treatment.Frontiers in endocrinology · 2025Review
- Advances in Functionalized Nanoparticles for Osteoporosis Treatment.International journal of nanomedicine · 2025Review
- Visomitin Attenuates Pathological Bone Loss by Reprogramming Osteoclast Metabolism via the STAT3/LDHB Axis.Research (Washington, D.C.) · 2025Article
- KCTD10 inhibits lung cancer metastasis and angiogenesis via ubiquitin-mediated β-catenin degradation.Frontiers in immunology · 2025Article
- β-Hydroxybutyrate suppresses M1 macrophage polarization through β-hydroxybutyrylation of the STAT1 protein.Cell death & disease · 2024Article
- Multifunctional nanomaterialsMaterials today. Bio · 2024Article
- Advances in the study of protein folding and endoplasmic reticulum-associated degradation in mammal cells.Journal of Zhejiang University. Science. B · 2024Review
Corrections and comments
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Authors and funding
15 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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