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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. Synopsis: 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. Loss of Sigma‐1 receptor was found to cause severe osteoporosis phenotype compared with WT mice.Activation of Sigma‐1 receptor both in vivo and in vitro rescued bone loss models and suppressed osteoclast formation.SERCA2 was interacted with Sigma‐1 receptor and degraded in ERAD pathway, leading to impaired osteoclast's relative gene expression.Long term use of dimemorfan in clinical practice made it a promising drug towards osteoporosis treatment. [ABSTRACT FROM AUTHOR]

Background: As an inflammatory factor and oncogenic driver protein, the pleiotropic cytokine macrophage migration inhibitory factor (MIF) plays a crucial role in the osteosarcoma microenvironment. Although 4‐iodo‐6‐phenylpyrimidine (4‐IPP) can inactivate MIF biological functions, its anti‐osteosarcoma effect and molecular mechanisms have not been investigated. In this study, we identified the MIF inhibitor 4‐IPP as a specific double‐effector drug for osteosarcoma with both anti‐tumour and anti‐osteoclastogenic functions. Methods: The anti‐cancer effects of 4‐IPP were evaluated by wound healing assay, cell cycle analysis, colony formation assay, CCK‐8 assay, apoptosis analysis, and Transwell migration/invasion assays. Through the application of a luciferase reporter, chromatin immunoprecipitation assays, and immunofluorescence and coimmunoprecipitation analyses, the transcriptional regulation of the NF‐κB/P‐TEFb complex on c‐Myb‐ and STUB1‐mediated proteasome‐dependent MIF protein degradation was confirmed. The effect of 4‐IPP on tumour growth and metastasis was assessed using an HOS‐derived tail vein metastasis model and subcutaneous and orthotopic xenograft tumour models. Results: In vitro, 4‐IPP significantly reduced the proliferation and metastasis of osteosarcoma cells by suppressing the NF‐κB pathway. 4‐IPP hindered the binding between MIF and CD74 as well as p65. Moreover, 4‐IPP inhibited MIF to interrupt the formation of downstream NF‐κB/P‐TEFb complexes, leading to the down‐regulation of c‐Myb transcription. Interestingly, the implementation of 4‐IPP can mediate small molecule‐induced MIF protein proteasomal degradation via the STUB1 E3 ligand. However, 4‐IPP still interrupted MIF‐mediated communication between osteosarcoma cells and osteoclasts, thus promoting osteoclastogenesis. Remarkably, 4‐IPP strongly reduced HOS‐derived xenograft osteosarcoma tumourigenesis and metastasis in an in vivo mouse model. Conclusions: Our findings demonstrate that the small molecule 4‐IPP targeting the MIF protein exerts an anti‐osteosarcoma effect by simultaneously inactivating the biological functions of MIF and promoting its proteasomal degradation. Direct destabilization of the MIF protein with 4‐IPP may be a promising therapeutic strategy for treating osteosarcoma. [ABSTRACT FROM AUTHOR]

Breathing process involves inhalation and exhalation of different gases in animals. The gas exchange of the breathing process plays a critical role in maintaining the physiological functions of living organisms. Although artificial breathing materials exhibiting volume expansion and contraction upon alternate exposure to different gases have been well explored, those being able to realize the gas exchange remain elusive. Herein, we report breathing micelles (BM) capable of inhaling nitric oxide (NO) and exhaling carbon monoxide (CO), both of which are endogenous gaseous signaling molecules. We demonstrate that BM can simultaneously scavenge overproduced NO and attenuate proinflammatory cytokines in lipopolysaccharide (LPS)‐challenged macrophage cells. In vivo studies revealed that BM outperformed conventional nonsteroidal anti‐inflammatory drugs such as dexamethasone (Dexa) in treatment of rheumatoid arthritis (RA) in adjuvant‐induced arthritis (AIA) rats, likely due to the combinatorial effect of NO depletion, CO‐mediated deactivation of inducible NO synthase (iNOS) and activation of heme oxygenase‐1 (HO‐1). This work provides new insights into artificial BM for potential biomedical applications. [ABSTRACT FROM AUTHOR]

Innentitelbild: Breathing Micelles for Combinatorial Treatment of Rheumatoid Arthritis (Angew. Keywords: anti-inflammatory; breathing micelles; carbon monoxide; nitric oxide; rheumatoid arthritis EN anti-inflammatory breathing micelles carbon monoxide nitric oxide rheumatoid arthritis 21974 21974 1 11/26/20 20201201 NES 201201 B Biomimetische "atmende" Mizellen b , die gleichzeitig Stickstoffoxid einatmen und Kohlenmonoxid ausatmen können, werden in der Zuschrift von T. You, J. Hu et al. auf S. 22048 vorgestellt. Anti-inflammatory, breathing micelles, carbon monoxide, nitric oxide, rheumatoid arthritis. [Extracted from the article]

Problem: The function of CD49a on human decidual natural killer (dNK) cells is unknown. Method of study: The expression of CD49a on dNK cells from human patients with recurrent spontaneous abortions or age‐matched healthy controls was analyzed by flow cytometry. DNK cells were treated with CD49a neutralizing antibody and analyzed for function (cytokines production and cytotoxic activity). Long non‐coding RNA (lncRNA) microarray analysis was used to identify a potential regulator of CD49a. Results: DNK cells from human patients who underwent recurrent spontaneous abortions had lower levels of CD49a and increased perforin, granzyme B, and IFN‐r expression, when compared to dNK cells from age‐matched healthy controls. Perforin, granzyme B, and IFN‐r expression levels in dNK cells were upregulated, while the migration and adhesion of dNK cells were downregulated by CD49a‐neutralizing antibody. By the 51Cr release assay, the killing activity of dNK cells also increased with CD49a neutralizing antibody. Further, lnc‐49a, a newly identified lncRNA, was shown to be a positive regulator of CD49a in primary human NK cells. Conclusion: CD49a is involved in the regulation of dNK cells functions, including cytotoxic activity, migration, and adhesion. Further, lnc‐49a is a positive regulator of CD49a in human primary dNK cells. [ABSTRACT FROM AUTHOR]