Augustin Latourte, Sarah Jaulerry, Alice Combier, Chahrazad Cherifi, Yohan Jouan, Thierry Grange, Julien Daligault, Hang-Korng Ea, Martine Cohen-Solal, Eric Hay, Pascal Richette
Objectives: Inflammatory mediators such as interleukin 6 (IL-6) are known to activate catabolic responses in chondrocytes during osteoarthritis (OA). This study aimed to investigate the role of a downstream target gene of IL-6, the serine protease inhibitor SerpinA3N, in the development of cartilage damage in OA.
Methods: RNA sequencing was performed in murine primary chondrocytes treated with IL-6, and identified target genes were confirmed in human and murine OA cartilage samples. Male cartilage-specific Serpina3n-deficient mice and control mice underwent meniscectomy (MNX) or sham surgery at 10 weeks of age. Intra-articular injections of SerpinA3N or sivelestat (an inhibitor of leucocyte elastase (LE), a substrate for SerpinA3N) were performed in wild-type mice after MNX. Joint damage was assessed 3-9 weeks after surgery by histology and micro-CT. The effect of sivelestat was assessed in cartilage explants exposed to macrophage-derived conditioned media.
Results: RNA sequencing revealed that SerpinA3N is a major target gene of IL-6 in chondrocytes. The expression of SerpinA3N is increased in OA cartilage. Conditional loss of SerpinA3N in chondrocytes aggravated OA in mice, while intra-articular injection of SerpinA3N limited joint damage. Chondrocytes did not produce serine proteases targeted by SerpinA3N. By contrast, macrophages produced LE on IL-6 stimulation. Sivelestat limited the cartilage catabolism induced by conditioned media derived from IL-6-stimulated macrophages. Additionally, an intra-articular injection of sivelestat is protected against OA in the MNX model.
Conclusions: SerpinA3N protects cartilage against catabolic factors produced by macrophages, including LE. SerpinA3N and LE represent new therapeutic targets to dampen cartilage damage in OA.
{"title":"SerpinA3N limits cartilage destruction in osteoarthritis by inhibiting macrophage-derived leucocyte elastase.","authors":"Augustin Latourte, Sarah Jaulerry, Alice Combier, Chahrazad Cherifi, Yohan Jouan, Thierry Grange, Julien Daligault, Hang-Korng Ea, Martine Cohen-Solal, Eric Hay, Pascal Richette","doi":"10.1136/ard-2024-225645","DOIUrl":"10.1136/ard-2024-225645","url":null,"abstract":"<p><strong>Objectives: </strong>Inflammatory mediators such as interleukin 6 (IL-6) are known to activate catabolic responses in chondrocytes during osteoarthritis (OA). This study aimed to investigate the role of a downstream target gene of IL-6, the serine protease inhibitor SerpinA3N, in the development of cartilage damage in OA.</p><p><strong>Methods: </strong>RNA sequencing was performed in murine primary chondrocytes treated with IL-6, and identified target genes were confirmed in human and murine OA cartilage samples. Male cartilage-specific <i>Serpina3n</i>-deficient mice and control mice underwent meniscectomy (MNX) or sham surgery at 10 weeks of age. Intra-articular injections of SerpinA3N or sivelestat (an inhibitor of leucocyte elastase (LE), a substrate for SerpinA3N) were performed in wild-type mice after MNX. Joint damage was assessed 3-9 weeks after surgery by histology and micro-CT. The effect of sivelestat was assessed in cartilage explants exposed to macrophage-derived conditioned media.</p><p><strong>Results: </strong>RNA sequencing revealed that SerpinA3N is a major target gene of IL-6 in chondrocytes. The expression of SerpinA3N is increased in OA cartilage. Conditional loss of SerpinA3N in chondrocytes aggravated OA in mice, while intra-articular injection of SerpinA3N limited joint damage. Chondrocytes did not produce serine proteases targeted by SerpinA3N. By contrast, macrophages produced LE on IL-6 stimulation. Sivelestat limited the cartilage catabolism induced by conditioned media derived from IL-6-stimulated macrophages. Additionally, an intra-articular injection of sivelestat is protected against OA in the MNX model.</p><p><strong>Conclusions: </strong>SerpinA3N protects cartilage against catabolic factors produced by macrophages, including LE. SerpinA3N and LE represent new therapeutic targets to dampen cartilage damage in OA.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":" ","pages":"1781-1790"},"PeriodicalIF":20.3,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141970470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cecilia Leijding, Suchada Kaewin, Kristofer M Andreasson, Begum Horuluoglu, Angeles Shunashy Galindo-Feria, Eveline Van Gompel, Maryam Dastmalchi, Stefano Gastaldello, Helene Alexanderson, Ingrid E Lundberg, Daniel C Andersson
{"title":"Serum from patients with idiopathic inflammatory myopathy induces skeletal muscle weakness.","authors":"Cecilia Leijding, Suchada Kaewin, Kristofer M Andreasson, Begum Horuluoglu, Angeles Shunashy Galindo-Feria, Eveline Van Gompel, Maryam Dastmalchi, Stefano Gastaldello, Helene Alexanderson, Ingrid E Lundberg, Daniel C Andersson","doi":"10.1136/ard-2024-225912","DOIUrl":"10.1136/ard-2024-225912","url":null,"abstract":"","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":" ","pages":"1796-1797"},"PeriodicalIF":20.3,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142091709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-13DOI: 10.1016/j.chom.2024.10.007
Alexandra Grote
Tuberculosis remains a formidable global health challenge, with Mycobacterium tuberculosis responsible for millions of cases and deaths annually. In this issue of Cell Host & Microbe, Worakitchanon et al. present a method to identify structural variants in Mtb and explore associations with bacterial phenotypes such as virulence and antibiotic resistance.
{"title":"INDELible impact: How structural variants drive virulence and resistance","authors":"Alexandra Grote","doi":"10.1016/j.chom.2024.10.007","DOIUrl":"https://doi.org/10.1016/j.chom.2024.10.007","url":null,"abstract":"Tuberculosis remains a formidable global health challenge, with <em>Mycobacterium tuberculosis</em> responsible for millions of cases and deaths annually. In this issue of <em>Cell Host & Microbe</em>, Worakitchanon et al. present a method to identify structural variants in Mtb and explore associations with bacterial phenotypes such as virulence and antibiotic resistance.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"5 1","pages":""},"PeriodicalIF":30.3,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601049","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-13DOI: 10.1016/j.chom.2024.10.010
Elena Monzel, Mahesh S. Desai
The functions of non-coding small RNAs (sRNAs) within the human microbiome remain largely unexplored. In this Cell Host & Microbe issue, El Mouali et al. identify Segatella RNA colonization factor (SrcF), a sRNA from a prevalent gut bacterium Segatella copri. SrcF promotes colonization of S. copri by regulating bacterial degradation of complex dietary carbohydrates.
{"title":"Bacterial small RNA makes a big impact for gut colonization","authors":"Elena Monzel, Mahesh S. Desai","doi":"10.1016/j.chom.2024.10.010","DOIUrl":"https://doi.org/10.1016/j.chom.2024.10.010","url":null,"abstract":"The functions of non-coding small RNAs (sRNAs) within the human microbiome remain largely unexplored. In this <em>Cell Host & Microbe</em> issue, El Mouali et al. identify <em>Segatella</em> RNA colonization factor (SrcF), a sRNA from a prevalent gut bacterium <em>Segatella copri</em>. SrcF promotes colonization of <em>S. copri</em> by regulating bacterial degradation of complex dietary carbohydrates.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"2 1","pages":""},"PeriodicalIF":30.3,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-13DOI: 10.1016/j.chom.2024.10.011
Wei Peng, Kim Orth
Microcins are antibacterial small proteins secreted by gram-negative bacteria. In this issue of Cell Host & Microbe, Kim et al. report the discovery of a V. cholerae microcin, MvcC. MvcC shows antibacterial activity against non-self V. cholerae strains, which do not encode the cognate immunity protein.
{"title":"A small microcin plays a big role in V. cholerae interbacterial competition","authors":"Wei Peng, Kim Orth","doi":"10.1016/j.chom.2024.10.011","DOIUrl":"https://doi.org/10.1016/j.chom.2024.10.011","url":null,"abstract":"Microcins are antibacterial small proteins secreted by gram-negative bacteria. In this issue of <em>Cell Host & Microbe</em>, Kim et al. report the discovery of a <em>V. cholerae</em> microcin, MvcC. MvcC shows antibacterial activity against non-self <em>V. cholerae</em> strains, which do not encode the cognate immunity protein.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"45 1","pages":""},"PeriodicalIF":30.3,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-13DOI: 10.1016/j.chom.2024.10.009
Charlie Y. Mo
Bacteriophages have evolved numerous mechanisms to evade targeting by CRISPR-Cas defense systems. However, the evolutionary origin of these so-called “anti-CRISPRs” remains poorly understood. In a recent issue of Nature, Katz et al.1 provide evidence that some anti-CRISPRs were derived from genes of the CRISPR-Cas systems themselves.
{"title":"If you can’t beat them, join them: Anti-CRISPR proteins derived from CRISPR-associated genes","authors":"Charlie Y. Mo","doi":"10.1016/j.chom.2024.10.009","DOIUrl":"https://doi.org/10.1016/j.chom.2024.10.009","url":null,"abstract":"Bacteriophages have evolved numerous mechanisms to evade targeting by CRISPR-Cas defense systems. However, the evolutionary origin of these so-called “anti-CRISPRs” remains poorly understood. In a recent issue of <em>Nature</em>, Katz et al.<span><span><sup>1</sup></span></span> provide evidence that some anti-CRISPRs were derived from genes of the CRISPR-Cas systems themselves.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"2 1","pages":""},"PeriodicalIF":30.3,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-13DOI: 10.1016/j.chom.2024.10.014
Xiaonan Han, Qingrui Huang, Jinghua Yan
In recent work, Mucker et al.1 demonstrated that mRNA-1769 outperforms modified vaccinia Ankara (MVA), which has been deployed against recent mpox virus (MPXV) outbreaks, in reducing clinical symptoms and controlling viral replication, highlighting its potential as a scalable, safe, and effective next-generation platform for orthopoxvirus vaccination.
{"title":"mRNA vaccines: A promising platform for safer, more effective next-generation Orthopoxvirus immunization","authors":"Xiaonan Han, Qingrui Huang, Jinghua Yan","doi":"10.1016/j.chom.2024.10.014","DOIUrl":"https://doi.org/10.1016/j.chom.2024.10.014","url":null,"abstract":"In recent work, Mucker et al.<span><span><sup>1</sup></span></span> demonstrated that mRNA-1769 outperforms modified vaccinia Ankara (MVA), which has been deployed against recent mpox virus (MPXV) outbreaks, in reducing clinical symptoms and controlling viral replication, highlighting its potential as a scalable, safe, and effective next-generation platform for orthopoxvirus vaccination.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"35 1","pages":""},"PeriodicalIF":30.3,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-13DOI: 10.1016/j.chom.2024.10.013
Huihui Sun, Guan-Hong Wang
In this issue of Cell Host & Microbe, Zhong et al.1 uncover gut microbiota-host connections that promote cognitive function in honeybees. They discover the role of the microbiota in lipid metabolism and the synthesis of lipid-derived neurotransmitters, which modulate the endocannabinoid system.
{"title":"Microbial alchemists unlock honeybee cognition","authors":"Huihui Sun, Guan-Hong Wang","doi":"10.1016/j.chom.2024.10.013","DOIUrl":"https://doi.org/10.1016/j.chom.2024.10.013","url":null,"abstract":"In this issue of <em>Cell Host & Microbe</em>, Zhong et al.<span><span><sup>1</sup></span></span> uncover gut microbiota-host connections that promote cognitive function in honeybees. They discover the role of the microbiota in lipid metabolism and the synthesis of lipid-derived neurotransmitters, which modulate the endocannabinoid system.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"36 1","pages":""},"PeriodicalIF":30.3,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601047","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-13DOI: 10.1038/s41564-024-01845-0
Plasmid conjugation has been extensively studied over the past decades. Yet, in most plasmids, the minimal region required for conjugation (the origin of transfer (oriT) sequence) is unknown. The characterization of known oriTs enabled the development of a validated method to identify genomic regions with novel families of oriTs across bacterial plasmids.
{"title":"A method to detect origin of transfer sequences for plasmid conjugation","authors":"","doi":"10.1038/s41564-024-01845-0","DOIUrl":"https://doi.org/10.1038/s41564-024-01845-0","url":null,"abstract":"Plasmid conjugation has been extensively studied over the past decades. Yet, in most plasmids, the minimal region required for conjugation (the origin of transfer (oriT) sequence) is unknown. The characterization of known oriTs enabled the development of a validated method to identify genomic regions with novel families of oriTs across bacterial plasmids.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"19 1","pages":""},"PeriodicalIF":28.3,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601053","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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