DOCSLIB.ORG

Exuberant Fibroblast Activity Compromises Lung Function Via ADAMTS4

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Exuberant Fibroblast Activity Compromises Lung Function Via ADAMTS4 Article Exuberant fibroblast activity compromises lung function via ADAMTS4 https://doi.org/10.1038/s41586-020-2877-5 David F. Boyd1, E. Kaitlynn Allen1, Adrienne G. Randolph2,3, Xi-zhi J. Guo1, Yunceng Weng4, Catherine J. Sanders1, Resha Bajracharya1, Natalie K. Lee5, Clifford S. Guy1, Peter Vogel6, Received: 16 July 2019 Wenda Guan4, Yimin Li4, Xiaoqing Liu4, Tanya Novak2,3, Margaret M. Newhams2, Accepted: 30 July 2020 Thomas P. Fabrizio5, Nicholas Wohlgemuth5, Peter M. Mourani7, PALISI Pediatric Intensive Care Influenza (PICFLU) Investigators*, Thomas N. Wight8, Stacey Schultz-Cherry5, Published online: 28 October 2020 Stephania A. Cormier9,10, Kathryn Shaw-Saliba11, Andrew Pekosz12, Richard E. Rothman11, Check for updates Kuan-Fu Chen13,14, Zifeng Yang4, Richard J. Webby5, Nanshan Zhong4, Jeremy Chase Crawford1 & Paul G. Thomas1 ✉ Severe respiratory infections can result in acute respiratory distress syndrome (ARDS)1. There are no efective pharmacological therapies that have been shown to improve outcomes for patients with ARDS. Although the host infammatory response limits spread of and eventually clears the pathogen, immunopathology is a major contributor to tissue damage and ARDS1,2. Here we demonstrate that respiratory viral infection induces distinct fbroblast activation states, which we term extracellular matrix (ECM)-synthesizing, damage-responsive and interferon-responsive states. We provide evidence that excess activity of damage-responsive lung fbroblasts drives lethal immunopathology during severe infuenza virus infection. By producing ECM-remodelling enzymes—in particular the ECM protease ADAMTS4—and infammatory cytokines, damage-responsive fbroblasts modify the lung microenvironment to promote robust immune cell infltration at the expense of lung function. In three cohorts of human participants, the levels of ADAMTS4 in the lower respiratory tract were associated with the severity of infection with seasonal or avian infuenza virus. A therapeutic agent that targets the ECM protease activity of damage-responsive lung fbroblasts could provide a promising approach to preserving lung function and improving clinical outcomes following severe respiratory infections. Respiratory infections are a leading cause of morbidity and mortal- proteases are upregulated and remodel the ECM, facilitating the migra- ity3. These infections can result in ARDS with pulmonary oedema tion of immune cells to sites of inflammation5,7. Non-immune lung cells, and hypoxia, causing mild to severe respiratory failure1. Much of including epithelial cells, endothelial cells and fibroblasts, coordi- the lung damage induced by viral infection is a result of infiltrating nate immune responses and directly mediate lung function8. Through immune cells, which kill infected and bystander cells4. Defining the their remodelling activity, specific cell populations can influence the mechanisms that alter the balance between pathogen clearance and outcome of infection and long-term sequelae, as has been described for immunopathology may enable identification of strategies to improve myofibroblasts and lung fibrosis9. The role of lung stromal cell popula- outcomes following ARDS2. Therapeutic targets include components tions in coordinating host responses to active respiratory infections of the lung ECM, which provides structural support that is critical has received less attention than their role in late-stage repair following for lung function and tissue-specific signals to coordinate immune pathogen clearance. While there is extensive literature on how immune responses5. cells regulate the host response to respiratory viral infection8, there is The ECM consists of structural proteins as well as proteases and less information on the heterogeneity and role of non-haematopoietic glycosidases that degrade or modify the ECM6. Upon lung injury, ECM cells. 1Department of Immunology, St Jude Children’s Research Hospital, Memphis, TN, USA. 2Boston Children’s Hospital, Department of Anesthesiology, Critical Care and Pain Medicine, Boston, MA, USA. 3Department of Anesthesia, Harvard Medical School, Boston, MA, USA. 4State Key Laboratory of Respiratory Diseases, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China. 5Department of Infectious Diseases, St Jude Children’s Research Hospital, Memphis, TN, USA. 6Veterinary Pathology Core, St Jude Children’s Research Hospital, Memphis, TN, USA. 7Section of Critical Care Medicine, Department of Pediatrics, University of Colorado School of Medicine and Children’s Hospital Colorado, Aurora, CO, USA. 8Matrix Biology Program, Benaroya Research Institute, Seattle, WA, USA. 9Department of Biological Sciences, Louisiana State University, Baton Rouge, LA, USA. 10Pennington Biomedical Research Center, Baton Rouge, LA, USA. 11Department of Emergency Medicine and Medicine, Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD, USA. 12Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. 13Department of Emergency Medicine of Chang Gung Memorial Hospital at Keelung, Keelung City, Taiwan. 14Clinical Informatics and Medical Statistics Research Center of Chang Gung University, Taoyuan, Taiwan. *A list of authors and their affiliations appears at the end of the paper. ✉e-mail: [email protected] 466 | Nature | Vol 587 | 19 November 2020 a Inuenza A PR8 b Mouse lung cells Fig. 1 | Single-cell gene-expression profiling of Single•cell T cells − suspension Type 1 epithelial Type 2 epithelial CD45 cells during severe influenza A virus C57BL/6 mice Mast 1 dpi 3 dpi 6 dpi cells Pericytes Smooth infection. a, Schematic of sample collection for 0 dpi 25 muscle cells scGEX. SSC, side scatter. b, t-distributed stochastic Ciliated B cells Collect whole lungs epithelial neighbour embedding (t-SNE) projection of mouse – Sort CD45 cells Run scGEX Myeloid Label individual 0 lung cells based on scGEX. Data from all time points 250K (5′ 10× Genomics) Club cells lung samples 200K Platelets Lymphatic and mice were aggregated (n = 5 (0, 1 and 3 dpi), and 150K -SNE2 t endothelial C SS 100K n = 4 (6 dpi)). Approximately 40,800 individual cells 50K –25 Neutrophils 0 are represented in the figure. c, t-SNE projection of 10–3 0 103 104 105 Fibroblasts Vascular endothelial CD45 Mesothelial mouse mesenchymal cells expressing Col1a2. −25 025 t-SNE1 d, t-SNE projection of mouse mesenchymal cells at c Mouse mesenchymal cells d Days post-infection e different time points after infection. e, Summary of 50 Damage- ECM- ECM synthesis 0 dpi responsive Wnt + βcat sig. SMCs (2) GSEA comparing all cells in each cluster (cluster 1, 50 1 dpi synthesizing Resting 10 (4) TGFβ sig. ESFibs (8) 3 dpi (8) n = 1,188; cluster 2, n = 1,123; cluster 4, n = 892; Inammatory 13 Myogenesis DRFibs (4) 25 6 dpi Notch sig. IRFibs (6) 25 cluster 6, n = 749; cluster 8, n = 681). βcat, β-catenin; 0 8 ROS Col13a1 (1) 4 7 Hypoxia resp., response; ROS, reactive oxygen species; sig., 5 0 Complement 0 11 3 signalling; SMCs, smooth muscle cells. -SNE2 6 -SNE2 Coagulation t 16 t 14 Angiogenesis f, Expression of key genes in mouse lung 2 15 17 1 TNFα via NF-κβ –25 12 18 –25 IFNα resp. mesenchymal cells. g, Kinetics of fibroblast Interferon- Inammatory resp. 19 9 Col13a1 responsive IL-6 JAK STAT3 activation states. Representative flow cytometry (6) –50 –50 –5 0510 –40 –20 0 20 –40 –20 020 for ITGA5, CD9 and BST2 staining. h, Frequency of Normalized enrichment score t-SNE1 t-SNE1 DRFib and IRFib activation states during infection – – – fgGated on CD45 EpCAM CD31 h Damage-responsive (0 dpi, n = 5; 3 dpi, n = 4; 6 dpi, n = 3; 9 dpi, n = 4; 12 dpi, Bst2 Eln DRFibs hi lo ) – 50 Il33 Lum 0 dpi 12 dpi (ITGA5 CD9 ) n = 4; 21 dpi, n = 5). Data are mean ± s.e.m. Irf7 Dcn lo 40 105 105 Ifnar2 Timp3 CD31 – M 30 Tnfrsf1a Vcan 4 104 CD9 10 hi Il1r1 5 Timp1 20 Cxcl1 Cd9 103 103 Resting lo Il6 Itga5 (ITGA5 ITGA 10 Tnfaip6 Mmp23 0 0 CD9hi) Nfkb1 Lox (% of EpCA 0 036912 21 Tgfbr3 0 103 104 105 0 103 104 105 Adamts4 Time after infection (d) Tgfbi Adamts5 ITGA5–APC Interferon-responsive ) ) ) CD9–PE ) 50 – 105 105 hi 40 ) (2 SMC ) (2 SMC IRFib (6 IRFib IRFib (6) IRFib IRFibs CD31 ) (8 ESFib (8 ESFib DRFib (4 DRFib ) DRFib (4 DRFib 4 4 BST2 10 10 hi hi – ) (5 Resting ) (5 Resting (ITGA5 CD9 hi M 30 hi 9 Per cent Average Per cent Average 3 3 BST2 ) 10 10 CD 20 expressed expression expressed expression hi 25 2 25 2 0 0 10 1 50 1 50 ITGA5 0 75 0 3 4 5 3 4 5 (% of EpCA 75 BST2–FITC 0 10 10 10 0 10 10 10 0 –1 100 –1 036912 21 EpCAM–BV421 Time after infection (d) including NF-κB signalling and hypoxia, whereas IRFibs were enriched Stromal responses to influenza infection for type-I-interferon-responsive pathways (Fig. 1e, f, Extended Data We sorted live, CD45− lung cells from mice 0, 1, 3 and 6 days after infec- Fig. 2b). Analysis of five human lung biopsies identified fibroblast acti- tion with influenza A virus and performed single-cell gene-expression vation states analogous to those defined in mouse lungs (Extended Data profiling (scGEX) identifying three main populations: fibroblasts, epi- Fig. 2c) with clusters enriched for ECM synthesis, NF-κB signalling and thelial cells and endothelial cells (Fig. 1a, b, Extended Data Fig. 1a, b). type-I interferon signalling (Extended Data Fig. 2c, d). High levels of viral mRNA, indicative of productive infection, were To validate these fibroblast activation states, we identified genes detected primarily in type I pneumocytes, ciliated epithelial cells and encoding surface-protein markers that were enriched in DRFibs and type II pneumocytes (Extended Data Fig. 1c). Fibroblasts were particu- IRFibs in mouse and human lungs (Fig. 1f, Extended Data Figs. 2d, larly dynamic, with multiple transcriptional states emerging following 3a, b). Upregulation of Itga5 and downregulation of Cd9 defined the infection (Fig. 1c, d, Extended Data Fig.
Load more

Recommended publications
  • Role of Cyclosporine in Gingival Hyperplasia: an in Vitro Study on Gingival Fibroblasts
    International Journal of Molecular Sciences Article Role of Cyclosporine in Gingival Hyperplasia: An In Vitro Study on Gingival Fibroblasts 1, , 2, 3 3 Dorina Lauritano * y , Annalisa Palmieri y, Alberta Lucchese , Dario Di Stasio , Giulia Moreo 1 and Francesco Carinci 4 1 Department of Medicine and Surgery, Centre of Neuroscience of Milan, University of Milano-Bicocca, 20126 Milan, Italy; [email protected] 2 Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, via Belmoro 8, 40126 Bologna, Italy; [email protected] 3 Multidisciplinary Department of Medical and Dental Specialties, University of Campania-Luigi Vanvitelli, 80138 Naples, Italy; [email protected] (A.L.); [email protected] (D.D.S.) 4 Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, 44121 Ferrara, Italy; [email protected] * Correspondence: [email protected]; Tel.: +39-335-679-0163 These authors contributed equally to this work. y Received: 25 November 2019; Accepted: 13 January 2020; Published: 16 January 2020 Abstract: Background: Gingival hyperplasia could occur after the administration of cyclosporine A. Up to 90% of the patients submitted to immunosuppressant drugs have been reported to suffer from this side effect. The role of fibroblasts in gingival hyperplasia has been widely discussed by literature, showing contrasting results. In order to demonstrate the effect of cyclosporine A on the extracellular matrix component of fibroblasts, we investigated the gene expression profile of human fibroblasts after cyclosporine A administration. Materials and methods: Primary gingival fibroblasts were stimulated with 1000 ng/mL cyclosporine A solution for 16 h. Gene expression levels of 57 genes belonging to the “Extracellular Matrix and Adhesion Molecules” pathway were analyzed using real-time PCR in treated cells, compared to untreated cells used as control.
    [Show full text]
  • Regulation of Procollagen Amino-Propeptide Processing During Mouse Embryogenesis by Specialization of Homologous ADAMTS Protease
    DEVELOPMENT AND DISEASE RESEARCH ARTICLE 1587 Development 133, 1587-1596 (2006) doi:10.1242/dev.02308 Regulation of procollagen amino-propeptide processing during mouse embryogenesis by specialization of homologous ADAMTS proteases: insights on collagen biosynthesis and dermatosparaxis Carine Le Goff1, Robert P. T. Somerville1, Frederic Kesteloot2, Kimerly Powell1, David E. Birk3, Alain C. Colige2 and Suneel S. Apte1,* Mutations in ADAMTS2, a procollagen amino-propeptidase, cause severe skin fragility, designated as dermatosparaxis in animals, and a subtype of the Ehlers-Danlos syndrome (dermatosparactic type or VIIC) in humans. Not all collagen-rich tissues are affected to the same degree, which suggests compensation by the ADAMTS2 homologs ADAMTS3 and ADAMTS14. In situ hybridization of Adamts2, Adamts3 and Adamts14, and of the genes encoding the major fibrillar collagens, Col1a1, Col2a1 and Col3a1, during mouse embryogenesis, demonstrated distinct tissue-specific, overlapping expression patterns of the protease and substrate genes. Adamts3, but not Adamts2 or Adamts14, was co-expressed with Col2a1 in cartilage throughout development, and with Col1a1 in bone and musculotendinous tissues. ADAMTS3 induced procollagen I processing in dermatosparactic fibroblasts, suggesting a role in procollagen I processing during musculoskeletal development. Adamts2, but not Adamts3 or Adamts14, was co-expressed with Col3a1 in many tissues including the lungs and aorta, and Adamts2–/– mice showed widespread defects in procollagen III processing. Adamts2–/– mice had abnormal lungs, characterized by a decreased parenchymal density. However, the aorta and collagen fibrils in the aortic wall appeared normal. Although Adamts14 lacked developmental tissue-specific expression, it was co-expressed with Adamts2 in mature dermis, which possibly explains the presence of some processed skin procollagen in dermatosparaxis.
    [Show full text]
  • What Are the Roles of Metalloproteinases in Cartilage and Bone Damage? G Murphy, M H Lee
    iv44 Ann Rheum Dis: first published as 10.1136/ard.2005.042465 on 20 October 2005. Downloaded from REPORT What are the roles of metalloproteinases in cartilage and bone damage? G Murphy, M H Lee ............................................................................................................................... Ann Rheum Dis 2005;64:iv44–iv47. doi: 10.1136/ard.2005.042465 enzyme moiety into an upper and a lower subdomain. A A role for metalloproteinases in the pathological destruction common five stranded beta-sheet and two alpha-helices are in diseases such as rheumatoid arthritis and osteoarthritis, always found in the upper subdomain with a further C- and the irreversible nature of the ensuing cartilage and bone terminal helix in the lower subdomain. The catalytic sites of damage, have been the focus of much investigation for the metalloproteinases, especially the MMPs, have been several decades. This has led to the development of broad targeted for the development of low molecular weight spectrum metalloproteinase inhibitors as potential therapeu- synthetic inhibitors with a zinc chelating moiety. Inhibitors tics. More recently it has been appreciated that several able to fully differentiate between individual enzymes have families of zinc dependent proteinases play significant and not been identified thus far, although a reasonable level of varied roles in the biology of the resident cells in these tissues, discrimination is now being achieved in some cases.7 Each orchestrating development, remodelling, and subsequent family does, however, have other unique domains with pathological processes. They also play key roles in the numerous roles, including the determination of physiological activity of inflammatory cells. The task of elucidating the substrate specificity, ECM, or cell surface localisation (fig 1).
    [Show full text]
  • Quantikine® ELISA
    Quantikine® ELISA Human ADAMTS13 Immunoassay Catalog Number DADT130 For the quantitative determination of human A Disintegrin And Metalloproteinase with Thombospondin type 1 motif, 13 (ADAMTS13) concentrations in cell culture supernates, serum, and plasma. This package insert must be read in its entirety before using this product. For research use only. Not for use in diagnostic procedures. TABLE OF CONTENTS SECTION PAGE INTRODUCTION .....................................................................................................................................................................1 PRINCIPLE OF THE ASSAY ...................................................................................................................................................2 LIMITATIONS OF THE PROCEDURE .................................................................................................................................2 TECHNICAL HINTS .................................................................................................................................................................2 MATERIALS PROVIDED & STORAGE CONDITIONS ...................................................................................................3 OTHER SUPPLIES REQUIRED .............................................................................................................................................4 PRECAUTIONS .........................................................................................................................................................................4
    [Show full text]
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • Cloning of ADAMTS2 Gene and Colony Formation Effect of ADAMTS2 in Saos-2 Cell Line Under Normal and Hypoxic Conditions, ADYU J SCI, 10(2), 413-426
    Aydogan Türkoğlu & Gültekin Tosun (2020) Cloning of ADAMTS2 Gene and Colony Formation Effect of ADAMTS2 in Saos-2 Cell Line Under Normal and Hypoxic Conditions, ADYU J SCI, 10(2), 413-426 Cloning of ADAMTS2 Gene and Colony Formation Effect of ADAMTS2 in Saos-2 Cell Line Under Normal and Hypoxic Conditions Sümeyye AYDOGAN TÜRKOĞLU1,*, Sinem GÜLTEKİN TOSUN2 1Balıkesir University, Faculty of Science and Literature, Department of Molecular Biology and Genetics, Balıkesir, Turkey [email protected], ORCID: 0000-0003-1754-0700 2Erciyes University, Institute of Health Sciences, Faculty of Veterinary Medicine, Department of Genetics, Kayseri, Turkey [email protected], ORCID: 0000-0002-3927-0089 Received: 03.05.2020 Accepted: 25.09.2020 Published: 30.12.2020 Abstract ADAMTS2 (a disintegrin and metalloproteinase with thrombospondin motifs 2), an N- propeptidase isoenzyme, is an enzyme involved in collagen biosynthesis by providing the amino ends of procollagen to be cut away. ADAMTS2 has anti-angiogenic activity as well as provides the processing of collagen. With this activity, it has become a target in cancer studies. Hypoxic regulation is a process that affects the expression of a large number of genes at the cellular level. Within the scope of our study, the cloning of the ADAMTS2 gene and its expression in Saos-2 (human bone carcinoma) cell line were performed ectopically. For this purpose, the transient transfection of the expression vector containing ADAMTS2 coding sequence was transfected by the calcium-phosphate precipitation method. Recombinant ADAMTS2 mRNA expression was checked by Real-Time PCR in Saos-2 cells. It was observed that there was a 50-fold increase in ADAMTS2 mRNA expression in the transfected Saos-2 cells compared to the control group.
    [Show full text]
  • Comparative Transcriptome Analysis of Embryo Invasion in the Mink Uterus
    Placenta 75 (2019) 16–22 Contents lists available at ScienceDirect Placenta journal homepage: www.elsevier.com/locate/placenta Comparative transcriptome analysis of embryo invasion in the mink uterus T ∗ Xinyan Caoa,b, , Chao Xua,b, Yufei Zhanga,b, Haijun Weia,b, Yong Liuc, Junguo Caoa,b, Weigang Zhaoa,b, Kun Baoa,b, Qiong Wua,b a Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun, China b State Key Laboratory for Molecular Biology of Special Economic Animal and Plant Science, Chinese Academy of Agricultural Sciences, Changchun, China c Key Laboratory of Embryo Development and Reproductive Regulation of Anhui Province, College of Biological and Food Engineering, Fuyang Teachers College, Fuyang, China ABSTRACT Introduction: In mink, as many as 65% of embryos die during gestation. The causes and the mechanisms of embryonic mortality remain unclear. The purpose of our study was to examine global gene expression changes during embryo invasion in mink, and thereby to identify potential signaling pathways involved in implantation failure and early pregnancy loss. Methods: Illumina's next-generation sequencing technology (RNA-Seq) was used to analyze the differentially expressed genes (DEGs) in implantation (IMs) and inter- implantation sites (inter-IMs) of uterine tissue. Results: We identified a total of 606 DEGs, including 420 up- and 186 down-regulated genes in IMs compared to inter-IMs. Gene annotation analysis indicated multiple biological pathways to be significantly enriched for DEGs, including immune response, ECM complex, cytokine activity, chemokine activity andprotein binding. The KEGG pathway including cytokine-cytokine receptor interaction, Jak-STAT, TNF and the chemokine signaling pathway were the most enriched.
    [Show full text]
  • ADAMTS13 and 15 Are Not Regulated by the Full Length and N‑Terminal Domain Forms of TIMP‑1, ‑2, ‑3 and ‑4
    BIOMEDICAL REPORTS 4: 73-78, 2016 ADAMTS13 and 15 are not regulated by the full length and N‑terminal domain forms of TIMP‑1, ‑2, ‑3 and ‑4 CENQI GUO, ANASTASIA TSIGKOU and MENG HUEE LEE Department of Biological Sciences, Xian Jiaotong-Liverpool University, Suzhou, Jiangsu 215123, P.R. China Received June 29, 2015; Accepted July 15, 2015 DOI: 10.3892/br.2015.535 Abstract. A disintegrin and metalloproteinase with thom- proteolysis activities associated with arthritis, morphogenesis, bospondin motifs (ADAMTS) 13 and 15 are secreted zinc angiogenesis and even ovulation [as reviewed previously (1,2)]. proteinases involved in the turnover of von Willebrand factor Also known as the VWF-cleaving protease, ADAMTS13 and cancer suppression. In the present study, ADAMTS13 is noted for its ability in cleaving and reducing the size of the and 15 were subjected to inhibition studies with the full-length ultra-large (UL) form of the VWF. Reduction in ADAMTS13 and N-terminal domain forms of tissue inhibitor of metallo- activity from either hereditary or acquired deficiency causes proteinases (TIMPs)-1 to -4. TIMPs have no ability to inhibit accumulation of UL-VWF multimers, platelet aggregation and the ADAMTS proteinases in the full-length or N-terminal arterial thrombosis that leads to fatal thrombotic thrombocy- domain form. While ADAMTS13 is also not sensitive to the topenic purpura [as reviewed previously (1,3)]. By contrast, hydroxamate inhibitors, batimastat and ilomastat, ADAMTS15 ADAMTS15 is a potential tumor suppressor. Only a limited app can be effectively inhibited by batimastat (Ki 299 nM). In number of in-depth investigations have been carried out on the conclusion, the present results indicate that TIMPs are not the enzyme; however, expression and profiling studies have shown regulators of these two ADAMTS proteinases.
    [Show full text]
  • ADAMTS Proteases in Vascular Biology
    Review MATBIO-1141; No. of pages: 8; 4C: 3, 6 ADAMTS proteases in vascular biology Juan Carlos Rodríguez-Manzaneque 1, Rubén Fernández-Rodríguez 1, Francisco Javier Rodríguez-Baena 1 and M. Luisa Iruela-Arispe 2 1 - GENYO, Centre for Genomics and Oncological Research, Pfizer, Universidad de Granada, Junta de Andalucía, 18016 Granada, Spain 2 - Department of Molecular, Cell, and Developmental Biology, Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA Correspondence to Juan Carlos Rodríguez-Manzaneque and M. Luisa Iruela-Arispe: J.C Rodríguez-Manzaneque is to be contacted at: GENYO, 15 PTS Granada - Avda. de la Ilustración 114, Granada 18016, Spain; M.L. Iruela-Arispe, Department of Molecular, Cell and Developmental Biology, UCLA, 615 Charles Young Drive East, Los Angeles, CA 90095, USA. [email protected]; [email protected] http://dx.doi.org/10.1016/j.matbio.2015.02.004 Edited by W.C. Parks and S. Apte Abstract ADAMTS (a disintegrin and metalloprotease with thrombospondin motifs) proteases comprise the most recently discovered branch of the extracellular metalloenzymes. Research during the last 15 years, uncovered their association with a variety of physiological and pathological processes including blood coagulation, tissue repair, fertility, arthritis and cancer. Importantly, a frequent feature of ADAMTS enzymes relates to their effects on vascular-related phenomena, including angiogenesis. Their specific roles in vascular biology have been clarified by information on their expression profiles and substrate specificity. Through their catalytic activity, ADAMTS proteases modify rather than degrade extracellular proteins. They predominantly target proteoglycans and glycoproteins abundant in the basement membrane, therefore their broad contributions to the vasculature should not come as a surprise.
    [Show full text]
  • The Diverse Roles of TIMP-3: Insights Into Degenerative Diseases of the Senescent Retina and Brain
    cells Review The Diverse Roles of TIMP-3: Insights into Degenerative Diseases of the Senescent Retina and Brain Jennifer M. Dewing 1, Roxana O. Carare 1, Andrew J. Lotery 1,2 and J. Arjuna Ratnayaka 1,* 1 Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, MP806, Tremona Road, Southampton SO16 6YD, UK; [email protected] (J.M.D.); [email protected] (R.O.C.); [email protected] (A.J.L.) 2 Eye Unit, University Hospital Southampton NHS Foundation Trust, Southampton SO16 6YD, UK * Correspondence: [email protected]; Tel.: +44-238120-8183 Received: 13 November 2019; Accepted: 19 December 2019; Published: 21 December 2019 Abstract: Tissue inhibitor of metalloproteinase-3 (TIMP-3) is a component of the extracellular environment, where it mediates diverse processes including matrix regulation/turnover, inflammation and angiogenesis. Rare TIMP-3 risk alleles and mutations are directly linked with retinopathies such as age-related macular degeneration (AMD) and Sorsby fundus dystrophy, and potentially, through indirect mechanisms, with Alzheimer’s disease. Insights into TIMP-3 activities may be gleaned from studying Sorsby-linked mutations. However, recent findings do not fully support the prevailing hypothesis that a gain of function through the dimerisation of mutated TIMP-3 is responsible for retinopathy. Findings from Alzheimer’s patients suggest a hitherto poorly studied relationship between TIMP-3 and the Alzheimer’s-linked amyloid-beta (Aβ) proteins that warrant further scrutiny. This may also have implications for understanding AMD as aged/diseased retinae contain high levels of Aβ. Findings from TIMP-3 knockout and mutant knock-in mice have not led to new treatments, particularly as the latter does not satisfactorily recapitulate the Sorsby phenotype.
    [Show full text]
  • Supplementary Table 1: Adhesion Genes Data Set
    Supplementary Table 1: Adhesion genes data set PROBE Entrez Gene ID Celera Gene ID Gene_Symbol Gene_Name 160832 1 hCG201364.3 A1BG alpha-1-B glycoprotein 223658 1 hCG201364.3 A1BG alpha-1-B glycoprotein 212988 102 hCG40040.3 ADAM10 ADAM metallopeptidase domain 10 133411 4185 hCG28232.2 ADAM11 ADAM metallopeptidase domain 11 110695 8038 hCG40937.4 ADAM12 ADAM metallopeptidase domain 12 (meltrin alpha) 195222 8038 hCG40937.4 ADAM12 ADAM metallopeptidase domain 12 (meltrin alpha) 165344 8751 hCG20021.3 ADAM15 ADAM metallopeptidase domain 15 (metargidin) 189065 6868 null ADAM17 ADAM metallopeptidase domain 17 (tumor necrosis factor, alpha, converting enzyme) 108119 8728 hCG15398.4 ADAM19 ADAM metallopeptidase domain 19 (meltrin beta) 117763 8748 hCG20675.3 ADAM20 ADAM metallopeptidase domain 20 126448 8747 hCG1785634.2 ADAM21 ADAM metallopeptidase domain 21 208981 8747 hCG1785634.2|hCG2042897 ADAM21 ADAM metallopeptidase domain 21 180903 53616 hCG17212.4 ADAM22 ADAM metallopeptidase domain 22 177272 8745 hCG1811623.1 ADAM23 ADAM metallopeptidase domain 23 102384 10863 hCG1818505.1 ADAM28 ADAM metallopeptidase domain 28 119968 11086 hCG1786734.2 ADAM29 ADAM metallopeptidase domain 29 205542 11085 hCG1997196.1 ADAM30 ADAM metallopeptidase domain 30 148417 80332 hCG39255.4 ADAM33 ADAM metallopeptidase domain 33 140492 8756 hCG1789002.2 ADAM7 ADAM metallopeptidase domain 7 122603 101 hCG1816947.1 ADAM8 ADAM metallopeptidase domain 8 183965 8754 hCG1996391 ADAM9 ADAM metallopeptidase domain 9 (meltrin gamma) 129974 27299 hCG15447.3 ADAMDEC1 ADAM-like,
    [Show full text]
  • Suramin Inhibits Osteoarthritic Cartilage Degradation by Increasing Extracellular Levels
    Molecular Pharmacology Fast Forward. Published on August 10, 2017 as DOI: 10.1124/mol.117.109397 This article has not been copyedited and formatted. The final version may differ from this version. MOL #109397 Suramin inhibits osteoarthritic cartilage degradation by increasing extracellular levels of chondroprotective tissue inhibitor of metalloproteinases 3 (TIMP-3). Anastasios Chanalaris, Christine Doherty, Brian D. Marsden, Gabriel Bambridge, Stephen P. Wren, Hideaki Nagase, Linda Troeberg Arthritis Research UK Centre for Osteoarthritis Pathogenesis, Kennedy Institute of Downloaded from Rheumatology, University of Oxford, Roosevelt Drive, Headington, Oxford OX3 7FY, UK (A.C., C.D., G.B., H.N., L.T.); Alzheimer’s Research UK Oxford Drug Discovery Institute, University of Oxford, Oxford, OX3 7FZ, UK (S.P.W.); Structural Genomics Consortium, molpharm.aspetjournals.org University of Oxford, Old Road Campus Research Building, Old Road Campus, Roosevelt Drive, Headington, Oxford, OX3 7DQ (BDM). at ASPET Journals on September 29, 2021 1 Molecular Pharmacology Fast Forward. Published on August 10, 2017 as DOI: 10.1124/mol.117.109397 This article has not been copyedited and formatted. The final version may differ from this version. MOL #109397 Running title: Repurposing suramin to inhibit osteoarthritic cartilage loss. Corresponding author: Linda Troeberg Address: Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Headington, Oxford OX3 7FY, UK Phone number: +44 (0)1865 612600 E-mail: [email protected] Downloaded
    [Show full text]