42
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Regulation of ADAMTS Proteases

      review-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          A disintegrin and metalloprotease with thrombospondin type I motifs (ADAMTS) proteases are secreted metalloproteinases that play key roles in the formation, homeostasis and remodeling of the extracellular matrix (ECM). The substrate spectrum of ADAMTS proteases can range from individual ECM proteins to entire families of ECM proteins, such as the hyalectans. ADAMTS-mediated substrate cleavage is required for the formation, remodeling and physiological adaptation of the ECM to the needs of individual tissues and organ systems. However, ADAMTS proteases can also be involved in the destruction of tissues, resulting in pathologies such as arthritis. Specifically, ADAMTS4 and ADAMTS5 contribute to irreparable cartilage erosion by degrading aggrecan, which is a major constituent of cartilage. Arthritic joint damage is a major contributor to musculoskeletal morbidity and the most frequent clinical indication for total joint arthroplasty. Due to the high sequence homology of ADAMTS proteases in their catalytically active site, it remains a formidable challenge to design ADAMTS isotype-specific inhibitors that selectively inhibit ADAMTS proteases responsible for tissue destruction without affecting the beneficial functions of other ADAMTS proteases. In vivo, proteolytic activity of ADAMTS proteases is regulated on the transcriptional and posttranslational level. Here, we review the current knowledge of mechanisms that regulate ADAMTS protease activity in tissues including factors that induce ADAMTS gene expression, consequences of posttranslational modifications such as furin processing, the role of endogenous inhibitors and pharmacological approaches to limit ADAMTS protease activity in tissues, which almost exclusively focus on inhibiting the aggrecanase activity of ADAMTS4 and ADAMTS5.

          Related collections

          Most cited references158

          • Record: found
          • Abstract: found
          • Article: found
          Is Open Access

          The EMBL-EBI search and sequence analysis tools APIs in 2019

          Abstract The EMBL-EBI provides free access to popular bioinformatics sequence analysis applications as well as to a full-featured text search engine with powerful cross-referencing and data retrieval capabilities. Access to these services is provided via user-friendly web interfaces and via established RESTful and SOAP Web Services APIs (https://www.ebi.ac.uk/seqdb/confluence/display/JDSAT/EMBL-EBI+Web+Services+APIs+-+Data+Retrieval). Both systems have been developed with the same core principles that allow them to integrate an ever-increasing volume of biological data, making them an integral part of many popular data resources provided at the EMBL-EBI. Here, we describe the latest improvements made to the frameworks which enhance the interconnectivity between public EMBL-EBI resources and ultimately enhance biological data discoverability, accessibility, interoperability and reusability.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Role of proinflammatory cytokines in the pathophysiology of osteoarthritis.

            Osteoarthritis (OA) is associated with cartilage destruction, subchondral bone remodeling and inflammation of the synovial membrane, although the etiology and pathogenesis underlying this debilitating disease are poorly understood. Secreted inflammatory molecules, such as proinflammatory cytokines, are among the critical mediators of the disturbed processes implicated in OA pathophysiology. Interleukin (IL)-1β and tumor necrosis factor (TNF), in particular, control the degeneration of articular cartilage matrix, which makes them prime targets for therapeutic strategies. Animal studies provide support for this approach, although only a few clinical studies have investigated the efficacy of blocking these proinflammatory cytokines in the treatment of OA. Apart from IL-1β and TNF, several other cytokines including IL-6, IL-15, IL-17, IL-18, IL-21, leukemia inhibitory factor and IL-8 (a chemokine) have also been shown to be implicated in OA and could possibly be targeted therapeutically. This Review discusses the current knowledge regarding the role of proinflammatory cytokines in the pathophysiology of OA and addresses the potential of anticytokine therapy in the treatment of this disease.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Matrix Metalloproteinase Inhibitors in Cancer Therapy: Turning Past Failures Into Future Successes

              The matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that degrade multiple components of the extracellular matrix. A large body of experimental and clinical evidence has implicated MMPs in tumor invasion, neoangiogenesis and metastasis, and therefore they represent ideal pharmacological targets for cancer therapy. From the 1990's to early 2000's synthetic inhibitors of MMPs (MMPIs) were studied in various cancer types. Unexpectedly, despite strongly promising preclinical data, all trials were unsuccessful in reducing tumor burden or improving overall survival; in addition, MMPIs had unforeseen, severe side effects. Two main reasons can explain the failure of MMPIs in clinical trials. It has now become apparent that some MMPs have anti-tumor effects; therefore, the broad-spectrum MMPIs used in the initial trials might block these MMPs and result in tumor progression. In addition, although MMPs are involved in the early stages of tumor progression, MMPIs were tested in patients with advanced disease, beyond the stage when these compounds could be effective. As more specific MMPIs are now available, MMP-targeting could be reconsidered for cancer therapy; however, new trials should be designed to test their anti-metastatic properties in early-stage tumors, and endpoints should focus on parameters other than decreasing metastatic tumor burden.
                Bookmark

                Author and article information

                Contributors
                Journal
                Front Mol Biosci
                Front Mol Biosci
                Front. Mol. Biosci.
                Frontiers in Molecular Biosciences
                Frontiers Media S.A.
                2296-889X
                29 June 2021
                2021
                : 8
                : 701959
                Affiliations
                Orthopaedic Research Laboratories, Leni and Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, NY, United States
                Author notes

                Edited by: Kazuhiro Yamamoto, University of Liverpool, United Kingdom

                Reviewed by: Salvatore Santamaria, Imperial College London, United Kingdom

                Wajid Waheed Bhat, Michigan State University, United States

                Dylan Edwards, University of East Anglia, United Kingdom

                *Correspondence: Dirk Hubmacher, dirk.hubmacher@ 123456mssm.edu

                This article was submitted to Protein Chemistry and Enzymology, a section of the journal Frontiers in Molecular Biosciences

                Article
                701959
                10.3389/fmolb.2021.701959
                8275829
                34268335
                9977fd2a-b4fe-41df-87e9-12c61ccdc551
                Copyright © 2021 Rose, Taye, Karoulias and Hubmacher.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 28 April 2021
                : 16 June 2021
                Funding
                Funded by: National Institute of Arthritis and Musculoskeletal and Skin Diseases 10.13039/100000069
                Funded by: Ines Mandl Research Foundation 10.13039/100017628
                Categories
                Molecular Biosciences
                Review

                extracellular matrix,arthritis,small molecule inhibitor,posttranslational modifications,alternative splicing,cartilage,aggrecan

                Comments

                Comment on this article