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      Drug Design, Development and Therapy (submit here)

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      Effects of losartan and atorvastatin on the development of early posttraumatic joint stiffness in a rat model

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          Abstract

          Background

          After a trauma, exuberant tissue healing with fibrosis of the joint capsule can lead to posttraumatic joint stiffness (PTJS). Losartan and atorvastatin have both shown their antifibrotic effects in different organ systems.

          Objective

          The purpose of this study was the evaluation of the influence of losartan and atorvastatin on the early development of joint contracture. In addition to joint angles, the change in myofibroblast numbers and the distribution of bone sialoprotein (BSP) were assessed.

          Study design and methods

          In this randomized and blinded experimental study with 24 rats, losartan and atorvastatin were compared to a placebo. After an initial joint injury, rat knees were immobilized with a Kirschner wire. Rats received either losartan, atorvastatin or a placebo orally daily. After 14 days, joint angle measurements and histological assessments were performed.

          Results

          Losartan increased the length of the inferior joint capsule. Joint angle and other capsule length measurements did not reveal significant differences between both drugs and the placebo. At cellular level both losartan and atorvastatin reduced the total number of myofibroblasts (losartan: 191±77, atorvastatin: 98±58, placebo: 319±113 per counting field, p<0.01) and the percentage area of myofibroblasts (losartan: 2.8±1.8% [ p<0.05], atorvastatin: 2.5±1.7% [ p<0.01], vs control [6.4±4%], respectively). BSP was detectable in equivalent amounts in the joint capsules of all groups with only a trend toward a reduction of the BSP-stained area by atorvastatin.

          Conclusion

          Both atorvastatin and losartan reduced the number of myofibroblasts in the posterior knee joint capsule of rat knees 2 weeks after trauma and losartan increased the length of the inferior joint capsule. However, these changes at the cellular level did not translate an increase in range of motion of the rats´ knee joints during early contracture development.

          Most cited references101

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          TGF-β signaling in fibrosis.

          Anna Biernacka, Marcin Dobaczewski, Nikolaos G Frangogiannis (2011)
          Transforming growth factor β (TGF-β) is a central mediator of fibrogenesis. TGF-β is upregulated and activated in fibrotic diseases and modulates fibroblast phenotype and function, inducing myofibroblast transdifferentiation while promoting matrix preservation. Studies in a wide range of experimental models have demonstrated the involvement of the canonical activin receptor-like kinase 5/Smad3 pathway in fibrosis. Smad-independent pathways may regulate Smad activation and, under certain conditions, may directly transduce fibrogenic signals. The profibrotic actions of TGF-β are mediated, at least in part, through induction of its downstream effector, connective tissue growth factor. In light of its essential role in the pathogenesis of fibrosis, TGF-β has emerged as an attractive therapeutic target. However, the pleiotropic and multifunctional effects of TGF-β and its role in tissue homeostasis, immunity and cell proliferation raise concerns regarding potential side effects that may be caused by TGF-β blockade. This minireview summarizes the role of TGF-β signaling pathways in the fibrotic response.
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            Potential therapeutic targets for cardiac fibrosis: TGFbeta, angiotensin, endothelin, CCN2, and PDGF, partners in fibroblast activation.

            Andrew Leask (2010)
            Fibrosis is one of the largest groups of diseases for which there is no therapy but is believed to occur because of a persistent tissue repair program. During connective tissue repair, "activated" fibroblasts migrate into the wound area, where they synthesize and remodel newly created extracellular matrix. The specialized type of fibroblast responsible for this action is the alpha-smooth muscle actin (alpha-SMA)-expressing myofibroblast. Abnormal persistence of the myofibroblast is a hallmark of fibrotic diseases. Proteins such as transforming growth factor (TGF)beta, endothelin-1, angiotensin II (Ang II), connective tissue growth factor (CCN2/CTGF), and platelet-derived growth factor (PDGF) appear to act in a network that contributes to myofibroblast differentiation and persistence. Drugs targeting these proteins are currently under consideration as antifibrotic treatments. This review summarizes recent observations concerning the contribution of TGFbeta, endothelin-1, Ang II, CCN2, and PDGF and to fibroblast activation in tissue repair and fibrosis and the potential utility of agents blocking these proteins in affecting the outcome of cardiac fibrosis.
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              The myofibroblast: paradigm for a mechanically active cell.

              Boris Hinz (2010)
              Tissues lose mechanical integrity when our body is injured. To rapidly restore mechanical stability a multitude of cell types can jump into action by acquiring a reparative phenotype-the myofibroblast. Here, I review the known biomechanics of myofibroblast differentiation and action and speculate on underlying mechanisms. Hallmarks of the myofibroblast are secretion of extracellular matrix, development of adhesion structures with the substrate, and formation of contractile bundles composed of actin and myosin. These cytoskeletal features not only enable the myofibroblast to remodel and contract the extracellular matrix but to adapt its activity to changes in the mechanical microenvironment. Rapid repair comes at the cost of tissue contracture due to the inability of the myofibroblast to regenerate tissue. If contracture and ECM remodeling become progressive and manifests as organ fibrosis, the outcome of myofibroblast activity will have more severe consequences than the initial damage. Whereas the pathological consequences of myofibroblast occurrence are of great interest for physicians, their mechano-responsive features render them attractive for physicists and bioengineers. Their well developed cytoskeleton and responsiveness to a plethora of cytokines fascinate cell biologists and biochemists. Finally, the question of the myofibroblast origin intrigues stem cell biologists and developmental biologists-what else can you ask from a truly interdisciplinary cell? Copyright 2009 Elsevier Ltd. All rights reserved.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Drug Des Devel Ther
                Journal ID (iso-abbrev): Drug Des Devel Ther
                Journal ID (publisher-id): DDDT
                Journal ID (pmc): dddt
                Title: Drug Design, Development and Therapy
                Publisher: Dove
                ISSN (Electronic): 1177-8881
                Publication date (Electronic): 30 July 2019
                Publication date Collection: 2019
                Volume: 13
                Pages: 2603-2618
                Affiliations
                [1 ] Department of Orthopaedics and Traumatology, Biomatics Group, University Medical Centre of the Johannes Gutenberg University , Mainz, Germany
                [2 ] Department of Traumatology and Orthopaedics 1, Westpfalz-Medical Centre Kaiserslautern , Kaiserslautern, Germany
                Author notes
                Correspondence: Andreas BaranowskiDepartment of Orthopaedics and Traumatology, University Medical Center Mainz , Langenbeckstraße 1, Mainz55131, GermanyTel +49 613 117 7292Fax +49 613 117 4043Email andreas.baranowski@ 123456unimedizin-mainz.de
                Author information
                http://orcid.org/0000-0001-7954-5289
                Article
                Publisher ID: 204135
                DOI: 10.2147/DDDT.S204135
                PMC ID: 6679684
                PubMed ID: 31440039
                SO-VID: 60737c74-16c5-4bc2-9325-d5a609b50530
                Copyright © © 2019 Baranowski et al.
                License:

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                Date received : 21 February 2019
                Date accepted : 27 June 2019
                Page count
                Figures: 9, Tables: 2, References: 113, Pages: 16
                Categories
                Subject: Original Research

                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: posttraumatic joint stiffness,knee joint contracture,rat model,myofibroblast,antifibrotic drugs,bone sialoprotein
                Data availability:
                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: posttraumatic joint stiffness, knee joint contracture, rat model, myofibroblast, antifibrotic drugs, bone sialoprotein

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