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      Integrins and cadherins as therapeutic targets in fibrosis

      Frontiers in Pharmacology

      Frontiers Media S.A.

      integrins, cadherins, fibrosis, macrophage, fibroblasts, epithelial cells

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          Abstract

          Fibrosis is the excessive deposition of extracellular matrix proteins into tissues leading to scar formation, disruption of normal tissue architecture and organ failure. Despite the large clinical impact of fibrosis, treatment options are limited. Adhesion molecules, in particular αvβ6 and α3β1 integrins and cadherin-11, have been demonstrated to be important mediators of tissue fibrosis. These data are reviewed here and provide the foundation for these molecules to be potential therapeutic targets for patients with fibrotic diseases.

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          Most cited references 58

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          Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease.

          Transforming growth factor-beta 1 (TGF-beta 1) is a multifunctional growth factor that has profound regulatory effects on many developmental and physiological processes. Disruption of the TGF-beta 1 gene by homologous recombination in murine embryonic stem cells enables mice to be generated that carry the disrupted allele. Animals homozygous for the mutated TGF-beta 1 allele show no gross developmental abnormalities, but about 20 days after birth they succumb to a wasting syndrome accompanied by a multifocal, mixed inflammatory cell response and tissue necrosis, leading to organ failure and death. TGF-beta 1-deficient mice may be valuable models for human immune and inflammatory disorders, including autoimmune diseases, transplant rejection and graft versus host reactions.
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            Integrin ligands at a glance.

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              Latent TGF-β structure and activation.

              Transforming growth factor (TGF)-β is stored in the extracellular matrix as a latent complex with its prodomain. Activation of TGF-β1 requires the binding of α(v) integrin to an RGD sequence in the prodomain and exertion of force on this domain, which is held in the extracellular matrix by latent TGF-β binding proteins. Crystals of dimeric porcine proTGF-β1 reveal a ring-shaped complex, a novel fold for the prodomain, and show how the prodomain shields the growth factor from recognition by receptors and alters its conformation. Complex formation between α(v)β(6) integrin and the prodomain is insufficient for TGF-β1 release. Force-dependent activation requires unfastening of a 'straitjacket' that encircles each growth-factor monomer at a position that can be locked by a disulphide bond. Sequences of all 33 TGF-β family members indicate a similar prodomain fold. The structure provides insights into the regulation of a family of growth and differentiation factors of fundamental importance in morphogenesis and homeostasis.
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                Author and article information

                Contributors
                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                1663-9812
                03 June 2014
                2014
                : 5
                Affiliations
                Section of Allergy, Immunology, and Rheumatology, Department of Medicine, Biology of Inflammation Center, Baylor College of Medicine , Houston, TX, USA
                Author notes

                Edited by: Lynne Anne Murray, MedImmune Ltd., UK

                Reviewed by: Paolo Sfriso, University of Padova, Italy; Eleonora Cianci, University G.d'Annunzio of Chieti, Italy

                *Correspondence: Sandeep K. Agarwal, Section of Allergy, Immunology, and Rheumatology, Department of Medicine, Biology of Inflammation Center, Baylor College of Medicine, One Baylor Plaza, Suite 672E, MS: BCM285, Houston, TX 77030, USA e-mail: skagarwa@ 123456bcm.edu

                This article was submitted to Inflammation Pharmacology, a section of the journal Frontiers in Pharmacology.

                Article
                10.3389/fphar.2014.00131
                4042084
                Copyright © 2014 Agarwal.

                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) or licensor 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.

                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 79, Pages: 7, Words: 6454
                Categories
                Pharmacology
                Review Article

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