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      Reduced primary cilia length and altered Arl13b expression are associated with deregulated chondrocyte Hedgehog signaling in alkaptonuria

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          Abstract

          Alkaptonuria (AKU) is a rare inherited disease resulting from a deficiency of the enzyme homogentisate 1,2‐dioxygenase which leads to the accumulation of homogentisic acid (HGA). AKU is characterized by severe cartilage degeneration, similar to that observed in osteoarthritis. Previous studies suggest that AKU is associated with alterations in cytoskeletal organization which could modulate primary cilia structure/function. This study investigated whether AKU is associated with changes in chondrocyte primary cilia and associated Hedgehog signaling which mediates cartilage degradation in osteoarthritis. Human articular chondrocytes were obtained from healthy and AKU donors. Additionally, healthy chondrocytes were treated with HGA to replicate AKU pathology (+HGA). Diseased cells exhibited shorter cilia with length reductions of 36% and 16% in AKU and +HGA chondrocytes respectively, when compared to healthy controls. Both AKU and +HGA chondrocytes demonstrated disruption of the usual cilia length regulation by actin contractility. Furthermore, the proportion of cilia with axoneme breaks and bulbous tips was increased in AKU chondrocytes consistent with defective regulation of ciliary trafficking. Distribution of the Hedgehog‐related protein Arl13b along the ciliary axoneme was altered such that its localization was increased at the distal tip in AKU and +HGA chondrocytes. These changes in cilia structure/trafficking in AKU and +HGA chondrocytes were associated with a complete inability to activate Hedgehog signaling in response to exogenous ligand. Thus, we suggest that altered responsiveness to Hedgehog, as a consequence of cilia dysfunction, may be a contributing factor in the development of arthropathy highlighting the cilium as a novel target in AKU.

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          Patched1 regulates hedgehog signaling at the primary cilium.

          Primary cilia are essential for transduction of the Hedgehog (Hh) signal in mammals. We investigated the role of primary cilia in regulation of Patched1 (Ptc1), the receptor for Sonic Hedgehog (Shh). Ptc1 localized to cilia and inhibited Smoothened (Smo) by preventing its accumulation within cilia. When Shh bound to Ptc1, Ptc1 left the cilia, leading to accumulation of Smo and activation of signaling. Thus, primary cilia sense Shh and transduce signals that play critical roles in development, carcinogenesis, and stem cell function.
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            Osteoarthritis.

            Osteoarthritis (OA) is characterized by degeneration of articular cartilage, limited intraarticular inflammation with synovitis, and changes in peri-articular and subchondral bone. Multiple factors are involved in the pathogenesis of OA, including mechanical influences, the effects of aging on cartilage matrix composition and structure, and genetic factors. Since the initial stages of OA involve increased cell proliferation and synthesis of matrix proteins, proteinases, growth factors, cytokines, and other inflammatory mediators by chondrocytes, research has focused on the chondrocyte as the cellular mediator of OA pathogenesis. The other cells and tissues of the joint, including the synovium and subchondral bone, also contribute to pathogenesis. The adult articular chondrocyte, which normally maintains the cartilage with a low turnover of matrix constituents, has limited capacity to regenerate the original cartilage matrix architecture. It may attempt to recapitulate phenotypes of early stages of cartilage development, but the precise zonal variations of the original cartilage cannot be replicated. Current pharmacological interventions that address chronic pain are insufficient, and no proven structure-modifying therapy is available. Cartilage tissue engineering with or without gene therapy is the subject of intense investigation. There are multiple animal models of OA, but there is no single model that faithfully replicates the human disease. This review will focus on questions currently under study that may lead to better understanding of mechanisms of OA pathogenesis and elucidation of effective strategies for therapy, with emphasis on mechanisms that affect the function of chondrocytes and interactions with surrounding tissues. 2007 Wiley-Liss, Inc.
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              Cilia and Hedgehog responsiveness in the mouse.

              The intraflagellar transport (IFT) proteins Ift172/Wimple and Polaris/Ift88 and the anterograde IFT motor kinesin-II are required for the production and maintenance of cilia. These proteins are also required for the activation of targets of the mouse Hedgehog (Hh) pathway by Gli transcription factors. The phenotypes of the IFT mutants, however, are not identical to mutants that lack Smoothened (Smo), an essential activator of the Hh pathway. We show here that mouse embryos that lack both Ift172 and Smo are identical to Ift172 single mutants, which indicates that Ift172 acts downstream of Smo. Ift172 mutants have a weaker neural patterning phenotype than Smo mutants, because Ift172, but not Smo, is required for proteolytic processing of Gli3 to its repressor form. Dnchc2 and Kif3a, essential subunits of the retrograde and anterograde IFT motors, are also required for both formation of Gli activator and proteolytic processing of Gli3. As a result, IFT mutants display a loss of Hh signaling phenotype in the neural tube, where Gli activators play the major role in pattern formation, and a gain of Hh signaling phenotype in the limb, where Gli3 repressor plays the major role. Because both anterograde and retrograde IFT are essential for positive and negative responses to Hh, and because cilia are present on Hh responsive cells, it is likely that cilia act as organelles that are required for all activity of the mouse Hh pathway.
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                Author and article information

                Contributors
                annalisa.santucci@unisi.it
                m.m.knight@qmul.ac.uk
                Journal
                J Cell Physiol
                J. Cell. Physiol
                10.1002/(ISSN)1097-4652
                JCP
                Journal of Cellular Physiology
                John Wiley and Sons Inc. (Hoboken )
                0021-9541
                1097-4652
                31 March 2017
                September 2017
                : 232
                : 9 ( doiID: 10.1002/jcp.v232.9 )
                : 2407-2417
                Affiliations
                [ 1 ] Institute of Bioengineering School of Engineering and Materials ScienceQueen Mary University of London LondonUnited Kingdom
                [ 2 ] Dipartimento di Biotecnologie Chimica e FarmaciaUniversità degli Studi di Siena SienaItaly
                Author notes
                [*] [* ] Correspondence

                Annalisa Santucci, Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via Aldo Moro 2, Siena 53100, Italy.

                Email: annalisa.santucci@ 123456unisi.it

                Correspondence

                Martin M. Knight, School of Engineering and Materials Science, Queen Mary University of London, Mile End Road, London E1 4NS, United Kingdom.

                Email: m.m.knight@ 123456qmul.ac.uk

                Author information
                http://orcid.org/0000-0002-4707-7756
                Article
                JCP25839
                10.1002/jcp.25839
                5484994
                28158906
                5afa16fc-4e5b-4a88-b024-6f3ceb1703b0
                © 2017 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals Inc.

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 25 November 2016
                : 11 January 2017
                : 02 February 2017
                Page count
                Figures: 5, Tables: 1, Pages: 11, Words: 8031
                Funding
                Funded by: Medical Research Council
                Award ID: MR/L002876/1
                Funded by: Royal College of Surgeons of England
                Funded by: Fondazione Telethon
                Award ID: GGP10058
                Funded by: Associazione Italiana Malati di Alcaptonuria (AimAKU)
                Award ID: ORPHA263402
                Categories
                Original Research Article
                Original Research Articles
                Custom metadata
                2.0
                jcp25839
                September 2017
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.1.2 mode:remove_FC converted:27.06.2017

                Anatomy & Physiology
                actin,alkaptonuria,chondrocyte,hedgehog signaling,primary cilium
                Anatomy & Physiology
                actin, alkaptonuria, chondrocyte, hedgehog signaling, primary cilium

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