DOCSLIB.ORG

Bone Homeostasis As a Multifaceted Puzzle: from WNT Ligands to Metal-Ion Transporters

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Bone Homeostasis As a Multifaceted Puzzle: from WNT Ligands to Metal-Ion Transporters Faculteit Farmaceutische, Biomedische en Diergeneeskundige Wetenschappen Bone Homeostasis as a Multifaceted Puzzle: From WNT Ligands to Metal-ion Transporters Bothomeostase als een Veelzijdige Puzzel: Van WNT Liganden tot Metaal-ion Transporters Proefschrift voorgelegd tot het behalen van de graad van Doctor in de Biomedische Wetenschappen aan de Universiteit Antwerpen te verdedigen door Gretl HENDRICKX Bone Homeostasis as a Multifaceted Puzzle: From WNT Ligands to Metal-ion Transporters Doctoral dissertation, University of Antwerp, Belgium ISBN: 978-94-6299-582-6 Author: G. Hendrickx Cover Design: Lien Campo, concept by G. Hendrickx Printing: Ridderprint BV © Copyright G. Hendrickx, Antwerpen 2017 All rights reserved. No parts of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means without prior permission of the holder of the copyright. Curiosity-Driven MEMBERS OF THE JURY Prof. Dr. Wim Van Hul, promotor Center of Medical Genetics, University of Antwerp and University Hospital of Antwerp, Belgium Dr. Eveline Boudin, co-promotor Center of Medical Genetics, University of Antwerp and University Hospital of Antwerp, Belgium Prof. Dr. Vincent Timmerman, chairman VIB Department of Molecular Genetics, University of Antwerp, Belgium Prof. Dr. Marc Cruts VIB Department of Molecular Genetics, University of Antwerp, Belgium Prof. Dr. Bart Loeys Center of Medical Genetics, University of Antwerp and University Hospital of Antwerp, Belgium Prof. Dr. Geert Carmeliet Department of Cellular and Molecular Medicine, KU Leuven, Belgium Prof. Dr. Martine Cohen-Solal Department of Rheumatology, University Paris-Diderot, France TABLE OF CONTENTS Table of Contents I. Summary/Samenvatting 9 II. Introduction 15 Chapter 1 17 A Look Behind The Scenes: The Risk and Pathogenesis of Primary Osteoporosis Gretl Hendrickx, Eveline Boudin and Wim Van Hul Nature Reviews Rheumatology 2015; 11;462–474 Chapter 2 51 An Introduction to WNT Signaling III. Objectives 59 IV. Results 65 Part 1 – Osteoporosis 67 Chapter 3 69 Variation in the Kozak Sequence of WNT16 Results in an Increased Translation and is Associated with Osteoporosis Related Parameters Gretl Hendrickx, Eveline Boudin, Igor Fijałkowski, Torben Leo Nielsen, Marianne Andersen, Kim Brixen and Wim Van Hul Bone 2014; 59:57-65 Chapter 4 91 WNT16 Requires Gα Subunits as Intracellular Partners for Both its Canonical and Non-Canonical WNT Signaling Activity in Osteoblasts Gretl Hendrickx, Eveline Boudin and Wim Van Hul Work in progress Table of Contents Chapter 5 109 Genetic Screening of WNT4 and WNT5B in Two Populations with Deviating Bone Mineral Densities Gretl Hendrickx, Eveline Boudin, Ellen Steenackers, Torben Leo Nielsen, Marianne Andersen, Kim Brixen and Wim Van Hul Calcified Tissue International 2017; 100:244–249 Part 2 – Hyperostosis Cranialis Interna 123 Chapter 6 125 Conditional Mouse Models Support the Role of SLC39A14 (ZIP14) in Hyperostosis Cranialis Interna and in Bone Homeostasis Gretl Hendrickx, Vere M. Borra, Ellen Steenackers, Timur A. Yorgan, Christophe Hermans, Eveline Boudin, Jérôme J. Waterval, Ineke D.C. Jansen, Tolunay Beker Aydemir, Niels Kamerling, Geert J. Behets, Christine Plumeyer, Patrick C. D’Haese, Björn Busse, Vincent Everts, Martin Lammens, Geert Mortier, Robert J. Cousins, Thorsten Schinke, Robert J. Stokroos, Johannes J. Manni and Wim Van Hul Submitted V. General Discussion 165 VI. List of Abbreviations 179 VII. Curriculum Vitae 185 VIII. Dankwoord 193 SUMMARY / SAMENVATTING 10 Summary/Samenvatting Summary Bone homeostasis is a process characterized by the constant and lifelong remodeling of bone tissue to sustain bone mineral density (BMD) and quality. Here, mainly genetic factors contribute to the determination of BMD, which is why genetic variation also contributes to the development of skeletal pathologies characterized by a too low or high BMD, encompassing a multifaceted spectrum. Osteoporosis is the most prevalent skeletal disorder, characterized by a low BMD and an increased fracture risk and with a complex genetic background. Just as well, there are bone disorders with deviating BMD values caused by only one mutation with a large impact on the skeleton. Unlike osteoporosis, these monogenic bone disorders are mostly rare. Studying BMD and bone homeostasis by means of different genetic skeletal disorders was already proven to be an efficient strategy. The aim of this thesis was therefore to further elucidate the regulation of BMD by performing genetic and functional research on two different bone disorders; osteoporosis and Hyperostosis Cranialis Interna. Osteoporosis was investigated in the first part of this thesis through the study of WNT4, WNT5B and WNT16, three genes associated with BMD in previous genetic studies and are all part of the WNT signaling pathway. First, a candidate gene association study of WNT16 identified additional associations with BMD at distinct skeletal sites. Further genetic screening of WNT16 in two populations with deviating BMD values detected a functional variant in the Kozak consensus sequence of WNT16, resulting in a higher translation efficiency and being associated with a higher BMD. A follow-up functional study investigating the mechanism of action of WNT16 on the canonical and non-canonical WNT signaling pathways demonstrated differential actions of WNT16 in different cell types and a possible orchestrating role for Gα subunits herein. In contrast to WNT16, genetic screening of WNT4 and WNT5B did not reveal interesting variants for further analysis. In the second part of this thesis, we performed research of Hyperostosis Cranialis Interna (HCI). HCI is a monogenic skeletal disorder characterized bone overgrowth at the calvarium and skull base, resulting in cranial nerve entrapment and associated symptoms. By performing whole- exome sequencing, we identified a mutation (p.L441R) in the SLC39A14 (ZIP14) gene, encoding a zinc transporter. In vitro studies indicated that the subcellular localization of p.L441R ZIP14 is disturbed with consequent defects in cellular zinc homeostasis. Two conditional knock-in mouse models were generated, overexpressing p.L438R Zip14 in osteoblasts and osteoclasts. Remarkably, the calvaria of these mice were unaffected, whereas the rest of the skeleton was affected by Zip14L438R in vivo. Both mouse models, and mainly the osteoblast-specific knock-in 11 Summary/Samenvatting mice, exhibit an increased cortical bone volume. Trabecular bone volume was differentially modulated by Zip14L438R, i.e. decreased (osteoblast knock-in) or unaffected (osteoclast knock-in). We therefore hypothesize that Zip14L438R, similar to estrogen and opposite to parathyroid hormone, modulates bone remodeling differently in the cortical and trabecular compartment. Of note, both knock-in models exhibit an increased cortical thickness, owing to an increased endosteal bone formation, which is the underlying cause of intracranial osteosclerosis in patients with HCI. We therefore believe we identified the disease causing gene for Hyperostosis Cranialis Interna and that this rare, unique bone disorder is the result of appropriate compensatory mechanisms in the appendicular skeleton and vertebral column and/or a calvarium-specific lack of such mechanism in HCI patients. In conclusion, by investigating two different bone disorders, we contributed to the genetic knowledge on BMD. Functional studies towards the mechanisms of action of WNT16 and ZIP14 additionally led to novel insights in the multifaceted process of bone homeostasis. 12 Summary/Samenvatting Samenvatting Bothomeostase is een proces dat gekenmerkt wordt door constante en levenslange remodellering van botweefsel om de botmineraaldensiteit (BMD) en –kwaliteit te onderhouden. Bij het bepalen van de BMD spelen voornamelijk genetische factoren een rol, waardoor genetische variatie ook bijdraagt tot de ontwikkeling van skeletaandoeningen die gekenmerkt worden door een abnormaal lage of hoge BMD en tezamen een veelzijdig spectrum aan botaandoeningen vormen. Osteoporose is de vaakst voorkomende botaandoening die gekenmerkt wordt door een verlaagde BMD, een verhoogd fractuurrisico en een complexe genetische achtergrond heeft. Anderzijds zijn er ook botaandoeningen met afwijkende BMD waarden die veroorzaakt worden door slechts één mutatie met een grote impact op het skelet. In tegenstelling tot osteoporose zijn deze monogene aandoeningen meestal zeldzaam. BMD en bothomeostase bestuderen door middel van onderzoek naar de genetische oorzaak van verschillende botaandoeningen, is in het verleden al een succesvolle strategie gebleken. Het doel van deze thesis was daarom om de regulatie van BMD beter te begrijpen door genetisch en functioneel onderzoek te verrichten op twee verschillende botaandoeningen; osteoporose en Hyperostosis Cranialis Interna. Osteoporose werd in het eerste deel van deze thesis onderzocht door de studie van WNT4, WNT5B en WNT16, drie genen die in voorafgaande genetische studies reeds werden geassocieerd met BMD en deel uitmaken van de WNT signaalweg. Vooreerst werden in een WNT16 kandidaatgen associatiestudie nog bijkomende associaties met BMD gevonden op verschillende plaatsen in het skelet. In een daaropvolgende genetische screening van WNT16 in twee populaties met afwijkende BMD waarden, detecteerden we een functionele variant in de Kozak consensus sequentie van WNT16. Deze variant verhoogt de translatie-efficiëntie en is geassocieerd met een verhoogde BMD. Een follow-up functionele studie naar het werkingsmechanisme
Load more

Recommended publications
  • Atypical Femur Fracture in an Adolescent Boy Treated with Bisphosphonates for X-Linked Osteoporosis Based on PLS3 Mutation Denise M
    Atypical femur fracture in an adolescent boy treated with bisphosphonates for X-linked osteoporosis based on PLS3 mutation Denise M. van de Laarschot BSc1, M. Carola Zillikens MD PhD 1 1 Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands Corresponding author at: Erasmus Medical Centre, PO Box 2040, 3000 CA Rotterdam, The Netherlands. Abstract Long-term use of bisphosphonates has raised concerns about the association with Atypical Femur Fractures (AFFs) that have been reported mainly in postmenopausal women. We report a case of an 18-year-old patient with juvenile osteoporosis based on X-linked osteoporosis due to a PLS3 mutation who developed a low trauma femoral fracture after seven years of intravenous and two years of oral bisphosphonate use, fulfilling the revised ASBMR diagnostic criteria of an AFF. The occurrence of AFFs has not been described previously in children or adolescents. The underlying monogenetic bone disease in our case strengthens the possibility of a genetic predisposition at least in some cases of AFF. We cannot exclude that a transverse fracture of the tibia that also occurred after a minor trauma at age 16 might be part of the same spectrum of atypical fractures related to the use of bisphosphonates. In retrospect our patient experienced prodromal pain prior to both the tibia and the femur fracture. Case reports of atypical fractures in children with a monogenetic bone disease such as Osteogenesis Imperfecta (OI) or juvenile osteoporosis are important to consider in the discussion about optimal
    [Show full text]
  • Differential Diagnosis: Brittle Bone Conditions Other Than OI
    Facts about Osteogenesis Imperfecta Differential Diagnosis: Brittle Bone Conditions Other than OI Fragile bones are the hallmark feature of osteogenesis imperfecta (OI). The mutations that cause OI lead to abnormalities within bone that result in increased bone turnover; reduced bone mineral content and decreased bone mineral density. The consequence of these changes is brittle bones that fracture easily. But not all cases of brittle bones are OI. Other causes of brittle bones include osteomalacia, disuse osteoporosis, disorders of increased bone density, defects of bone, and tumors. The following is a list of conditions that share fragile or brittle bones as a distinguishing feature. Brief descriptions and sources for further information are included. Bruck Syndrome This autosomal recessive disorder is also referred to as OI with contractures. Some people now consider this to be a type of OI. National Library of Medicine Genetics Home Reference: http://ghr.nlm.nih.gov Ehlers-Danlos Syndrome (EDS) Joint hyperextensibility with fractures; this is a variable disorder caused by several gene mutations. Ehlers-Danlos National Foundation http://www.ednf.org Fibrous Dysplasia Fibrous tissue develops in place of normal bone. This weakens the affected bone and causes it to deform or fracture. Fibrous Dysplasia Foundation: https://www.fibrousdysplasia.org ‎ Hypophosphatasia This autosomal recessive disorder affects the development of bones and teeth through defects in skeletal mineralization. Soft Bones: www.softbones.org; National Library of Medicine Genetics Home Reference: http://ghr.nlm.nih.gov/condition Idiopathic Juvenile Osteoporosis A non-hereditary transient form of childhood osteoporosis that is similar to mild OI (Type I) National Osteoporosis Foundation: www.nof.org McCune-Albright Syndrome This disorder affects the bones, skin, and several hormone-producing tissues.
    [Show full text]
  • WO 2010/115932 Al
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 14 October 2010 (14.10.2010) WO 2010/115932 Al (51) International Patent Classification: AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, A61K 31/675 (2006.01) A61K 45/06 (2006.01) CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, A61K 38/00 (2006.01) A61P 19/08 (2006.01) DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, A61K 39/395 (2006.01) A61P 19/10 (2006.01) HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, (21) International Application Number: ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, PCT/EP20 10/054605 NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, (22) International Filing Date: SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, 7 April 2010 (07.04.2010) TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (26) Publication Language: English GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, (30) Priority Data: ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, 61/167,688 8 April 2009 (08.04.2009) US TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, (71) Applicant (for all designated States except US): NO- MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, SM, VARTIS AG [CH/CH]; Lichtstrasse 35, CH-4056 Basel TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, (CH).
    [Show full text]
  • Het Beschrijf
    Universiteit Gent Academiejaar 2006 – 2007 HET BESCHRIJF INTERNSHIP AT A LITERARY ORGANISATION Verhandeling voorgelegd aan de Faculteit Letteren en Wijsbegeerte voor het verkrijgen van de graad van master in de Meertalige Promotor: Prof. Dr. Geert Jacobs Bedrijfscommunicatie, door Sara Clauw. TABEL MET BESCHRIJVING VAN DE STAGE: VOORAAN IN TE VOEGEN BIJ DE SCRIPTIE Bedrijf Stagebegeleider Afdeling Taken Talen Periode Het beschrijf vzw Brigitte Neervoort / ondersteuning communicatie: schrijven N, E 2 mei – 28 juni A. Dansaertstraat 46 nieuwsbrieven, persbericht, teksten websites, 2007 1000 Brussel nalezen teksten, vertaalwerk… ondersteuning productie programma’s, (25 dagen) Telefoon : (02) 223 68 32 expo’s 2 ACKNOWLEDGEMENTS There are a number of people I would like to thank for their help with this dissertation. First of all I want to thank the people at Het beschrijf for giving me the opportunity to do my internship in their organisation. I am no less grateful to professor Geert Jacobs and Luc de Bie for their useful hints and advice. Finally, I would like to thank my family for their help and comments. 3 CONTENTS ACKNOWLEDGEMENTS ..................................................................................................... 3 CONTENTS .............................................................................................................................. 4 PREFACE ................................................................................................................................. 5 1. HET BESCHRIJF ...............................................................................................................
    [Show full text]
  • Osteogenesis Imperfecta: Recent Findings Shed New Light on This Once Well-Understood Condition Donald Basel, Bsc, Mbbch1, and Robert D
    COLLABORATIVE REVIEW Genetics in Medicine Osteogenesis imperfecta: Recent findings shed new light on this once well-understood condition Donald Basel, BSc, MBBCh1, and Robert D. Steiner, MD2 TABLE OF CONTENTS Overview ...........................................................................................................375 Differential diagnosis...................................................................................380 Clinical manifestations ................................................................................376 In utero..........................................................................................................380 OI type I ....................................................................................................376 Infancy and childhood................................................................................380 OI type II ...................................................................................................377 Nonaccidental trauma (child abuse) ....................................................380 OI type III ..................................................................................................377 Infantile hypophosphatasia ....................................................................380 OI type IV..................................................................................................377 Bruck syndrome .......................................................................................380 Newly described types of OI .....................................................................377
    [Show full text]
  • Reiner Bartl Christoph Bartl Biology, Diagnosis, Prevention, Therapy
    Reiner Bartl Christoph Bartl Bone Disorders Biology, Diagnosis, Prevention, Therapy 123 Bone Disorders Reiner Bartl • Christoph Bartl Bone Disorders Biology, Diagnosis, Prevention, Therapy With a contribution by Andrea Baur-Melnyk and Tobias Geith Prof. Dr. med. Reiner Bartl PD Dr. med. Christoph Bartl Osteoporosis Center Munich ZOOOM (Center of Orthopaedics, Kaufi ngerstr. 15 Osteoporosis and Sports Medicine, Munich Munich) Germany Rosa-Bavaresestr. 1 Munich Germany With a contribution by Prof. Dr. med. Andrea Baur-Melnyk and Dr. med. Tobias Geith Department of Clinical Radiology University of Munich-Grosshadern Marchioninistrasse 15 Munich, Germany All coloured illustrations from Harald Konopatzki, Heidelberg. All two-coloured and blackline illustrations from Reinhold Henkel†, Heidelberg. ISBN 978-3-319-29180-2 ISBN 978-3-319-29182-6 (eBook) DOI 10.1007/978-3-319-29182-6 Library of Congress Control Number: 2016944148 © Springer International Publishing Switzerland 2017 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifi cally the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfi lms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specifi c statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication.
    [Show full text]
  • Skeletal Imaging of Nutritional Disorders in Children
    CRIMSONpublishers http://www.crimsonpublishers.com Clinical Image Nov Tech Nutri Food Sci ISSN: 2640-9208 Skeletal Imaging of Nutritional Disorders in Children Kakarla Subbarao* KIMS Foundation and Research Centre, India *Corresponding author: Kakarla Subbarao, MS, D.Sc. (HON), FRCR, FACR, FICP, FSASMA, FCCP, FICR, FCGP, Chairman, KIMS Foundation and Research Centre, Minister road, Sec- 500003, Telangana, India Submission: September 06, 2017; Published: January 22, 2018 Abstract Imaging of skeleton plays a major role in the diagnosis of nutritional disorders in children. The disorders can be 1) Deficiency2) Toxic (Overdose). and the grading of diagnosis of degrees of osteoporosis. The differential diagnosis is also discussed. The common deficiency disorders include rickets, scurvy, osteoporosis and anemias. Conventional radiology is adequate in the diagnosis, except in Keywords: Rickets, scurvy; Osteoporosis; Fluorosis; Lead poisoning; Vitamin A and D overdose; Radiological characteristics Introduction The toxic disorders include hypervitaminosis A and D. Other causes Despite governmental and nongovernmental service programs include plumbism, hypercalcemia, steroids, heparin over use, in improving pediatric nutrition with supplementary foods, it antiepiliptic drugs and flurosis. is not uncommon to see children with nutritional deficiency Pathophysiology of Rickets disorders. Most of them reflect upon the musculoskeletal system. The deposition of mineral in cartilage needs adequate amounts osteoporosis, hypoprotenemia and anemias. The conventional The major deficiency disorders include nutritional rickets, scurvy, radiological appearances are classical and very rarely are it needed to have advanced imaging methods. However, quantitative computed of both calcium and phosphorous. If these are deficient failure of new osteoid is less due to inhibition of osteoclastic resorption of matrix. tomography (CT), dual-energy photon absorptiometry, and dual- bone mineralization takes place.
    [Show full text]
  • Osteoporosis in Children 173:6 R185–R197 Review
    V Saraff and W Ho¨ gler Osteoporosis in children 173:6 R185–R197 Review ENDOCRINOLOGY AND ADOLESCENCE Osteoporosis in children: diagnosis and management Correspondence Vrinda Saraff and Wolfgang Ho¨ gler should be addressed Department of Endocrinology and Diabetes, Birmingham Children’s Hospital, Steelhouse Lane, to W Ho¨ gler Birmingham B4 6NH, UK Email [email protected] Abstract Osteoporosis in children can be primary or secondary due to chronic disease. Awareness among paediatricians is vital to identify patients at risk of developing osteoporosis. Previous fractures and backaches are clinical predictors, and low cortical thickness and low bone density are radiological predictors of fractures. Osteogenesis Imperfecta (OI) is a rare disease and should be managed in tertiary paediatric units with the necessary multidisciplinary expertise. Modern OI management focuses on functional outcomes rather than just improving bone mineral density. While therapy for OI has improved tremendously over the last few decades, this chronic genetic condition has some unpreventable, poorly treatable and disabling complications. In children at risk of secondary osteoporosis, a high degree of suspicion needs to be exercised. In affected children, further weakening of bone should be avoided by minimising exposure to osteotoxic medication and optimising nutrition including calcium and vitamin D. Early intervention is paramount. However, it is important to identify patient groups in whom spontaneous vertebral reshaping and resolution of symptoms occur to avoid unnecessary treatment. Bisphosphonate therapy remains the pharmacological treatment of choice in both primary and secondary osteoporosis in children, despite limited evidence for its use in the latter. The duration and intensity of treatment remain a concern for long- term safety.
    [Show full text]
  • Genetic Factors in Bone Disorders. Osteogenesis Imperfecta, Juvenile
    GENETIC FACTORS HEINI IN BONE DISORDERS HARTIKKA Osteogenesis imperfecta, juvenile osteoporosis and stress fractures Faculty of Medicine, Department of Medical Biochemistry and Molecular Biology, Biocenter Oulu, University of Oulu OULU 2005 HEINI HARTIKKA GENETIC FACTORS IN BONE DISORDERS Osteogenesis imperfecta, juvenile osteoporosis and stress fractures Academic Dissertation to be presented with the assent of the Faculty of Medicine, University of Oulu, for public discussion in Auditorium of the Medipolis (Kiviharjuntie 11), on May 26th, 2005, at 10 a.m. OULUN YLIOPISTO, OULU 2005 Copyright © 2005 University of Oulu, 2005 Supervised by Professor Leena Ala-Kokko Reviewed by Professor Heikki Kröger Professor Risto Penttinen ISBN 951-42-7717-1 (nid.) ISBN 951-42-7718-X (PDF) http://herkules.oulu.fi/isbn951427718X/ ISSN 0355-3221 http://herkules.oulu.fi/issn03553221/ OULU UNIVERSITY PRESS OULU 2005 Hartikka, Heini, Genetic factors in bone disorders. Osteogenesis imperfecta, juvenile osteoporosis and stress fractures Faculty of Medicine, Department of Medical Biochemistry and Molecular Biology, Biocenter Oulu, University of Oulu, P.O.Box 5000, FIN-90014 University of Oulu, Finland 2005 Oulu, Finland Abstract Genetic factors and their resulting phenotypes were evaluated in three different bone disorders: osteogenesis imperfecta (OI), juvenile idiopathic osteoporosis (JIO), and stress fractures. The spectrum of the OI phenotypes caused by mutations in the COL1A1 and COL1A2 genes is well defined, but the mechanisms by which the variations affect the hearing phenotype are not well- known. A total of 54 Finnish OI patients with previously diagnosed hearing loss, or aged 35 or more years, were analyzed here for mutations in COL1A1, or COL1A2. Altogether, 49 mutations were identified, of which 41 were novel.
    [Show full text]
  • Osteoporosis in Childhood and Adolescence
    0021-7557/03/79-06/481 Jornal de Pediatria Copyright © 2003 by Sociedade Brasileira de Pediatria REVIEW ARTICLE Osteoporosis in childhood and adolescence Lúcia M.A. Campos,1 Bernadete L. Liphaus,2 Clóvis A.A. Silva,3 Rosa M.R. Pereira4 Abstract Objective: To review recent data concerning osteoporosis and osteopenia in childhood and adolescence, focusing on diagnosis, prevention and treatment. Sources of data: Literature review of Medline and Lilacs databases (1992 to 2002). Summary of the findings: Childhood osteoporosis is defined and classified. Imaging and laboratory diagnostic techniques are emphasized, as well as prevention and drug treatment. Conclusions: Pediatricians should identify the risk factors for osteoporosis and guide patients in terms of its prevention and treatment. J Pediatr (Rio J). 2003;79(6):481-8: Osteoporosis, children, adolescents. Introduction Osteoporosis is a significant health problem all over expectancy.2 Osteopenia and osteoporosis are no longer the world. From the age of 50 onwards, 30% of women exclusively the concern of adults and older people, since and 13% of men may suffer some type of fracture.1 It is the bone mineral density of these age groups is dependent estimated that the incidence of fractures will quadruple upon the peak bone mass acquired by the end of the over the next 50 years as a result of increased life- second decade of life.3 The pediatrician has the responsibility of guaranteeing the conditions necessary for children and adolescents to develop the best possible 1. MSc. Assistant physician, Rheumatology Unit, Instituto da Criança do quality of bone mass, avoiding fractures in adult life.
    [Show full text]
  • Genetic Diseases Related with Osteoporosis
    Chapter 2 Genetic Diseases Related with Osteoporosis Margarita Valdés-Flores, Leonora Casas-Avila and Valeria Ponce de León-Suárez Additional information is available at the end of the chapter http://dx.doi.org/10.5772/55546 1. Introduction Osteoporosis is a disease entity characterized by the progressive loss of bone mineral density (BMD) and the deterioration of bone microarchitecture, leading to the development of frac‐ tures. Its classification encompasses two large groups, primary and secondary osteoporosis [1]. Primary osteoporosis is the disease’s most common form and results from the progressive loss of bone mass related to aging and unassociated with other illness, a natural process in adult life; its etiology is considered multifactorial and polygenic. This form currently represents a growing worldwide health problem due in part, to the contemporary environmental condi‐ tions of modern civilization. Risk factors that are considered as “modifiable” also play an important role and include physical activity, dietary habits and eating disorders. Furthermore, there is another group of associated risk factors that are considered “non-modifiable”, including gender, age, race, a personal and/or family history of fractures that in turn, indirectly reflect the degree of genetic susceptibility to this disease [2-4]. Secondary osteoporosis encompasses a large heterogeneous group of primary conditions favoring osteoporosis development. Table 1 summarizes some of the disease entities associated to primary and secondary osteoporosis. 1.1. Genetic aspects of primary osteoporosis This form of osteoporosis results from the interaction of several environmental and genetic factors, leading to difficulties in its study. It is not easy to define the magnitude of the effect of genetic susceptibility since it is a trait determined by multiple genes whose products affect the bone phenotype; moreover, the environmental factors compromising bone mineral density are also difficult to analyze.
    [Show full text]
  • Diving Deeper Into the Blue: a Case of Osteogenesis Imperfecta with Ocular Involvement Undiagnosed for 25 Years
    Title: Diving deeper into the blue: a case of osteogenesis imperfecta with ocular involvement undiagnosed for 25 years Author(s): Janki H Parikh, OD, Mariya Skreydel OD, MS, Rochelle Mozlin, OD, MPH, FCOVD, FAAO Abstract: A detailed look into a 25-year old female’s seemingly benign history and ocular exam aids in diagnosing and properly managing her long-undetected osteogenesis imperfecta. I. Case History • Patient demographics: 25-year-old Indian female • Chief complaint: Patient presents with floaters OU and concern about blueish tint in sclera OU • Ocular, medical history: o Myopia OU: Patient wears SV glasses and Proclear Daily contact lenses. o Endoscopic Skull Base Encephalocele Surgery (June 2013): Patient reports she had a continuous cerebrospinal fluid (CSF) leak out of her left nostril for 20 years. She was misdiagnosed with allergic rhinitis by several providers and treated with anti-histamines and steroid nasal sprays for years. CSF leak resolved with surgery after CT and MRI scans revealed herniation of frontal lobe tissue into the left nasal cavity from a skull base fracture at 18 months of age. o Headaches: frequent severe throbbing frontal headaches, resolved after surgery • Medications: None • Other salient information: Patient reports father has similar blueish tint in his eyes. He became deaf at the age of 35; unknown etiology at this time. Patient is being followed by an ENT yearly; hearing in left ear is slightly below average. Patient reports weakness, easy bruising, and several fractures in past (skull base, both arms, leg, floating ribs, toe fractures, and finger dislocation) from very minor trauma. II.
    [Show full text]