Phd Thesis Final

GENETICS AND EPIDEMIOLOGY OF ECTOPIC CALCIFICATION ANA RITA PIMENTEL DO COUTO RENDEIRO Dissertação de Doutoramento em Ciências Biomédicas 2009 Ana Rita Couto Rendeiro EctopicCalciifications Genetics andEpidemiology of Porto 2009 ANA RITA PIMENTEL DO COUTO RENDEIRO GENETICS AND EPIDEMIOLOGY OF ECTOPIC CALCIFICATION Dissertação de Candidatura ao grau de Doutor em Ciências Biomédicas, submetida ao Instituto de Ciências Biomédicas de Abel Salazar da Universidade do Porto. Orientador – Doutor Matthew Brown Categoria – Professor Afiliação – University of Oxford (U.K)/University of Queensland (Australia) Co-Orientador – Doutor Jorge Sequeiros Categoria – Professor Catedrático Afiliação – Instituto de Ciências Biomédicas de Abel Salazar (IBMC), Universidade do Porto Co-Orientador – Doutor Jácome Bruges Armas Categoria – Chefe de Serviço de Medicina Interna Afiliação – Hospital de Santo Espírito de Angra do Heroísmo PORTO, 2009 PRECEITOS LEGAIS De acordo com o disposto no nº2 do Artigo 8º do Decreto-Lei nº388/70, nesta dissertação foram utilizados os resultados dos trabalhos publicados ou em vias de publicação abaixo indicados. No cumprimento do disposto no referido Decreto-Lei, a autora desta dissertação declara que interveio na concepção e execução do trabalho experimental, na interpretação dos resultados e redacção dos resultados publicados ou em preparação, sob o nome de Couto AR: According to the nº2 of artigo 8º of the Decreto-lei nº 388/70, in this dissertation were used experimental results published or submitted to publication as stated bellow. The author of this dissertation declares that she participated in the setting up of the studies, execution of experimental work and data interpretation of all the works stated bellow, under the name of Couto, AR: 1. Bruges-Armas J, Couto AR , Timms A, Santos MR, Bettencourt BF, Peixoto MJ, Colquhoun K, McNally EG, Carneiro V, Herrero-Beaumont G, Brown MA. Ectopic calcification among families in the Azores: clinical and radiologic manifestations in families with diffuse idiopathic skeletal hyperostosis and chondrocalcinosis. Arthritis Rheum. 2006 Apr;54(4):1340-9. 2. Couto AR , Brown MA. Genetic factors in the pathogenesis of CPPD crystal deposition disease. Curr Rheumatol Rep. 2007 Jun;9(3):231-6. 3. Couto AR , Bruges-Armas J, Peach CA, Chapman K, Brown MA, Wordsworth BP, Zhang Y. A novel LEMD3 mutation common to patients with osteopoikilosis with and without melorheostosis. Calcif Tissue Int . 2007 Aug;81(2):81-4. 4. Jordana X, Galtés I, Couto AR , Gales L, Damas M, Lima M, Bruges-Armas J. The coexistence of ankylosing spondylitis and diffuse idiopathic skeletal hyperostosis - a postmortem diagnosis. Clin Rheumatol . 2009 Mar;28(3):353-6. 5. Bruges Armas J, Couto AR , Bettencourt BF. Spondyloarthritis, Diffuse Idiopathic Skeletal Hyperostosis and Chondrocalcinosis. In: Molecular Mechanisms of Spondyloarthropathies. Series: Advances in Experimental Medicine and Biology, Vol. 649; López-Larrea, Carlos; Díaz-Peña, Roberto (Eds.) 2009, Approx. 340 p., Hardcover ISBN: 978-1-4419-0297- 9. Manuscripts in Preparation 6. Couto AR , Zhang Y, Timms A, Sims AM, Santos MR, Martins L, Soares M, Bruges Armas J, Sequeiros J, Brown M. Investigating ANKH and ENPP1 in Slovakian families with chondrocalcinosis. 7. Couto AR , Timms A, Sims AM, Santos MR, Garrett F, Pinheiro JP, Soares M, Dutra I, Martins L, Sousa P, Parreira B, Peixoto MJ, Zhang Y, Sequeiros J, Bruges Armas J, Brown M. Genetic aspects of DISH and chondrocalcinosis families. 8. Couto AR , Brown MA. CPPD crystal deposition disease. In: Clinical Genomics: Practical Applications in Adult Patient Care. McGraw Hill LIST OF ABBREVIATIONS ACVR1 – activin A receptor type I GAG – glycosaminoglycan ADHR - autosomal dominant hypophosphatemic rickets GALNT3 – GalNAc transferase 3 AHO – Albright hereditary osteodystrophy GNAS1 – guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas ALPL – alkaline phosphatase liver GWAS – genome wide association study AS – ankylosing spondylitis HA – hydroxyapatite ASARM - acidic serine- and aspartate-rich MEPE-associated motif HAMP – hepcidin precursor ATP7B – copper-transporting ATPase 2 HFE – hereditary haemochromatosis protein precursor BCP – basic calcium phosphate HGD – homogentisate 1,2-dioxygenase BMPs – bone morphogenetic protein HJV – hemojuvelin precursor BOS – Buschke-Ollendorf syndrome HLA – human leukocyte antigen CASR – calcium sensing receptor HRPT2 – hyperparathyroidism 2 CC – chondrocalcinosis HRPT3 – hyperparathyroidism 3 CILP/NTPPH – cartilage intermediated layer protein/nucleotide pyrophosphohydrolase IBD – identical by descent CLCNKB – chloride channel protein CIC-Kb IBS – identical by state COL11A2 – collagen type XI, alpha 2 IGF – insulin like growth factor COL2A1 – collagen type II, alpha 1 IL23 – interleukin 23 COL6A1 – collagen type VI, alpha 1 LEMD3 – LEM domain containing 3 COMP – cartilage oligomeric matrix protein LIMK1 – LIM domain kinase 1 CPDD – calcium pyrophosphate deposition disease LMNA – lamin A/C CPPD – calcium pyrophosphate dehydrate LMSv2 – linkage mapping set version 2 CREST – calcinosis, Raynaud’s phenomenom, esophageal MED – multiple epiphyseal dysplasia dysmotility, sclerodactily, telangiectasias MEN1 – multiple endocrine neoplasia 1 CS – chondroitin sulphate MEPE – matrix extracellular phosphoglycoprotein DISH – diffuse idiopathic skeletal hyperostosis MGP – matrix gla protein DMP1 – Dentine Matrix protein MHC – major histocompatability complex DNA – deoxyribonucleic acid MV – matrix vesicles ECM – extracellular matrix NCPs – non-collagenous proteins EDS – energy dispersive spectrometry NPT2a - Solute Carrier family 34 (Sodium/Phosphate cotransporter) ELN – elastin Member 1;SLC34A1 ENPP1– ectonucleotide pyrophosphatase 1 NTPPPH – nucleoside triphosphate pyrophosphohydrolase EPOS – European Prospective Osteoporosis Study OA – osteoarthritis ePPi – extracellular inorganic pyrophosphate OPLL – ossification of posterior longitudinal ligament ERAP – endoplasmic reticulum aminopeptidase 1 OPN – osteopontin FBAT – family based associated test PCR – polymerase chain reaction FGF – Fibroblast growth Factor PCR-SSO – polymerase chain reaction -vsequence specific primers FPN1 – ferroportin 1 LIST OF ABBREVIATIONS (Cont.) PHEX - Phosphate-regulating gene with homologies to SLC34A1 – solute carrier family 34 member 1 endopeptidases on the X chromosome SLC40A1 – solute carrier family 40 member 1 PPi – inorganic pyrophosphate SLC9A3R1 – solute carrier family 9 isoform A3 regulatory factor 1 PSACH – pseudoachondroplasia SNP – single nucleotide polymorphism PTH – parathormone TDT – transmission disequilibrium test PTHrP – parathormone related peptide TFR2 – transferrin receptor 2 PTPN22 – protein tyrosine phosphatase TGF-B – transforming growth factor beta RA – rheumatoid arthritis TIBC – total iron binding capacity RANK – tumor necrosis factor receptor superfamily member 11a TIO –tumour induced osteomalacia RFC2 – replication factor C 2 VDR – vitamin D receptor RFLP – restriction fragment length polymorphism VDREs – vitamin D responsive elements SAMD3 –sterile alpha motif domain containing 3 VEGF-A – vascular endothelial growth factor A SEM – scanning electron microscopy vWFA – von Willebrand Factor A sFRP4 – secreted frizzled related protein XLH – X-linked Hypophosphatemia SI – sacroiliac XRM – X-ray elemental microanalyser SLC12A3 – solute carrier family 12 member 3 INDEX INDEX ................................................................................................................................................ 1 ABSTRACT ....................................................................................................................................... 4 RESUMO ............................................................................................................................................ 6 RÉSUME ............................................................................................................................................. 8 1. INTRODUCTION ................................................................................................................. 10 1.1 MINERAL HOMEOSTASIS ................................................................................................... 11 1.1.1 Calcium homeostasis ...................................................................................................... 11 1.1.2 Phosphate homeostasis ................................................................................................. 13 1.1.3 Inorganic pyrophosphate homeostasis .......................................................................... 15 1.2 MINERAL DEPOSITION ....................................................................................................... 17 1.2.1 Organelles - matrix vesicles ............................................................................................ 17 1.2.2 Cells - chondrocytes ....................................................................................................... 18 1.2.3 Tissues – cartilage and enthesis ..................................................................................... 19 1.2.3.1 Cartilage ...................................................................................................................... 20 1.2.3.2 Entheses ...................................................................................................................... 22 1.3 MOUSE MODELS SHOWING ECTOPIC CALCIFICATION .....................................................

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