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Thesis Is Presented for the Degree of Doctor of Philosophy of the University of Western Australia School of Biomedical Sciences Pathology 2018

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Thesis Is Presented for the Degree of Doctor of Philosophy of the University of Western Australia School of Biomedical Sciences Pathology 2018 IDENTIFICATION OF GENES REGULATING OSTEOARTHRITIS DEVELOPMENT USING A MOUSE PHENOTYPE LIBRARY JACOB JOHN KENNY This thesis is presented for the degree of Doctor of Philosophy of The University of Western Australia School of Biomedical Sciences Pathology 2018 i THESIS DECLARATION I, Jacob John Kenny, certify that: This thesis has been substantially accomplished during enrolment in the degree. This thesis does not contain material which has been accepted for the award of any other degree or diploma in my name, in any university or other tertiary institution. No part of this work will, in the future, be used in a submission in my name, for any other degree or diploma in any university or other tertiary institution without the prior approval of The University of Western Australia and where applicable, any partner institution responsible for the joint-award of this degree. This thesis does not contain any material previously published or written by another person, except where due reference has been made in the text. The work(s) are not in any way a violation or infringement of any copyright, trademark, patent, or other rights whatsoever of any person. The research involving animal data reported in this thesis was assessed and approved by The University of Western Australia Animal Ethics Committee. Approval #: RA/3/500/87. The research involving animals reported in this thesis followed The University of Western Australia and national standards for the care and use of laboratory animals. The work described in this thesis was funded by the National Health and Medical Research Council. APP1127156 – “Gene mining for novel molecular determinants of the skeleton”. This research was supported by an Australian Government Research Training Program (RTP) Scholarship. Technical assistance was kindly provided by Professor Grant Morahan, Sylvia Young and Dr Ramesh Ram for their support with gene mapping and the management of Geneminer software that is described throughout the thesis. Mr Kai Chen and Ms Dian Teguh for support in primary cell culture used for RNA analysis described in Chapter 3, section 3.2.7. Mr Jinbo Yuan for his fantastic help managing the CC mice collection as we received them. This thesis does not contain work that I have published, nor work under review for publication. Signature: Date: 13/11/2018 ii ABSTRACT Osteoarthritis (OA) is a degenerative joint disease with a slow progression that affects the articular cartilage of synovial joints. It is characterized by the destruction of articular cartilage resulting in pain and limited mobility in the affected joint of sufferers, with treatment being limited to pain management and joint replacement. It is well understood that the end stage of OA is the loss of cartilage due to wearing of the joint, however the contribution of many factors in the synovial joint such as the bone, connective tissue and muscle, synovium and immune system all contribute to the pathogenesis of OA. Considering that not all cases of OA are a result of a post-traumatic event, investigation of spontaneous forms of OA is of great importance to observe the disease progression without a mechanical initiation. Investigation of spontaneous OA in human genome wide association (GWAS), twin and family studies has suggested a heritability component that requires the investigation of genetic factors affecting OA development. Current mouse models rely on the initiation of knee OA by mechanical or chemical intervention, with limited consistent spontaneous models available. Without a better understanding of the genetics and how each of the factors contribute to the end stage of OA, alternative interventions and diagnostic tools will remain limited to very few aspects of the disease. Using recombinant inbred mouse strains is an effective way of investigating the genetic component of OA. The Collaborative Cross is a large scale funnel breeding scheme derived from eight founder mouse strains for the purpose of capturing approximately 90% of variation in the mouse genome. The resulting recombinant inbred strains are vastly phenotypically diverse and can be screened for a range of genetically heritable traits such as knee OA. This study utilized knee joints of over 275 aged CC mice across 50 strains representing middle and old aged populations that were each screened using histological iii techniques and scored for severity using the Osteoarthritis Research Society International (OARSI) guidelines for knee OA assessment in the mouse. Analysis of parameters such as severity in the total cohort, 8-12 month and >12 month cohorts and the incidence of any OARSI scored OA and severe scores >3 were performed. Quantitative Trait Locus (QTL) mapping was conducted on 222 mice across 43 strains to identify candidate genes responsible for the severity and risk of OA. Confirmation of candidate genes was conducted by investigating gene expression, protein interaction, correlation with human GWAS datasets and publications and qPCR. A total of 7 loci were identified with 2 reaching genome wide significance with more than 90 genes being identified in the study. Analysis of these genes for potential candidates revealed 8 genome wide significant genes: Myo1f, Daxx, Col11a2, Tap2, Glis3, Cd274 Pdcd1lg2 and Il33. Of these genes, Col11a2, Il33 and Glis3 have been confirmed in human studies of OA, while Daxx, Tap2, Cd274 and Pdcd1lg2 all have been implicated in studies of other forms of arthritis. Myo1f was identified as a novel candidate as it showed expression in osteoclasts and bone and interacted as part of a network with other known OA related candidates. A further 8 genes that reached a suggestive threshold which were also investigated: Cdh4, Col9a3, Cdh13, Obscn, Tab1, Epas1, Jak2 and Dkk1. Of these Col9a3, Epas1, Jak2 and Dkk1 were confirmed in human studies of OA with Tab1 and Cdh13 being implicated in other forms of arthritis. Of the potentially novel candidates, Obscn was found to interact with RhoA, which has a role in a pathway responsible for the induction of chondrocyte differentiation. Future studies of candidate gene knockout animal models and investigation of protein interactions will provide a clearer insight into the involvement of these candidate genes and how they contribute to the development of OA. iv In summary, the results presented in this study validates the use of the collaborative cross for the characterization of spontaneous OA and the identification of known and novel OA susceptibility genes across all of the involved cell and tissue types. The identification of genes found in human OA studies also validates the use of mouse models for future studies of heritable spontaneous OA. v TABLE OF CONTENTS Thesis Declaration……………………………………………………….……………...…….ii Abstract..……………………………………………………….……………………..iii Table Of Contents……………………………………………………………………vi List Of Figures and Tables………………………………….………………………..x Acknowledgements…………………………….…………………………………….xv Published Abstracts and Articles...……………………………………..……….....xix Abbreviations………………………………………….………………………….....xxi Chapter 1 ......................................................................................................................... 1 Literature Review............................................................................................................ 1 1.1 Arthritis .................................................................................................................. 2 1.2 Osteoarthritis ......................................................................................................... 2 1.3 Characterization .................................................................................................... 3 1.4 Clinical Presentation ............................................................................................. 4 1.5 Diagnosis ................................................................................................................. 4 1.6 Synovial Joint Anatomy ........................................................................................ 5 1.6.1 Bone ................................................................................................................... 5 1.6.2 Articular Cartilage ............................................................................................. 8 1.6.3 Synovium ......................................................................................................... 10 1.6.4 Ligaments and Meniscus ................................................................................. 11 1.6.5 Muscle ............................................................................................................. 12 1.7 Treatment ............................................................................................................. 12 1.8 Risk Factors .......................................................................................................... 14 1.9 Biological Processes ............................................................................................. 15 1.9.1 Endochondral Ossification .............................................................................. 15 1.9.2 Pro-inflammatory Cytokines ........................................................................... 18 1.9.3 Anti-inflammatory Cytokines .......................................................................... 20 1.9.4 Matrix Degrading Enzymes ............................................................................. 21 1.9.4.1 Matrix Metalloproteinases .......................................................................
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