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Understanding the Role of Transforming Growth Factor Beta Signalling and Epigenomics in Osteoarthritis

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Understanding the role of Transforming Growth Factor Beta signalling and Epigenomics in Osteoarthritis by ©Erfan Aref-Eshghi A thesis submitted to the School of Graduate Studies In partial fulfilment of the requirements for the degree of Doctor of Philosophy in Medicine - Human Genetics Discipline of Genetics, Faculty of Medicine Memorial University of Newfoundland St. John’s, Newfoundland and Labrador, Canada May 2016 i Abstract Osteoarthritis (OA) is the most common form of arthritis with a high socioeconomic burden, with an incompletely understood etiology. Evidence suggests a role for the transforming growth factor beta (TGF-ß) signalling pathway and epigenomics in OA. The aim of this thesis was to understand the involvement of the TGF-ß pathway in OA and to determine the DNA methylation patterns of OA-affected cartilage as compared to the OA-free cartilage. First, I found that a common SNP in the BMP2 gene, a ligand in the Bone morphogenetic protein (BMP) subunit of TGF-ß pathway, was associated with OA in the Newfoundland population. I also showed a genetic association between SMAD3 - a signal transducer in the TGF-ß subunit of the TGF-ß signalling pathway - and the total radiographic burden of OA. I further demonstrated that SMAD3 is over-expressed in OA cartilage, suggesting an over activation of the TGF-ß signalling in OA. Next, I examined the connection of these genes in the regulation of matrix metallopeptidase 13 (MMP13) - an enzyme known to destroy extracellular matrix in OA cartilage - in the context of the ‎TGF-ß signalling. The analyses showed that TGF-ß, MMP13, and SMAD3 were overexpressed in OA cartilage, whereas the expression of BMP2 was significantly reduced. The expression of TGF-ß ‎was positively correlated with that of SMAD3 and MMP13, suggesting that TGF-ß signalling is involved in up-regulation of MMP13. This regulation, however, appears not to be controlled by SMAD3 signals, possibly due to the involvement of collateral signalling, and to be suppressed by BMP ‎regulation in healthy cartilage, whose levels were reduced in end-stage OA. ‎ In a genome-wide DNA methylation analysis, I reported CpG sites ‎differentially methylated in OA and showed that the cartilage methylome has a potential to ‎distinguish between OA-affected ii and non-OA cartilage. Functional clustering analysis of the ‎genes harbouring differentially methylated loci revealed that they are enriched in the skeletal system morphogenesis ‎pathway, which could ‎be a potential candidate for further OA studies. Overall, ‏the findings from the present thesis provide evidence that the TGF-ß signalling ‎pathway is associated with the development of OA, and epigenomics might be involved as a ‎potential mechanism in OA. iii Acknowledgements I would like to thank, first and foremost, my supervisor, Dr. Guangju Zhai, who gave me the opportunity to work under his supervision and to enjoy being a member of the research team in the Newfoundland Osteoarthritis Study (NFOAS). I also appreciate the support and advice I received from my supervisory committee, Drs. Andrew Furey and Guang Sun, particularly for their inputs into this thesis project. I would also like to remember my previous co-supervisor, Dr. Roger Green, who sadly and unexpectedly passed away in August 2015. Roger, you will be missed, and I will never forget the assistance I received from you in various steps of this project. To everyone who assisted me with this work and helped in solving the problems at different stages of the project. Special thanks to Ming Liu, Patricia Harper, Yuhua Zhang, Edward Yaskowiak, Hongwei Zhang, Zoha Rabie, Michelle Simms, and all the staff at the operating rooms of the Health Sciences and St. Clare’s Mercy Hospitals, who directly and indirectly contributed to this work. To all my friends in St. John’s: thanks for helping me not feel lonely as a new-comer. Special thanks to Atefeh and Justin, who filled my spare time with adventures, and to Shirin and Uzair, whom I shared with lots of memories over the course of my stay in St. John’s. Thanks to all the Feild Hall residents who made me feel like living in a great family in all these years far from home, and thanks to everyone else with whom I shared coffee, had a small talk and made friend or acquaintance in St. John’s, those who made this experience unique. And finally, to my parents and younger sister: thanks for your continued support and hearing your son’s concerns from thousands of kilometres away. I could not have done this without you. iv Table of Contents Abstract ........................................................................................................................................... ii Acknowledgements ........................................................................................................................ iv List of Tables ................................................................................................................................ vii List of Figures ................................................................................................................................ ix List of Abbreviations ...................................................................................................................... x Co-authorship Statement ............................................................................................................... xii Chapter one: Introduction ............................................................................................................... 1 1.1. An introduction to osteoarthritis (OA) ................................................................................. 2 1.1.1. Definition ....................................................................................................................... 2 1.1.2. Pathology of OA ............................................................................................................ 5 1.1.3. Signs and symptoms of OA ........................................................................................... 9 1.1.4. Diagnosis ..................................................................................................................... 11 1.1.5. Management ................................................................................................................ 15 1.2. Epidemiology ..................................................................................................................... 17 1.2.1. Prevalence and incidence of OA ................................................................................. 17 1.2.2. Socio-economic burden of OA .................................................................................... 21 1.3. Aetiology and risk factors .................................................................................................. 22 1.3.1. Environmental Factors ................................................................................................. 22 1.3.1.1. Age ........................................................................................................................ 22 1.3.1.2. Sex......................................................................................................................... 23 1.3.1.3. Obesity .................................................................................................................. 24 1.3.1.4. Physical activity, lifestyle, and occupations ......................................................... 25 1.3.1.5. Injuries and joint abnormalities ............................................................................ 26 1.3.2. Genetics ....................................................................................................................... 27 1.3.2.1. Familial aggregation - family based studies ......................................................... 28 1.3.2.2. Heritability - Twin studies .................................................................................... 32 1.3.2.3. Linkage analysis .................................................................................................... 35 1.3.2.4. Candidate gene studies .......................................................................................... 37 1.3.2.5. GWAS ................................................................................................................... 40 1.3.2.6. Epigenetics ............................................................................................................ 43 1.4. Transforming growth factor beta signalling pathway in osteoarthritis .............................. 45 1.5. Hypotheses and objectives ................................................................................................. 49 Chapter two: Attempt to replicate the published osteoarthritis associated genetic variants in the Newfoundland & Labrador Population ......................................................................................... 52 Abstract ..................................................................................................................................... 53 Introduction ............................................................................................................................... 54 v Methods ..................................................................................................................................... 55 Results ......................................................................................................................................
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