Understanding the role of transforming growth factor beta signalling and epigenomics in osteoarthritis
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 involve...
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ftmemorialuniv:oai:research.library.mun.ca:12106 2023-10-01T03:57:39+02:00 Understanding the role of transforming growth factor beta signalling and epigenomics in osteoarthritis Aref-Eshghi, Erfan 2016-05 application/pdf https://research.library.mun.ca/12106/ https://research.library.mun.ca/12106/1/thesis.pdf en eng Memorial University of Newfoundland https://research.library.mun.ca/12106/1/thesis.pdf Aref-Eshghi, Erfan <https://research.library.mun.ca/view/creator_az/Aref-Eshghi=3AErfan=3A=3A.html> (2016) Understanding the role of transforming growth factor beta signalling and epigenomics in osteoarthritis. Doctoral (PhD) thesis, Memorial University of Newfoundland. thesis_license Thesis NonPeerReviewed 2016 ftmemorialuniv 2023-09-03T06:48:38Z 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 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 ... Thesis Newfoundland Memorial University of Newfoundland: Research Repository |
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Memorial University of Newfoundland: Research Repository |
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language |
English |
description |
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 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 ... |
format |
Thesis |
author |
Aref-Eshghi, Erfan |
spellingShingle |
Aref-Eshghi, Erfan Understanding the role of transforming growth factor beta signalling and epigenomics in osteoarthritis |
author_facet |
Aref-Eshghi, Erfan |
author_sort |
Aref-Eshghi, Erfan |
title |
Understanding the role of transforming growth factor beta signalling and epigenomics in osteoarthritis |
title_short |
Understanding the role of transforming growth factor beta signalling and epigenomics in osteoarthritis |
title_full |
Understanding the role of transforming growth factor beta signalling and epigenomics in osteoarthritis |
title_fullStr |
Understanding the role of transforming growth factor beta signalling and epigenomics in osteoarthritis |
title_full_unstemmed |
Understanding the role of transforming growth factor beta signalling and epigenomics in osteoarthritis |
title_sort |
understanding the role of transforming growth factor beta signalling and epigenomics in osteoarthritis |
publisher |
Memorial University of Newfoundland |
publishDate |
2016 |
url |
https://research.library.mun.ca/12106/ https://research.library.mun.ca/12106/1/thesis.pdf |
genre |
Newfoundland |
genre_facet |
Newfoundland |
op_relation |
https://research.library.mun.ca/12106/1/thesis.pdf Aref-Eshghi, Erfan <https://research.library.mun.ca/view/creator_az/Aref-Eshghi=3AErfan=3A=3A.html> (2016) Understanding the role of transforming growth factor beta signalling and epigenomics in osteoarthritis. Doctoral (PhD) thesis, Memorial University of Newfoundland. |
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thesis_license |
_version_ |
1778529582467514368 |