The underlying molecular regulators and their effects on mineralisation in the trabecular bone microenvironment and osteoblast of primary hip osteoarthritis.
| dc.contributor.advisor | Fazzalari, Nicola L. | en |
| dc.contributor.advisor | Atkins, Gerald | en |
| dc.contributor.advisor | Hopwood, Blair | en |
| dc.contributor.author | Kumarasinghe, Duminda Dananjaya | en |
| dc.contributor.school | School of Medical Sciences | en |
| dc.date.issued | 2012 | en |
| dc.description.abstract | Primary hip osteoarthritis (OA) is emerging as a dynamic pathology, developing over a long period and involving many tissue types of the joint, including the bone. Previous studies have established differential gene expression, changes in microarchitectural indices, altered cellular characteristics and material properties in the bone of primary hip OA. These studies suggest that OA is a systemic disease involving the bone and validate the assessment of molecular changes to further investigate this complex disease. The aim of the studies herein was to further characterise the altered gene expression profile in both OA bone and osteoblasts, and compare these with control (CTL) bone and cells, respectively. The first study examined differential gene expression, histomorphometric indices and relationships between these, in femoral trabecular bone from OA patients and CTL subjects, with the aim of identifying molecular changes consistent with structural and remodelling indices in the OA pathology. The second and third studies used primary osteoblasts derived from female hip OA cases against CTL to investigate the expression of candidate OA disease genes during osteoblast differentiation and mineralisation, in terms of calcium apposition and elemental composition of the mineral. A number of alterations in gene expression, histomorphometric indices and correlations were identified in OA bone compared to CTL. Notably, significant relationships observed in CTL bone between critical components of the Wnt/β-catenin signalling pathway (e.g. CTNNB1) and regulators of osteoblastogenesis (e.g. TWIST1) with indices of bone formation and structure were absent in OA bone. Conversely, the expression of MMP25, a regulator of matrix degradation, and indices of bone resorption were correlated exclusively in OA. In the second study fundamental differences in osteoblast behaviour were identified in cells cultured ex vivo from OA bone. The Ca:P ratio was significantly more varied in OA compared to CTL. Calcium apposition and mineral composition changed significantly over time. Genes associated with osteoblast differentiation were analysed with respect to the mineral measures. TWIST1 mRNA expression was elevated and correlated with SMAD3 mRNA levels in the OA cohort during the time course. Associations were observed between TNAP, OCN, TWIST1, TGFβ1, SMAD3 mRNA levels and mineral measures in OA against CTL. Temporal differences between SMAD3 mRNA expression and mineral composition were also found in OA. The third study concerned genes involved directly with the regulation of osteoblast/osteocyte mediated mineralisation. Analysis revealed that PHEX and PTEN mRNA expression were higher and more varied in OA. PHEX mRNA expression correlated with PTEN throughout the time course in OA cultures, both genes also correlated with Ca apposition. Other OAspecific patterns of gene correlations were identified, including those between MEPE and OCN, and MEPE and DMP1. Additionally, associations between gene expression and mineral measure were significantly different in OA; including those between MEPE and Ca apposition, as well as the Ca:P ratio, DMP1 and the Ca:P ratio, and PTEN and the Ca:C and P:C ratios. Together, these findings suggest that inherent molecular changes in the bone and importantly, its constituent osteoblasts, contribute to the pathology of primary hip OA. These studies strongly imply that at least in the case of primary hip OA, the bone should be considered as an important contributor to the disease aetiology. The differentially expressed molecules identified herein associated with microarchitectural and compositional changes offer avenues for further experimental investigations and, potentially, novel therapeutic targets. | en |
| dc.description.dissertation | Thesis (Ph.D.) -- University of Adelaide, School of Medical Sciences, 2012 | en |
| dc.identifier.uri | http://hdl.handle.net/2440/87113 | |
| dc.provenance | Copyright material removed from digital thesis. See print copy in University of Adelaide Library for full text. This electronic version is made publicly available by the University of Adelaide in accordance with its open access policy for student theses. Copyright in this thesis remains with the author. This thesis may incorporate third party material which has been used by the author pursuant to Fair Dealing exceptions. If you are the owner of any included third party copyright material you wish to be removed from this electronic version, please complete the take down form located at: http://www.adelaide.edu.au/legals | en |
| dc.subject | bone; osteoarthritis; osteoblast; hip; gene expression; calcium; mineral; mineralisation; electron microscopy; cell culture | en |
| dc.title | The underlying molecular regulators and their effects on mineralisation in the trabecular bone microenvironment and osteoblast of primary hip osteoarthritis. | en |
| dc.type | Thesis | en |
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