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Title: Investigating the effects of glucose exposure on synoviocytes and chondrocytes as a model for musculoskeletal ageing
Author: Tregilgas, L.
ISNI:       0000 0004 7428 5029
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2017
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Introduction: It is well established that elevated glucose exposure is a major factor in the progression of the ageing process in the vascular system. There is a growing body of evidence that suggests similar effects in the musculoskeletal system. A trend showing increasing levels of glucose consumption has been shown globally over the past 50 years, with a postulated link to a similar growth in metabolic disorders and diabetes incidence. The list of secondary pathologies associated with diabetes, characterised by chronic elevated blood glucose levels, has been extended in recent years to include musculoskeletal disorders such as joint-stiffening and osteoarthritis. The goal of this project was to characterise potential age-related effects of life-long excessive glucose consumption, with the key area of focus being the human knee-joint. The majority of this research has been carried out on key cell types native to the human knee-joint that are equally implicated in the onset and progression of joint disorders - fibroblast-like synoviocytes; and articular chondrocytes. Results: The major glucose transporters expressed in synoviocytes and chondrocytes were shown to be those that are known to be non-insulin dependent with a high affinity for glucose, indicating the sensitivity of these cells to extracellular fluctuations in glucose concentrations. Two high-glucose concentrations were used (11mM and 30mM). Data showed an increase in glucose uptake, dose-dependently, at 16h (n = 5). Glucose uptake was reduced by 73% after 14d of 30mM glucose exposure (P < 0.01, n = 5). The more physiological treatment, given over a short time-period (11mM, 16 hours), showed the largest effect on synoviocyte methylation (n = 3). Interestingly, the increase in glucose uptake, relative to the 5.5mM control, did not change over time in the 11mM treatment (P = 0.632, n = 5), although a significant hypomethylation of CpG sites was only observed in these cells after 16 hours. Cellular adhesion markers (protocadherins) were among the most commonly differentially-methylated genomic regions in this treatment group. The largest level of significant transcriptional changes was observed in the 11mM treatment after 14d. Microarray data implicating DNA damage was not corroborated by observed DNA strandbreaks, but a trend in the data might suggest a larger effect of the 11mM treatment (n = 3, not significant). Conclusions: A great deal of prior research into the effects of glucose on ageing has used a concentration of 30mM as the standard high-glucose treatment. The data from the current study shows that there is a propensity for a more physiologically relevant 11mM treatment to cause DNA hypomethylation – which is consistent with ageing - in key cells implicated in musculoskeletal pathologies. Other potential downstream effects include DNA damage and cell adhesion. The effects of a more modest 11mM glucose treatment could also prove to be more profound than those of the 30mM treatment, due to a sustained high-glucose exposure. This is in contrast to the celluloprotective reduction in glucose uptake following a 30mM glucose treatment for 14 days. In addition, this work provides a significantly more detailed understanding of the effects of high-glucose exposure in cells from synovial joints.
Supervisor: Laird, Elizabeth ; Clegg, Peter ; Loughlin, John ; Reynard, Louise ; Tew, Simon Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral