The role of endocrine and other factors in the remodelling underpinning Graves’ orbitopathy

Draman, Mohd Shazli 2016. The role of endocrine and other factors in the remodelling underpinning Graves’ orbitopathy. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

In Graves’ orbitopathy (GO) tissue remodelling by increased proliferation, excess adipogenesis and hyaluronan overproduction, cause exophthalmos. My initial work followed reports by others of enophthalmos in some glaucoma patients treated with Bimatoprost (prostaglandin F2α, PGF2α) eye drops. I hypothesized that this could be due to reduced proliferation or adipogenesis and/or increased lipolysis; any of which could improve GO. In vitro models used to investigate possible mechanisms demonstrated that PGF2α reduced proliferation by prolongation of G2/M (flow cytometry) and adipogenesis (evaluated morphologically, by oil red O staining and QPCR measurement of adipogenesis markers) of 3T3-L1 and human orbital fibroblasts (OF). These effects were reversible upon drug withdrawal. GO OFs proliferated significantly more rapidly and also displayed higher adipogenic potential than non-GO. There was no effect of PGF2α, on basal or norepinephrine-induced lipolysis in 3T3-L1 or human OFs, either GO or non-GO. The data helped us secure NISCHR funding for a clinical trial ‘Prostaglandin F2-alpha eye drops (Bimatoprost) in thyroid eye disease: a randomised controlled double blind crossover trial’. Following informed consent, 31 clinically inactive (late phase) GO patients were randomised to receive Bimatoprost or placebo eye drops daily for three months followed by a two-month drug washout period before switching to the opposite treatment for three months. I concluded that 3 months Bimatoprost treatment is not effective in reducing proptosis in late phase GO patients. Mysubsequent work investigated truncated TSHR variants (TSHR_v2) and thyrostimulin. The former could act as TSH/TRAB binding proteins whilst the latter could bind to and activate the TSHR and contribute to GO pathogenesis. I found no evidence of a role for thyrostimulin in GO. TSHR_v2 transcripts and protein are more abundant than full length TSHR in OF and during adipogenesis are significantly higher in GO than non-GO. TSHR_v2 may be secreted and provide a binding protein for TSHR ligands and thus alter intracellular TSHR signalling. GD patients lose weight during active disease but gain more following treatment. Our group reported that TSHR activation leads to a ‘browning’ of fat from various depots. I performed ex vivo analysis on neck fat for brown, beige and white adipose tissue markers. The samples were GD patients (previously hyperthyroid/positive TSAB), toxic goitre (previously hyperthyroid/no TSAB) and euthyroid. I found no difference in expression of UCP1 and PGC1α. There were general reductions in ZIC1, CITED1, HOXC9 and LEPTIN markers in GD which may explain the altered body composition in these patients.

Item Type:	Thesis (PhD)
Status:	Unpublished
Schools:	Medicine
Subjects:	R Medicine > R Medicine (General)
Date of First Compliant Deposit:	2 May 2017
Last Modified:	11 Dec 2020 03:16
URI:	https://orca.cardiff.ac.uk/id/eprint/100130

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