Local glucocorticoids generation in the inflamed joint: regulation and functional consequences

Nanus, Dominika Ewa (2016). Local glucocorticoids generation in the inflamed joint: regulation and functional consequences. University of Birmingham. Ph.D.

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Abstract

Inflammatory arthritis is common. In some patients it progresses to rheumatoid arthritis (RA) whilst in other it spontaneously resolves. There is a particular interest in endogenous anti-inflammatory mechanisms that might be implicated in disease resolution. Amongst these is the role of endogenously produced glucocorticoids (GCs) and in particular 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme that converts biologically inactive GCs such as cortisone into its active counterpart cortisol. This thesis assessed how the 11β-HSD1 enzyme is regulated in patients with inflammatory arthritis, in normal and RA synovial tissue / fluid, and what the functional consequences of expression were. I observed that 11β-HSD1 enzyme is expressed in different populations of fibroblasts and CD68 positive macrophages present in both lining and sub-lining layer of RA synovium. Subsequently, I showed that synovial fibroblasts were able to activate GCs and that this was enhanced by pro-inflammatory cytokines. I also demonstrated that synovial fluid neutrophils isolated from patients with RA express mRNA for 11β-HSD1 enzyme and may therefore represent an important site of local GCs metabolism. I demonstrated that there is an increase in the global measure of 11β-HSD1 activity in patients with active established RA and psoriatic arthritis and that this is inhibited by anti-TNFα therapy. I have also shown that patients with a new onset of synovitis whose disease subsequently resolved had significantly lower levels of systemic 11β-HSD1 activity at presentation when compared with patients whose synovitis persisted. This observation appears contrary to that predicted on the basis of previous work examining 11β-HSD1 activity in patients with established rheumatic diseases. In contrast to the previous results, these data raise the possibility that a high total body 11β-HSD1 activity during early arthritis may reduce the probability of disease resolution. Overall, it is still unclear whether local metabolism of endogenous GCs through the 11β-HSD system is beneficial or detrimental during synovial inflammation, and therefore further clarification is required recognising that the effects of endogenous GCs may be different at different stages of disease.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):