The role of pre-receptor steroid metabolism in the therapeutic application of glucocorticoids

Fenton, Chloe (2020). The role of pre-receptor steroid metabolism in the therapeutic application of glucocorticoids. University of Birmingham. Ph.D.

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Abstract

Glucocorticoids (GCs) are widely used in the treatment of chronic inflammatory diseases such as rheumatoid arthritis (RA). Unfortunately, their application is limited by side effects including GC-induced osteoporosis (GIO). The GC-activating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) has been shown to mediate side effects associated with therapeutic GCs, suggesting that 11β-HSD1 inhibition may be effective in managing their deleterious side effect profile. In this thesis, I have examined the contribution of 11β-HSD1 to therapeutic actions and off target bone side effects of therapeutic GCs in the TNF-transgenic (TNF-tg) murine model of chronic polyarthritis. TNF-tg animals receiving the GC corticosterone in drinking water (100 mg/L) demonstrated a significant reduction in markers of inflammation, disease activity, synovitis and inflammatory bone loss. In contrast, TNF-tg animals with transgenic deletion of 11β-HSD1 (TNF11βKO) showed a marked resistance to GC-induced changes showing more severe, persistent inflammation and inflammatory bone loss, despite being protected from GIO driven by suppression of anabolic bone formation. Local and systemic bone loss in TNF11βKO animals receiving GCs, was underpinned by increased inflammatory activation of osteoclasts. This study demonstrates a fundamental role for 11β-HSD1 in mediating the anti-inflammatory and bone protective actions of therapeutic GCs in murine models of chronic polyarthritis.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):