Endocrine Abstracts

Background: Rheumatoid arthritis (RA) is a chronic inflammatory disease characterised by progressive joint destruction and inflammatory activation and hyperproliferation of synoviocytes. We have previously reported a marked shift towards reduced local androgen metabolism in active RA, driven by changing expression of SRD5A1 and AKR1C3 within macrophages. In this study we examined the role of altered androgen metabolism and availability in the inflammatory function of both macr...

The glucocorticoid (GC) activating enzyme 11β-HSD1 is potently upregulated within macrophages and synovial fibroblasts of inflamed joints, where it increases therapeutic GC signalling and regulates their anti-inflammatory profiles. Whilst in vitro studies have demonstrated the importance of autocrine signalling in this context, the importance of paracrine signalling remains poorly defined. In this study, we examined the role of 11β-HSD1 in paracrine GC signalling bet...

Objective: Therapeutic glucocorticoids (GCs) are used to treat chronic inflammatory disease, due to their anti-inflammatory effects. Despite their efficacy, chronic exposure to GCs elicits undesirable side effects, including muscle atrophy. 11 beta-hydroxysteroid dehydrogenase 1 (11β-HSD1) activates GCs within muscle, is induced by inflammation, and has previously shown to drive GC-induced muscle wasting. We examined the role of 11β-HSD1 in mediating muscle wasting i...

Dysregulated recruitment of leukocytes across endothelial cells into target tissues is a hallmark of the pathology of most chronic inflammatory diseases (CIDs). We have identified a novel homeostatic pathway that regulates T-cell migration during inflammation. The pathway is impaired in patients with CIDs such as type-1-diabetes and rheumatoid arthritis (RA), and is also attenuated in the elderly. The dysregulation of this pathway across all conditions is caused by a lower lev...

Muscle wasting is a common feature of inflammatory myopathies. Glucocorticoids (GCs), whilst effective at suppressing inflammation and inflammatory muscle loss, also cause myopathy with prolonged administration. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a bidirectional GC activating enzyme, potently up-regulated by inflammation within mesenchymal derived tissues. We assessed the regulation of this enzyme with inflammation in muscle and examined its functi...

Both therapeutic glucocorticoids (GCs) and chronic inflammation are powerful inducers of systemic bone loss, resulting in osteoporosis and increased morbidity. Whilst GCs suppress inflammation, it is unclear how these factors interact to determine net bone metabolism. We investigated the balance between osteo-protective and osteo-destructive properties of GCs in the TNF-tg model of chronic inflammatory disease. Wild-type (WT) and TNF-tg mice were treated with corticosterone (1...

In chronic inflammatory disease, an increased proportion of M1 polarised macrophages have been shown to contribute to inflammation and tissue damage through the production of pro-inflammatory cytokines such as TNFα. Previously, we have identified expression of the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which converts inactive glucocorticoids (GCs) to their active counterparts, in M1 polarised macrophages in vivo. We hypothesised that 11β...

Steroid sulphatase (STS) is the primary enzyme for desulphating steroids from their inactive to their active forms. Principal substrates include steroid precursors oestrone-sulphate and dehydroepiandrosterone sulfate. Alterations in STS activity can directly affect local concentrations of oestradiol, testosterone and dihydrotestosterone; steroids that are frequently dysregulated in disease. Despite the importance of STS activity on steroid synthesis, little is known about its ...

Glucocorticoid signalling is essential during embryonic lung development, with both the global and epithelial glucocorticoid receptor (GR) null mice presenting with lung atelectasis and post natal lethality. In this study, we examined the role of glucocorticoid signalling within mesenchymal tissues. To study the role of the GR in mesenchymal tissues during embryogenesis we crossed GRflox mice with Dermo1-Cre mice to generate GRDermo1 mice, where the GR gene was cond...

Rheumatoid arthritis (RA) is associated with a loss of lean mass and a corresponding increase in fat mass. How fat accumulation in RA is linked to synovial inflammation is unknown. Wnts comprise a family of secreted glycoproteins that are crucial in regulating adipocyte proliferation, apoptosis and differentiation. Recently we demonstrated that endogenously generated glucocorticoids (GCs) alter the pattern of wnt secretion by synovial fibroblasts (SFs), favouring production of...