Endocrine Abstracts

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...

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...

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...

Muscle wasting remains a significant complication in patients with inflammatory disease where it contributes to disability, risk of falls and early mortality. Interestingly, muscle wasting in patients with glucocorticoid excess mirrors that observed in patients with inflammatory disease. We have previously reported that the glucocorticoid activating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is potently up-regulated within mesenchymal derived cell popu...

Synovial fibroblasts (SFs) form a substantial component of inflamed rheumatoid synovium and generate endogenous glucocorticoids (GCs) during inflammation. Recently, production of DKK-1 (a Wnt signalling inhibitor that reduces bone formation) by SFs in response to TNFα has been proposed to be the master regulator of inflammatory osteoporosis. We have identified that in addition to TNFα, GCs potently induce DKK-1 secretion. This may provide a novel mechanism whereby lo...

Variation in endogenous glucocorticoid (GC) activity during inflammation has been linked to susceptibility to developing rheumatoid arthritis (RA). It has been shown that in patients with RA inflamed synovial tissue can generate active GCs through the expression of the 11β-hydroxysteroid dehydrogenase type 1 enzyme (11β-HSD1), which converts cortisone to cortisol. We examined whether the total body activity of 11β-HSD1 or its expression within synovium was assoc...

Within the synovium of patients with rheumatoid arthritis (RA), synovial fibroblasts generate active corticosteroids through expression of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). In vitro, this enzyme is strongly up-regulated by pro-inflammatory cytokines such as tumour necrosis factor α (TNFα) and IL1β. In this study, we determined the relationship between inflammation and global 11β-HSD1 activity in vivo, in a clini...

Intra-articular (IA) glucocorticoids (GCs) injections are effective in controlling joint inflammation but limited by short duration of action and off-target side effects. Gellan sheared hydrogels (SHs) area drug delivery vehicle, with unique thinning properties and enhanced release kinetics. We hypothesise that a combination of SHs and pre-receptor metabolism activated GCs provide slow-release drug delivery to target inflammation and minimise side-effects. We the release kinet...

Active androgens exert immunomodulatory actions at sites of inflammation and lower levels are implicated in the increased incidence of rheumatoid arthritis (RA) in females. However, inflammatory regulation of intracrine androgen metabolism within cell populations at sites of inflammation remain poorly defined. In this study we characterised immune and stromal cell androgen metabolism in RA patients and assessed their functional significance. Using the online Accelerating Medic...