Abstract
ObjectiveIn rheumatoid arthritis, the enzyme 11 beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is highly expressed at sites of inflammation, where it converts inactive glucocorticoids (GC) to their active counterparts. In conditions of GC excess it has been shown to be a critical regulator of muscle wasting and bone loss. Here we examine the contribution of 11β-HSD1 to the pathology of persistent chronic inflammatory disease. MethodsTo determine the contribution of 11β-HSD1 to joint inflammation, destruction and systemic bone loss associated with persistent inflammatory arthritis, we generated mice with global and mesenchymal specific 11β-HSD1 deletions in the TNF-transgenic (TNF-tg) model of chronic polyarthritis. Disease severity was determined by clinical scoring. Histology was assessed in formalin fixed sections and fluorescence-activated cell sorting (FACS) analysis of synovial tissue was performed. Local and systemic bone loss were measured by micro computed tomography (micro-CT). Measures of inflammation and bone metabolism were assessed in serum and in tibia mRNA. ResultsGlobal deletion of 11β-HSD1 drove an enhanced inflammatory phenotype, characterised by florid synovitis, joint destruction and systemic bone loss. This was associated with increased pannus invasion into subchondral bone, a marked polarisation towards pro-inflammatory M1 macrophages at sites of inflammation and increased osteoclast numbers. Targeted mesenchymal deletion of 11β-HSD1 failed to recapitulate this phenotype suggesting that 11β-HSD1 within leukocytes mediate its protective actions in vivo. ConclusionsWe demonstrate a fundamental role for 11β-HSD1 in the suppression of synovitis, joint destruction, and systemic bone loss. Whilst a role for 11β-HSD1 inhibitors has been proposed for metabolic complications in inflammatory diseases, our study suggests that this approach would greatly exacerbate disease severity.
Highlights
The 11 beta-hydroxysteroid dehydrogenase (11β-HSD) type 1 enzyme determines tissue specific exposure to endogenous and therapeutic glucocorticoids (GCs)
We crossed the TNF-tg mouse onto the 11β-HSD1 global knock out (KO) mouse to generate TNF-tg animals with deletion of 11β-HSD1 (TNF‐tg11βKO)
Significant corticosterone generation was observed in wild type (WT) and TNF-tg animals but not 11β-KO and TNF‐tg11βKO mice (Fig. 1b)
Summary
The 11 beta-hydroxysteroid dehydrogenase (11β-HSD) type 1 enzyme determines tissue specific exposure to endogenous and therapeutic glucocorticoids (GCs). 11β-HSD1 is highly expressed and active at sites of inflammation in diseases such as rheumatoid arthritis (RA), increasing local exposure to GCs [3,4,5,6]. 0.2 mg/ml 0.2 mg/ml 0.5 mg/ml 0.2 mg/ml 0.2 mg/ml 0.2 mg/ml 0.2 mg/ml 0.2 mg/ml 0.2 mg/ml 0.2 mg/ml 0.2 mg/ml 0.5 mg/ml 0.2 mg/ml 0.2 mg/ml humans [15] and is widely used to assess therapeutic interventions [15,16,17] This model has been invaluable in delineating the pathophysiology of RA, demonstrating the prominence of tumour necrosis factor alpha (TNFα) in the inflammatory cytokine cascade [18].To date, no study has examined the impact of global 11β-HSD1 deletion in models of chronic inflammatory arthritis. We investigated the consequences of global and mesenchymal specific 11βHSD1 deletion in the Tg197 (TNF-tg) murine model of chronic polyarthritis
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