11 Beta-hydroxysteroid dehydrogenase type 1 regulates synovitis, joint destruction, and systemic bone loss in chronic polyarthritis. (August 2018)

• Record Type: Journal Article
• Authors: Hardy, R.S.; Fenton, C.; Croft, A.P.; Naylor, A.J.; Begum, R.; Desanti, G.; Buckley, C.D.; Lavery, G.; Cooper, M.S.; Raza, K.
• Is Part Of: Journal of autoimmunity. Volume 92(2018)
• Page Start: 104
• Page End: 113
• Publication Date: 2018-08
• Subjects: Autoimmunity -- Periodicals; Autoimmune diseases -- Periodicals; Autoantibodies -- Periodicals; Autoimmune Diseases -- Periodicals; Auto-immunité -- Périodiques; Maladies auto-immunes -- Périodiques; Electronic journals; 616.978005
• DOI: 10.1016/j.jaut.2018.05.010
• Languages: English
• ISSNs: 0896-8411

Abstract

Abstract: Objective: In 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. Methods: To 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. Results: Global 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. Conclusions: We 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: 11β-HSD1 is critical in suppressing joint destruction and bone loss in chronic polyarthritis. Global Deletion drives florid synovitis, joint destruction and systemic bone loss. Characterised by a marked polarisation of macrophages towards an M1 phenotype. Mesenchymal deletion does not reproduce the global KO phenotype. Indicates that therapeutic inhibitors of 11β-HSD1 would exacerbate disease severity.