11 Beta-hydroxysteroid dehydrogenase type 1 regulates synovitis, joint destruction, and systemic bone loss in chronic polyarthritis.
J Autoimmun
; 92: 104-113, 2018 08.
Article
em En
| MEDLINE
| ID: mdl-29891135
ABSTRACT
OBJECTIVE:
In rheumatoid arthritis, the enzyme 11 beta-hydroxysteroid dehydrogenase type 1 (11ß-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 11ß-HSD1 to the pathology of persistent chronic inflammatory disease.METHODS:
To determine the contribution of 11ß-HSD1 to joint inflammation, destruction and systemic bone loss associated with persistent inflammatory arthritis, we generated mice with global and mesenchymal specific 11ß-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 11ß-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 11ß-HSD1 failed to recapitulate this phenotype suggesting that 11ß-HSD1 within leukocytes mediate its protective actions in vivo.CONCLUSIONS:
We demonstrate a fundamental role for 11ß-HSD1 in the suppression of synovitis, joint destruction, and systemic bone loss. Whilst a role for 11ß-HSD1 inhibitors has been proposed for metabolic complications in inflammatory diseases, our study suggests that this approach would greatly exacerbate disease severity.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Artrite
/
Artrite Reumatoide
/
Sinovite
/
Reabsorção Óssea
/
11-beta-Hidroxiesteroide Desidrogenase Tipo 1
/
Inflamação
/
Articulações
/
Macrófagos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
J Autoimmun
Assunto da revista:
ALERGIA E IMUNOLOGIA
Ano de publicação:
2018
Tipo de documento:
Article