11 Beta-hydroxysteroid dehydrogenase type 1 regulates synovitis, joint destruction, and systemic bone loss in chronic polyarthritis

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.

Local steroid activation is a critical mediator of the anti-inflammatory actions of therapeutic glucocorticoids

“…11β-HSD1 KO animals with global 11β-HSD1 deletion were crossed with TNF-tg animals to generate TNF-tg 11βKO animals as previously described. 8 Mesenchymal 11β-HSD1 KO animals were generated by crossing flx/flx-HSD11B1 mice with Twist2-cre mice to generate 11βHSD1flx/flx/Twist2cre animals, which were paired with TNF-tg animals to produce TNFtg 11βHSD1flx/flx/Twist2cre (TNF-tg 11βflx/tw2cre ). [9][10][11] Myeloid targeted 11β-HSD1 KO animals were generated by crossing flx/flx-HSD11B1 mice with LysM-cre mice to generate 11βHSD1flx/ flx/LysMcre animals, which were paired with TNF-tg animals to produce TNF-tg 11βHSD1flx/flx/LysMcre (TNF-tg 11βflx/LysMcre ).…”

Unravelling how glucocorticoids work in rheumatoid arthritis

“…Mice defective in 11β-HSD1 develop exaggerated joint inflammation in acute and chronic model of arthritis. 6,7 11β-HSD1 activity within macrophages appears to be critical in restraining inflammation in these models. 8 It would be interesting to know whether the responses seen by Koenen et al with dexamethasone are similar using glucocorticoids that are regulated by 11β-HSD1 such as those typically used to treat patients with RA.…”

Arthritis and the role of endogenous glucocorticoids

“…Further analysis revealed that while B-cell numbers remained unchanged, there was a significant increase in CD3 + , CD4 + , and CD8 + T-cells, pro-inflammatory M1 macrophages and neutrophils in TNF-tg 11βKO arthritic mice compared to TNF-tg mice. 226 Collectively, these studies suggest that global endogenous GC signaling, when enhanced by increased 11β-HSD1 activity, has predominately antiinflammatory effects in the joint (Table 2). Furthermore, to mechanistically determine whether GR dimerization is required for producing the anti-inflammatory effects of GCs in arthritis, GR dim mice have been utilized in both AIA and K/BxN STA mouse models.…”