11β-Hydroxysteroid dehydrogenase type 1 within muscle protects against the adverse effects of local inflammation

Abstract

Muscle wasting is a common feature of inflammatory myopathies. Glucocorticoids (GCs), although 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 that is potently upregulated by inflammation within mesenchymal‐derived tissues. We assessed the regulation of this enzyme with inflammation in muscle, and examined its functional impact on muscle. The expression of 11β‐HSD1 in response to proinflammatory stimuli was determined in a transgenic murine model of chronic inflammation (TNF‐Tg) driven by overexpression of tumour necrosis factor (TNF)‐α within tissues, including muscle. The inflammatory regulation and functional consequences of 11β‐HSD1 expression were examined in primary cultures of human and murine myotubes and human and murine muscle biopsies ex vivo. The contributions of 11β‐HSD1 to muscle inflammation and wasting were assessed in vivo with the TNF‐Tg mouse on an 11β‐HSD1 null background. 11β‐HSD1 was significantly upregulated within the tibialis anterior and quadriceps muscles from TNF‐Tg mice. In human and murine primary myotubes, 11β‐HSD1 expression and activity were significantly increased in response to the proinflammatory cytokine TNF‐α (mRNA, 7.6‐fold, p < 0.005; activity, 4.1‐fold, p < 0.005). Physiologically relevant levels of endogenous GCs activated by 11β‐HSD1 suppressed proinflammatory cytokine output (interkeukin‐6, TNF‐α, and interferon‐γ), but had little impact on markers of muscle wasting in human myotube cultures. TNF‐Tg mice on an 11β‐11β‐HSD1 knockout background developed greater muscle wasting than their TNF‐Tg counterparts (27.4% less; p < 0.005), with smaller compacted muscle fibres and increased proinflammatory gene expression relative to TNF‐Tg mice with normal 11β‐HSD1 activity. This study demonstrates that inflammatory stimuli upregulate 11β‐HSD1 expression and GC activation within muscle. Although concerns have been raised that excess levels of GCs may be detrimental to muscle, in this inflammatory TNF‐α‐driven model, local endogenous GC activation appears to be an important anti‐inflammatory response that protects against inflammatory muscle wasting in vivo. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Cellular and genetic models of H6PDH and 11β‐HSD1 function in skeletal muscle

“…5 Glucocorticoids are known to increase the expression and activity of 11β-HSD1, which may be an important physiological mechanism to locally increase available glucocorticoid and restrain the acute inflammatory process, a response potentially perturbed in disease. 20,21 We show here that glucocorticoid signalling increases the expression of 11β-HSD1 and H6PDH, but not G6PT in muscle. In the context of endogenous or exogenous glucocorticoid excess, upregulation of 11β-HSD1 in muscle may represent an unwanted "side-effect" exacerbating myopathy.…”

“…11β‐Hydroxysteroid dehydrogenase type 1 expression is regulated by a plethora of hormones and cytokines, acting to increase or decrease the ability of target cells to generate glucocorticoid . Glucocorticoids are known to increase the expression and activity of 11β‐HSD1, which may be an important physiological mechanism to locally increase available glucocorticoid and restrain the acute inflammatory process, a response potentially perturbed in disease . We show here that glucocorticoid signalling increases the expression of 11β‐HSD1 and H6PDH, but not G6PT in muscle.…”

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

“…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] ]. Resident mesenchymal derived populations such as fibroblast like synoviocytes (FLS) are important sites of 11β-HSD1 mediated GC activation in response to inflammation, which feeds back to suppress pro-inflammatory signalling in vitro [ [3] , [4] , [5] , [6] , [7] , [8] , [9] ]. 11β-HSD1 is also expressed in synovial leukocyte populations, including macrophages, lymphocytes and dendritic cells where it dampens pro-inflammatory signalling and promotes resolution [ 5 , 6 , [10] , [11] , [12] , [13] , [14] ].…”

TNFα depleting therapy improves fertility and animal welfare in TNFα-driven transgenic models of polyarthritis when administered in their routine breeding

“…Infliximab has previously been shown to be highly efficacious in abrogating disease activity and joint destruction in the hTNFtg mouse when given once weekly at 8 mg/kg by intraperitoneal injection, and is routinely administered in our breeding programmes of these animals. 2 , 20 …”

“…Upon starting infliximab the mice were scored three times weekly (Monday, Wednesday and Friday) for inflammatory joint scores (supplementary Table 1) and collective clinical scoring of weight loss, behaviour, mobility, grimace, severity and duration of joint inflammation (supplementary Table 2) as previously reported. 20 …”