Institute of Inflammation and Ageing, ARUK Rheumatoid Arthritis Centre of Excellence, MRC ARUK Centre for Musculoskeletal Ageing, University of Birmingham, Birmingham, UK; Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK.
Institute of Inflammation and Ageing, ARUK Rheumatoid Arthritis Centre of Excellence, MRC ARUK Centre for Musculoskeletal Ageing, University of Birmingham, Birmingham, UK; Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK.
J Autoimmun. 2018 Aug;92:104-113. doi: 10.1016/j.jaut.2018.05.010. Epub 2018 Jun 8.
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.
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.
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.
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.
在类风湿关节炎中，酶 11β-羟类固醇脱氢酶 1（11β-HSD1）在炎症部位高度表达，在那里将无活性的糖皮质激素（GC）转化为其活性形式。在 GC 过多的情况下，它已被证明是肌肉减少和骨丢失的关键调节剂。在这里，我们研究了 11β-HSD1 对持续性慢性炎症性疾病病理学的贡献。
为了确定 11β-HSD1 对与持续性炎症性关节炎相关的关节炎症、破坏和系统性骨丢失的贡献，我们在 TNF 转基因（TNF-tg）慢性多关节炎模型中生成了全身性和间充质特异性 11β-HSD1 缺失的小鼠。通过临床评分确定疾病严重程度。对福尔马林固定切片进行组织学评估，并对滑膜组织进行荧光激活细胞分选（FACS）分析。通过微计算机断层扫描（micro-CT）测量局部和系统性骨丢失。通过血清和胫骨 mRNA 评估炎症和骨代谢的测量。
全身性 11β-HSD1 缺失导致炎症表型增强，其特征为滑膜炎症、关节破坏和系统性骨丢失。这与软骨下骨的侵袭性增加、炎症部位促炎 M1 巨噬细胞的明显极化以及破骨细胞数量的增加有关。靶向间充质 11β-HSD1 缺失未能重现这种表型，表明白细胞中的 11β-HSD1 在体内介导其保护作用。
我们证明了 11β-HSD1 在抑制滑膜炎、关节破坏和系统性骨丢失中的基本作用。虽然 11β-HSD1 抑制剂已被提议用于炎症性疾病的代谢并发症，但我们的研究表明，这种方法将极大地加剧疾病的严重程度。
