11 Beta-hydroxysteroid dehydrogenase type 1 regulates synovitis, joint destruction, and systemic bone loss in chronic polyarthritis.
11 Beta-hydroxysteroid dehydrogenase type 1 regulates synovitis, joint destruction, and systemic bone loss in chronic polyarthritis.
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DOI：
10.1016/j.jaut.2018.05.010
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发表时间：
2018-08
影响因子：
12.8
通讯作者：
Raza K
中科院分区：
文献类型：
--
作者：
Hardy RS;Fenton C;Croft AP;Naylor AJ;Begum R;Desanti G;Buckley CD;Lavery G;Cooper MS;Raza K
在类风湿性关节炎中，酶11 β-羟基类固醇脱氢酶1型（11β-HSD 1）在炎症部位高度表达，在那里它将非活性糖皮质激素（GC）转化为活性对应物。在GC过量的情况下，它已被证明是肌肉萎缩和骨丢失的关键调节剂。在这里，我们研究了11β-HSD 1对持续性慢性炎症性疾病病理学的贡献。为了确定11β-HSD 1对与持续性炎性关节炎相关的关节炎症、破坏和全身性骨丢失的贡献，我们在慢性多关节炎的TNF转基因（TNF-tg）模型中产生了具有整体和间充质特异性11β-HSD 1缺失的小鼠。通过临床评分确定疾病严重程度。在福尔马林固定切片中评估组织学，并对滑膜组织进行荧光激活细胞分选（FACS）分析。通过微型计算机断层扫描（micro-CT）测量局部和全身骨丢失。在血清和胫骨mRNA中评估炎症和骨代谢的测量。11β-HSD 1的整体缺失导致炎症表型增强，其特征在于华丽的滑膜炎、关节破坏和全身性骨丢失。这与血管翳侵入软骨下骨增加、炎症部位的促炎M1巨噬细胞明显极化和破骨细胞数量增加相关。11β-HSD 1的靶向间充质缺失未能重现这种表型，表明白细胞内的11β-HSD 1介导其体内保护作用。我们证明了11β-HSD 1在抑制滑膜炎、关节破坏和全身性骨丢失中的基本作用。虽然已经提出了11β-HSD 1抑制剂在炎症性疾病的代谢并发症中的作用，但我们的研究表明，这种方法会大大加剧疾病的严重程度。11β-HSD 1在抑制慢性多发性关节炎的关节破坏和骨丢失方面至关重要。全局缺失导致关节滑膜炎、关节破坏和全身性骨丢失。以巨噬细胞向M1表型的显著极化为特征。间充质缺失不再现整体KO表型。表明11β-HSD 1的治疗性抑制剂会加重疾病的严重程度。
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. 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.
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影响因子：
4.9
作者：
Hardy, Rowan S.;Filer, Andrew;Hewison, Martin
通讯作者：
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