Cell type specific action of glucocorticoids in inflammation and bone integrity of rheumatoid arthritis

糖皮质激素在类风湿关节炎炎症和骨完整性中的细胞类型特异性作用

• 批准号: 168861521
• 负责人: Professor Dr. Jan Tuckermann
• 金额: --
• 依托单位: Institut für Molekulare Endokrinologie der Tiere
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/168861521?language=en
• 关键词: Cell; type; specific; action; glucocorticoids

Rheumatoid arthritis (RA) is a severe chronic inflammation of the joints which is accompanied by joint destruction and bone loss. Because of their potent anti-inflammatory action, glucocorticoids (GCs) are among the main therapeutic drugs used for treatment of RA. Their usefulness is however hampered by the fact that chronic GC treatment causes osteoporosis as one of the side effects.Although GCs have been in use for 60 years, it is not yet known which cell types and which molecular mechanisms are responsible for the beneficial effects and which ones are involved in the expression of the side effects of GC treatment in RA. The aim of this proposal is to determine the cell types involved in the influence of steroids on inflammation and on bone architecture in the context of rheumatoid arthritis.In our preliminary work we exploited conditional glucocorticoid receptor (GR) mutant mice in acute rheumatoid arthritis and GC induced osteoporosis models. We demonstrated that the GR is essential in T cells for mediating steroid-induced suppression of acute inflammation in antigen induced arthritis, but is dispensable in myeloid cells. Furthermore we showed that homo-dimerization of the GR is important for this process. In GC induced osteoporosis we found that monomeric GR in osteoblasts is sufficient to mediate this side effect, presumably via suppression of cytokine expression in the osteoblasts.With these results we now have the tools in hand to address the following questions, which are essential for the understanding of GC action in steroid therapy of RA:1. Is the presence of the GR dimer in certain T cell subsets required for antiinflammatory GC effects in RA?2. Do GCs also influence bone remodelling in RA by affecting T cells?3. Do GCs influence bone turnover and the inflammatory response in RA by affecting cytokine expression of non-hematopoietic cells (e.g. osteoblasts, adipocytes and synovial cells)?Using an approach with conditional GR mutant mice and co-culture experiments of primary immune and mesenchymal cells, we expect to gain a detailed understanding of the complex mechanisms involved in steroid therapy of an inflammatory bone disease. Our research program is well embedded in the fields of immunological diseases and bone diseases by our own expertise and co-operations with experts in these areas. Our findings will be fundamental to improve steroid therapy of rheumatoid arthritis and to develop novel treatment paradigms for this severe chronic disease. We therefore strongly feel that this program is suitable for the priority program “Immunobone-Osteoimmunology”.

类风湿性关节炎（RA）是一种严重的慢性关节炎症，伴有关节破坏和骨丢失。由于其有效的抗炎作用，糖皮质激素（GC）是用于治疗RA的主要治疗药物之一。然而，它们的有用性受到以下事实的阻碍，即慢性GC治疗导致骨质疏松症作为副作用之一。虽然GC已经使用了60年，但尚不清楚哪些细胞类型和哪些分子机制负责有益的效果，以及哪些参与了GC治疗RA的副作用的表达。本提案的目的是确定参与类固醇对炎症和骨结构的影响的细胞类型，在类风湿关节炎的背景下，在我们的初步工作中，我们利用条件性糖皮质激素受体（GR）突变小鼠在急性类风湿关节炎和GC诱导的骨质疏松症模型。我们证明了GR在T细胞中是介导类固醇诱导的对抗原诱导的关节炎的急性炎症的抑制所必需的，但在骨髓细胞中是不可缺少的。此外，我们表明，同源二聚的GR是很重要的这个过程。在GC诱导的骨质疏松症中，我们发现成骨细胞中的单体GR足以介导这种副作用，可能是通过抑制成骨细胞中的细胞因子表达，有了这些结果，我们现在有了解决以下问题的工具，这些问题对于理解GC在RA类固醇治疗中的作用至关重要：1. GR二聚体在RA中的某些T细胞亚群中的存在是否是RA中AGG-GC效应所必需的？2. GC是否也通过影响T细胞影响RA的骨重建？3. GC是否通过影响非造血细胞（例如成骨细胞、脂肪细胞和滑膜细胞）的细胞因子表达来影响RA的骨转换和炎症反应？使用条件性GR突变小鼠和原代免疫细胞和间充质细胞共培养实验的方法，我们期望获得对炎症性骨病类固醇治疗中涉及的复杂机制的详细了解。我们的研究计划是很好地嵌入在免疫性疾病和骨骼疾病的领域，通过我们自己的专业知识和合作，在这些领域的专家。我们的研究结果将是根本的，以改善类固醇治疗类风湿关节炎，并开发新的治疗模式，这种严重的慢性疾病。因此，我们强烈认为该计划适合优先计划“免疫骨-骨免疫学”。