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

类风湿性关节炎（RA）是一种严重的关节慢性炎症，伴随着关节破坏和骨质流失。由于其有效的抗炎作用，糖皮质激素（gc）是用于治疗类风湿性关节炎的主要治疗药物之一。然而，慢性GC治疗的副作用之一是骨质疏松症，这一事实阻碍了它们的实用性。尽管GC已经使用了60年，但尚不清楚哪些细胞类型和分子机制负责GC治疗在RA中的有益作用，哪些细胞类型和分子机制参与GC治疗副作用的表达。本建议的目的是确定在类风湿性关节炎的背景下类固醇对炎症和骨结构的影响所涉及的细胞类型。在我们的初步工作中，我们利用条件糖皮质激素受体（GR）突变小鼠建立急性类风湿关节炎和GC诱导骨质疏松模型。我们证明了GR在T细胞中介导类固醇诱导的抗原诱导关节炎急性炎症抑制是必不可少的，但在髓细胞中是必不可少的。此外，我们还证明了GR的同二聚化在这一过程中是重要的。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细胞因子的表达。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在类固醇治疗RA中的作用至关重要：GR二聚体是否存在于某些T细胞亚群中是RA抗炎GC作用的必要条件？GCs是否也通过影响T细胞影响RA的骨重塑？GCs是否通过影响非造血细胞（如成骨细胞、脂肪细胞和滑膜细胞）的细胞因子表达来影响骨转换和RA的炎症反应？通过条件GR突变小鼠和原代免疫细胞和间充质细胞共培养实验，我们期望对炎性骨病类固醇治疗的复杂机制有一个详细的了解。我们的研究项目通过我们自己的专业知识和与这些领域的专家合作，很好地融入了免疫疾病和骨骼疾病领域。我们的发现将对改善类风湿性关节炎的类固醇治疗和开发这种严重慢性疾病的新治疗范例具有重要意义。因此，我们强烈认为该项目适合优先项目“免疫骨-骨免疫学”。

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”.