Dissecting the osteoimmunological role of dickkopf-1 in arthritis and glucocorticoidinduced bone loss

剖析 dickkopf-1 在关节炎和糖皮质激素引起的骨质流失中的骨免疫作用

• 批准号: 168825475
• 负责人: Professor Dr. Lorenz C. Hofbauer
• 金额: --
• 依托单位: Bereich Endokrinologie, Diabetes und Knochenstoffwechselerkrankungen
• 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 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/168825475?language=en
• 关键词: Dissecting; osteoimmunological; role; dickkopf; arthritis

Glucocorticoids (GCs) are effective drugs in the treatment of inflammatory diseases, including various forms of arthritis. However, their use is limited by negative effects on bone mass and strength, resulting in increased osteoporotic fractures. GCs have adverse effects on bone cells, as they enhance osteoblast and osteocyte apoptosis and stimulate the receptor activator of NF-κB ligand (RANKL)/osteoprotegerin (OPG) ratio, translating into enhanced osteoclastogenesis. We recently demonstrated that RANKL blockade with a monoclonal antibody (denosumab) prevented loss of bone mass and strength that followed the administration of the glucocorticoid prednisolone. While this study demonstrated that targeting RANKL can prevent glucocorticoid-induced osteoporosis (GIO), the mechanistic details of how the glucocorticoid receptor (GR) mediates its therapeutic and skeletal side effects are still unclear. Recently, selective GR agonists (SEGRA) have been developed that favour transrepression of genes (required for therapeutic efficacy) over transactivation of genes (causing side effects). In this project, we plan to characterize the ability of novel SEGRAs to suppress inflammation while sparing the skeleton in vitro and in vivo, and to analyze the underlying mechanisms. Using murine GIO and arthritis models, we will assess the anti-inflammatory efficacy and pro-osteoporotic potential of these SEGRAs and compare them to prednisolone. Moreover, the interactions of SEGRAs with the RANKL/OPG system and Wnt signaling antagonists will be assessed. Detailed knowledge of the molecular mechanisms of GR signaling in bone and immune cells may help to identify GCs with an improved skeletal profile which may benefit patients affected by inflammatory disorders.

糖皮质激素(GCs)是治疗炎症性疾病的有效药物，包括各种形式的关节炎。然而，它们的使用受到骨量和强度的负面影响的限制，导致骨质疏松性骨折增加。骨钙素对骨细胞有不良影响，因为它们促进成骨细胞和骨细胞的凋亡，刺激核因子受体激活剂B配体(RANKL)/骨保护素(OPG)的比率，转化为促进破骨细胞的形成。我们最近证明，RANKL用单抗(地诺舒单抗)阻断可防止糖皮质激素强的松龙治疗后骨量和强度的丢失。虽然这项研究证明靶向RANKL可以预防糖皮质激素诱导的骨质疏松症(GIO)，但糖皮质激素受体(GR)如何介导其治疗和骨骼副作用的机制细节仍不清楚。最近，选择性GR激动剂(SEGRA)已经被开发出来，它们更倾向于反式抑制基因(治疗效果所需)而不是反式激活基因(引起副作用)。在这个项目中，我们计划在体外和体内表征新的SEGRAs在抑制炎症的同时保留骨骼的能力，并分析其潜在的机制。利用小鼠GIO和关节炎模型，我们将评估这些SEGRAs的抗炎效果和促进骨质疏松的潜力，并将它们与强的松龙进行比较。此外，将评估SEGRAs与RANKL/OPG系统和Wnt信号拮抗剂的相互作用。详细了解GR信号在骨骼和免疫细胞中的分子机制可能有助于识别骨骼结构得到改善的GC，这可能有利于受炎症性疾病影响的患者。