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

糖皮质激素（GC）是治疗炎性疾病（包括各种形式的关节炎）的有效药物。然而，它们的使用受到对骨量和强度的负面影响的限制，导致骨质疏松性骨折增加。GC对骨细胞具有不利影响，因为它们增强成骨细胞和骨细胞凋亡，并刺激NF-κB配体受体激活因子（RANKL）/骨保护素（OPG）比率，转化为增强的破骨细胞生成。我们最近证明，RANKL阻断与单克隆抗体（狄诺塞麦）防止骨量和强度的损失后，给予糖皮质激素泼尼松龙。虽然这项研究表明，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，已经开发了选择性GR激动剂（SEGRA），其有利于基因的反式阻遏（治疗功效所需的）而不是基因的反式激活（引起副作用）。在这个项目中，我们计划在体外和体内表征新型SEGRA抑制炎症同时保留骨骼的能力，并分析其潜在机制。使用小鼠GIO和关节炎模型，我们将评估这些SEGRA的抗炎功效和促炎潜力，并将其与泼尼松龙进行比较。此外，将评估SEGRA与RANKL/OPG系统和Wnt信号传导拮抗剂的相互作用。对骨和免疫细胞中GR信号传导的分子机制的详细了解可能有助于鉴定具有改善的骨骼特征的GC，这可能使受炎性疾病影响的患者受益。

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.