The role of Siglec-9/ Siglec-E in osteoclastogenesis

唾液酸结合免疫球蛋白样凝集素(Siglecs)是识别糖蛋白和糖脂中含唾液酸结构的跨膜受体。Siglec-9及其小鼠同系物Siglec-E属于CD33相关Siglec亚群，主要表达于髓系细胞。一些研究表明Siglec-9/Siglec-E影响中性粒细胞和巨噬细胞的迁移和细胞因子的释放。骨吸收破骨细胞是巨噬细胞样前体细胞融合形成的巨型多核细胞。到目前为止，它们是否也受到Siglec-9/Siglec-E的影响尚不清楚。我们的初步体外数据强烈表明Siglec-9/Siglec-E可以增加破骨细胞的生成。此外，注射针对Siglec-E的抗体可以减轻小鼠血清转移性关节炎模型中的炎症和骨破坏。拟议的项目的目标是确定Siglec-9/Siglec-E在动态平衡和炎症条件下破骨细胞形成中的作用，并研究Siglec-9/Siglec-E是否可能是治疗类风湿关节炎等疾病的炎症性骨丢失的合适靶点。为此，我们将在两种非炎症性骨质疏松症模型和两种关节炎模型中，研究Siglec-E缺陷小鼠在动态平衡条件下的骨表型。此外，我们还将研究Siglec-9/Siglec-E影响破骨细胞生成的机制，并确定Siglec-9在类风湿关节炎患者关节中的表达模式。

Sialic acid-binding immunoglobulin-like lectins (Siglecs) are transmembrane receptors that recognize sialic acid-containing structures in glycoproteins and glycolipids. Siglec-9 and its murine homologue Siglec-E belong to the CD33-related Siglec subgroup and are mainly expressed on myeloid cells. Several studies have shown Siglec-9/ Siglec-E to influence migration and cytokine release of neutrophil granulocytes and macrophages. Bone resorbing osteoclasts are giant, multinucleated cells that develop by the fusion of macrophage-like precursor cells. Whether they are also affected by Siglec-9/ Siglec-E is not known so far. Our preliminary in vitro data strongly suggest Siglec-9/ Siglec-E to increase osteoclastogenesis. In addition, the injection of antibodies directed against Siglec-E attenuated inflammation and bone destruction in a murine serum-transfer arthritis model.The goal of the proposed project is to determine the role of Siglec-9/ Siglec-E in osteoclastogenesis under homeostatic and inflammatory conditions and to investigate, whether Siglec-9/ Siglec-E might be a suitable target for the treatment of inflammatory bone loss in diseases like rheumatoid arthritis. For this purpose, we will characterize the bone phenotype of Siglec-E deficient mice under homeostatic conditions, in two non-inflammatory osteoporosis models and in two arthritis models. In addition, we will investigate the mechanisms, by which Siglec-9/ Siglec-E influences osteoclastogenesis and determine the expression pattern of Siglec-9 in the joints of patients with rheumatoid arthritis.