The role of the heparansulfate proteoglycan syndecan-1 in bone metabolism

跨膜肝素硫酸酯蛋白多糖syndecan-1作为细胞和环境之间的信号介质。特别是在应激条件下，syndecan蛋白的存在代表了显著的生存优势。Syndecans是生长因子或信号分子的共受体，是结合细胞外基质分子的介质，影响细胞粘附或细胞骨架的形成，在细胞迁移中起重要作用。Syndecan-1在骨形成甚至骨折愈合过程中在骨髓间充质细胞中表达。一些研究假设syndecan-1在组织损伤区域（如损伤）招募细胞或介导细胞-细胞接触粘附或迁移（如白细胞）中的作用。在幼龄小鼠（4个月）中，syndecan-1缺失导致腰椎和胫骨骨小梁结构减少。此外，syndecan-1缺失小鼠表现出较低的骨骼生物力学强度。原发性成骨细胞（sdc1-/-）的初步研究。与野生型相比，这种骨形成减少并不是由成骨细胞分化或矿化改变引起的。结果表明，在破骨细胞发生过程中，成骨细胞与破骨细胞之间的细胞通讯受到破坏。在我们的项目中，我们希望通过成骨细胞和破骨细胞前体细胞的共培养来表征syndecan-1在破骨细胞分化过程中的功能，这可能会揭示由于syndecan-1缺乏导致的这些细胞类型的交流差异，这可能对体内骨的形成和组织很重要。为了描述syndecan-1在发育过程中骨稳态中的功能，我们将从组织学上分析不同年龄（胚胎、新生儿到18个月）小鼠的骨结构和骨髓腔室的细胞组成。此外，在该项目的第二部分，我们希望利用小鼠骨折模型研究syndecan-1在骨折愈合等炎症过程中的可能功能。愈合进展将特别关注内软骨成骨过程。这一部分将通过细胞培养实验来支持，使用受重要生长因子和细胞因子刺激的骨细胞，这些细胞因子和细胞因子将被表征其具有和缺乏syndecan-1的功能。我们的研究结果将为在骨愈合过程中，syndecan蛋白家族在细胞和环境之间的界面上的各种功能提供重要的见解。

The transmembrane heparansulphate proteoglycan syndecan-1 acts as a mediator of signals between the cell and its environment. Especially under stress conditions, the presence of syndecan proteins represents a significant survival advantage. Syndecans act as co-receptor for growth factors or signaling molecules, as mediator for binding extracellular matrix molecules and influence cell adhesion or formation of cytoskeleton which is important in cell migration. Syndecan-1 is expressed in mesenchymal cells of the bone marrow while bone formation and even during fracture healing. Several studies postulate the role of syndecan-1 in recruitment of cells to regions of tissue damage (e.g. injury) or mediation of cell-cell-contacts for adhesion or transmigration (e.g. leukocytes). Absence of syndecan-1 leads to decreased trabecular bone structures of lumbar spine and tibia in young mice (4 month). Additionally, syndecan-1 deficient mice show less biomechanical strength of the bone. Initial studies of primary osteoblasts (sdc1-/-. vs. wild type) showed yet that this decreased bone formation is not caused by an altered osteoblast differentiation or mineralization. But it was shown that die communication between osteoblasts and osteoclasts within the osteoclastogenesis was impaired. In our project we want to characterize the function of syndecan-1 during osteoclast differentiation using co-cultures of osteoblast- and osteoclast precursor cells that may shed light on differences in the communication of these cell types due to syndecan-1 deficiency, which may be important for bone formation and organization in vivo. To charakterize the function of syndecan-1 in bone homoestasis during development we will analyse histologically the bone structure of mice at different ages (embryo, neonatal to 18 month) and the cell composition of the bone marrow compartment. Furthermore, in a second part of the project, using a mouse fracture model we want to investigate a possible function of syndecan-1 in inflammatory processes like fracture healing. The healing progression will be characterized with particular focus on the enchondral ossification process. This part will be supported by cell culture experiments using bone cells stimulated with important growth factors and cytokines which will than be characterized for their function with and lacking syndecan-1. Our result will provide important insights in the great variety of functions of the syndecan protein family at the interface between the cell and its environment during bone healing.