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

硫酸乙酰肝素蛋白聚糖syndecan-1在骨代谢中的作用

• 批准号: 259129953
• 负责人: Professor Dr. Richard Stange
• 金额: --
• 依托单位: Institut für Muskuloskelettale Medizin
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/259129953?language=en
• 关键词: role; heparansulfate; proteoglycan; syndecan; bone

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.

跨膜硫酸乙酰肝素蛋白聚糖多配体蛋白聚糖-1作为细胞与其环境之间的信号介质。特别是在应激条件下，多配体蛋白聚糖蛋白的存在代表了显著的存活优势。多配体聚糖作为生长因子或信号分子的共受体，作为结合细胞外基质分子的介体，并影响细胞粘附或细胞骨架的形成，这在细胞迁移中是重要的。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。多配体蛋白聚糖-1在组织损伤（例如损伤）区域的细胞募集或介导细胞-细胞接触以粘附或迁移（例如白细胞）中的作用。syndecan-1的缺乏导致年轻小鼠（4个月）腰椎和胫骨的骨小梁结构减少。此外，syndecan-1缺陷小鼠显示出更低的骨生物力学强度。对原代成骨细胞（sdc 1-/-.与野生型相比）表明这种骨形成的减少不是由改变的成骨细胞分化或矿化引起的。但在破骨细胞发生过程中，成骨细胞与破骨细胞之间的通讯受到了破坏。在我们的项目中，我们希望使用成骨细胞和破骨细胞前体细胞的共培养物来表征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缺陷导致的这些细胞类型的通信差异，这可能对体内骨形成和组织很重要。为了研究syndecan-1在发育过程中骨内稳态中的作用，我们将对不同年龄（胚胎、新生至18月龄）小鼠的骨结构和骨髓室的细胞组成进行组织学分析。此外，在该项目的第二部分，我们希望使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。愈合进展的特征将特别关注软骨内骨化过程。这一部分将得到细胞培养实验的支持，细胞培养实验使用重要的生长因子和细胞因子刺激的骨细胞，然后将表征它们在多配体蛋白聚糖-1和缺乏多配体蛋白聚糖-1的情况下的功能。我们的研究结果将为多配体蛋白聚糖家族在骨愈合过程中细胞与环境之间的界面上的各种功能提供重要的见解。