Regulation of the phenotypic stability of chondrocytes by transmembrane heparan sulfate proteoglycans of the syndecan family

经研究，syndecan家族的跨膜硫酸肝素蛋白聚糖可以结合多种蛋白质，从而介导细胞中一系列不同的功能。Sdc-4在骨折愈合、伤口愈合和骨关节炎（OA）等应激情况下非常重要。在我的初步研究中，我发现在发育过程中，Sdc-4可以被Sdc-2补偿，但在骨性关节炎和骨折愈合等疾病中，Sdc-2不能补偿。此外，我已经证明Sdc-4参与WNT信号转导，这在胚胎发生和OA过程中都很重要。基于我的初步数据，我因此假设Sdc-2和-4在调节软骨细胞表型和分化中起着至关重要的作用。在我的项目中，我想重点研究WNT通过syndecans，特别是Sdc-2和4诱导信号转导的机制。此外，我想利用分离软骨细胞的体外分析和野生型和syndecan缺陷动物的体内研究来研究WNT信号通路在调节软骨细胞表型稳定性及其在OA中的功能中的作用。这笔拨款的结果将有助于更好地了解OA的致病机制，并有助于为这种疾病的新治疗方法铺平道路。

Transmembrane heparan sulfate proteoglycans of the syndecan family have been proposed to bind a large variety of proteins and thereby mediate an array different functions in cells. Sdc-4 is of major importance during stress situtations like fracture healing, wound healing and in osteoarthritis (OA). In my prelimiary studies I have shown that Sdc-4 can be compensated by Sdc-2 during development, but not during diseases like OA and fracture healing. Furthermore, I have shown that Sdc-4 is involved in WNT signal transduction, which is important in both processes of embryogenesis and OA. Based on my preliminary data I therefore hypothezise that Sdc-2 and -4 play a vital role in regulating chondrocyte phenotype and differentiation. In my project, I want to focus on the mechanisms of WNT induced signal transduction via syndecans, particularly Sdc-2 and-4. Furthermore, I want to use in both in vitro analyses with isolated chondrocytes and in vivo studies using wild type and syndecan- deficient animals to investigate the role of WNT signalling pathways in regulating the phenotypic stability of chondrocytes and their function in OA.. The results of this grant will lead to a better understanding of pathogenic mechanisms of OA and help to pave the path to new therapeutic approaches for this disease.