Heparan sulfate in Degenerating Joint Diseases

在这个项目中，我们旨在研究硫酸肝素(HS)在退行性关节疾病中的作用。除了结构功能外，胞外蛋白多糖网络的HS还调节生长因子信号转导，并与许多胞外蛋白结合。在研究一个软骨细胞中HS合成酶Ext1可以克隆缺失的小鼠株系时，我们发现关节表面有肥大细胞的克隆，表明HS在维持关节表面的功能中。在这里，我们计划在Ext1缺陷小鼠中引入软骨退行性疾病。低配型等位基因Ext1将被用来降低整个关节表面的HS水平。在Parralel中，Ext1的克隆缺失将产生缺乏HS的细胞。我们将使用关键韧带解剖(OA)和分别针对RA和PSA的转基因小鼠系hTNFtg和TTP-/-来诱导骨关节炎(OA)、类风湿性关节炎(RA)和银屑病关节炎(PSA)。将使用组织学和分子方法跟踪疾病的进展。将注意确定炎症、蛋白酶水平和与关节疾病有关的信号因素的变化。识别出的蛋白质与HS的相互作用将进行生化分析。由于软骨细胞中HS的载体失落Syndecan-4已被证明对OA具有保护作用，我们将研究Ext1；Syndecan-4突变和硫酸盐化模式改变的突变中的OA进展。

In this project we aim to investigate the role of heparan sulfate (HS) in degenerating joint diseases. Besides their structural function, HS of the extracellular proteoglycan network regulate growth factor signaling and bind to many extracellular proteins. Investigating a mouse line, in which the HS synthesizing enzyme Ext1 can be clonally deleted in chondrocytes, we found clones of hypertrophic cells in the articular surface, indicating a function HS in maintaining the joint surface. Here we plan to introduce cartilage degenerating diseases in Ext1 deficient mice. A hypomorpic allele of Ext1 will be used to generally decrease HS levels across the articular surface. In parralel clonal deletion of Ext1 will produce cells lacking HS. We will induce osteoarthritis (OA), rheumathoid arthritis (RA) and psoriasis arthritis (PsA) using crucial ligament dissections (OA) and the transgenic mouse lines hTNFtg and TTP-/- for RA and PsA, respectively. The progression of the disease will be followed using histological and molecular methods. Care will be taken to identify alterations in inflammation, protease levels and signaling factors implicated in joint diseases. The interaction of identified proteins with HS will be analyzed biochemically. As loss Syndecan-4, a carrier of HS in chondrocytes, has been shown to protect against OA, we will investigate OA progression in Ext1;Syndecan-4 mutants and in mutants with altered patterns of sulfation.