Heparan sulfate in Degenerating Joint Diseases

在这个项目中，我们的目的是调查硫酸乙酰肝素（HS）在退行性关节疾病中的作用。除了它们的结构功能之外，细胞外蛋白聚糖网络的HS调节生长因子信号传导并结合许多细胞外蛋白。研究小鼠系，其中HS合成酶Ext 1可以在软骨细胞中克隆删除，我们发现在关节表面肥大细胞的克隆，表明功能HS在维持关节表面。在这里，我们计划在Ext 1缺陷小鼠中引入软骨退行性疾病。Ext 1的低形态等位基因通常用于降低整个关节面的HS水平。平行地，Ext 1的克隆缺失将产生缺乏HS的细胞。我们将使用关键韧带剥离（OA）和分别用于RA和PsA的转基因小鼠系hTNFtg和TTP-/-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。将注意识别与关节疾病有关的炎症、蛋白酶水平和信号传导因子的改变。将对鉴定的蛋白质与HS的相互作用进行生物化学分析。由于损失Syndecan-4，在软骨细胞中的HS载体，已被证明可以防止OA，我们将调查在Ext 1，Syndecan-4突变体和突变体的硫酸化模式改变的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.