DEGRADATION PRODUCTS OF THE CARTILAGE MATRIX INFLUENCE

软骨基质影响的降解产物

基本信息

批准号：
6299825
负责人：
GENE HOMANDBERG
金额：
$ 17.02万
依托单位：
RUSH UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-01-01 至 2000-12-31
项目状态：
已结题

项目摘要

Osteoarthritis (OA) is a non-inflammatory disease, even though there may be inflammatory episodes. Thus, the typical inflammatory mediators may not continuously induce chondrocytic chondrolysis (cartilage breakdown mediated by the endogenous chondrocytes). During the non-inflammatory periods, there may be other mediators of damage. We propose that degradation components of the extracellular matrix (ECM) play active roles in driving matrix destruction. We have documented that fibronectin (Fn) fragments (Fn-f) enhance catabolic mediator levels and induce matrix metalloproteinases (MMPs), resulting in cartilage degradation. Further, our preliminary data show that collagen type II (col II) fragments (col- f) and hyaluronan (HA) fragments (HA-f) also induce cartilage damage. Thus, while the components of the normal ECM influence the synthesis, assembly and degradation of macromolecules by chondrocytes, the fragmented components of the damaged matrix alter this influence or feedback- regulation and contribute to progression of damage. A key point is that the parent molecules may also be elevated in various states of OA, and would contribute to enhanced levels of ECM fragments. It is also likely that the ECM fragments alter synthesis of matrix molecules under and certain conditions, these may enhance reparative processes, as shown for the Fn-f. Thus, the ECM fragments may complete the linkage between damage and subsequent attempted repair in OA. Characterization of the effects of fragment should suggest means of intervention to reduce metabolic damage and thereby facilitate repair in OA. We propose (1) to investigate whether enhancement of Fn levels by anabolic factors added to cartilage ultimately contributes to cartilage damage through generation of Fn-f. We will also test whether injection of Fn-f into rabbit knee joints, in an established model, also leads to enhanced levels of Fn, which ultimately would contribute to cartilage damage. We propose (2) to investigate the activities of collagen type II fragments (col-f) and HA fragments (HA-f) in mediating damage to cartilage explants in bovine and human tissue and regulating chondrocyte metabolism, based on our preliminary observations that these fragments do cause loss of PG and induction of MMPs in cartilage explants. Their effects on cartilage damage when injected into rabbit knee joints will also be assessed. We propose (3) to investigate the role of the Fn-binding integrin, col II binding anx V and HA binding CD44 in the regulation of cartilage homeostasis by the respective fragments, based on preliminary data that suggest involvement of these receptors.

骨关节炎（OA）是一种非炎症性疾病，即使发炎发作。因此，典型的炎症介体可能不会连续诱导软骨细胞软骨溶解（软骨破裂由内源软骨细胞介导）。在非炎症期间时期，可能还有其他损害的调解人。我们提出了这一点细胞外基质（ECM）的降解成分发挥活性作用在驾驶矩阵破坏中。我们已经记录了纤连蛋白（FN）片段（FN-F）增强分解代谢介质水平并诱导基质金属蛋白酶（MMP），导致软骨降解。更远，我们的初步数据表明，II型胶原蛋白（Col II）片段（Col- F）和透明质酸（HA）碎片（HA-F）也会诱发软骨损伤。因此，尽管正常ECM的成分影响合成，但由软骨细胞（碎片）组装和降解大分子受损矩阵的组件改变了这种影响或反馈 - 调节并有助于损害的进展。一个关键是在OA的各个状态下，母分子也可以升高，并且将有助于提高ECM碎片水平。也可能 ECM片段改变了基质分子的合成和某些条件，这些条件可能会增强修复过程，如图所示 FN-F。因此，ECM片段可以完成损坏之间的联系并随后在OA中进行维修。效果的表征碎片应提出干预手段以减少代谢损害从而促进OA的维修。我们建议（1）调查是否通过添加到软骨中的合成代谢因素对FN水平的提高最终通过产生FN-F会导致软骨损伤。我们也会测试在已建立的模型，也导致FN级别提高，最终将导致软骨损伤。我们建议（2）调查胶原型II型片段（Col-F）和HA片段（HA-F）的活动在介导牛和人组织中软骨外植体的损害中根据我们的初步观察，调节软骨细胞代谢这些碎片确实会导致PG的丢失和MMP的诱导软骨外植体。注射到软骨伤害时，它们的影响还将评估兔膝关节。我们建议（3）调查 FN结合整合素，Col II结合Anx V和HA结合的作用 CD44在各自的软骨稳态调节中片段，基于提示这些参与的初步数据受体。