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，尽管可能存在是炎症发作。因此，典型的炎症介质可能不会持续诱导软骨细胞软骨溶解（软骨破裂由内源性软骨细胞介导）。非炎症期间期间，可能还有其他损害媒介。我们建议细胞外基质（ECM）的降解成分发挥积极作用驱动矩阵破坏。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) 碎片 (col- f) 和透明质酸 (HA) 片段 (HA-f) 也会引起软骨损伤。因此，虽然正常 ECM 的成分会影响合成，软骨细胞组装和降解大分子，碎片受损基质的成分会改变这种影响或反馈- 调节并促进损害的进展。一个关键点是母体分子在 OA 的各种状态下也可能升高，并且将有助于提高 ECM 碎片的水平。也有可能 ECM 片段改变了基质分子的合成在某些条件下，这些可能会增强修复过程，如图所示 Fn-f。因此，ECM碎片可能完成损伤之间的联系以及随后尝试在 OA 中进行修复。影响的表征片段应建议减少代谢损伤的干预方法从而促进 OA 的修复。我们建议（1）调查是否最终添加到软骨中的合成代谢因子提高 Fn 水平通过生成 Fn-f 导致软骨损伤。我们也会测试是否将 Fn-f 注射到兔子膝关节中，在既定的模型，也会导致 Fn 水平提高，最终将导致软骨损伤。我们建议（2）调查 II 型胶原片段 (col-f) 和 HA 片段 (HA-f) 的活性介导牛和人体组织中软骨外植体的损伤根据我们的初步观察，调节软骨细胞代谢这些片段确实会导致 PG 丢失和 MMP 诱导软骨外植体。注射后对软骨损伤的影响兔子膝关节也将被评估。我们建议（3）进行调查 Fn 结合整合素、col II 结合 anx V 和 HA 结合的作用 CD44 通过各自的调节软骨稳态碎片，基于表明这些参与的初步数据受体。