DEGRADATION PRODUCTS OF THE CARTILAGE MATRIX INFLUENCE

骨关节炎（OA）是一种非炎症性疾病，即使可能有 是炎症发作。因此，典型的炎症介质可能不 连续诱导软骨细胞软骨溶解（软骨分解 由内源性软骨细胞介导）。在非炎症性 在此期间，可能还有其他损害介质。我们建议 细胞外基质（ECM）的降解成分起着积极的作用 破坏母体的关键我们已经证明，纤维连接蛋白（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（MMPs），导致软骨降解。此外，本发明还 我们的初步数据显示II型胶原（col II）片段（col- f）和透明质酸（HA）片段（HA-f）也诱导软骨损伤。 因此，虽然正常ECM的组分影响合成， 软骨细胞组装和降解大分子， 受损基质的成分改变了这种影响或反馈- 调节并促进损害的进展。一个关键点是， 在OA的各种状态下，母体分子也可能升高， 将有助于增强ECM碎片的水平。也很可能 ECM片段改变了基质分子的合成， 在某些情况下，这些可能会增强修复过程，如 Fn-f。因此，ECM片段可以完成损伤之间的连接， 以及随后在OA中尝试修复。影响的特征 片段应建议干预手段，以减少代谢损伤 从而促进OA的修复。我们建议（1）调查是否 最终通过添加到软骨中的合成代谢因子增强Fn水平 通过产生Fn-f导致软骨损伤。我们还将 在建立的兔膝关节模型中， 模型，也导致Fn水平的提高，这最终将 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 介导牛和人组织中软骨外植体的损伤， 根据我们的初步观察， 这些片段确实会导致PG的丢失和MMPs的诱导， 软骨外植体。它们对软骨损伤的影响， 还将评估兔膝关节。我们建议（3）调查 Fn结合整联蛋白、col II结合anx V和HA结合的作用 CD 44在软骨稳态调节中的作用 碎片，根据初步数据，表明参与这些 受体。

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.