DEGRADATION PRODUCTS OF THE CARTILAGE MATRIX INFLUENCE

软骨基质影响的降解产物

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/6299825
• 关键词: CD44 molecule; animal tissue; antisense nucleic acid; articular cartilage; cartilage metabolism; chondrocytes; collagen; extracellular matrix; fibronectins; human tissue; hyaluronate; insulinlike growth factor; integrins; interleukin 1; laboratory rabbit; metalloendopeptidases; molecular pathology; osteoarthritis; protein biosynthesis; protein degradation; protein purification; receptor binding; tissue /cell culture; transforming growth factors; western blottings

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 是炎症性发作。因此，典型的炎症介质可能不会 持续诱导软骨细胞性软骨溶解(软骨破裂 由内源性软骨细胞介导)。在非炎症性疾病期间 在此期间，可能会有其他损害调解人。我们建议 细胞外基质(ECM)的降解成分起着积极的作用 在推动母体毁灭方面。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)，导致软骨退化。此外， 我们的初步数据显示，II型胶原(COL II)片段(COL-II) F)和透明质酸(HA)片段(HA-f)也会导致软骨损伤。 因此，虽然正常ECM的成分影响合成， 软骨细胞大分子的组装和降解，碎裂的 受损矩阵的成分改变了这种影响或反馈- 监管和促进损害的进展。一个关键点是， 母体分子也可以在不同的OA状态下升高，并且 将有助于提高ECM碎片的水平。它也有可能是 ECM片段改变了基质分子在和 某些情况下，这些可能会加强修复过程，如图所示 国民阵线-f。因此，ECM片段可以完成损伤之间的链接 以及随后在骨关节炎中的修复尝试。对影响的表征 碎片应建议采取干预措施以减少代谢损伤 从而便于在办公自动化中进行修复。我们建议(1)调查是否 软骨中最终添加合成代谢因子对纤维连接蛋白水平的影响 通过FN-f的生成促进软骨损伤。我们还将 测试兔膝关节内注射FN-f是否在建立的 模型，也会导致FN水平的提高，这最终将 会导致软骨损伤。我们建议(2)调查 II型胶原片段(COL-f)和透明质酸片段(HA-f)的活性 在介导牛和人组织中软骨移植损伤的过程中 根据我们的初步观察，调节软骨细胞的代谢 这些片段确实会导致PG的丢失和MMPs的诱导 软骨移植。注射给药对软骨损伤的影响 还将对兔膝关节进行评估。我们建议(3)调查 FN结合整合素、COLII结合ANX V和HA结合的作用 CD44在调控软骨内环境平衡中的作用 根据初步数据显示，这些碎片 感受器。