IGF BINDING PROTEINS IN ARTICULAR CARTILAGE

胰岛素样生长因子结合蛋白在关节软骨中的作用。胰岛素样生长因子-1 （IGF-1）是关节软骨基质代谢的重要合成代谢/稳态因子。软骨对这种生长因子的敏感性随着年龄的增长而降低，有人认为这与igf结合蛋白（igf - bp）的变化有关。后者形成了一个多功能的调控系统，可以与IGF的作用产生痛苦或对抗。重要的是，最近有报道称，在人类骨关节炎（OA）期间，IGF-BP mrna增加，并且与正常年龄匹配的对照组相比，培养的OA软骨细胞释放的IGF-BP水平增加。本研究的工作假设是，在正常软骨中，IGF- bp -2增强了IGF的作用，而IGF- bp -6拮抗它们，并且在衰老和OA过程中，IGF- bp的拮抗和拮抗性质和平衡发生了变化。本可行性研究的具体目的是：1]发展分子生物学方法，特别是反义寡脱氧核苷酸（ODN）技术，抑制关节软骨中IGF-BP的表达。拟议的研究将在表征良好的牛关节软骨系统中测试对IGF-BP-2的反义odn。预计这些模型研究将作为一个起点，深入研究IGF-BP-2和其他igf - bp在牛和人软骨基质代谢中的作用。2]开展igf - bp在人软骨衰老和骨关节炎过程中的系统研究。蛋白质将直接从新鲜关节软骨中提取，并通过pi先前开发的方法进行分析。从长远来看，这些研究将有助于更好地理解软骨对IGF反应的机制，并且这些信息将有助于制定合理的方案来优化老化和OA软骨中的IGF和基质功能。

The Role of Insulin-like Growth Factor Binding Proteins in Articular Cartilage. Insulin-like growth factor-1 (IGF-1) is an important anabolic/homeostatic factor for articular cartilage matrix metabolism. The sensitivity of cartilage to this growth factor decreases with age, and it has been suggested that this is related to changes in IGF-binding proteins (IGF-BPs). The latter form a versatile regulatory system that can agonize with or antagonize IGF action. Importantly, there are recent reports that IGF-BP mRNAs are increased during human osteoarthritis (OA), and that increased levels of IGF-BPs are released from cultured OA chondrocytes, as compared to normal age-matched controls. The working hypothesis of this investigation is that in normal cartilage, IGF-BP-2 enhances the actions of IGF, while IGF-BP-6 antagonizes them, and that the nature and balance of the agonistic and antagonistic IGF-BPs changes during aging and OA. The specific aims of the present feasibility study are: 1] To develop molecular biological methods, specifically antisense oligodeoxynucleotide (ODN) techniques, to inhibit IGF-BP expression in articular cartilage. The proposed studies will test antisense ODNs to IGF-BP-2 in a well characterized bovine articular cartilage system. It is expected that these model studies will serve as a departure point to launch an in-depth investigation of the role of IGF-BP-2 and other IGF-BPs in matrix metabolism in bovine and human cartilage. 2] To initiate systematic studies to analyze IGF-BPs during aging and osteoarthritis in human cartilage. Proteins will be directly extracted from fresh articular cartilages and analyzed by methods previously developed by the P.I. It is proposed that in the long term, these studies will lead to a better understanding of the mechanisms underlying the response of cartilage to IGF and that this information will facilitate the development of rational protocols to optimize IGF and matrix function in aging and OA cartilage.