PATHOLOGIC STUDIES IN A HUMAN MODEL OF OSTEOARTHROSIS

骨关节病（OA）是一种非常常见的疾病。 虽然其 发病机制知之甚少，概念已经出现，它反映了 关节软骨破坏过程之间的不平衡， 修，有利于前者。 这项研究将解决这一不平衡问题， 为什么软骨修复逐渐失败。 的结果 目前的研究表明，许多参与软骨形成的软骨细胞， 修复经历了一个分化过程， 其发生在分化的生长板软骨细胞中。 的 与这一过程相关的生物合成变化可以解释许多 OA软骨中观察到的生化变化，可能有助于 加速软骨退化。 本研究的目的是确定 与此动态过程相关的生物合成事件， 细胞在分化过程中产生的基质，以及 检查所选药剂对这些参数的体外作用。 由于关节软骨修复的局灶性， 随着时间的推移，评估过程中遇到的困难， 骨骼生长板呈现出高度有序的空间结构， 构成软骨细胞的时间事件的表征 将采用微分法来确定上述参数， OA关节软骨的研究。 生长板和OA关节 软骨将通过光镜和电镜免疫进行研究， 凝集素组织化学、放射自显影和原位杂交。 基质组分单克隆抗体：I-VI、IX（G）、X（M）和 1 α，2 α，3 α胶原蛋白; 4-和6-硫酸软骨素，角质素 硫酸盐和透明质酸结合区，软骨亚结构 蛋白聚糖;连接蛋白;纤连蛋白;和特异性 将使用骨骼原胶原mRNA。 从生化角度确认 显微镜观察，软骨的微量样品对应于 软骨细胞分化的不同阶段和软骨的程度 将通过HPLC和SDS-PAGE方法在器官培养中研究修复， 确定同位素标记的存在和相对比例 主要和次要胶原蛋白和糖胺聚糖在新合成 基质和潜在的治疗剂对这些的影响 参数 这些研究应提供一个全面的看法， 两种组织中的软骨细胞分化，深入了解为什么软骨 修复在OA中失败，以及治疗的新想法。

Osteoarthrosis (OA) is an extremely common disorder. Although its pathogenesis is poorly understood, the concept has emerged that it reflects an imbalance between the processes of articular cartilage destruction and repair favoring the former. This study will address this imbalance and focus on why cartilage repair progressively fails. The results from the current grant indicate that many of the chondrocytes involved in cartilage repair go through a differentiation process that closely resembles that which occurs in differentiating growth plate chondrocytes. The biosynthetic changes associated with this process may account for many of the observed biochemical alterations in OA cartilage and may contribute to accelerated cartilage degradation. The goal of this study is to define the biosynthetic events associated with this dynamic process, characterize the matrix produced by the cells as they proceed through differentiation, and examine the in vitro effect of selected agents on these parameters. Because of the focal nature of articular cartilage repair and the difficulties encountered in assessing the process over time, the normal skeletal growth plate which exhibits a highly organized spacial representation of the temporal events that constitute chondrocyte differentiation will be employed to define the above parameters and guide studies of the OA articular cartilage. Growth plate and OA articular cartilage will be studied by light and electron microscopic immune and lectin histochemistry, autoradiography, and in situ hybridization. Monoclonal antibodies to matrix components: types I-VI, IX (G), X (M), and 1alpha, 2alpha, 3alpha collagens; chondroitin-4-and -6- sulfate, keratan sulfate and hyaluronic acid binding region, substructures of cartilage proteoglycan; link protein; fibronectin; and cDNA probes to specific skeletal procollagen mRNAs will be employed. To biochemically confirm the microscopic observations, microsamples of the cartilages corresponding to different stages of chondrocyte differentiation and degrees of cartilage repair will be studied in organ culture by HPLC and SDS-PAGE methods to determine the presence of and relative proportions of isotopically labelled major and minor collagens and glycosaminoglycans in newly synthesized matrix and the effects of potential therapeutic agents on these parameters. These studies should provide a comprehensive view of chondrocyte differentiation in the two tissues, insights into why cartilage repair is fails in OA, and new ideas for therapy.